REVIEW URRENT C OPINION

Congenital cytomegalovirus: what the otolaryngologist should know Melanie Duval and Albert H. Park

Purpose of review Cytomegalovirus (CMV) is an important cause of congenital sensorineural hearing loss (SNHL) that may represent up to 20% of nonsyndromic cases. Congenital CMV is an unrecognized cause of SNHL that all otolaryngologists should be aware of as it represents the only treatable cause of congenital SNHL. Recent findings The current review highlights the recent advances on congenital CMV, including methods of diagnosis and prevention of progression of hearing loss with valganciclovir treatment. A recent study has shown that 6 months of oral valganciclovir treatment of infants with congenital CMV disease improves audiologic and neurodevelopmental outcomes to at least 2 years of age. Early treatment could, thus, have an important impact on these children. Summary Increased awareness of congenital CMV SNHL by an otolaryngologist should lead to increased testing, and thus diagnosis, of this condition in newborns diagnosed with congenital SNHL. Prompt treatment with valganciclovir in these patients may consequently lead to prevention of progressive SNHL. Further research toward a CMV vaccine is hoped to eventually lead to prevention of congenital CMV. Keywords congenital cytomegalovirus infection, newborn hearing screening, sensorineural hearing loss, valganciclovir

INTRODUCTION Cytomegalovirus (CMV) is an unrecognized but important cause of congenital hearing loss. A recent Triological Society Best Practice [1] article titled ‘What is the optimal workup for a child with bilateral sensorineural hearing loss?’ failed to mention any role of CMV testing for these children. Rutherford et al. [2] surveyed members of the American Society of Pediatric Otolaryngology to determine the trends in the evaluation of pediatric sensorineural hearing loss (SNHL). They noted that few respondents ordered CMV testing and mentioned that testing for infectious causes of SNHL is low yield. This lack of awareness is surprising as CMV is estimated to account for 20% or more of SNHL in young children and is perhaps the only type of SHNL that can be treated [3]. More children may be affected by CMV than by other, better known childhood conditions, such as Down syndrome, fetal alcohol syndrome and spina bifida [4]. This hearing loss has detrimental effects on speech and language development and incurs the major cost associated with congenital CMV infection that has been estimated to be $4 billion a year, a cost similar to that of the much

better known condition, otitis media [5]. This review will focus on why you should consider CMV when evaluating the child with SNHL, the rationale for early diagnosis and treatment.

WHAT IS CONGENITAL CYTOMEGALOVIRUS-INDUCED HEARING LOSS? Human CMV is a DNA virus that belongs to the Herpesviridae family. Disseminated or symptomatic congenital CMV can cause petechiae, hepatomegaly, splenomegaly and damage to the infant’s central nervous system. Asymptomatic children, which is a bit of a misnomer, may present with hearing loss Division of Otolaryngology-Head and Neck Surgery, Department of Surgery and Pediatrics, University of Utah, Salt Lake City, Utah, USA Correspondence to Albert H. Park, MD, Division of Otolaryngology-Head and Neck Surgery, 50 North Medical Drive, 3C 120, Salt Lake City, UT 84132, USA. Tel: +1 801 662 5666; fax: +1 801 662 5662; e-mail: [email protected] Curr Opin Otolaryngol Head Neck Surg 2014, 22:495–500 DOI:10.1097/MOO.0000000000000104

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KEY POINTS  Congenital CMV is one of the most common causes of nongenetic congenital SNHL.  Early detection of congenital CMV infection is necessary in order to confirm the diagnosis.  Recent evidence suggests that antiviral treatment of children with congenital CMV SNHL may stabilize or improve hearing thresholds.  Further studies on the effectiveness of antiviral therapy with long-term follow-up are needed to confirm the long-term effectiveness of this treatment.

alone and in a large proportion of these children, the hearing loss will be progressive with normal hearing at birth. A major issue to recognize with this classification is that 85–90% of children with congenital CMV present with asymptomatic infection, but 6–25% of these children will either present with or develop SNHL later in life [6,7]. The ramification for the clinician is that the typical child with congenital CMV will look like a normal child. Another important issue not commonly recognized with this condition is that prior immunity for the mother will not necessarily protect the fetus from infection [8]. In fact, the number of children with congenital CMV infection is higher from mothers with prior immunity (e.g., mothers who are already seropositive). One reason for this apparently paradoxical finding is that different viral strains do not provide immunologic protection from disease and the overall higher prevalence of seropositive women in the general population. A study from Boppana et al. [9] demonstrated a higher incidence of different CMV strains in seropositive mothers with infected offspring. The audiologic characteristics of this condition can make diagnosis and treatment challenging. One challenge of diagnosing children with CMVinduced SNHL is that more than 60% of these children will have passed their newborn hearing screening [10]. Newborn hearing screening cannot be used to diagnose the majority of children with this infection. The severity and laterality of SNHL range from unilateral (38–50%) to bilateral (50–62%), with variable onset from newborn or later (5–18%), and with differing natural history from fluctuating (16–23%) or progressive (11–50%) or even improved thresholds (18%). Some children may have SNHL limited to the high frequencies only (32%) [7,11,12]. These features have been described in cochleovestibular anomalies and connexin mutations. Thus, there is no pathognomonic 496

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audiologic feature of this infection. Many of these patients will present with progressive hearing loss. Longitudinal studies by Dahle et al. [6] and Fowler et al. [11] have shown that children who present with SNHL have a 50% chance of developing further progressive loss. Delayed onset in children with initially normal hearing is also common. In a study by Fowler et al. [10] wherein children were followed for 72 months with serial audiograms, 7% of these children developed late-onset hearing loss between 12 and 72 months of age. We have identified a de-novo onset of hearing loss in a symptomatically CMV-infected child as late as 9 years of age.

HOW DOES CYTOMEGALOVIRUS CAUSE HEARING LOSS? It remains unclear how and why CMV causes hearing loss. Temporal bone studies have shown evidence of inflammation and viral seeding in the inner ear’s endolymph and perilymph [13]. There have been several clinical studies trying to correlate viral load and hearing loss risk [14]. In a smaller study, Noyola et al. [15] found that children who shed CMV for a shorter length of time were more likely to have hearing loss and progressive hearing loss. Rosenthal et al. [14], however, found that longer duration of viral shedding (as measured by age at last culture-positive visit) may be a predictor of delayed hearing loss. High CMV viral loads at birth have been associated with hearing loss [16]. A key question is whether the systemic viral load correlates to what is happening in the inner ear. We found in a guinea pig model for CMV-induced SNHL that saliva, blood and urine CMV polymerase chain reaction (PCR) did not always correlate with hearing loss [17]. Some investigators have questioned whether the host immune response rather than the virulence of the virus causes hearing loss [18]. Harris et al. [19] found better hearing outcomes in a guinea pig model of CMV labyrinthitis when the animals were immunosuppressed. Schachtele et al. [18] developed a neonatal mouse model of profound SNHL and found that murine CMV infection induced cochlear hair cell death by 21 days postinfection, despite a clear lack of direct infection of hair cells. They detected a robust and chronic inflammatory response, including a prolonged increase in reactive oxygen species production by infiltrating macrophages [18]. On the other hand, we have recently discovered strain-specific susceptibility to murine-induced CMV labyrinthitis. Mice (C57/B6) resistant to CMV-induced hearing loss did not have detectable CMV-green fluorescent protein expression of virus in the temporal bone; mouse strains (balb/c) susceptible to hearing loss showed Volume 22  Number 6  December 2014

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Congenital cytomegalovirus and hearing Duval and Park

murine CMV-green fluorescent protein expression in the spiral ganglion and scala tympani [20].

HOW IS A DIAGNOSIS OF CYTOMEGALOVIRUS MADE? As the majority of congenital CMV infections are asymptomatic, the diagnosis relies on culture-based or PCR methods. In order to distinguish between congenital and postnatal CMV infection, a urine or saliva specimen should be obtained within the first 2–3 weeks of life. In children presenting within the first 2 weeks of life, CMV PCR can effectively be performed using either a saliva swab or urine sample. Wet saliva CMV PCR was previously shown to be 100% sensitive and 99.9% specific, whereas dry saliva CMV PCR has a sensitivity and specificity of 97.4% and 99.9%, respectively [21]. We have identified two infants who had a false-positive result from a saliva sample. Presumably, the breast milk from the seropositive mothers resulted in the abnormal result. For that reason, we recommend waiting at least 90 min after breastfeeding to obtain a saliva sample and to obtain a confirmatory urine sample in those infants with a positive saliva result. In children diagnosed after the first 3 weeks of life, use of dried blood spot (DBS), which is obtained in most newborns within the first week of life, can be used to perform a retrospective CMV DNA analysis. The use of DBS is, however, limited by a poor sensitivity of 34%, which is likely attributable to the lower CMV viral load found in blood as compared to urine or saliva [22]. The poor sensitivity of DBS CMV PCR makes it unsuitable for mass screening for congenital CMV. However, the test’s specificity of 99.9% implicates that a positive DBS is diagnostic of congenital CMV infection and may be useful to confirm the diagnosis if treatment is considered [22].

RATIONALE FOR EARLY CYTOMEGALOVIRUS TESTING In February 2013, representative Ronda Menlove and our CMV working group introduced a bill to the Utah legislature to increase overall awareness about congenital CMV infection and to mandate early testing for newborns less than 3 weeks of age who fail their second hearing screen. Later in July, this bill was passed, and Utah became the first state to implement early CMV testing of all infants who fail their newborn hearing screen. This law directed the Department of Health to coordinate CMV testing of all infants under 3 weeks of age who fail their newborn hearing screening twice and to create an educational program for parents, child care

programs, school nurses and healthcare providers about the natural history of CMV, its transmission, diagnosis and treatment. Our group recently presented results using a sequential diagnostic paradigm that included CMV testing for children with SNHL [23 ]. Eightythree children underwent CMV testing, imaging and a genetic evaluation. Those with confirmed or probable CMV-induced SNHL made up 30% of all children tested. A cost estimate analysis comparing these tests demonstrated that early CMV testing had the lowest cost for all types of hearing loss. These recent events highlight the rapidly changing issues in CMV research and public policy, and the importance for clinicians to be aware of the benefits of early CMV detection. The Utah legislation was an attempt to identify a proportion of CMV-infected children at the greatest risk to develop CMV-induced progressive SNHL. The advantages of early diagnosis include directed serial audiologic testing for those at risk for progressive hearing loss, opportunities for parental education, prevention for at risk patients and antiviral therapy. As these children may shed the virus in their urine and saliva for years, careful hygiene through frequent hand washing, avoidance of kissing on the lips and not sharing utensils and toys could reduce potential transmission. These preventive measures have been demonstrated to reduce transmission to pregnant mothers, the group at the highest risk for congenital CMV transmission [24–26]. &

TREATMENT Last October, the National Institute of Allergy and Infectious Disease Collaborative Antiviral Study Group (CASG) presented a phase III trial of 6 weeks versus 6 months of oral valganciclovir, a prodrug of ganciclovir, for children less than 30 days of age with congenital CMV disease. They demonstrated that 6 months of oral valganciclovir treatment of infants with congenital CMV disease improves audiologic and neurodevelopmental outcomes to at least 2 years of age [27]. The major toxicities associated with ganciclovir and valganciclovir are bone marrow depression, specifically neutropenia [28]. Twenty-nine of the 46 (63%) ganciclovir-treated patients for CMVinduced SNHL developed grade 3 or 4 neutropenia. Of the 29 ganciclovir-treated patients developing neutropenia, 14 required dosage adjustment and four had the drug permanently discontinued. Neutropenia was observed only during the first 3 months of treatment, mainly during intravenous ganciclovir administration in a study by Amir et al. [29]. Two of the 12 patients who developed

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neutropenia required discontinuation of treatment for 2–3 days until the absolute neutrophil count normalized. Renal toxicity has also been documented in the ganciclovir studies; however, these patients were frequently taking other nephrotoxic medications, making it difficult to ascribe the toxicity to ganciclovir. Animal studies have demonstrated impaired fertility and carcinogenic

properties following ganciclovir exposure in mice. No toxicity has been reported in any pediatric patient, despite its widespread use in pediatric transplantation. Valganciclovir appears to cause less adverse effects than ganciclovir. In the recent CASG study, they also found less neutropenia with valganciclovir compared with an earlier CASG study using

SNHL

History and physical examination, audiologic findings

Diagnosis apparent

Positive

Idiopathic diagnosis

Positive

Definitive CMV induced SNHL (3 weeks of age)

Negative

Idiopathic diagnosis*

DBS PCR CMV assay Negative Negative

Positive

Definitive CMV induced SNHL

Positive

Possible or probable CMV induced SNHL

Genetic or inner ear dysplasia

Idiopathic diagnosis

MRI brain AND temporal bone; serial audiologic testing

Positive

Negative

Probable CMV induced SNHL

Idiopathic diagnosis

Go to idiopathic diagnosis *

FIGURE 1. Sequential approach for pediatric sensorineural hearing loss. CMV, cytomegalovirus; DBS, dried blood spot; SNHL, sensorineural hearing loss. 498

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intravenous ganciclovir and no excess neutropenia with continuation of antiviral therapy from 6 weeks to 6 months. Approximately 21% of the children undergoing 6-months therapy had grade 3 or 4 neutropenia. Three patients required temporary cessation of their valganciclovir because their absolute neutrophil count was less than 500 [27].

OUR APPROACH Our approach for the child with SNHL is shown in Fig. 1. If a diagnosis of CMV is made, we will recommend an ophthalmologic evaluation and an MRI of the brain. We have detected CMV chorioretinitis in these patients. We have also detected intracranial abnormalities in about 33% of children with probable or confirmed congenital CMV-induced SNHL. These are in children who had no apparent central nervous system abnormalities. We also recommend serial audiologic testing and counsel families about the natural history, risks for transmission and need to follow good hygiene practices. Valganciclovir therapy is offered for these patients. Treatment is currently limited to symptomatic infants secondary to the risks associated with antiviral therapy and the fact that the majority of asymptomatic infants with congenital CMV will not develop symptoms. The current practice for valganciclovir therapy is a 6-month course using a dose of 16 mg/kg/dose twice a day [30]. Monitoring for neutropenia is achieved by performing a complete blood count, transaminase levels, BUN and creatinine every 2–4 weeks while the child is under treatment. Development of persistent neutropenia will be treated by temporary cessation of treatment and reinitiating treatment after an adequate neutrophil count is achieved. We have treated 19 children with confirmed or probable congenital CMV-induced SNHL. Studies published thus far have been limited to infants treated before 1 month of age [27]. Although we have attempted treatment in older infants, we have anecdotally observed poorer outcome when treatment is initiated after 6 weeks of age. Two patients required temporary cessation of valganciclovir. One child developed elevated transaminases; the other child had low absolute neutrophil count values. Abnormalities for both patients resolved with dose adjustment.

hand washing and avoidance of ill contacts during pregnancy, have been shown to be mildly efficacious [26], vaccination is a promising way that may allow eradication of the disease. In addition, the United States Institute of Medicine determined in 2000 that a vaccine that would prevent congenital CMV would be expected to be a highly effective intervention [31]. There are currently a variety of CMV vaccine development strategies underway. Some of these aim to stimulate humoral immunity, whereas others aim to stimulate cell-mediated immunity [32]. Some of the obstacles to the development of an effective vaccine have included the need for an immunologic marker that predicts protection from CMV disease, incomplete understanding of CMV epidemiology and transmission and high virus diversity and propensity for infection by multiple virus strains. As prior exposure to CMV does not confer complete protection from transmission, any vaccine will need to be more effective than seropositivity. Although some phase I and II studies have shown a decreased risk of acquiring primary CMV infection in seronegative women of child bearing age, no study has been large enough to evaluate the impact of vaccination on the incidence of congenital CMV. In a study of 438 women of childbearing age by Pass et al. [33], 1% of newborns in the vaccine group and 3% of newborns in the placebo group were diagnosed with congenital CMV (P ¼ 0.41).

CONCLUSION Congenital CMV is an important cause of congenital SNHL in children and should be considered an underlying cause in children with isolated hearing loss and progressive hearing loss. Early detection is crucial to confirm the diagnosis and initiate antiviral treatment, which may slow or reverse the progression of hearing loss. Congenital CMV is an exciting field for otolaryngologists as it represents one of the few causes of preventable and treatable hearing loss in children. It is currently an area of intense research and much progress on the diagnosis, treatment and prevention of this condition can be expected in the coming years. Acknowledgements None.

VACCINATION Despite advancements in the diagnosis and treatment of congenital CMV, the optimal intervention is prevention. Although hygiene measures, such as

Conflicts of interest The authors have no funding, financial relationships or conflicts of interest to disclose.

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hart CK, Choo DI. What is the optimal workup for a child with bilateral sensorineural hearing loss? Laryngoscope 2013; 123:809–810. 2. Rutherford KD, Lerer TS, Schoem SR, Valdez TA. Evaluation of pediatric sensorineural hearing loss: a survey of pediatric otolaryngologists. Ann Otol Rhinol Laryngol 2011; 120:674–681. 3. Hicks T, Fowler K, Richardson M, et al. Congenital cytomegalovirus infection and neonatal auditory screening. J Pediatr 1993; 123:779–782. 4. Ross SA, Fowler KB, Ashrith G, et al. Hearing loss in children with congenital cytomegalovirus infection born to mothers with preexisting immunity. J Pediatr 2006; 148:332–336. 5. Committee to Study Priorities for Vaccine Development, Division of Health Promotion and Disease Prevention, Institute of Medicine, National Academy of Sciences. Vaccines for the 21st century: a tool for decisionmaking. Stratton KR, Durch JS, Lawrence RS, editors. Washington, DC: National Academies Press; 2000. 6. Dahle AJ, Fowler KB, Wright JD, et al. Longitudinal investigation of hearing disorders in children with congenital cytomegalovirus. J Am Acad Audiol 2000; 11:283–290. 7. Fowler KB, Boppana SB. Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 2006; 35:226–231. 8. Stagno S, Pass RF, Dworsky ME, et al. Congenital cytomegalovirus infection: the relative importance of primary and recurrent maternal infection. N Engl J Med 1982; 306:945–949. 9. Boppana SB, Fowler KB, Britt WJ, et al. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics 1999; 104:55–60. 10. Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children with hearing loss caused by congenital cytomegalovirus infection be missed? J Pediatr 1999; 135:60–64. 11. Fowler KB, McCollister FP, Dahle AJ, et al. Progressive and fluctuating sensorineural hearing loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr 1997; 130:624–630. 12. Foulon I, Naessens A, Foulon W, et al. A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr 2008; 153:84–88. 13. Teissier N, Delezoide AL, Mas AE, et al. Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol 2011; 122:763–774. 14. Rosenthal LS, Fowler KB, Boppana SB, et al. Cytomegalovirus shedding and delayed sensorineural hearing loss: results from longitudinal follow-up of children with congenital infection. Pediatr Infect Dis J 2009; 28:515–520. 15. Noyola DE, Demmler GJ, Williamson WD, et al., Congenital CMV Longitudinal Study Group. Cytomegalovirus urinary excretion and long term outcome in children with congenital cytomegalovirus infection. Congenital CMV Longitudinal Study Group. Pediatr Infect Dis J 2000; 19:505–510. 16. Boppana SB, Fowler KB, Pass RF, et al. Congenital cytomegalovirus infection: association between virus burden in infancy and hearing loss. J Pediatr 2005; 146:817–823.

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17. Park A, Mann D, Error M, et al. Comparative analysis of detection methods for congenital cytomegalovirus infection in a guinea pig model. JAMA Otolaryngol Head Neck Surg 2013; 139:82–86. 18. Schachtele SJ, Mutnal MB, Schleiss MR, Lokensgard JR. Cytomegalovirusinduced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 2011; 17:201–211. 19. Harris JP, Fan JT, Keithley EM. Immunologic responses in experimental cytomegalovirus labyrinthitis. Am J Otolaryngol 1990; 11:304–308. 20. Wang Y, Patel R, Ren C, et al. A comparison of different murine models for cytomegalovirus-induced sensorineural hearing loss. Laryngoscope 2013; 123:2801–2806. 21. Boppana SB, Ross SA, Shimamura M, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med 2011; 364:2111–2118. 22. Boppana SB, Ross SA, Novak Z, et al. Dried blood spot real-time polymerase chain reaction assays to screen newborns for congenital cytomegalovirus infection. JAMA 2010; 303:1375–1382. 23. Park AH, Duval M, McVicar S, et al. A diagnostic paradigm including & cytomegalovirus testing for idiopathic pediatric sensorineural hearing loss. Laryngoscope 2014. [Epub ahead of print] Great reference on the diagnostic work-up for congenital SNHL. 24. Adler SP, Finney JW, Manganello AM, Best AM. Prevention of child-to-mother transmission of cytomegalovirus by changing behaviors: a randomized controlled trial. Pediatr Infect Dis J 1996; 15:240–246. 25. Picone O, Vauloup-Fellous C, Cordier AG, et al. A 2-year study on cytomegalovirus infection during pregnancy in a French hospital. BJOG 2009; 116:818–823. 26. Vauloup-Fellous C, Picone O, Cordier AG, et al. Does hygiene counseling have an impact on the rate of CMV primary infection during pregnancy? Results of a 3-year prospective study in a French hospital. J Clin Virol 2009; 46:S49–S53. 27. Kimberlin DW, Jester P, Sanchez PJ et al. Six months versus six weeks of oral valganciclovir for infants with symptomatic congenital cytomegalovirus (CMV) disease with and without central nervous system (CNS) involvement: results of a Phase III, randomized, double-blind, placebo-controlled, multinational study. Oral abstract session: late breaker oral abstracts, IDWeek 2013. https://idsa.confex.com/idsa/2013/webprogram/Paper43178.html. [Accessed 15 June 2014]. 28. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003; 143:16–25. 29. Amir J, Wolf DG, Levy I. Treatment of symptomatic congenital cytomegalovirus infection with intravenous ganciclovir followed by long-term oral valganciclovir. Eur J Pediatr 2010; 169:1061–1067. 30. Kimberlin DW, Acosta EP, Sanchez PJ. Pharmacokinetics and pharmacodynamics assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. J Infect Dis 2008; 197:836–845. 31. Arvin AM, Fast P, Myers M, et al. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 2004; 39:233–239. 32. Schleiss MR. Prospects for development and potential impact of a vaccine against congenital cytomegalovirus infection. J Pediatr 2007; 151:564– 570. 33. Pass RF, Zhang C, Evans A, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009; 360:1191–1199.

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Congenital cytomegalovirus: what the otolaryngologist should know.

Cytomegalovirus (CMV) is an important cause of congenital sensorineural hearing loss (SNHL) that may represent up to 20% of nonsyndromic cases. Congen...
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