Infections Cause Hearing Loss

Otitis Media

A longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion. FW Henderson, AM Collier, MA Sanyal, JM Watkins, DL Fairclough, WA Clyde Jr, FW Denny. N Engl J Med 1982 Jun 10;306(23):1377-1383. 14-year longitudinal study. "The incidence of this disorder was increased in children with viral respiratory infections (average relative risk, 3.2; P less than 0.0001). Infection with respiratory syncytial virus, influenza virus (type A or B), and adenovirus conferred a greater risk of otitis media than did infection with parainfluenza virus, enterovirus, or rhinovirus. Colonization of the nasopharynx with Str. pneumoniae or H. influenzae had a lesser effect on the incidence of the disease (average relative risk; 1.5; P less than 0.01). Infections with the viruses more closely associated with acute otitis media (respiratory syncytial virus, adenovirus, and influenza A or B) were correlated with an increased risk of recurrent disease."

Henderson - N Engl J Med 1982 abstract / PubMed

Acute otitis media and respiratory virus infections. O Ruuskanen, M Arola, A Putto-Laurila, J Mertsola, O Meurman, MK Viljanen, P Halonen. Pediatr Infect Dis J 1989 Feb;8(2):94-99. 4524 cases of acute otitis media. "Acute otitis media was diagnosed in 57% of respiratory syncytial virus, 35% of influenza A virus, 33% of parainfluenza type 3 virus, 30% of adenovirus, 28% of parainfluenza type 1 virus, 18% of influenza B virus and 10% of parainfluenza type 2 virus infections. These observations show a clear association of respiratory virus infections with acute otitis media."

Ruuskanen - Pediatr Infect Dis J 1989 abstract / PubMed

Adenovirus infection enhances in vitro adherence of Streptococcus pneumoniae. A Håkansson, A Kidd, G Wadell, H Sabharwal, C Svanborg. Infect Immun 1994 Jul;62(7):2707-2714. In A549 cells. "Adenovirus (types 1, 2, 3, and 5) commonly causing respiratory tract infections increased the binding of adherent S. pneumoniae strains to the cells. This effect was not seen for other adenovirus types. Adenovirus infection did not change the adherence of cells of poorly adhering strains of S. pneumoniae or H. influenzae. The increase in adherence of S. pneumoniae could be inhibited by the DNA synthesis inhibitor cytosine arabinofuranoside, which is known to block the late phase of the adenovirus infection. When electron microscopy was used, there was no evidence that virus particles bound directly to bacteria. Adherence was not affected by pretreatment of the cells with virus particles or viral proteins. This suggested that adenovirus infection upregulated receptors for S. pneumoniae."

Håkansson / Infect Immun 1994 full article
Håkansson - Infect Immun 1994 full article / PubMed Central

Increasing prevalence of recurrent otitis media among children in the United States. BP Lanphear, RS Byrd, P Auinger, CB Hall. Pediatrics 1997 Mar;99(3):E1. "BACKGROUND: The number of visits for otitis media, the most common diagnosis among preschool children, has increased during the past decade. This study was undertaken to determine whether there has been a concurrent increase in the prevalence of recurrent otitis media among children in the United States and to identify risk factors or demographic changes to explain the increase. METHODS: Secondary analyses of cross-sectional data from the Child Health Supplement to the 1981 and 1988 National Health Interview Surveys (n = 5189 [1981] and n = 6209 [1988]) were done to identify temporal changes in the prevalence and any associated risk factors of recurrent otitis media among children <6 years of age. RESULTS: Recurrent otitis among preschool children increased from 18.7% in 1981 to 26% in 1988 (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.4, 1.7). Although the prevalence of recurrent otitis increased with age, the greatest increase in recurrent otitis media occurred in infants (OR = 1.9, CI = 1.3, 2.9)." "These data indicate that there has been a 44% increase in the prevalence of recurrent otitis media among preschool children in the United States from 1981 to 1988; an excess of 1.8 million children with recurrent otitis media."

Lanphear - Pediatrics 1997 abstract / PubMed
Lanphear / Pediatrics 1997 full article

Epidemiology of otitis media onset by six months of age. KA Daly, JE Brown, BR Lindgren, MH Meland, CT Le, GS Giebink. Pediatrics 1999 Jun;103(6 Pt 1):1158-1166. 596 infants from a health maintenance organization. 39% had an episode and 20% had recurrent otitis media. "[R]espiratory tract infection (relative risk [RR] 7.5), day care (RR 1. 7), >1 sibling (RR 1.4), maternal, paternal, and sibling OM history (RR 1.6, 1.5, and 1.7, respectively) were significantly related to early OM onset. ROM was related to respiratory tract infection (RR 9. 5), day care (RR 1.9), conjunctivitis (RR 2.0), maternal OM history (RR 1.9), and birth in the fall (RR 2.6)."

Daly - Pediatrics 1999 abstract / PubMed

Importance of respiratory viruses in acute otitis media. T Heikkinen, T Chonmaitree. Clin Microbiol Rev 2003 Apr;16(2):230-241. Review. "[A]mple evidence derived from studies ranging from animal experiments to extensive clinical trials supports a crucial role for respiratory viruses in the etiology and pathogenesis of acute otitis media. Viral infection of the upper respiratory mucosa initiates the whole cascade of events that finally leads to the development of acute otitis media as a complication." "The relatively low rates of viral detection in nasopharyngeal specimens from children with AOM have raised doubts about the extent of viral involvement in the development of this disease. With the increasing availability of PCR-based assays, however, it has become obvious that the low rates have been caused by underdetection of existing viruses in studies where viral detection has been based only on viral culture and/or antigen detection methods. PCR has proved especially valuable in diagnosing rhinovirus infections, for which other methods have been suboptimal."

Heikkinen / Clin Microbiol Rev 2003 full article
Heikkinen - Clin Microbiol Rev 2003 full article / PubMed Central

Trends in otitis media among children in the United States. P Auinger, BP Lanphear, HJ Kalkwarf, ME Mansour. Pediatrics 2003 Sep;112(3 Pt 1):514-520. From the Third National Health and Nutrition Examination Survey, 1988-1991 and 1991-1994. "After controlling for risk factors for OM, the prevalence of OM from phase I to phase II increased from 66.7% to 69.7% (odds ratio [OR] = 1.1; 95% confidence interval [CI] =.99, 1.1), early-onset OM increased from 41.1% to 45.8% (OR = 1.1; 95% CI = 1.03, 1.2), and repeated OM increased from 34.8% to 41.1% (OR = 1.2; 95% CI = 1.1, 1.4). This observed increase corresponds to 561,000 and 720,000 more children having early-onset OM and repeated OM, respectively."

Auinger / Pediatrics 2003 full article

Toll-like receptor 2-dependent NF{kappa}B activation is involved in nontypeable Haemophilus influenzae-induced MCP-1 up-regulation in the spiral ligament fibrocytes of the inner ear. SK Moon, JI Woo, HY Lee, R Park, J Shimada, H Pan, R Gellibolian, DJ Lim. Infection and Immunity 2007 Jul;75(7):3361-3372. Spiral ligament fibrocytes recognize pathogens and secrete cytokines, causing high-frequency hearing loss and labyrinthitis.

Moon - Infection and Immunity 2007 full article / PubMed Central

Immunopathogenesis of polymicrobial otitis media. LO Bakaletz. J Leukoc Biol 2010 Feb;87(2):213-222. Review. "One mechanism for the commonly observed association between a concurrent URT virus infection and subsequent bacterial superinfection is a result of the fact that cells infected with certain viruses are more permissive to bacterial adherence, ultimately leading to secondary infection and disease. The relevance of this hypothesis to pathogenesis of OM has been demonstrated as a result of the fact that many URT viruses do indeed augment adherence by specific bacterial pathogens of OM. For example, influenza A virus increases the adherence of S. pneumoniae to mouse tracheal epithelial cells but not of NTHI to chinchilla tracheal epithelium in organ culture. Infection with AV types 1, 2, 3, and 5 significantly enhances the binding of adherent strains of S. pneumoniae, which had been isolated from the NP of children with frequent episodes of AOM, to human lung epithelial cells in vitro. Similarly, RSV infection of A549 cells significantly enhances attachment by NTHI that specifically express one of several known adhesins. By flow cytometry, El Ahmer et al. showed that viral infection significantly increased adherence by all three groups of microorganisms most commonly associated with AOM and chronic OM to influenza A virus-infected Hep-2 cells. Through the use of a panel of mAb directed against specific cell-surface antigens, these latter investigators found that infection of Hep-2 cells with influenza A virus resulted in a significant increase in expression of known receptors for adherence used by several Gram-negative bacteria. More recently, it was shown that URT viruses can induce up-regulated expression of carcinoembryonic antigen-related cell adhesion molecule 1, ICAM1, and platelet-activating receptor, additional eukaryotic receptors known to be used for adherence by multiple human mucosal pathogens. Thus, virus-induced up-regulation of host cell-surface antigens that serve as bacterial receptor sites appears to be a common theme in the pathogenesis of OM as well as other diseases of the respiratory tract... Even in the absence of a concurrent viral URT infection, children are colonized with the organisms that induce OM soon after birth. At 6 months of age, 26% of infants are colonized already with M. catarrhalis, 24% with S. pneumoniae, and 9% with NTHI. By 1 year of age, these percentages increased to 72%, 54%, and 33%, respectively. Early colonization is associated with early, initial episodes of AOM, and colonization with S. pneumoniae or H. influenzae in the first year of life increases the risk of becoming otitis-prone fourfold... There is an additional, direct relationship between how frequently children are colonized by the pathogens of OM and the frequency of occurrence of AOM... Among the viruses, influenza virus, parainfluenza virus, rhinovirus, coronavirus, RSV, and AV are those most commonly linked with AOM [70, 87, 88]; however, of these, rhinovirus and RSV are often more commonly identified than others [89]. Whereas rhinoviruses are typically more frequently identified by culture and other molecular mechanisms, RSV is more commonly associated with concurrent AOM. This strong association between RSV and concurrent AOM has been reported by many laboratories [66, 68, 90,91,92,93,94,95,96]." Amoxicillin concentrations in middle ear fluid are lower when a viral infection is also present.

Bakaletz / J Leukoc Biol 2010 full article
Bakaletz - J Leukoc Biol 2010 full article / PubMed Central

Racial/ethnic and socioeconomic disparities in the prevalence and treatment of otitis media in children in the United States. DF Smith, EF Boss. Laryngoscope 2010 Nov;120(11):2306-2312. "Of 428 abstracts identified, 15 met inclusion criteria. Articles addressed OM prevalence (12 of 15), risk factors (9 of 15), and tympanostomy tube insertion (4 of 15). Minority racial/ethnic groups studied were Black (11 of 15), Hispanic (6 of 15), American Indian/Alaska Native (2 of 15), and Asian (1 of 15). Predominant findings showed: 1) the most common identified risk factor for OM is socioeconomic status; 2) considerable variability exists concerning racial/ethnic disparities in disease prevalence; and 3) White children are more likely to undergo tympanostomy tube insertion compared to Black or Hispanic children."

Smith - Laryngoscope 2010 abstract / PubMed

Viral-bacterial interactions and risk of acute otitis media complicating upper respiratory tract infection. MM Pettigrew, JF Gent, RB Pyles, AL Miller, J Nokso-Koivisto, T Chonmaitree. J Clin Microbiol 2011 Nov;49(11):3750-3755. "In unadjusted analyses of data from 194 children, adenovirus, bocavirus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were significantly associated with AOM (χ(2) p-values<0.05). Children with high respiratory syncytial virus load (≥3.16 × 10(7) copies/ml) experienced increased acute otitis media risk. Higher viral loads of bocavirus and metapneumovirus were not significantly associated with acute otitis media. In adjusted models controlling for the presence of key viruses, bacteria, and acute otitis media risk factors, acute otitis media risk was independently associated with: high RSV viral load with Streptococcus pneumoniae [OR 4.40, 95% CI (1.90, 10.19)]; Haemophilus influenzae [OR 2.04 95% CI (1.38, 3.02)]; risk was higher for presence of bocavirus and H. influenzae together [OR 3.61, 95% CI (1.90, 6.86)]. Acute otitis media risk differs by the specific viruses and bacteria involved. Acute otitis media prevention efforts should consider methods for reducing infections caused by respiratory syncytial virus, bocavirus, and adenovirus in addition to acute otitis media bacterial pathogens."

Pettigrew - J Clin Microbiol 2011 full article / PubMed Central
Pettigrew / J Clin Microbiol 2011 full article

Rhinovirus Attenuates Non-typeable Hemophilus influenzae-stimulated IL-8 Responses via TLR2-dependent Degradation of IRAK-1. BL Unger, AN Faris, S Ganesan, AT Comstock, MB Hershenson, US Sajjan. PLoS Pathog 2012;8(10):e1002969. In mice and cell culture, "we demonstrate for the first time that RV infection delays bacterial clearance in vivo and suppresses NTHi-stimulated chemokine responses via degradation of IRAK-1. Based on these observations, we speculate that modulation of TLR-dependent innate immune responses by RV may predispose the host to secondary bacterial infection, particularly in patients with underlying chronic respiratory disorders."

Unger / PLoS Pathog 2012 full article

Influenza-induced inflammation drives pneumococcal otitis media. KR Short, PC Reading, LE Brown, J Pedersen, B Gilbertson, ER Job, KM Edenborough, MN Habets, A Zomer, PW Hermans, DA Diavatopoulos, OL Wijburg. Infect Immun 2013 Mar;81(3):645-652. "Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication."

Short - Infect Immun 2013 abstract / PubMed

Seasonality of acute otitis media and the role of respiratory viral activity in children. C Stockmann, K Ampofo, AL Hersh, ST Carleton, K Korgenski, X Sheng, AT Pavia, CL Byington. Pediatr Infect Dis J 2013 Apr;32(4):314-319. 96,418 respiratory viral tests during 9 seasons of respiratory viral activity (2002 to 2010) in Utah. "46,460 (48%) were positive. The most commonly identified viruses were respiratory syncytial virus (22%), rhinovirus (8%), influenza (8%), parainfluenza (4%), human metapneumovirus (3%) and adenovirus (3%). AOM was diagnosed during 271,268 ambulatory visits. There were significant associations between peak activity of respiratory syncytial virus, human metapneumovirus, influenza A and office visits for AOM. Adenovirus, parainfluenza and rhinovirus were not associated with visits for AOM."

Stockmann - Pediatr Infect Dis J 2013 abstract / PubMed

Sudden Sensorineural Hearing Loss

Are enterovirus infections a co-factor in sudden hearing loss? R Mentel, Kaftan H, U Wegner, A Reissmann, L Gürtler. J Med Virol 2004 Apr;72(4):625-629. 55 patients. "Serological screening of these patients for HSV and VZV failed to reveal significant differences between the patient group and the controls. In contrast, enterovirus sequences were detected by RT-PCR in 40% of the patient group, but in none of the controls, suggesting that enterovirus infections may be associated with sudden hearing loss."

Mentel - J Med Virol 2004 abstract / PubMed

Assessment of variation throughout the year in the incidence of idiopathic sudden sensorineural hearing loss. DN Jourdy, LA Donatelli, JD Victor, SH Selesnick. Otol Neurotol 2010 Jan;31(1):53-57. 97 patients. "Overall, no evidence was found for an uneven distribution or for a peak either by chi2 (p > 0.1), which assesses for any uneven distribution, or by the circular mean (p > 0.1), which assesses for a pattern of seasonal variation. In the subset of patients (24 of 97; 24.7%) who reported experiencing an upper respiratory infection before or concurrent with the onset of ISSHL, no evidence was found for an uneven distribution of hearing loss onset throughout the year either by chi2 (p > 0.1) or by the circular mean (p > 0.1)."

Jourdy - Otol Neurotol 2010 abstract / PubMed

Systematic review of the evidence for the etiology of adult sudden sensorineural hearing loss. JK Chau, JR Lin, S Atashband, RA Irvine, BD Westerberg. Laryngoscope 2010 May;120(5):1011-1021. 23 articles with "Randomized controlled trials, prospective cohort studies, and retrospective reviews of consecutive patients in which a clear definition of SSNHL was stated and data from consecutive patients were reported with respect to etiology of hearing loss." "The suspected etiologies for patients suffering sudden sensorineural hearing loss included idiopathic (71.0%), infectious disease (12.8%), otologic disease (4.7%), trauma (4.2%), vascular or hematologic (2.8%), neoplastic (2.3%), and other causes (2.2%)."

Chan - Laryngoscope 2010 abstract / PubMed

Sudden Sensorineural Hearing Loss: Subclinical Viral and Toxoplasmosis Infections as Aetiology and How They Alter the Clinical Course. D Kikidis, TP Nikolopoulos, G Kampessis, G Stamatiou, A Chrysovergis. ORL J Otorhinolaryngol Relat Spec 2011 Mar 8;73(2):110-115. 84 consecutive patients. "All patients were assessed for specific IgM antibodies against cytomegalovirus, herpes simplex virus, toxoplasma and Epstein-Barr virus. All were treated with intravenous steroids and assigned to two groups: 76 IgM negative (NV group) and 8 IgM positive (no history of acute infection - V group). Results: The mean hearing level at presentation was 86.5 dB HL (median, 100) in the V group and 60.7 dB HL (median, 61) in the NV group. The difference was statistically significant (p = 0.003). The mean hearing level following treatment was 81.8 dB HL (median, 88) in the V group and 48.7 dB HL (median, 39) in the NV group. The difference was statistically significant (p = 0.004). There was a considerable improvement in hearing after treatment only in the NV group (p < 0.000001). Conclusions: Recent subclinical viral or toxoplasmosis infections may be involved in the pathogenesis of SSHL (in approx. 10% of cases), suggesting that SSHL is not a single disease. When certain viruses or toxoplasmoses are involved, the hearing is much worse in comparison to patients with no such indication of infection."

Kikidis - ORL J Otorhinolaryngol Relat Spec 2011 abstract / PubMed

CMV is a Leading Cause of Deafness and Mental Impairment in Children

Progressive hearing loss in infants with asymptomatic congenital cytomegalovirus infection. WD Williamson, GJ Demmler, AK Percy, FI Catlin. Pediatrics 1992 Dec;90(6):862-866. 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)."

Williamson - Pediatrics 1992 abstract / PubMed

Specific chromosome 1 breaks induced by human cytomegalovirus. EA Fortunato, ML Dell'Aquila, DH Spector. Proc Natl Acad Sci 2000 Jan 18;97(2):853-858. "Unlike infection on release from G0, human fibroblasts infected in S-phase are refractory to viral protein expression. The majority of the S-phase-infected cells move through mitosis and by 24 h pi (hpi) are back in G1, where viral gene expression can then initiate. If DNA damage occurred in this cycling population, the cells could divide before virus replication, resulting in one of the daughter cells being free of viral genomes. This daughter cell could be a reservoir for genetic damage, opening up the possibility that disease syndromes might stem from this early damage rather than be because of active viral replication and cell lysis in the infected individual.... A major question for the future is: what genes lie at these breakpoints? The possible targets residing near 1q42 include: the ADPRT locus involved in DNA repair and replication; a potential tumor suppressor gene, whose deletion has been connected to the development of gliomas; the major 5S rRNA locus; and the USH2A gene. The possible targets that reside near 1q21 include: a different proposed tumor suppressor gene deleted in several primary breast tumors, the PSU1 small nuclear RNA locus, and the DFNA7 gene."

Fortunato / Proc Natl Acad Sci 2000 full article

Report and Recommendations: NIDCD Workshop on Congenital Cytomegalovirus Infection and Hearing Loss. National Institute on Deafness and Other Communication Disorders, March 19-20, 2002. Summaries of work at the University of Alabama, Birmingham; Baylor College of Medicine; and the Collaborative Antiviral Study Group. "In limited population-based studies of hearing loss in infants, which have included virologic ascertainment of congenital infection, the results have suggested that CMV infection is a leading cause of sensorineural hearing loss and perhaps the leading cause in children."

NIDCD Workshop on Congenital Cytomegalovirus Infection and Hearing Loss, 2002 / NIDCD

Etiology of severe sensorineural hearing loss in children: independent impact of congenital cytomegalovirus infection and GJB2 mutations. H Ogawa, T Suzutani, Y Baba, S Koyano, N Nozawa, K Ishibashi, K Fujieda, N Inoue, K Omori. J Infect Dis 2007 Mar 15;195(6):782-788. 67 Japanese children with severe sensorineural hearing loss. "Congenital CMV infection and GJB2 mutations were identified in 15% and 24% of the patients, respectively. HHV-6 was not detected. All children with CMV-associated cases developed SNHL before they were 2 years old. Most children with CMV-associated SNHL had no obvious clinical abnormality at birth, and their viral loads were lower than those of symptomatic children."

Ogawa / J Infect Dis 2007 full article

GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection. SA Ross, Z Novak, RA Kumbla, K Zhang, KB Fowler, S Boppana. Pediatr Res 2007 Jun;61(6):687-691. 149 children with congenital CMV infection and 380 uninfected neonates. "The study population was predominantly African American, and 4.3% of the subjects were carriers of a connexin 26 mutation. The overall frequency of GJB2 mutations was significantly higher in the group of children with CMV infection and hearing loss (21%) compared with those with CMV infection and normal hearing (3%, p = 0.017) and the group of uninfected newborns (3.9%, p = 0.016). Eight previously reported mutations (M34T, V27I, R127H, F83L, R143W, V37I, V84L, G160S), and four novel mutations (V167M, G4D, A40T, and R160Q) were detected. None of the study children had the 342-kb deletion (delGJB6-D13S1830) in GJB6, which suggests that this mutation does not play a role in hereditary deafness in the African American population. Although GJB2 mutations were detected in children with and without CMV-related hearing loss, those with hearing loss had a higher frequency of GJB2 mutations."

Ross - Pediatr Res 2007 abstract / PubMed

Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. A Kenneson, MJ Cannon. Rev Med Virol 2007 Jul-Aug;17(4):253-276. "The overall birth prevalence of congenital CMV infection was 0.64%, but varied considerably among different study populations. About 11% of live-born infants with congenital CMV infection were symptomatic, but the inter-study differences in definitions of symptomatic cases limit the interpretation of these data. Non-white race, low socioeconomic status (SES), premature birth, and neonatal intensive care unit admittance were risk factors for congenital CMV infection. Birth prevalence increased with maternal CMV seroprevalence. Maternal seroprevalence accounted for 29% of the variance in birth prevalence between study populations. Maternal seroprevalence and birth prevalence were both higher in study populations that were ascertained at birth rather than in the prenatal period. Thus, timing of ascertainment should be considered when interpreting birth prevalence estimates. Birth prevalence was inversely correlated with mean maternal age, but this relationship was not significant when controlling for maternal seroprevalence. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Possible maternal primary infections (i.e. seropositive mother with CMV IgM) resulted in congenital infections about 20% of the time, but are likely to represent a mixture of primary and recurrent infections."

Kenneson - Rev Med Virol 2007 abstract / PubMed

Human cytomegalovirus (HCMV) and hearing impairment: infection of fibroblast cells with HCMV induces chromosome breaks at 1q23.3, between loci DFNA7 and DFNA49 -- both involved in dominantly inherited, sensorineural, hearing impairment. M Nystad, T Fagerheim, V Brox, EA Fortunato, Ø Nilssen. Mutat Res 2008 Jan 1;637(1-2):56-65. "In this work we demonstrate, using fine mapping techniques, that HCMV infection in S-phase fibroblast cells induces genetic damage at 1q23.3, within a maximal region of 37 kb, containing five low copy repeat (LCR) elements. The breakpoint is situated between two hearing impairment (HI) loci, DFNA49 and DFNA7, and in close proximity to the MPZ gene previously shown to be involved in autosomal dominant Charcot-Marie-Tooth syndrome (CMT1B) with auditory neuropathy."

Nystad - Mutat Res 2008 author manuscript / PubMed Central

Polymorphisms within human cytomegalovirus chemokine (UL146/UL147) and cytokine receptor genes (UL144) are not predictive of sequelae in congenitally infected children. J Heo, S Petheram, G Demmler, JR Murph, SP Adler, J Bale, TE Sparer. Virology 2008 Aug 15;378(1):86-96. 51 HCMV isolates from congenitally infected children and 13 isolates from children in childcare. "There was no statistically significant correlation between UL146 and UL144 genotypes and HCMV disease and/or sequelae. However, there were some groups that had a relatively large proportion of asymptomatic outcomes. These included UL146 group 8 (7/8 asymptomatic) and UL146 group 10 (3/3 asymptomatic). UL144 group B had 11/15 (73%) asymptomatic. UL146 and UL144 genes remained stable in serial isolates from children in daycare for intervals up to three years."

Heo - Virology 2008 author manuscript / PubMed Central

Epidemiological impact and disease burden of congenital cytomegalovirus infection in Europe. A Ludwig, H Hengel. Euro Surveill 2009 Mar 5;14(9):26-32. Review. "In Europe, congenital cytomegalovirus (CMV) infection is the leading cause of neurological disabilities in children, causing severe sequelae such as sensorineural hearing loss, neurodevelopmental delay or blindness." "The prevalence of CMV infection at birth is related to the CMV seroprevalence in women of childbearing age, with a reported increase of 10% in maternal seroprevalence correspondending to a 0.26% increase in CMV birth prevalence. Multiple studies have shown that the overall CMV seroprevalence in women of childbearing age depends on age, parity, ethnicity and social status, and differs between countries and regions. A low socioeconomic status is a risk factor for CMV seroprevalence and congenital CMV infection."

Ludwig & Hengel / Euro Surveill 2009 full article

Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells. MH Luo, H Hannemann, AS Kulkarni, PH Schwartz, JM O'Dowd, EA Fortunato. J Virol 2010 Apr;84(7):3528-3541. "Quantitative PCR, Western blot, and immunofluorescence assays confirmed that the mRNA and protein levels of four hallmark NPC proteins (nestin, doublecortin, sex-determining homeobox 2, and glial fibrillary acidic protein) were decreased by HCMV infection. The decreases required active viral replication and were due, at least in part, to proteasomal degradation."

Luo / J Virol 2010 full article
Luo - J Virol 2010 full article / PubMed Central

Sensorineural hearing loss in a pediatric population: association of congenital cytomegalovirus infection with intracranial abnormalities. JW Kimani, CA Buchman, JK Booker, BY Huang, M Castillo, CM Powell, KE Weck. Arch Otolaryngol Head Neck Surg 2010 Oct;136(10):999-1004. In children with sensorineural hearing loss. "Of 109 patients, 11 (10%) had positive results for CMV DNA; 10 of the 11 had normal GJB2 sequence and had negative test results for the mtDNA 1555A>G mutation. Brain MRI scans for 97 patients demonstrated a higher proportion of abnormalities in patients with positive CMV test results (80%) compared with those with no detectable CMV DNA (33%) (P = .006). GJB2 mutations and the mtDNA 1555A>G mutation were seen in 10 of 88 patients (11%) and 1 of 97 patients (1%) with SNHL, respectively... The presence of brain abnormalities in most patients with congenital CMV infection suggests that neurological damage in otherwise asymptomatic patients may not be limited to SNHL. Congenital CMV infection accounted for a significant proportion of patients with SNHL, with an incidence rate comparable with that of GJB2-related SNHL"

Kimani - Arch Otolaryngol Head Neck Surg 2010 abstract / PubMed

Congenital cytomegalovirus infection in pediatric hearing loss. S Misono, KC Sie, NS Weiss, ML Huang, M Boeckh, SJ Norton, B Yueh. Arch Otolaryngol Head Neck Surg 2011 Jan;137(1):47-53. 222 children 4 years and older with hearing loss born in Washington State, and 222 matched controls. "Congenital CMV infection was detected in 1.4% of controls and in 9.9% of cases (odds ratio, 10.5; 95% confidence interval, 2.6-92.4). An estimated 8.9% of HL in children in Washington can be attributed to CMV infection. After inclusion of an additional 132 children with HL (for a total of 354 cases in the case cohort), we observed that children with congenital CMV had more severe HL (P < .001) and higher proportions of progressive (P = .02) and unilateral (P = .002) HL compared with children without congenital CMV infection. In the 35 children with congenital CMV infection, there was no relationship between neonatal CMV load and severity of HL."

Misono - Arch Otolaryngol Head Neck Surg 2011 abstract / PubMed

Association between the cytomegalovirus seroprevalence and hearing loss in early childhood. T Devdariani, K Gogberashvili, N Manjavidze, G Kamkamidze. Georgian Med News 2011 Jun;(195):61-65. 15 children with SNHL, 30 healthy controls. "CMV specific IgG antibodies were positive in 14 (93,3%) of 15 patients from the study group and in 14 (46.7%) of 30 children from the control group (p=0.003)."

Devdariani - Georgian Med News 2011 abstract / PubMed

Congenital cytomegalovirus - time to diagnosis, management and clinical sequelae in Australia: opportunities for earlier identification. BJ McMullan, P Palasanthiran, CA Jones, BM Hall, PW Robertson, J Howard, WD Rawlinson. Med J Aust 2011 Jun 20;194(12):625-629. 195 infants with cCMV, including 126 definite and 69 probable cases. "During the period of study, neonatal hearing screening was introduced for most Australian infants. Detection of hearing loss increased from 19% of cCMV cases in 1999-2003 to 31% in 2004-2009."

McMullan - Med J Aust 2011 abstract / PubMed

Late-onset sensorineural hearing loss due to asymptomatic congenital cytomegalovirus infection retrospectively diagnosed by polymerase chain reaction using preserved umbilical cord. M Ikeno, A Okumura, Y Ito, S Abe, M Saito, T Shimizu. Clin Pediatr (Phila) 2011 Jul;50(7):666-668. No abstract.

Ikeno / Clin Pediatr (Phila) 2011 login

Clinical profile of hearing loss in children with congenital cytomegalovirus (CMV) infection: CMV DNA diagnosis using preserved umbilical cord. S Furutate, S Iwasaki, SY Nishio, H Moteki, S Usami. Acta Otolaryngol 2011 Sep;131(9):976-982. 134 children up to age 12 with bilateral (46 children) or unilateral (88 children) SNHL, by PCR. "CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL."

Furutate - Acta Otolaryngol 2011 abstract / PubMed

Is lenticulostriated vasculopathy a sign of central nervous system insult in infants with congenital CMV infection? J Amir, M Schwarz, I Levy, Y Haimi-Cohen, J Pardo. Arch Dis Child 2011 Sep;96(9):846-850. 92 infants diagnosed with congenital CMV infection, studied until age 4. "In 50 (54.3%) infants, LSV was detected on initial brain ultrasound. Among these patients, 21 (42%) infants had other ultrasonographic findings consistent with congenital CMV infection; 11 (22%) had other symptoms of CNS involvement and in 18 (36%) cases the only abnormal finding was LSV. In 9 of the 18 infants with LSV as the only finding on initial examination, antiviral therapy was not started. Hearing deterioration developed in all nine infants between ages 4 and 34 months. Subsequent to these cases, the authors modified their therapy protocol and began treating congenital CMV infants with only LSV. 9 infants were treated and all maintained normal hearing after 8-27 months of follow-up (p<0.01)."

Amir - Arch Dis Child 2011 abstract / PubMed

Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population. AY Yamamoto, MM Mussi-Pinhata, L Isaac Mde, FR Amaral, CG Carvalheiro, DC Aragon, AK Manfredi, SB Boppana, WJ Britt. Pediatr Infect Dis J 2011 Dec;30(12):1043-1046. "Of 12,195 infants screened, 121 (1%) were infected with CMV and 12 (10%) had symptomatic infection at birth. Hearing function could be assessed in 102/121 children who underwent at least one auditory brainstem evoked response testing at a median age of 12 months. SNHL was observed in 10/102 (9.8%; 95% confidence interval: 5.1-16.7) children. Median age at the latest hearing evaluation was 47 months (12-84 months). Profound loss (>90 dB) was found in 4/5 children with bilateral SNHL while all 5 children with unilateral loss had moderate to severe deficit. The presence of symptomatic infection at birth (odds ratio, 38.1; 95% confidence interval: 1.6-916.7) was independently associated with SNHL after adjusting for intrauterine growth restriction, gestational age, gravidity, and maternal age. Among 10 infants with SNHL, 6 (60%) were born to mothers with nonprimary CMV infection."

Yamamoto - Pediatr Infect Dis J 2011 abstract / PubMed

Long-term outcome in preterm children with human cytomegalovirus infection transmitted via breast milk. A Bevot, K Hamprecht, I Krägeloh-Mann, S Brosch, R Goelz, B Vollmer. Acta Paediatr 2012 Apr;101(4):e167-172. 41 preterm children (born before 32 weeks of gestation or birth weight <1500 g; 20 HCMV positive, 21 HCMV negative. "In both groups, irrespective of the presence or absence of a history of HCMV infection, performance in assessments of cognitive and motor function was within the normal range. However, significant differences between the HCMV-positive and the HCMV-negative group were found in both motor and cognitive function, with poorer performance in the HCMV-positive group. There were no significant differences in anthropometric parameters, and all 20 HCMV-positive children had normal hearing function."

Bevot - Acta Paediatr 2012 abstract / PubMed

Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology. E Karltorp, S Hellström, I Lewensohn-Fuchs, E Carlsson-Hansén, PI Carlsson, ML Engman. Acta Paediatr 2012 Aug;101(8):e357-362. "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."

Karltorp - Acta Paediatr 2012 abstract / PubMed

Urine viral load and correlation with disease severity in infants with congenital or postnatal cytomegalovirus infection. J Nijman, AM van Loon, LS de Vries, C Koopman-Esseboom, F Groenendaal, CS Uiterwaal, MA Verboon-Maciolek. J Clin Virol 2012 Jun;54(2):121-124. "Seventeen infants with congenital CMV infection and 45 infants with postnatal CMV infection were included. Thirteen/17 (76%) congenitally infected infants had clinical symptoms of CMV infection at birth and 11/17 (65%) had cerebral abnormalities diagnosed by neuro-imaging. None of the four asymptomatic infants had cerebral abnormalities. Of the postnatally infected infants 43/45 (96%) did not develop any clinical symptoms of CMV infection, but in 23/45 (51%) cerebral abnormalities such as lenticulostriate vasculopathy and germinolytic cysts were identified. The median CMV load in postnatally infected infants was significantly lower than in congenitally infected infants (1.0×10(5)copies/ml versus 8.5×10(6)copies/ml, p<0.001, respectively)."

Nijman - J Clin Virol 2012 abstract / PubMed

Congenital Cytomegalovirus Is the Second Most Frequent Cause of Bilateral Hearing Loss in Young French Children. V Avettand-Fenoël, S Marlin, C Vauloup-Fellous, N Loundon, M François, V Couloigner, I Rouillon, V Drouin-Garraud, L Laccourreye, F Denoyelle, T Guilleminot, S Grabar, M Leruez-Ville. J Pediatr 2012 Sep 26;pii: S0022-3476(12)00926-2. "One hundred children with bilateral hearing loss were included at a median age of 15 months; the prevalence of cCMV was 8% (8/100) (95% CI, 2.7%-13.3%) in this population and 15.4% (8/52) in the subpopulation of children with profound bilateral hearing loss. Delayed neurodevelopment and brain abnormalities on computed tomography scan were found more often in children with cCMV than in children with hearing loss without cCMV (P = .027, P = .005). In 6 of 8 cCMV cases, cCMV infection had not been diagnosed before the study."

Avettand-Fenoël - J Pediatr 2012 abstract / PubMed

Adaptive reconfiguration of the human NK-cell compartment in response to cytomegalovirus: a different perspective of the host-pathogen interaction. A Muntasell, C Vilches, A Angulo, M López-Botet. Eur J Immunol 2013 Apr;43(5):1133-1141. "As discussed in this review, human cytomegalovirus (HCMV) infection in healthy individuals is associated with a variable and persistent increase of NK cells expressing the CD94/NKG2C activating receptor. The expansion of NKG2C+ NK cells reported in other infectious diseases is systematically associated with HCMV co-infection. The functionally mature NKG2Cbright NK-cell subset expanding in HCMV+ individuals displays inhibitory Ig-like receptors (KIR and LILRB1) specific for self HLA class I, and low levels of NKp46 and NKp30 activating receptors. Such reconfiguration of the NK-cell compartment appears particularly marked in immunocompromised patients and in children with symptomatic congenital infection, thus suggesting that its magnitude may be inversely related with the efficiency of the T-cell-mediated response."

Muntasell - Eur J Immunol 2013 abstract / PubMed

The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model. JJ de Vries, EW van Zwet, FW Dekker, AC Kroes, PH Verkerk, AC Vossen. Rev Med Virol 2013 Jul;23(4):241-249. "It was estimated that, for all population seroprevalences, nonprimary maternal infections are responsible for the majority of congenital CMV infections. This proportion increased with seroprevalence, ranging from 57% (95%CI 24-85%) to 96% (95% CI 88-99%) for seroprevalences of 30% to 95%. Our meta-analysis (six reports) showed that the risk of hearing loss after nonprimary infection was 11% (28/253 children, 95% CI 7-15%) versus 13% (50/385 children, 95% CI 10-16%) after primary infection. Incorporating this risk into our model, we estimated that nonprimary infections also accounted for the majority of CMV-related hearing loss. This proportion ranged from 53% (95% CI 13-86%) to 95% (95% CI 62-99%) for seroprevalences of 30% to 95%."

de Vries - Rev Med Virol 2013 abstract / PubMed

The "silent" global burden of congenital cytomegalovirus. S Manicklal, VC Emery, T Lazzarotto, SB Boppana, RK Gupta. Clin Microbiol Rev 2013 Jan;26(1):86-102. Review. "Indeed, CMV causes more cases of congenital disease than the combination of 29 currently screened conditions in most American states and is more common than several disorders included in newborn screening in European Union countries..."

Manicklal - Clin Microbiol Rev 2013 full article / PubMed Central
Manicklal / Clin Microbiol Rev 2013 full article

Cytomegalovirus in the Neonate: Immune Correlates of Infection and Protection. MR Schleiss. Clin Dev Immunol 2013;2013:501801. Review.

Schleiss - Clin Dev Immunol 2013 full article / PubMed Central
Schleiss / Clin Dev Immunol 2013 full article

Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene? LQ Li, JJ Tan, Y Zhou, JL Yu. Pediatr Res 2013 Aug;74(2):121-126. 159 neonates (63 with and 96 without CMV infection). "The incidence of SNHL was 12.7% in CMV-infected but 0% in uninfected children aged 1-1.5 y (P = 0.000). Similar mutation rates of the GJB2 gene were observed in neonates with or without CMV infection (34.9 vs. 32.3%, respectively, P = 0.734). No significant difference in the mutation rate of GJB2 was found among neonates with CMV infection and SNHL, those with CMV infection and normal hearing, and uninfected newborns with normal hearing (P = 0.438)."

Li - Pediatr Res 2013 abstract / PubMed

Distribution of cytomegalovirus gN variants and associated clinical sequelae in infants. E Paradowska, A Jabłońska, M Studzińska, P Suski, B Kasztelewicz, B Zawilińska, M Wiśniewska-Ligier, K Dzierżanowska-Fangrat, T Woźniakowska-Gęsicka, J Czech-Kowalska, B Lipka, M Kornacka, D Pawlik, T Tomasik, M Kosz-Vnenchak, ZJ Leśnikowski. J Clin Virol 2013 Sep;58(1):271-275. Number of subjects not stated in abstract. "A significant association between the HCMV gN4 genotype and the incidence of neurological disorders was observed (p=0.045)."

Paradowska - J Clin Virol 2013 abstract / PubMed

Later Passage Neural Progenitor Cells from Neonatal Brain Are More Permissive for Human Cytomegalovirus Infection. X Pan, XJ Li, XJ Liu, H Yuan, JF Li, YL Duan, HQ Ye, YR Fu, GH Qiao, CC Wu, B Yang, XH Tian, KH Hu, LF Miao, XL Chen, J Zheng, S Rayner, PH Schwartz, WJ Britt, J Xu, MH Luo. J Virol 2013 Oct;87(20):10968-10979. "In this study NPC cultures derived at different gestational ages were evaluated after short (passage 3-6) and extended (passage11-20) in vitro passage for biological and virological parameters... extended passage cultures showed evidence of differentiation, increased viral entry, and more efficient production of infectious progeny."

Pan - J Virol 2013 abstract / PubMed

Human fetal inner ear involvement in congenital cytomegalovirus infection. L Gabrielli, MP Bonasoni, D Santini, G Piccirilli, A Chiereghin, B Guerra, MP Landini, MG Capretti, M Lanari, T Lazzarotto. Acta Neuropathol Commun 2013 Oct 2;1(1):63. 20 fetuses. "Immunohistochemistry revealed that CMV was positive in 14/20 brains (70%) and in the inner ears of 9/20 fetuses (45%). In the cases with inner ear infection, the marginal cell layer of the stria vascularis was always infected, followed by infection in the Reissner's membrane. The highest tissue viral load was observed in the inner ear with infected Organ of Corti. Vestibular labyrinth showed CMV infection of sensory cells in the utricle and in the crista ampullaris.US cerebral anomalies were detected in 6 cases, and in all those cases, the inner ear was always involved. In the other 14 cases with normal brain scan, histological brain damage was present in 8 fetuses and 3 of them presented inner ear infection."

Gabrielli - Acta Neuropathol Commun 2013 abstract / PubMed

Long-term audiological follow-up of children with congenital cytomegalovirus. L Royackers, E Rector, N Verhaert, C Desloovere. B-ENT 2013;Suppl 21:57-64. 98 congenitally CMV-infected children. "In the treated group, 37.5% of the children had stable hearing loss, and 37.5% had progressive and/or fluctuating hearing loss... The hearing threshold improved in 25.0%. The improvement took place during or shortly after treatment. Hearing loss remained stable in 33.3% of the untreated symptomatic children, while progression or fluctuation occurred in 55.5%. In the asymptomatic group, hearing loss was most commonly stable (63.6%)."

Royackers - B-ENT 2013 abstract / PubMed

Cytomegalovirus-induced brain malformations in fetuses. N Teissier, C Fallet-Bianco, AL Delezoide, A Laquerrière, P Marcorelles, S Khung-Savatovsky, J Nardelli, S Cipriani, Z Csaba, O Picone, JA Golden, T Van Den Abbeele, P Gressens, H Adle-Biassette. J Neuropathol Exp Neurol 2014 Feb;73(2):143-158. "16 infected human fetal brains aged 23 to 28.5 gestational weeks. Nine cases were microcephalic, 10 had extensive cortical lesions, 8 had hippocampal abnormalities, and 5 cases showed infection of the olfactory bulb. The density of CMV-immunolabeled cells correlated with the presence of microcephaly and the extent of brain abnormalities. Innate and adaptive immune responses were present but did not react against all CMV-infected cells. Cytomegalovirus infected all cell types but showed higher tropism for stem cells/radial glial cells."

Teissier - J Neuropathol Exp Neurol 2014 abstract / PubMed

Incidence and impact of CMV infection in very low birth weight infants. KM Turner, HC Lee, SB Boppana, WA Carlo, DA Randolph. Pediatrics 2014 Mar;133(3):e609-615. "Eighteen of 4594 VLBW infants had congenital CMV (0.39%; 95% confidence interval, 0.25%-0.62%). An additional 16 infants (0.35%; 95% confidence interval, 0.21%-0.57%) were identified who acquired CMV postnatally. Congenital CMV was not associated with death. Compared with controls, congenitally infected VLBW infants were more likely to have hearing loss at initial screening (67% vs 9%, P < .0001) and confirmed at follow-up (83% vs 2.1%, P < .0001). Congenital CMV was also associated with abnormal neuroimaging (72% vs 25%, P < .0001) and adverse developmental motor outcomes (43% vs 9%, P = .02). Acquired CMV was not associated with any adverse outcomes."

Turner - Pediatrics 2014 abstract / PubMed

Spectrum of Disease and Outcome in Children with Symptomatic Congenital Cytomegalovirus Infection. AM Dreher, N Arora, KB Fowler, Z Novak, WJ Britt, SB Boppana, SA Ross. J Pediatr 2014 Apr;164(4):855-859. 178 infants. "Two or more clinical findings were detected at birth in 91% of referred infants, and only 58% of screened infants (P < .001). Significantly more children in the referred group had hearing loss compared with screened infants (P = .009). Fifty-one percent of screened children were free of sequelae compared with only 28% of the referred group (P < .003)."

Dreher - J Pediatr 2014 abstract / PubMed

Long-term neurobiological consequences of early postnatal hCMV-infection in former preterms: A Functional MRI Study. M Dorn, K Lidzba, A Bevot, R Goelz, TK Hauser, M Wilke. Hum Brain Mapp 2014 Jun;35(6):2594-606. 34 infected, 37 controls. "There were significant activation differences in the left hippocampus (PT > HC and PThCMV+ > HC), and in the right anterior cingulate cortex (PThCMV- > PThCMV+ ) when performing the language task. Surprisingly, only a small region in the occipital cortex showed a significant activation difference (HC > PT HCMV- ) when performing the visuospatial task. Targeted analyses revealed differences in gray matter volume, but not density, in several brain regions."

Dorn - Hum Brain Mapp 2014 abstract / PubMed

Impaired balance and neurodevelopmental disabilities among children with congenital cytomegalovirus infection. E Karltorp, U Löfkvist, I Lewensohn-Fuchs, K Lindström, M Eriksson Westblad, K Teär Fahnehjelm, L Verrecchia, ML Engman. Acta Paediatr 2014 Nov;103(11):1165-1173. 26 children with congenital CMV, 13 children with connexin 26 mutations as controls. "The majority of the children with congenital CMV infection (88%) displayed balance disturbances, including walking at a later age, but there were no cases in the control group. The CMV group also displayed frequent neurodevelopmental disabilities and feeding difficulties."

Karltorp - Acta Paediatr 2014 abstract / PubMed

Hearing Loss and Congenital CMV Infection: A Systematic Review. J Goderis, E De Leenheer, K Smets, H Van Hoecke, A Keymeulen, I Dhooge. Pediatrics 2014 Nov;134(5):972-982. Based on 10 population-based natural history studies, 14 longitudinal cohort studies, and 13 retrospective studies. "The prevalence of cCMV in developed countries is 0.58% (95% confidence interval, 0.41-0.79). Among these newborns 12.6% (95% confidence interval, 10.2-16.5) will experience hearing loss: 1 out of 3 symptomatic children and 1 out of 10 asymptomatic children. Among symptomatic children, the majority have bilateral loss; among asymptomatic children, unilateral loss predominates. In both groups the hearing loss is mainly severe to profound. Hearing loss can have a delayed onset, and it is unstable, with fluctuations and progression. Among hearing-impaired children, cCMV is the causative agent in 10% to 20%."

Goderis - Pediatrics 2014 abstract / PubMed

Evolutive Leukoencephalopathy in Congenital Cytomegalovirus Infection. G Krakar, I Dakovic, S Delin, VM Bosnjak. J Child Neurol 2015 Jan;30(1):93-95. Case report. "Neonatal brain MRI showed most of characteristic findings in congenital cytomegalovirus infection with most prominent white matter abnormalities and cortical dysplasia. MRI follow-up images showed that cortical dysgenesis remained unchanged and static, whereas white matter abnormalities evolved over the years."

Krakar - J Child Neurol 2015 abstract / PubMed

Valganciclovir for symptomatic congenital cytomegalovirus disease. DW Kimberlin, PM Jester, et al., National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med 2015 Mar 5;372(10):933-943. Randomized, placebo-controlled trial of 86 neonates. "Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003)."

Kimberlin - N Engl J Med 2015 abstract / PubMed

Neuro-Imaging Findings in Infants with Congenital Cytomegalovirus Infection: Relation to Trimester of Infection. N Oosterom, J Nijman, J Gunkel, TF Wolfs, F Groenendaal, MA Verboon-Maciolek, LS de Vries. Neonatology 2015 Mar 10;107(4):289-296. "Thirty-six infants were eligible for analysis. cUS was performed in all and cranial MRI in 20 infants. Migrational disorders were only diagnosed using MRI (p < 0.01). In 17 infants trimester of infection was ascertained. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (5 confirmed on MRI) and adverse sequelae; 3 had no/mild abnormalities on cUS/MRI and normal outcome. Two out of 3 infants infected during the second trimester with no/mild abnormalities on cUS/MRI had normal outcome; 1 with mild cUS and MRI abnormalities developed sensorineural hearing loss. Four infants infected during the third trimester with no/mild abnormalities on cUS/MRI had normal outcome."

Oosterom - Neonatology 2015 abstract / PubMed

Chorioretinal scars and visual deprivation are common in children with cochlear implants after congenital cytomegalovirus infection. K Teär Fahnehjelm, M Olsson, C Fahnehjelm, I Lewensohn-Fuchs, E Karltorp. Acta Paediatr 2015 Jul;104(7):693-700. 26 congenital CMV children, and 26 control children with Cx26 mutation. "We found unilateral chorioretinal macular scars that reduced best corrected visual acuity ≤ 0.3 in five (19%) of the children with congenital CMV, but in none of the children with Cx26 (p=0.15). Ocular motility problems were more common among children with congenital CMV, but the difference was not significant (p=0.20). The vestibuloocular reflex was more frequently pathological in children with congenital CMV (p= 0.011)."

Teär Fahnehjelm - Acta Paediatr 2015 abstract / PubMed

High Cytomegalovirus (CMV) DNAemia Predicts CMV Sequelae in Asymptomatic Congenitally Infected Newborns Born to Women With Primary Infection During Pregnancy. G Forner, D Abate, C Mengoli, G Palù, N Gussetti. J Infect Dis 2015 Jul 1;212(1):67-71. 23 newborns with congenital asymptomatic CMV infection. "Ten infants developed postnatal sequelae, whereas twenty-three infants remained asymptomatic. Fifty percent of babies cleared CMV in blood and urine within 3 and 36 months, respectively. Logistic multivariate regression revealed that the risk of neonatal clinical disease crossed the level of 50% with a DNAemia at birth of ≥12 000 copies/mL (P = .0002). The risk of hearing deficit crossed the level of 50% with a DNAemia at birth of ≥ 17 000 copies/mL (P = .0001)."

Forner - J Infect Dis 2015 abstract / PubMed

Evaluation of 98 immunocompetent children with cytomegalovirus infection: importance of neurodevelopmental follow-up. E Çelikel, H Tezer, S Kanik-Yuksek, B Gülhan, A Ozkaya-Parlakay, N Yaralı. Eur J Pediatr 2015 Aug;174(8):1101-1107. Median age at admission was 5.6 months, and included 3.06% with known congenital and 36.7% with possible congenital infection. At follow-up, "There were intracranial calcification in 5.1 % and eye findings in 5.1 %. On follow-up of patients, complete improvement (59.1 %), neuromotor developmental delay (11.2 %), epilepsy (10.2 %), hearing loss (3.06 %), hemolytic anemia (2.04 %), and growth retardation (1.02 %) were detected."

Çelikel - Eur J Pediatr 2015 abstract / PubMed

Disorders in Children With Congenital Cytomegalovirus Infection. S Bernard, S Wiener-Vacher, T Van Den Abbeele, N Teissier. Pediatrics 2015 Oct;136(4):e887-895. 52 children with congenital CMV infection and sensorineural impairment. "Forty-eight children (92.3%) had hearing loss and vestibular disorders. Of those, vestibular disorders were complete and bilateral in 33.3%, partial and bilateral in 43.7%, and partial and unilateral in 22.9%. Serial testing in 14 children showed stable vestibular function in 50% and deterioration in 50%. Congenital CMV infection has a negative impact on postural development that is correlated with neurologic and vestibular impairment. Vestibular disorders were significantly associated with hearing disorders, but their respective severities showed no concordance."

Bernard - Pediatrics 2015 abstract / PubMed

Cytomegalovirus Genotype Distribution Among Congenitally and Postnatally Infected Patients: Association of Particular Glycoprotein (g)B and gN Types With Symptomatic Disease. P Brañas, D Blázquez-Gamero, A Galindo, C Prieto, I Olabarrieta, I Cuadrado, L Folgueira. Open Forum Infect Dis 2015 Oct 7;2(4):ofv151. 48 congenital, 58 postnatally infected cases. "All of the genotypes were similarly represented among cohorts, and the most prevalent were the UL144B, gB1, and gN1 genotypes. The gB2 genotype was associated with abnormal image findings by ultrasound and/or magnetic resonance in congenital infection (odds ratio [OR], 6.2; 95% confidence interval [CI], 1.1-34.3; P = .036); the gN1 genotype was associated with an elevated risk of developing neurological disorders (OR, 7.0; 95% CI, 1.1-45.9; P = .043). Both gN1 and gB2 were independent factors for symptomatic infection. Statistical analyses showed no association between any UL144 genotype and disease severity."

Brañas - Open Forum Infect Dis 2015 full article / PubMed Central

Combined genetic variants of human cytomegalovirus envelope glycoproteins as congenital infection markers. MC Arcangeletti, R Vasile Simone, I Rodighiero, F De Conto, MC Medici, D Martorana, C Chezzi, A Calderaro. Virol J 2015 Nov 26;12(1):202. 40 urine samples from infants with congenital (n = 19) or post-natal (n = 21) HCMV infection. "While gB genomic variants were quite homogeneously represented in both paediatric groups, the gN4 genotype significantly prevailed in congenitally infected children (89.5 %) vs post-natally infected children (47.6 %), with a predominance of the gN4c variant (47.4 %). A similar trend was observed for gO3 (52.6 % vs 19 %)."

Arcangeletti - Virol J 2015 full article / PubMed Central
Arcangeletti / Virol J 2015 full article

Risk of congenital disease in 46 infected fetuses according to gestational age of primary human cytomegalovirus infection in the mother. M Zavattoni, M Rustico, B Tassis, G Lombardi, M Furione, A Piralla, F Baldanti. J Med Virol 2016 Jan;88(1):120-126. "17/28 (60.7%) asymptomatic and 18/18 (100%) symptomatic fetuses/newborns were infected as a consequence of a primary maternal HCMV infection acquired ≤8 weeks of gestational age, while 11/28 (39.3%) asymptomatic and 0/18 (0%) symptomatic fetuses/newborns were congenitally infected when maternal infection was acquired >8 weeks' gestation. Symptomatic fetal infections appeared to be associated with a maternal primary infection occurring at ≤ 8 weeks' gestation."

Zavattoni - J Med Virol 2016 abstract / PubMed

Neurological outcomes in symptomatic congenital cytomegalovirus-infected infants after introduction of newborn urine screening and antiviral treatment. K Nishida, I Morioka, Y Nakamachi, Y Kobayashi, T Imanishi, S Kawano, S Iwatani, T Koda, M Deguchi, K Tanimura, D Yamashita, KI Nibu, T Funakoshi, M Ohashi, N Inoue, K Iijima, H Yamada. Brain Dev 2016 Feb;38(2):209-216. 32 (0.5%) of 6348 newborns were positive for CMV, with 16 symptomatic.and 12 treated. "Four infants developed severe impairment (33%), three developed mild impairment (25%), and five developed normally (42%)."

Nishida - Brain Dev 2016 abstract / PubMed

Correlation Between White Matter Lesions and Intelligence Quotient in Patients With Congenital Cytomegalovirus Infection. Y Inaba, M Motobayashi, M Nishioka, T Kaneko, S Yamauchi, Y Kawasaki, N Shiba, SY Nishio, H Moteki, M Miyagawa, Y Takumi, SI Usami, K Koike. Pediatr Neurol 2016 Feb;55:52-57. 8 of 9 children with congenital CMV and sensorineural hearing loss had white matter lesions. "We observed increased white matter lesion volume was associated with lower intelligence quotient scores (R2 = 0.533, P = 0.026) but not with autism spectrum disorders."

Inaba - Pediatr Neurol 2016 abstract / PubMed

Hearing outcome of infants with congenital cytomegalovirus and hearing impairment. E Bilavsky, K Shahar-Nissan, J Pardo, J Attias, J Amir. Arch Dis Child 2016 May;101(5):433-438. "Hearing impairment at birth was found in 54 (36.2%) of the 149 infants diagnosed with symptomatic cCMV, and found in 77 affected ears; unilateral in 31 (57.4%) and bilateral in 23 (42.6%). After 1 year of antiviral treatment and a long-term follow-up of the 77 affected ears at baseline, 50 (64.9%) had improved, 22 (28.6%) remained unchanged and 5 (6.5%) had deteriorated. Most improved ears (38/50=76%) returned to normal hearing. Improvement was most likely to occur in infants born with mild or moderate hearing loss and less in those with severe impairment."

Bilavsky - Arch Dis Child 2016 abstract / PubMed

Hearing in Children with Congenital Cytomegalovirus Infection: Results of a Longitudinal Study. J Goderis, A Keymeulen, K Smets, H Van Hoecke, E De Leenheer, A Boudewyns, C Desloovere, R Kuhweide, M Muylle, L Royackers, I Schatteman, I Dhooge. J Pediatr 2016 May;172:110-115.e2. 123 symptomatic and 256 asymptomatic children. "In the group with symptomatic cCMV, 63% had hearing loss, compared with 8% in the group with asymptomatic cCMV. Delayed-onset hearing loss occurred in 10.6% of symptomatic cCMV and in 7.8% of asymptomatic cCMV."

Goderis - J Pediatr 2016 abstract / PubMed

Region selective reductions in brain apparent diffusion coefficient in CMV-infected fetuses. G Yaniv, C Hoffmann, B Weisz, S Lipitz, E Katorza, D Kidron, D Bergman, A Biegon. Ultrasound Obstet Gynecol 2016 May;47(5):600-607. MRIs of 58 CMV-infected fetus, versus normal controls. "ADC values of the CMV-infected fetuses significantly and negatively correlated with GA in all brain regions except the basal ganglia. The cerebellum had the steepest decline (r =0.52, P < .0001). Maternal age correlated positively with ADC in the frontal lobe (P < .05). Age at infection and overt pathological changes did not significantly affect ADC. ADC values of affected fetuses were significantly reduced in the frontal (P < .0001), parietal (P < .0001), occipital (P = .0005), and temporal (P = .001) lobes and thalamus (P = .006) compared to non-infected fetuses."

Yaniv - Ultrasound Obstet Gynecol 2016 abstract / PubMed

Prevalence and clinical aspects of CMV congenital Infection in a low-income population. LJ Marin, E Santos de Carvalho Cardoso, SM Bispo Sousa, L Debortoli de Carvalho, MF Marques Filho, MR Raiol, SR Gadelha. Virol J 2016 Aug 31;13:148. Viral DNA was found in 1.19 % (25/2100) newborns. "Approximately 12 % of children presented symptoms. One death and two auditory alterations were detected during the monitored period."

Marin - Virol J 2016 full article / PubMed Central
Marin / Virol J 2016 full article

Follow-up of infants with congenital cytomegalovirus and normal fetal imaging. J Amir, J Atias, N Linder, J Pardo. Arch Dis Child Fetal Neonatal Ed 2016 Sep;101(5):F428-32. 98 infants born to mothers with primary CMV infection. "52 (53.1%) infants received early antiviral treatment for central nervous system symptoms or signs, mainly lenticulostriatal vasculopathy on postnatal ultrasonography (88.5%). Sensorineural hearing loss was found on first examination in 16 infants (25 ears), of whom 10 also had cranial ultrasound findings; another five with late-onset hearing loss were also treated... Most infants with moderate and severe hearing loss were infected in the first trimester (10 vs 2, p=0.053). At the last assessment, eight children (10 ears) still had hearing loss, including two with bilateral loss who underwent a cochlear implant."

Amir - Arch Dis Child Fetal Neonatal Ed 2016 abstract / PubMed

Asymptomatic congenital cytomegalovirus infection with neurological sequelae: A retrospective study using umbilical cord. M Uematsu, K Haginoya, A Kikuchi, N Hino-Fukuyo, K Ishii, T Shiihara, M Kato, A Kamei, S Kure. Brain Dev 2016 Oct;38(9):819-826. "Among 54 congenital CMV patients, major neurological symptoms included intellectual disability (n=51, 94.4%), hearing impairment (n=36, 66.7%) and cerebral palsy (n=21, 38.9%), while microcephaly (n=16, 29.6%) and epilepsy (n=14, 25.9%) were less common. In a brain magnetic resonance imaging (MRI) study, cortical dysplasia was observed in 27 CMV-positive patients (50.0%), and all patients (100%) had cerebral white matter (WM) abnormality. Intracranial calcification was detected by CT in 16 (48.5%) of 33 CMV-positive patients."

Uematsu - Brain Dev 2016 abstract / PubMed

Primary maternal cytomegalovirus infections: accuracy of fetal ultrasound for predicting sequelae in offspring. M Leyder, A Vorsselmans, E Done, K Van Berkel, G Faron, I Foulon, A Naessens, A Jansen, W Foulon, L Gucciardo. Am J Obstet Gynecol 2016 Nov;215(5):638. 69 fetuses. "Fetal ultrasound anomalies were detected in 37.7% of pregnant women with primary cytomegalovirus infection acquired in early pregnancy and proven fetal infection, and were confirmed by autopsy or postnatal clinical evaluation in 73.9%. Autopsy or postnatal clinical evaluation also detected cytomegalovirus-related anomalies in 55% of infants with normal fetal ultrasound evaluations."

Leyder - Am J Obstet Gynecol 2016 abstract / PubMed

Symptomatic congenital cytomegalovirus disease following non-primary maternal infection: a retrospective cohort study. E Hadar, E Dorfman, R Bardin, R Gabbay-Benziv, J Amir, J Pardo. BMC Infect Dis 2017 Jan 5;17(1):31. 107 cases. "Disease severity is not similar in affected newborns, with a higher incidence of abnormal brain sonographic findings, following primary versus non-primary maternal CMV infection (76.8% vs. 8.3%, p < .001)."

Hadar - BMC Infect Dis 2017 full article / PubMed Central
Hadar / BMC Infect Dis 2017 full article

Screening for seemingly healthy newborns with congenital cytomegalovirus infection by quantitative real-time polymerase chain reaction using newborn urine: an observational study. A Yamaguchi, T Oh-Ishi, T Arai, H Sakata, N Adachi, S Asanuma, E Oguma, H Kimoto, J Matsumoto, H Fujita, T Uesato, J Fujita, K Shirato, H Ohno, T Kizaki. BMJ Open 2017 Jan 20;7(1):e013810. "The incidence of cCMV infection was 60/23 368 (0.257%; 95% CI 0.192% to 0.322%)... AABR testing revealed abnormalities in 171 of the 22 229 (0.769%) newborns whose parents approved hearing screening. Of these 171 newborns, 22 had SNHL (12.9%), and 5 of these 22 were infected with cCMV (22.7%)... MRI revealed CNS damage, including white matter abnormalities, in 83.0% of newborns with cCMV."

Yamaguchi - BMJ Open 2017 full article / PubMed Central
Yamaguchi / BMJ Open 2017 full article

Comparison of the Motor Performance and Vestibular Function in Infants with a Congenital Cytomegalovirus Infection or a Connexin 26 Mutation: A Preliminary Study. L Maes, A De Kegel, H Van Waelvelde, E De Leenheer, H Van Hoecke, J Goderis, I Dhooge. Ear Hear 2017 Jan/Feb;38(1):e49-e56. 40 subjects. "Symptomatic hearing-impaired cCMV children demonstrated a significantly lower gross motor performance compared with the control group (p = 0.005), the asymptomatic cCMV group (p = 0.034), and the Cx26 group (0.016). In this symptomatic hearing-impaired cCMV group, 4 out of 8 children had absent cVEMP responses that were related to the weakest gross motor performance."

Maes - Ear Hear 2017 abstract / PubMed

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening. KB Fowler, FP McCollister, DL Sabo, AG Shoup, KE Owen, JL Woodruff, E Cox, LS Mohamed, DL Choo, SB Boppana; CHIMES Study. Pediatrics 2017 Feb;139(2) pii: e20162128. 99 945 newborns. "Overall, 7.0% of CMV-positive infants did not pass NHS [newborn hearing screening] compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy." "43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS."

Fowler - Pediatrics 2017 abstract / PubMed

Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection. TM Lanzieri, W Chung, M Flores, P Blum, AC Caviness, SR Bialek, SD Grosse, JA Miller, G Demmler-Harrison; Congenital Cytomegalovirus Longitudinal Study Group. Pediatrics 2017 Mar;139(3). pii: e20162610. 92 patients, 51 controls. "At age 18 years, SNHL prevalence was 25% (95% confidence interval [CI]: 17%-36%) among case-patients and 8% (95% CI: 3%-22%) in controls (hazard ratio [HR]: 4.0; 95% CI: 1.2-14.5; P = .02)."

Lanzieri - Pediatrics 2017 abstract - PubMed

Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection - register-based study from Finland. L Puhakka, M Renko, M Helminen, V Peltola, T Heiskanen-Kosma, M Lappalainen, HM Surcel, T Lönnqvist, H Saxen. Infect Dis (Lond) 2017 Jun;49(6):445-453. 26 babies with symptomatic congenital CMV infection. "The majority of the symptomatic congenital CMV infections (54%) were due to maternal non-primary infection, 27% due to maternal primary infection in the first trimester or near conception, and 19% during the second or third trimester. Long-term sequelae occurred in 59% of patients: in 6/7 after primary infection in the first trimester, in 0/5 after primary infection in the second or third trimester, and in 9/14 after non-primary infection."

Puhakka - Infect Dis (Lond) 2017 abstract / PubMed

The Serological Evidence of Cytomegalovirus Infection as a Potent Aetiological Factor for Cleft Lip/Palate, Mental Retardation and Deafness. DV Divya, MGS Prasad, AN Radhakrishna, SP Reddy, K Pratyusha, KVKS Kumar, RV Sandeep. J Clin Diagn Res 2017 Jun;11(6):ZC51-ZC54. 60 cases, 20 controls. "In the study group (Group1, 2 and 3) children, the overall positivity for HCMV- specific IgG was 100% and 5% borderline to IgM antibodies whereas in the control group (Group 4) it was 80% negative to HCMV- specific IgG and 100% negative to IgM antibodies."

Divya - J Clin Diagn Res 2017 full article / PubMed Central

Long-term outcomes of children with symptomatic congenital cytomegalovirus disease. TM Lanzieri, J Leung, AC Caviness, W Chung, M Flores, P Blum, SR Bialek, JA Miller, SS Vinson, MR Turcich, RG Voigt, G Demmler-Harrison. J Perinatol 2017 Jul;37(7):875-880. "Among 76 case-patients followed through median age of 13 (range: 0-27) years, 56 (74%) had SNHL, 31 (43%, n=72) had intellectual disability and 18 (27%, n=66) had vision impairment; 28 (43%, n=65) had intellectual disability and SNHL with/without vision impairment. Microcephaly was significantly associated with each of the three outcomes."

Lanzieri - J Perinatol 2017 abstract / PubMed

Congenital Cytomegalovirus Infection and Permanent Hearing Loss in Rural North Indian Children. L Dar, D Namdeo, P Kumar, A Thakar, S Kant, S Rai, PK Singh, M Kabra, KB Fowler, SB Boppana. Pediatr Infect Dis J 2017 Jul;36(7):670-673. 20 cases. "[Permanent congenital or early-onset hearing loss] was 20-fold higher in neonates with cCMV (2/20, 10%) than those without (9/1700, 0.5%; p<0.01). None of 11 infants with PCEHL had connexin 26 mutations."

Dar - Pediatr Infect Dis J 2017 abstract / PubMed

Risks factors for congenital CMV infection following primary and non-primary maternal infection: a prospective neonatal screening study using PCR in saliva. M Leruez-Ville, JF Magny, S Couderc, C Pichon, M Parodi, L Bussières, T Guilleminot, I Ghout, Y Ville. Clin Infect Dis 2017 Aug 1;65(3):398-404. 11,715 consecutive newborns in France. "Maternal seroprevalence was 61%, birth prevalence was 0.37%, resulting from primary and non-primary infections in 52% and 47.7% of cases respectively. The risk to deliver an infected baby after primary infection was increased in younger (OD=7.9), parous (OD=4.1) women born in high resources countries (OD=5.2) and from higher income groups (p=0.019). The only 2 risk factors to deliver an infected baby after non-primary infection were to be young (OD=4.6) and unemployed (OD=5.8). The risk to deliver an infected baby was 4-fold higher in women seronegative before their pregnancy (p=0.021)."

Leruez-Ville - Clin Infect Dis 2017 abstract / PubMed

Human cytomegalovirus IE2 protein disturbs brain development by dysregulating neural stem cell maintenance and the polarization of migrating neurons. D Han, SH Byun, J Kim, M Kwon, SJ Pleasure, JH Ahn, K Yoon. J Virol 2017 Sep 2017;91(17):11 e00799-00817. "IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP... Our data suggest that the wide spectrum of clinical outcomes ranging from mental retardation to microcephaly caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone."

Han - J Virol 2017 abstract / PubMed

Long-term Visual and Ocular Sequelae in Patients with Congenital Cytomegalovirus Infection. H Jin, GJ Demmler-Harrison, DK Coats, EA Paysse, A Bhatt, JC Edmond, KG Yen, P Steinkuller, J Miller; Congenital CMV Longitudinal Study Group. Pediatr Infect Dis J 2017 Sep;36(9):877-882. 77 symptomatic, 109 asymptomatic, and 51 control patients. "Fourteen of the 77 (18.2%) symptomatic and none of the asymptomatic and control subjects had severe visual impairments (p ≤ 0.006)... The most common visual or ocular sequelae in the symptomatic group were strabismus (23.4%), chorioretinal scars (19.5%), cortical visual impairment (14.3%), nystagmus (14.3%), and optic nerve atrophy (11.7%)."

Jin - Pediatr Infect Dis J 2017 abstract / PubMed

Outcomes of congenital cytomegalovirus disease following maternal primary and non-primary infection. A Giannattasio, P Di Costanzo, A De Matteis, P Milite, D De Martino, L Bucci, MR Augurio, C Bravaccio, T Ferrara, L Capasso, F Raimondi. J Clin Virol 2017 Sep 14;96:32-36. 158 cases, 93 from mothers with primary and 65 with secondary CMV infection. "An impaired neurodevelopmental outcome was observed in 23.7% of patients of Group 1 and in 24.6% cases of Group 2. Similarly, the frequency of hearing loss did not differ between the two groups (25.8% versus 26.2%, respectively)."

Giannattasio - J Clin Virol 2017 abstract / PubMed

Analysis of archived newborn dried blood spots (DBS) identifies congenital cytomegalovirus as a major cause of unexplained pediatric sensorineural hearing loss. L Meyer, B Sharon, TC Huang, AC Meyer, KE Gravel, LA Schimmenti, EC Swanson, HE Herd, N Hernandez-Alvarado, KR Coverstone, M McCann, MR Schleiss. Am J Otolaryngol 2017 Sep-Oct;38(5):565-570. "In total, 15 of the 57 children with unexplained SNHL tested positive for CMV DNA in their DBS (26%)."

Meyer - Am J Otolaryngol 2017 abstract / PubMed

Intelligence and Academic Achievement With Asymptomatic Congenital Cytomegalovirus Infection. AS Lopez, TM Lanzieri, AH Claussen, SS Vinson, MR Turcich, IR Iovino, RG Voigt, AC Caviness, JA Miller, WD Williamson, CM Hales, SR Bialek, G Demmler-Harrison; Congenital Cytomegalovirus Longitudinal Study Group. Pediatrics 2017 Nov;140(5):e20171517. 78 with normal hearing, 11 with SNHL, 40 controls. "Patients with SNHL had full-scale intelligence and receptive vocabulary scores that were 7.0 and 13.1 points lower, respectively, compared with controls, but no significant differences were noted in these scores among patients with normal hearing and controls."

Lopez - Pediatrics 2017 abstract / PubMed

Long-term impairment attributable to congenital cytomegalovirus infection: a retrospective cohort study. MJ Korndewal, AM Oudesluys-Murphy, ACM Kroes, MAB van der Sande, HE de MelkerE, ACTM Vossen. Dev Med Child Neurol 2017 Dec;59(12):1261-1268. 133 cases, 274 controls. "Moderate to severe long-term impairment was diagnosed in 24.8% (33 out of 133) of all cCMV-positive children (53.8% in symptomatic, 17.8% in asymptomatic), compared with 12.0% (33 out of 274) of cCMV-negative children. Sensorineural hearing loss was seen only in five cCMV-positive children (3.8%). Developmental delays were diagnosed more often in cCMV-positive children than cCMV-negative children: motor (12.0% vs 1.5%), cognitive (6.0% vs 1.1%), and speech-language (16.5% vs 7.3%). Long-term impairment in multiple domains was more frequent in symptomatic (19.2%) and asymptomatic (8.4%) cCMV-positive children than cCMV-negative children (1.8%)."

Korndewal - Dev Med Child Neurol 2017 abstract / PubMed

Neonatal and long-term ophthalmological findings in infants with symptomatic and asymptomatic congenital cytomegalovirus infection. MG Capretti, C Marsico, S Guidelli Guidi, A Ciardella, G Simonazzi, S Galletti, L Gabrielli, T Lazzarotto, G Faldella. J Clin Virol 2017 Dec;97:59-63. 18 symptomatic, 30 asymptomatic infected infants. "Funduscopic abnormalities were identified in neonatal period in 7/18 (39%) symptomatic infants and in none of the infants without other clinical and instrumental abnormalities at birth (P<0.001); chorioretinal scars were the most common finding (5/18 cases, 28%). Strabismus was detected in 1/18 (5.5%) symptomatic infants during the first years of life. Visual impairment at last follow-up evaluation was suspected or detected in 4/18 (22%) symptomatic infants and in none of the asymptomatic infants at birth (P=0.01). Ophthalmological abnormalities were associated with other signs of central nervous system (CNS) involvement (P<0.001)."

Capretti - J Clin Virol 2017 abstract / PubMed

Neonatal screening for congenital CMV infection stresses the importance of maternal nonprimary infection even in an area where prenatal serology testing is common. V Papaevangelou, Z Christoni, C Vliora, C Kottaridi, A Fotiou, A Malamitsi-Puchner, A Mentis, P Karakitsos, A Syggelou. J Matern Fetal Neonatal Med 2017 Dec 27:1-4. 980 / 1287 (76.1%) of mothers were CMV+. " cCMV incidence was 0.47%. All newborns were asymptomatic; 9/10 were born post nonprimary maternal infection; two developed sensorineural hearing loss."

Papaevangelou - J Matern Fetal Neonatal Med 2017 abstract / PubMed

Congenital cytomegalovirus in Japan: More than 2 year follow up of infected newborns. S Koyano, I Morioka, A Oka, H Moriuchi, K Asano, Y Ito, T Yoshikawa, H Yamada, T Suzutani, N Inoue; Japanese Congenital Cytomegalovirus Study Group. Pediatr Int 2018 Jan;60(1):57-62. Among the 43 asymptomatic cases, "the rate of CMV-associated late-onset sequelae was 7~12%. All 7 symptomatic infants without treatment developed sequelae, while 3 of the 10 treated cases were free from any sequelae."

Morioka - Pediatr Int 2018 abstract / PubMed

Sequelae of congenital cytomegalovirus (cCMV) following maternal primary infection are limited to those acquired in the first trimester of pregnancy. V Faure-Bardon, JF Magny, M Parodi, S Couderc, P Garcia, AM Maillotte, M Benard, D Pinquier, D Astruc, H Patural, P Pladys, S Parat, B Guillois, A Garenne, L Bussières, T Guilleminot, J Stirnemann, I Ghout, Y Ville, M Leruez-Ville. Clin Infect Dis 2019 Oct 15;69(9):1526-1532. 260 fetuses/neonates. "At a median follow-up of 24 months, the proportion of SNHL and/or neurologic sequelae were 32.4% (95%IC 23.72, 42.09) after maternal primary infection in first trimester, and 0 (0, 6.49) and 0 (0, 11.95) after infection in second and third trimester respectively (p<.0001)."

Faure-Bardon - Clin Infect Dis 2019 abstract / PubMed

Contribution of congenital cytomegalovirus (cCMV) to permanent hearing loss in a highly seropositive population: "The BraCHS study". AY Yamamoto, ART Anastasio, ET Massuda, ML Isaac, AKS Manfredi, JMS Cavalcante, A Carnevale-Silva, KB Fowler, S Boppana, WJ Britt, MM Mussi-Pinhata. Clin Infect Dis 2020 Mar 17;70(7):1379-1384. "The rate of permanent HL resulting from cCMV was 8 per 11,887 infants (0.7 per 1000 live births). The prevalence ratio of hearing loss among infants with cCMV compared to CMV-uninfected infants was 89.5 (CI95%:39.7-202.0)."

Yamamoto - Clin Infect Dis 2020 abstract / PubMed

Maternal cytomegalovirus immune status and hearing loss outcomes in congenital cytomegalovirus-infected offspring. GJ Demmler-Harrison, JA Miller; Houston Congenital Cytomegalovirus Longitudinal Study Group. PLoS One 2020 Oct 9;15(10):e0240172. "Fifty Seven (74%) of the 77 symptomatic children had hearing loss by 18 years of age, including 9 of the 12 (75%) who were born to mothers with primary infection and 48 (79%) of the 61 with unknown type of maternal infection." 20% of 109 asymptomatic children developed hearing loss.

Demmler-Harrison / PLoS One 2020 full article

Prenatal cranial MR findings in fetuses with suspected CMV infection: Correlation with postnatal outcome and differential diagnostic considerations. S Goergen, Z Lim, J Clark, M Teoh, K Humnabadkar, M Fahey, M Giles. J Med Imaging Radiat Oncol 2020 Dec;64(6):769-778. 11/18 cases CMV+. "Polymicrogyria in fetuses with cCMV, undetected with prenatal US, was associated with [cerebral palsy]."

Goergen - J Med Imaging Radiat Oncol 2020 abstract / PubMed

See Also:

CMV and Social Class

EBV and CMV Can Cause Mental Impairment in Children

Primary Epstein-Barr virus infections in children have traditionally been considered asymptomatic, or causing merely temporary malaise. However, a new study has implicated EBV in neurological deficits in children, finding five cases within a year just in the small state of Rhode Island. And, there are probably a much greater number of less serious cases. EBV is known to occur much earlier in life in lower socioeconomic groups. None of the anti-smoker studies blaming parental smoking for children's impulsivity, inappropriate behavior, lack of cognitive skills and judgment, etc., has ever considered the role of this or any other infection. They pass out lifestyle questionnaires, and falsely pretend that this is sufficient to control for confounding. Therefore, this claim should be considered yet another example of confounding by infection, and thrown on the junk heap with the rest.

Persistent preceding focal neurological deficits in children with chronic Epstein-Barr encephalitis. JM Caruso, GA Tung, GC Gascon, J Rogg, I Davis, WD Brown. J Child Neurol 2000 Dec;15(12):791-796. "Also, Dr. Caruso told Reuters Health, 'serum tests may come back negative, and physicians would think the patient doesn't have that disorder. Just like in varicella, it can show up negative in serum but positive in CSF polymerase chain reaction testing." (Reuters Health 2001. link died)

Caruso - J Child Neurol 2000 abstract / PubMed

Neurological complications of acute and persistent Epstein-Barr virus infection in paediatric patients. M. Hausler, VT Ramaekers, M Doenges, K Schweizer, K Ritter, L Schaade. J Med Virol 2002 Oct;68(2):253-263. "Neurological complications of Epstein-Barr virus (EBV) have been reported almost exclusively in the course of acute primary infections. The role of EBV in paediatric neurological disease was investigated prospectively over a 2-year period, searching for acute primary, chronic, and reactivated EBV infections. Active EBV infections were diagnosed in 10/48 patients, including two with acute primary EBV infections (cranial neuritis and cerebellitis), one with chronic active infection (T/NK cell lymphoma with cranial neuritis), and seven with reactivated infections."

Hausler - J Med Virol 2002 abstract / PubMed

What incites new daily persistent headache in children? KJ Mack. Pediatr Neurol 2004 Aug;31(2):122-125. "This study asked what incites the development of a new daily persistent headache in children. A total of 175 children with chronic daily headache were prospectively identified and observed by the author. Of these patients, 40 (23%) with a new daily persistent headache were identified. These patients had no significant prior headache history. Seventeen patients (43%) had the onset of their symptoms during an infection. Of these patients, over half had positive Epstein-Barr virus serology at the onset of symptoms."

Mack - Pediatr Neurol 2004 abstract / PubMed

Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study. GM Khandaker, J Stochl, S Zammit, G Lewis, PB Jones. Schizophr Res 2014 Sep;158(1-3):19-24. 356-401 subjects. "About 25% of the sample was exposed to EBV at age 4. EBV exposure was associated with subsequent risk of definite PE in adolescence; OR 5.37 (95% CI 1.71-16.87), which remained significant after confounding adjustment. EBV-exposed individuals compared with unexposed performed worse on all IQ measures; mean difference in full-scale IQ 4.15 (95% CI 0.44-7.87); however, this was explained by socio-demographic differences. The EBV-PE association was not explained by IQ."

Khandaker - Schizophr Res 2014 abstract / PubMed

MRI findings in children with congenital cytomegalovirus infection retrospectively diagnosed with dried umbilical cord. H Kidokoro, A Shiraki, Y Torii, M Tanaka, H Yamamoto, H Kurahashi, K Maruyama, A Okumura, J Natsume, Y Ito. Neuroradiology 2020 Nov 17 Epub ahead of print. 30/31 had a white matter (WM) abnormality predominant in the deep WM of the parietal lobe.

Kidokoro - Neuroradiology 2020 abstract / PubMed

Early-childhood cytomegalovirus (CMV) infection and children's neurocognitive development. SM Lee, R Mitchell, JA Knight, T Mazzulli, C Relton, EK Moez, RJ Hung. Int J Epidemiol 2020 Dec 11 Epub ahead of print. CMV infection was associated with suboptimal IQ at 8 years, but not at 15 years old.

Lee - Int J Epidemiol 2020 abstract / PubMed

See also:

Confounding By Infection
EBV & Socioeconomic Status

Enterovirus 71

Attention-Deficit/Hyperactivity-Related Symptoms Among Children With Enterovirus 71 Infection of the Central Nervous System. SS Gau, LY Chang, LM Huang, TY Fan, YY Wu, TY Lin. Pediatrics 2008 Aug;122(2):e452-e458. "86 children 4 to 16 years old with virus-culture-confirmed enterovirus 71 infection and central nervous system involvement diagnosed 3 to 7 years before the study and 172 control subjects, matched for age, gender, and parents' education levels... The children previously infected with enterovirus 71 had higher scores than matched control subjects on teacher- and mother-rated scales of inattention, hyperactivity-impulsivity, oppositional symptoms, and attention-deficit/hyperactivity disorder index. The rate of elevated attention-deficit/hyperactivity disorder-related symptoms among children with enterovirus 71 central nervous system infection was 20%, whereas that rate among matched control subjects was only 3%. They also had more internalizing problems. Their verbal and performance IQs, as well as verbal comprehension indices, were significantly inversely correlated with symptoms of inattention, hyperactivity-impulsivity, and attention-deficit/hyperactivity disorder index scores."

Gau - Pediatrics 2008 abstract / PubMed

Confounding Issues

Effect of Maternal Smoking During Pregnancy on Offspring's Cognitive Ability: Empirical Evidence for Complete Confounding in the US National Longitudinal Survey of Youth. G. David Batty, PhD, Geoff Der, MS and Ian J. Deary, PhD. Pediatrics 2006 Sep;118(3):943-950.

BACKGROUND. Numerous studies have reported that maternal cigarette smoking during pregnancy is related to lower IQ scores in the offspring. Confounding is a crucial issue in interpreting this association.

METHODS. In the US National Longitudinal Survey of Youth 1979, IQ was ascertained serially during childhood using the Peabody Individual Achievement Test, the total score for which comprises results on 3 subtests: mathematics, reading comprehension, and reading recognition. Maternal IQ was assessed by using the Armed Forces Qualification Test. There were 5578 offspring (born to 3145 mothers) with complete information for maternal smoking habits, total Peabody Individual Achievement Test score, and covariates.

RESULTS. The offspring of mothers who smoked 1 pack of cigarettes per day during pregnancy had an IQ score (Peabody Individual Achievement Test total) that was, on average, 2.87 points lower than children born to nonsmoking mothers. Separate control for maternal education (0.27-IQ-point decrement) and, to a lesser degree, maternal IQ (1.51-IQ-point decrement) led to marked attenuation of the maternal-smoking–offspring-IQ relation. A similar pattern of results was seen when Peabody Individual Achievement Test subtest results were the outcomes of interest. The only exception was the Peabody Individual Achievement Test mathematics score, in which adjusting for maternal IQ essentially led to complete attenuation of the maternal-smoking–offspring-IQ gradient (0.66-IQ-point decrement). The impact of controlling for physical, behavioral, and other social indices was much less pronounced than for maternal education or IQ.

CONCLUSIONS. These findings suggest that previous studies that did not adjust for maternal education and/or IQ may have overestimated the association of maternal smoking with offspring cognitive ability.

Batty / Pediatrics 2006 abstract

Infections cause depression, delinquency

Depression in medical illness: the role of the immune system. R Yirmiya. West J Med 2000;173(5):333-336.

Yirmiya / Medscape - West J Med 2000 full article
Yirmiya / West J Med 2000 full article (with e-response)

Raised levels of plasma interleukin-1beta in major and postviral depression. BM Owen, D Eccleston, LN Ferrier, H Young. Acta Psychiatrica Scandinavica 2001;103(3):226-228; and: Further evidence of cytokine involvement in major and post-viral depression. Veronica Rose, Doctor's Guide 2001 Apr 2.

Owen - Acta Psychiatrica Scandinavica 2001 abstract / PubMed
Owen / Doctor's Guide News 2001

Borna disease virus linked with severe mood disorders. Medscape - Reuters Health news re: Mol Psychiatry 2001;6:481-491. A more sensitive immune assay finds that immune complex levels are 10 times higher than with earlier methods.

Bode / Medscape - Reuters Health news 2001
Bode's earlier studies / Medscape abstracts

See Also:

CMV Causes Mental Decline


cast 11-13-20

cast 12-10-12