Burden of sequelae and healthcare resource utilization in the first year of life in infants born with congenital cytomegalovirus (cCMV) infection in Germany: A retrospective statutory health insurance claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany. METHODS: A retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life. RESULTS: Between 2014-2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, p<0.01) presented with at least one sequela during the first year of life, including intrauterine growth retardation (42.6% vs. 5.3%, p<0.01), sensorineural hearing loss (SNHL) to deafness (38.9% vs. 2.2%, p<0.01), and motor development disorders (33.3% vs. 10.9%, p<0.01). Further, 13.0% of cCMV90 infants (vs. 2.3%, p<0.01) suffered from visual impairment. In cCMV21-S cohort, intrauterine growth retardation (79.2% vs. 6.0%, p<0.01), prematurity (54.2% vs. 7.3%, p<0.01), and motor development disorders (50.0% vs. 11.0%, p<0.01) were the most frequent sequelae. Infants in the cCMV90 and cCMV21-S cohort had, on average, 7.3 times and 9.5 times more hospitalizations and 2.0 times and 2.1 times more outpatient physician visits than their respective controls (p<0.01). Hospitalized infants with cCMV stayed, on average, significantly longer in hospital compared to their controls (cCMV90 cohort: 30.3 days vs. 9.0 days, p<0.01; cCMV21-S cohort: 46.5 days vs. 9.3 days, p<0.01). CONCLUSIONS: cCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.

Clinical Value of Serial Quantitative Analysis of Cytomegalovirus DNA in Blood and Saliva Over the First 24 Months of Life in Congenital Infection: The French Cymepedia Cohort.

OBJECTIVE: To evaluate cytomegalovirus (CMV) viral load dynamics in blood and saliva during the first 2 years of life in symptomatic and asymptomatic infected infants and to identify whether these kinetics could have practical clinical implications. STUDY DESIGN: The Cymepedia cohort prospectively included 256 congenitally infected neonates followed for 2 years. Whole blood and saliva were collected at inclusion and months 4 and 12, and saliva at months 18 and 24. Real-time CMV polymerase chain reaction (PCR) was performed, results expressed as log10 IU/mL in blood and in copies per milliliter in saliva. RESULTS: Viral load in saliva progressively decreased from 7.5 log10 at birth to 3.3 log10 at month 24. CMV PCR in saliva was positive in 100% and 96% of infants at 6 and 12 months, respectively. In the first month of life, neonatal saliva viral load of less than 5 log10 was related to a late CMV transplacental passage. Detection in blood was positive in 92% of neonates (147/159) in the first month of life. No viral load threshold values in blood or saliva could be associated with a high risk of sequelae. Neonatal blood viral load of less than 3 log10 IU/mL had a 100% negative predictive value for long-term sequelae. CONCLUSIONS: Viral loads in blood and saliva by CMV PCR testing in congenital infection fall over the first 24 months. In this study of infants affected mainly after primary maternal infection during pregnancy, all salivary samples were positive in the first 6 months of life and sequelae were not seen in infants with neonatal blood viral load of less than 3 log10 IU/mL.

The epidemiology and disease burden of congenital TORCH infections among hospitalized children in China: A national cross-sectional study.

BACKGROUND: Congenital TORCH (Toxoplasma gondii (T. gondii), rubella virus (RV), cytomegalovirus (CMV), and herpes simplex virus (HSV)) infections are associated with a variety of adverse prenatal and neonatal events, including miscarriage, malformations and developmental abnormalities, and they remain an issue that cannot be neglected in China. However, the current research focuses more on the general screening of TORCH in women of childbearing age, and the medical information of children hospitalized due to congenital and perinatal TORCH infections has not been described in detail. This study summarized and analyzed the epidemiological characteristics, clinical manifestations, length of stay (LOS), and the disease burden of hospitalized children diagnosed with congenital TORCH infections in 27 children's hospitals in China. METHODOLOGY: Based on the face sheet of discharge medical records (FSMRs) of hospitalized children in 27 tertiary children's hospitals collected in the Futang Research Center of Pediatric Development and aggregated into FUTang Update medical REcords (FUTURE), we summarized and analyzed the epidemiological characteristics, clinical manifestations, LOS, the disease burden (in US dollars, USD) and potential risk factors for hospitalized children diagnosed with congenital toxoplasmosis, congenital rubella syndrome, congenital cytomegalovirus infection, and congenital HSV in 27 children's hospitals in China from 2015 to 2020. RESULTS: One hundred seventy-three patients aged 0-<1 year were hospitalized for congenital TORCH infections. Among infections with TORCH, hospitalization with congenital toxoplasmosis was the least common, with only five cases were reported (2.89%), while the LOS was the highest. The proportion of patients with congenital rubella syndrome (CRS) was 15.61%, and 86% of children hospitalized with CRS had cardiovascular malformations, and the economic burden was the highest. Congenital CMV infection cases accounted for the largest proportion (76.30%). Overall, 5.20% of patients were infected with HSV, and the expense of hospitalization for congenital HSV infection was relatively low. CONCLUSION: In the present study, the hospitalization proportion due to congenital TORCH infection was extremely low (17.56 per 100,000 neonates), indicating that China's congenital TORCH infection prevention and control policies remain effective. The lowest proportion of patients was hospitalized with congenital toxoplasmosis, while the LOS was the longest. The economic burden of CRS was heavy, and infants are recommended be vaccinated against RV in a timely manner. Congenital CMV infections accounted for the largest proportion of patients, suggesting that the disease burden of congenital CMV infection cannot be ignored, and the prevention of congenital CMV infection during pregnancy is still an important issue that needs to pay attention. The expense of hospitalization for congenital HSV infection was relatively low, while the disease burden increases significantly when patients develop complications. These data illustrate the importance of improving screening for congenital TORCH infections in the early diagnosis and treatment of neonatal patients.

Estimated Cost-effectiveness of Newborn Screening for Congenital Cytomegalovirus Infection in China Using a Markov Model.

Importance: Congenital cytomegalovirus infection (cCMVi) is one of the most common infections associated with childhood hearing loss. Prevention and mitigation of cCMVi-related hearing loss will require an increase in newborn screening, which is not yet available in China. Objective: To estimate the cost-effectiveness of newborn screening strategies for cCMVi from the perspective of the Chinese health care system. Design, Setting, and Participants: A decision tree for a simulated cohort population of 15 000 000 live births was developed to compare the costs and health effects of 3 mutually exclusive interventions: (1) no screening, (2) targeted screening using CMV polymerase chain reaction assay for newborns who fail a universal hearing screening, and (3) universal screening for CMV among all newborns. Markov diagrams were used to evaluate the lifetime horizon (76 years). Main Outcomes and Measures: Cost, hearing-related health outcomes, and incremental cost-effectiveness ratios (ICERs) were estimated based on a direct medical costs perspective. Costs and ICERs were reported in 2018 US dollars. Results: Incidence of cCMVi among newborns was reported to be approximately 0.7% in China. Targeted screening was less costly but also less effective than universal screening, identifying 41% of cases needing antiviral treatment and preventing nearly half of less severe or profound hearing loss. To avoid 1 CMV-related severe or profound hearing loss, 13 and 16 newborns need to be treated by targeted and universal screening, respectively. The ICERs of targeted and universal screening vs no screening were $79 and $2087 per quality-adjusted life-year gained, respectively, at the discounted rate of 3.5%. Both screening options were cost-effective for the Chinese health care system based on the willingness-to-pay threshold of 3 × gross domestic product per capita. The sensitivity analysis showed that the prevalence of cCMVi, as well as diagnosis and treatment costs, were key factors that may be associated with decision-making. Conclusions and Relevance: To achieve cost-effectiveness and best health outcomes, universal screening could be considered for the Chinese population. While the results are specific to China, the model may easily be adapted for other countries.

Diagnosis and medical care for congenital cytomegalovirus infection: An observational study using claims data in Japan, 2010 to 2017.

Although early detection and intervention may improve the outcome of the congenital cytomegalovirus (cCMV) infection, few studies assessed the real-world clinical practice for cCMV patients. We analyzed medical claims data to assess the patterns of diagnoses and medical care for cCMV patients.We used a subset of medical claims database (JMDC Claims Database) in Japan, covering 207,547 newborns between April 2010 and March 2017 and observed for at least 6 months. The diagnosis of cCMV and related symptoms and sequelae and medical care, including essential examinations and antiviral treatment, were identified using standardized codes.Overall, we identified 53 (25.5 per 100,000 newborns) cCMV patients diagnosed within 6 months after birth; of these, 83% were diagnosed within 1 month and 68% had at least 1 cCMV-related symptom at birth. Objective hearing tests and fundus examinations were performed within 6 months in 60% and 30% of patients, respectively. Antivirals were prescribed in 26% of patients. During the observation period (median = 33 months), sensorineural hearing loss (49%) and developmental problems (28%) were commonly identified as cCMV-related sequelae. The proportions of the patients continuously followed up with objective hearing tests up to 36 months were 30% in total and 56% in antiviral-treated patients, respectively.The cCMV patients did not necessarily receive a timely diagnosis nor continuous follow-ups in usual clinical practice. Although the universal screening for cCMV may, if implemented, facilitate early diagnosis, it should be accompanied by strategic follow-up plans to support timely interventions.

Reduced economic burden of AIDS-defining illnesses associated with adherence to antiretroviral therapy.

OBJECTIVES: We assessed the economic burden of AIDS-defining illnesses (ADIs), which was further stratified by adherence to antiretroviral therapy (ART). METHODS AND MATERIALS: A nationwide longitudinal cohort of 18,234 incident cases with HIV followed for 11years was utilized. Adherence to ART was measured by medication possession ratio (MPR). Generalized estimating equations modeling was used to estimate the cost impact of ADIs. RESULTS: Having opportunistic infections increased the annual cost by 9% (varicella-zoster virus infection) to 98% (cytomegalovirus disease), while the annual costs increased by 26% (Kaposi's sarcoma) to 95% (non-Hodgkin's lymphoma) in the year when AIDS-related cancer occurred. ADIs occurred more frequently in the years with low adherence for ART compared to the high-adherence years (e.g., 0.1≤MPR<0.8 vs. MPR≥0.8, event rate of cytomegalovirus disease 4.03% vs. 0.51%). The annual baseline costs in the years with MPR<0.1, 0.1≤MPR<0.8, and MPR≥0.8 were $250, $4,752, and $8,990 (in 2018 USD), respectively. The economic impact of ADIs in the years with low adherence (MPR<0.1) was larger than that in the high-adherence years (MPR≥0.8) (e.g., MPR<0.1 vs. MPR≥0.8, annual cost increased by 244% vs. 9% when candidiasis occurred). CONCLUSIONS: Adherence to ART may increase the baseline medical costs but mitigate the incidence and economic burden of ADIs.

Economic cost of congenital CMV in the UK.

OBJECTIVE: Congenital cytomegalovirus (cCMV) is the most common infectious cause of congenital disability. It can disrupt neurodevelopment, causing lifelong impairments including sensorineural hearing loss and developmental delay. This study aimed, for the first time, to estimate the annual economic burden of managing cCMV and its sequelae in the UK. DESIGN: The study collated available secondary data to develop a static cost model. SETTING: The model aimed to estimate costs of cCMV in the UK for the year 2016. PATIENTS: Individuals of all ages with cCMV. MAIN OUTCOME MEASURES: Direct (incurred by the public sector) and indirect (incurred personally or by society) costs associated with management of cCMV and its sequelae. RESULTS: The model estimated that the total cost of cCMV to the UK in 2016 was £732 million (lower and upper estimates were between £495 and £942 million). Approximately 40% of the costs were directly incurred by the public sector, with the remaining 60% being indirect costs, including lost productivity. Long-term impairments caused by the virus had a higher financial burden than the acute management of cCMV. CONCLUSIONS: The cost of cCMV is substantial, predominantly stemming from long-term impairments. Costs should be compared against investment in educational strategies and vaccine development programmes that aim to prevent virus transmission, as well as the value of introducing universal screening for cCMV to both increase detection of children who would benefit from treatment, and to build a more robust evidence base for future research.

Costo-efectividad de dos esquemas de prevención de la infección por citomegalovirus en pacientes con trasplante renal y riesgo intermedio en Colombia.

Introducción. El citomegalovirus es la causa más frecuente de infección en pacientes con trasplante renal. Existen dos estrategias de similar efectividad para prevenirlo: la profilaxis universal con valganciclovir durante 90 días o el tratamiento anticipado verificando la carga viral semanal y aplicándolo solo si esta es positiva.Objetivo. Determinar cuál de estas dos estrategias sería más costo-efectiva en pacientes de riesgo intermedio en Colombia.Materiales y métodos. Se diseñó un árbol de decisiones bajo la perspectiva del tercer pagador considerando únicamente los costos médicos directos en pesos colombianos (COP) del 2014 durante un periodo de un año en una población de pacientes con riesgo intermedio para citomegalovirus (donante positivo y receptor positivo, o donante negativo y receptor positivo). Las probabilidades de transición se extrajeron de los estudios clínicos y se validaron con expertos mediante el método Delphi.Los costos de los procedimientos se basaron en el manual tarifario ISS 2001, con un incremento del 33 % a partir del índice de precios al consumidor (IPC) en salud de 2014, en tanto que los de los medicamentos se extrajeron de las circulares del Ministerio de Salud y del Sistema de Información de Medicamentos (Sismed).Resultados. La profilaxis universal con valganciclovir resultó ser menos costosa y se asoció con una menor probabilidad de infección. El costo promedio del primer año de tratamiento anticipado sería de COP$ 30'961.290, mientras que el universal sería de COP$ 29'967.834, es decir, un costo 'incremental' de COP$ 993.456.Conclusiones. Para los pacientes de riesgo intermedio con trasplante renal en Colombia, la profilaxis universal es la mejor estrategia por ser menos costosa y reducir el riesgo de infección.

Congenital cytomegalovirus infection.

Each year, thousands of children are born with or develop permanent disabilities such as hearing loss, vision loss, motor and cognitive deficits from congenital CMV infection (cCMV). However, awareness of cCMV and its associated sequelae is very low in pregnant women and healthcare providers. Both targeted and universal approaches to screen newborns for CMV infection are now achievable due to recent scientific advances including the development of a rapid, high-throughput method for detecting CMV in saliva, the efficacy of antiviral treatment in symptomatic infants, and the demonstration of cost effectiveness of CMV screening. Future studies are needed to address gaps in our understanding on the role of non-primary maternal CMV infections, the evaluation of antiviral treatment in asymptomatic infants, and the implementation of prevention strategies for cCMV.

Costo-efectividad de dos esquemas de prevención de la infección por citomegalovirus en pacientes con trasplante renal y riesgo intermedio en Colombia / Cost-effectiveness of two prevention cytomegalovirus infection schemes in renal transplant patients at intermediate risk in Colombia

Resumen Introducción. El citomegalovirus es la causa más frecuente de infección en pacientes con trasplante renal. Existen dos estrategias de similar efectividad para prevenirlo: la profilaxis universal con valganciclovir durante 90 días o el tratamiento anticipado verificando la carga viral semanal y aplicándolo solo si esta es positiva. Objetivo. Determinar cuál de estas dos estrategias sería más costo-efectiva en pacientes de riesgo intermedio en Colombia. Materiales y métodos. Se diseñó un árbol de decisiones bajo la perspectiva del tercer pagador considerando únicamente los costos médicos directos en pesos colombianos (COP) del 2014 durante un periodo de un año en una población de pacientes con riesgo intermedio para citomegalovirus (donante positivo y receptor positivo, o donante negativo y receptor positivo). Las probabilidades de transición se extrajeron de los estudios clínicos y se validaron con expertos mediante el método Delphi. Los costos de los procedimientos se basaron en el manual tarifario ISS 2001, con un incremento del 33 % a partir del índice de precios al consumidor (IPC) en salud de 2014, en tanto que los de los medicamentos se extrajeron de las circulares del Ministerio de Salud y del Sistema de Información de Medicamentos (Sismed). Resultados. La profilaxis universal con valganciclovir resultó ser menos costosa y se asoció con una menor probabilidad de infección. El costo promedio del primer año de tratamiento anticipado sería de COP$ 30'961.290, mientras que el universal sería de COP$ 29'967.834, es decir, un costo 'incremental' de COP$ 993.456. Conclusiones. Para los pacientes de riesgo intermedio con trasplante renal en Colombia, la profilaxis universal es la mejor estrategia por ser menos costosa y reducir el riesgo de infección.

Abstract Introduction: Cytomegalovirus (CMV) is the most frequent opportunistic infection after renal transplantation. There are two strategies for its prevention: Universal prophylaxis, with valganciclovir for 90 days, and anticipated therapy, using weekly viral load surveillance, and therapy only if positive. Meta-analysis directly comparing both strategies have shown them to have similar effectiveness. Objective: To determine which strategy is more cost-effective in intermediate risk patients in Colombia. Materials and methods: We designed a third-party payer perspective decision tree, considering only direct medical costs in 2014 Colombian pesos (COP) (USD$ 1=COP$ 2,000) and a time horizon of one year. The target population was intermediate CMV risk patients (positive receptor). Transition probabilities were extracted from clinical studies, validated with a Delphi expert panel method; procedural costs were obtained from the ISS 2001 manual with a 33% increment based on the Consumer Price Index for 2014, while medication costs were obtained from the official Ministry of Health information system. Results: Universal prophylaxis with valganciclovir was dominant, with lower costs and less probability of infection. The average cost of the first year in anticipated therapy would be COP$ 30,961,290, whereas in the case of universal therapy the cost would be COP$ 29,967,834 (incremental cost of COP$ 993,456). Conclusions: For Colombian renal transplant patients at intermediate risk for CMV infection, universal prophylaxis strategy is the best option.

A National Survey of the Prevalence and Impact of Cytomegalovirus Infection Among Hospitalized Patients With Ulcerative Colitis.

GOALS: To estimate the effect of cytomegalovirus (CMV) in patients with ulcerative colitis (UC), and compare these outcomes to patients with CMV without UC. BACKGROUND: The impact of CMV infection in UC is not well understood. STUDY: We analyzed records from the Nationwide Inpatient Sample (NIS) of patients with UC and CMV between 2006 and 2012. Differences in outcomes were determined between patients with UC and CMV and those with UC without CMV. Secondary analysis compared outcomes of patients with UC and CMV to patients with CMV alone. RESULTS: Patients with UC and CMV (n=145) had longer length of stay (16.31 vs. 5.52 d, P<0.0001), higher total charges ($111,835.50 vs. $39.895, P=0.001), and were less likely to be discharged home without services (50.0% vs. 81.83%, P<0.0001) compared with patients with UC without CMV (n=32,290). On regression analysis, CMV was significantly associated with higher total charges (P<0.01) and longer length of stay (P<0.01), but not for increased need for colorectal surgery. When comparing patients with UC and CMV to patients with CMV alone (n=14,960), patients with CMV alone had a higher Charlson Comorbidity Index and a trend toward higher in-hospital mortality. CONCLUSIONS: CMV infection in hospitalized patients with UC is associated with a longer length of stay, increased total charges, and fewer routine discharges, but not increased surgery or mortality. Patients with CMV alone had the worst outcomes of all groups suggesting that CMV in UC patients may not have the same negative impact as in other diseases.

First estimates of the potential cost and cost saving of protecting childhood hearing from damage caused by congenital CMV infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) is an important cause of childhood deafness, which is modifiable if diagnosed within the first month of life. Targeted screening of infants who do not pass their newborn hearing screening tests in England is a feasible approach to identify and treat cases to improve hearing outcome. AIMS: To conduct a cost analysis of targeted screening and subsequent treatment for cCMV-related sensorineural hearing loss (SNHL) in an, otherwise, asymptomatic infant, from the perspective of the UK National Health Service (NHS). METHODS: Using data from the newborn hearing screening programme (NHSP) in England and a recent study of targeted screening for cCMV using salivary swabs within the NHSP, we estimate the cost (in UK pounds (£)) to the NHS. The cost of screening (time, swabs and PCR), assessing, treating and following up cases is calculated. The cost per case of preventing hearing deterioration secondary to cCMV with targeted screening is calculated. RESULTS: The cost of identifying, assessing and treating a case of cCMV-related SNHL through targeted cCMV screening is estimated to be £6683. The cost of improving hearing outcome for an infant with cCMV-related SNHL through targeted screening and treatment is estimated at £14 202. CONCLUSIONS: The costs of targeted screening for cCMV using salivary swabs integrated within NHSP resulted in an estimate of cost per case that compares favourably with other screening programmes. This could be used in future studies to estimate the full economic value in terms of incremental costs and incremental health benefits.

Auditory steady state response in hearing assessment in infants with cytomegalovirus / Importancia de lainclusion de larespuesta auditiva de estado estable en la evaluacion auditiva en lactantes concitomegalovirus / Resposta auditiva de estado estavel na avaliacao auditiva em lactentes com citomegalovirus

OBJECTIVE: To report an infant with congenital cytomegalovirus and progressive sensorineural hearing loss, who was assessed by three methods of hearing evaluation. CASE DESCRIPTION: In the first audiometry, at four months of age, the infant showed abnormal response in Otoacoustic Emissions and normal Auditory Brainstem Response (ABR), with electrophysiological threshold in 30dBnHL, in both ears. With six months of age, he showed bilateral absence of the ABR at 100dBnHL. The behavioral observational audiometry was impaired due to the delay in neuropsychomotor development. At eight months of age, he was submitted to Auditory Steady State Response (ASSR) and the thresholds were 50, 70, absent in 110 and in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the right ear, and 70, 90, 90 and absent in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the left ear. COMMENTS: In the first evaluation, the infant had abnormal Otoacoustic Emission and normal ABR, which became altered at six months of age. The hearing loss severity could be identified only by the ASSR, which allowed the best procedure for hearing aids adaptation. The case description highlights the importance of the hearing status follow-up for children with congenital cytomegalovirus. .

OBJETIVO: Relatar el caso de un lactante con citomegalovirus congénito y disacusianeurosensorial progresiva, analizado por tres métodos de evaluación auditiva. DESCRIPCIÓN DEL CASO: En la primera evaluación auditiva, a los cuatro meses de edad, el lactante presentó ausencia de Emisiones Otoacústicas (EOA) y Potencial Evocado Auditivo de Tronco Encefálico (PEATE) dentro de los estándares de normalidad para la franja de edad, con umbral electrofisiológico en 30dBnHL, bilateralmente. Con seis meses, presentó ausencia de PEATE bilateral en 100dBnHL. La evaluación comportamental de la audición se mostró perjudicada debido al retardo en el desarrollo neuropsicomotor. A los ocho meses, fue sometido al examen de Respuesta Auditiva de Estado Estable (RAEE) y los umbrales encontrados fueron 50, 70, ausente en 110 y en 100dB, respectivamente para 500, 1.000, 2.000 y 4.000Hz, a la derecha, y 70, 90, 90 y ausente en 100dB, respectivamente para 500, 1.000, 2.000 y 4.000, a la izquierda. COMENTARIOS: En la primera evaluación, el lactante presentó alteración auditiva en el examen de EOA y PEATE normal, que pasó a ser alterado a los seis meses de edad. La intensidad de la pérdida auditiva solo puede identificarse por el examen de RAEE, permitiendo establecer la mejor conducta en la adaptación de aparato de amplificación sonora individual. Se subraya la importancia del seguimiento audiológico para niños con CMV congénito. .

OBJETIVO: Relatar o caso de um lactente com citomegalovírus congênito e disacusia neurossensorial progressiva, analisado por três métodos de avaliação auditiva. DESCRIÇÃO DO CASO: Na primeira avaliação auditiva, aos quatro meses de idade, o lactente apresentou ausência de Emissões Otoacústicas (EOA) e Potencial Evocado Auditivo de Tronco Encefálico (PEATE) dentro dos padrões de normalidade para a faixa etária, com limiar eletrofisiológico em 30dBnHL, bilateralmente. Com seis meses, apresentou ausência de PEATE bilateral em 100dBnHL. A avaliação comportamental da audição mostrou-se prejudicada devido ao atraso no desenvolvimento neuropsicomotor. Aos oito meses, foi submetido ao exame de Resposta Auditiva de Estado Estável (RAEE) e os limiares encontrados foram 50, 70, ausente em 110 e em 100dB, respectivamente para 500, 1.000, 2.000 e 4.000Hz, à direita, e 70, 90, 90 e ausente em 100dB, respectivamente para 500, 1.000, 2.000 e 4.000Hz, à esquerda. COMENTÁRIOS: Na primeira avaliação, o lactente apresentou alteração auditiva no exame de EOA e PEATE normal, que passou a ser alterado aos seis meses de idade. A intensidade da perda auditiva só pôde ser identificada pelo exame de RAEE, permitindo estabelecer a melhor conduta na adaptação de aparelho de amplificação sonora individual. Ressalta-se a importância do acompanhamento audiológico para crianças com CMV congênito. .

PD-1 analysis on CD28(-) CD27(-) CD4 T cells allows stimulation-independent assessment of CMV viremic episodes in transplant recipients.

Expression of the inhibitory receptor programmed death 1 (PD-1) on cytomegalovirus (CMV)-specific CD4 T cells defines a phenotype associated with CMV viremia in transplant recipients. Moreover, CD28(-) CD27(-) double negativity is known as a typical phenotype of CMV-specific CD4 T cells. Therefore, the co-expression of inhibitory receptors on CD28(-) CD27(-) CD4 T cells was assessed as a rapid, stimulation-independent parameter for monitoring CMV complications after transplantation. Ninety-three controls, 67 hemodialysis patients and 81 renal transplant recipients were recruited in a cross-sectional and longitudinal manner. CMV-specific CD4 T cell levels quantified after stimulation were compared to levels of CD28(-) CD27(-) CD4 T cells. PD-1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression on CD28(-) CD27(-) CD4 T cells were related to viremia. A percentage of ≥0.44% CD28(-) CD27(-) CD4 T cells defined CMV seropositivity (93.3% sensitivity, 97.1% specificity), and their frequencies correlated strongly with CMV-specific CD4 T cell levels after stimulation (r = 0.73, p < 0.0001). Highest PD-1 expression levels on CD28(-) CD27(-) CD4 T cells were observed in patients with primary CMV viremia and reactivation (p < 0.0001), whereas CTLA-4 expression was only elevated during primary CMV viremia (p < 0.05). Longitudinal analysis showed a significant increase in PD-1 expression in relation to viremia (p < 0.001), whereas changes in nonviremic patients were nonsignificant. In conclusion, increased PD-1 expression on CD28(-) CD27(-) CD4 T cells correlates with CMV viremia in transplant recipients and may serve as a specific, stimulation-independent parameter to guide duration of antiviral therapy.

Auditory steady state response in hearing assessment in infants with cytomegalovirus.

OBJECTIVE: To report an infant with congenital cytomegalovirus and progressive sensorineural hearing loss, who was assessed by three methods of hearing evaluation. CASE DESCRIPTION: In the first audiometry, at four months of age, the infant showed abnormal response in Otoacoustic Emissions and normal Auditory Brainstem Response (ABR), with electrophysiological threshold in 30dBnHL, in both ears. With six months of age, he showed bilateral absence of the ABR at 100dBnHL. The behavioral observational audiometry was impaired due to the delay in neuropsychomotor development. At eight months of age, he was submitted to Auditory Steady State Response (ASSR) and the thresholds were 50, 70, absent in 110 and in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the right ear, and 70, 90, 90 and absent in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the left ear. COMMENTS: In the first evaluation, the infant had abnormal Otoacoustic Emission and normal ABR, which became altered at six months of age. The hearing loss severity could be identified only by the ASSR, which allowed the best procedure for hearing aids adaptation. The case description highlights the importance of the hearing status follow-up for children with congenital cytomegalovirus.

Nosocomial Pneumocystis jirovecii pneumonia: lessons from a cluster in kidney transplant recipients.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an important infection-related complication, whose mode of transmission remains uncertain. METHODS: We investigated a nosocomial cluster of 14 PJP cases (11 confirmed and 3 probable) in kidney transplant recipients using epidemiological and genotyping methods. RESULTS: Poisson regression calculated an incidence density ratio of 42.8 (95% confidence interval [CI], 14.1-129.3) versus background 0.64 cases of 1000 patient-years (P<0.001). All patients presented with respiratory failure, 10 required ventilation, two died, and six transplants failed, costing $31,854 (±SD $26,048) per patient. Four-locus multilocus sequence typing analysis using DNA extracts from 11 confirmed cases identified two closely related genotypes, with 9 of 11 sharing an identical composite multilocus sequence typing genotype. Contact tracing found colocalization of cases within clinic waiting areas, suggesting person-to-person transmission. Minimal and maximal PJP incubation periods were 124±83 to 172±71 days, respectively. Oropharyngeal washes from outpatient staff and ambient air samples were negative for P. jirovecii DNA. Cohort analysis (14 cases vs. 324 unaffected clinic control patients) identified independent risk factors including previous cytomegalovirus infection (odds ratio [OR], 65.9; 95% CI, 7.9-550; P<0.001), underlying pulmonary disease (OR, 10.1; 95% CI, 2.3-45.0; P=0.002), and transplant dysfunction (OR=1.61 per 10 mL/min/1.73 m, 95% CI, 1.15-2.25, P=0.006). The outbreak was controlled by reintroduction of trimethoprim/sulfamethoxazole prophylaxis to all potentially exposed clinic patients and its extension to 12 months in recent recipients. CONCLUSIONS: Nosocomial PJP clusters are likely due to interhuman transmission by airborne droplets to susceptible hosts. Prompt recognition and a strategy of early preemptive blanket PJP prophylaxis to all exposed transplant clinic recipients from the third confirmed case are recommended to limit outbreak escalation.

Compassionate use: a story of ethics and science in the development of a new drug.

This history chronicles the unusual development of the antiviral drug ganciclovir. The first compound with activity against human cytomegalovirus (CMV), ganciclovir was so clearly efficacious that a placebo-controlled clinical trial could not ethically be done, and the FDA rejected the first application to market the drug. Used to treat a blinding eye infection in patients with AIDS, the story of ganciclovir paralleled the spread of the AIDS epidemic. Both ganciclovir and AIDS caught the federal government off guard. Caught in a Catch-22 situation, the pharmaceutical company developing ganciclovir gave the drug away free for five years under compassionate use guidelines. The problems encountered in the development of ganciclovir provide guidance on how future drugs to treat life-threatening diseases can be developed.

An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes.

The effect of herpesvirus co-infections (HHV-6, HHV-7) on cytomegalovirus (CMV) disease and its response to therapy is unknown. We prospectively analyzed herpesvirus co-infections in transplant recipients with CMV disease. All patients received 3 weeks of antiviral therapy. Samples were collected at baseline (day 0) and then day 3, 7, 14 and 21 poststart of therapy. Viral load testing for CMV, HHV-6 and HHV-7 was done using quantitative PCR assays in 302 patients of whom 256 had documented symptomatic CMV viremia. In this subset, day 0 HHV-6 co-infection was present in 23/253 (9.1%) and HHV-7 in 17/253 (6.7%). Including those positive at any time point raised the prevalence to 79/256 (30.9%) for HHV-6 and 75/256 (29.3%) for HHV-7. Viral co-infection did not influence the response of CMV disease to antiviral therapy. Baseline CMV viral loads, time to eradication and risk of recurrence were similar in patients with and without HHV-6 or HHV-7 co-infection. Ganciclovir and valganciclovir had no clear effect on HHV-6 and HHV-7 viremia. In conclusion, herpesvirus co-infections are common in patients with CMV disease but with standard antiviral therapy, no clear clinical effects are discernable. Routine monitoring for viral co-infection in patients with CMV disease is not indicated.

Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment.

BACKGROUND: Congenital cytomegalovirus (CMV) infection is a cause of sensorineural hearing loss (SNHL) in children, but the magnitude of its contribution is uncertain. Quantifying the impact of congenital CMV infection requires an evidence-based assessment using a standard case definition of hearing loss. OBJECTIVES: To determine the frequency of bilateral moderate to profound SNHL in children with congenital CMV infection and to estimate the CMV-attributable fraction of bilateral moderate to profound SNHL. STUDY DESIGN: A systematic review of studies of children with congenital CMV infection ascertained in an unbiased manner through universal newborn screening for CMV using viral culture in urine or saliva specimens in combination with a review of the literature on congenital CMV infection and hearing loss, including articles of all types. RESULTS: Approximately, 14% of children with congenital CMV infection develop SNHL of some type, and 3-5% develop bilateral moderate to profound SNHL. Among all children with bilateral moderate to profound SNHL, we estimate that 15-20% of cases are attributable to congenital CMV infection. CONCLUSIONS: Congenital CMV infection is one of the most important causes of hearing loss in young children, second only to genetic mutations, and is potentially preventable.