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. Author manuscript; available in PMC: 2015 Jul 7.
Published in final edited form as: Rev Med Virol. 2011 Jun 15;21(4):240–255. doi: 10.1002/rmv.695

Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection

Michael J Cannon 1,*, Terri B Hyde 2, D Scott Schmid 2
PMCID: PMC4494736  NIHMSID: NIHMS699552  PMID: 21674676

SUMMARY

Congenital cytomegalovirus (CMV) infections are a leading cause of sensorineural hearing loss (SNHL) and neurological impairment. Congenital transmission of CMV can occur with maternal primary infection, reactivation, or reinfection during pregnancy. We reviewed studies of CMV shedding in bodily fluids (defined as CMV detected by culture or CMV DNA detected by polymerase chain reaction). Following diagnosis at birth, children with congenital CMV infection exhibited the highest prevalences of CMV shedding (median = 80%, number of sample population prevalences [N] = 6) and duration of shedding, with a steep decline by age five. Healthy children attending day care shed more frequently (median = 23%, N = 24) than healthy children not attending day care (median = 12%, N = 11). Peak shedding prevalences in children occurred at 1–2 years of age, confirming that young children are the key transmission risk for pregnant women. CMV shedding among children was more prevalent in urine specimens than in oral secretions (median prevalence difference = 11.5%, N = 12). Adults with risk factors such as STD clinic attendance had higher shedding prevalences (median = 22%, N = 20) than adults without risk factors (median = 7%, N = 44). In adults with risk factors, CMV was shed more frequently in urine; in adults without risk factors genital shedding was most common. The prevalence of CMV shedding in nine sample populations of pregnant women increased with advancing gestation. In seven sample populations of children with congenital CMV infection, higher viral load at birth was consistently associated with an elevated risk of SNHL. Higher CMV viral load at birth also consistently correlated with the presence of symptoms of congenital CMV at birth. Published 2011. This article is a US Government work and is in the public domain in the USA.

INTRODUCTION

Adults can become infected with cytomegalovirus (CMV) through a variety of transmission routes, including contact with bodily fluids of children or adults who are shedding the virus, sexual activity, blood transfusion, and organ transplantation [1]. In most cases, CMV infection in immunocompetent adults does not lead to symptomatic disease [1]; however, active CMV infection during pregnancy can result in transmission to the fetus [2] that can in turn result in permanent damage, including SNHL, intellectual disability and, rarely, death [3,4]. The risk of permanent damage appears to be highest among children whose mother experienced primary CMV infection during gestation [5,6]. It has been estimated that more than half a million women of child-bearing age in the United States of America will experience primary CMV infection each year [7].

As with all human herpesviruses, CMV establishes a life-long latent infection during primary infection, and the virus may reactivate at any time with shedding of infectious CMV in saliva, urine and other bodily secretions [1]. Reinfection with a different CMV strain is also associated with shedding [5]. CMV infection and shedding are generally asymptomatic [8], so that individuals are unlikely to know that they have been infected or are shedding the virus. Infants and young children often acquire CMV infection through breastfeeding [9,10] or through contact with other children who are actively shedding virus [11]. Infants and young children may continue shedding virus for a year or more, and probably serve as the leading source for primary infection in women of reproductive age [12–16].

In order to better understand exposures that place women at risk for CMV primary infection or reinfection during pregnancy, we reviewed the available literature on the frequency, magnitude, and risk factors for CMV shedding in various populations.

METHODS

Definition of terms

In this review, we define CMV ‘shedding’ as the presence of CMV detected by culture techniques (e.g. traditional or rapid shell vial) or CMV DNA detected by polymerase chain reaction (PCR; e.g. nested or non-nested)[17]. The testing method is specified in the Tables.

For simplicity and to facilitate comparisons, specimens from the oral cavity, including throat swabs and mouth rinses, were categorized as ‘oral secretions’; cervical and vaginal swabs and lavages were categorized as ‘genital secretions’; and white blood cells, peripheral blood mononuclear cells, and peripheral mononuclear lymphocytes were categorized as ‘blood’.

We grouped adults according to whether or not they had factors that may be associated with CMV infection or shedding. These CMV risk factors included being sexually transmitted disease (STD) clinic attendees, men who have sex with men (MSM), and women with congenitally infected children.

Because of its relatively frequent occurrence in the literature, we created one category for analysis called ‘children with medical conditions’. These children came from studies of children hospitalized for various reasons (other than congenital CMV infection) or children who were institutionalized because of disabilities.

Many studies measured more than one CMV shedding prevalence. This could be because they studied more than one population (e.g. adults and children), more than one specimen type (e.g. urine and oral secretions), or more than one time point (e.g. all three pregnancy trimesters). We used the term ‘sample population prevalence’ to specify each of these shedding prevalences. Thus, some of the figures have more than one data point from a single study. These multiple sample population prevalences are each listed in the Tables.

Study selection and presentation

We identified studies of CMV shedding published from 1965 through 2009 by carrying out Medline searches using key words such as ‘cytomegalovirus’ or ‘CMV’ and ‘shedding’, ‘culture’, ‘PCR’, ‘epidemiology’, or ‘prevalence’. Additional studies were identified through the reference lists in the articles we retrieved. Because there are numerous studies on CMV shedding, we limited the scope of the review by excluding studies that primarily focused on congenital CMV birth prevalence, breast feeding, shedding in amniotic fluid, HIV-infected individuals, organ transplant recipients, or assay validation. In general, we also excluded studies of fewer than 25 participants. However, we included all studies regardless of sample size that examined CMV viral load, duration of shedding, or frequency of sequelae in children with congenital CMV, because few studies addressed these topics.

Because of space constraints, tables (numbered A1–A5) whose data are displayed in figures are placed in the online appendix in order of appearance. Tables whose data are not displayed in figures are shown in the main text and numbered 1–3 in order of appearance. Study categories used in the various tables included congenitally infected children, healthy children enrolled in day care, healthy children not enrolled in day care, children with medical conditions, seroconverters, adolescents who were shedding CMV, adults with CMV risk factors, and adults without CMV risk factors. For congenitally infected children, diagnostic results were excluded because, by definition, the shedding prevalence at diagnosis is 100%.

RESULTS

From 56 studies, we identified 112 sample population prevalences measured in a single specimen type (e.g. urine, oral secretions) at a single point in time (Figure 1, Tables A1 and A2). From these prevalences, we found that following their diagnosis at birth, congenitally infected children had the highest prevalences of shedding (median = 80%, N = 6). Among other children, shedding was more common among those in day care centers (median = 23%, N = 24) than among those not in day care centers (median = 12%, N = 11) or those with medical conditions (median = 9%, N = 7). Adults with CMV risk factors had prevalences of shedding similar to children in day care centers (median = 22%, N = 20), whereas adults without risk factors had the lowest prevalences of shedding (median = 7%, N = 44).

Figure 1.

Figure 1

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Prevalences of cytomegalovirus (CMV) shedding in various studies that measured a single specimen type (e.g. urine, oral secretions) at a single point in time. Each circle represents the result from an individual study (listed in Tables A2 & A3 [11,14,18–22,27,28,30–32,39,54–78] [79–95]). Studies that measured more than one specimen type have more than one circle plotted above. Prevalences were not stratified by age

Table A1.

CMV shedding prevalence according to specimen typea

Country Demographics/Sampling Method Testing Method Specimen Type(s) Sample size Shedding %
Category I. Congenitally infected children
England [78] Random selection of specimens from 80 congenitally infected children followed for up to 5 years Culture Urine 109 83
Oral secretions 101 63
US-Alabama [28] 104 congenitally infected children followed for up to 7 years Culture Urine 772 77
Oral secretions 484 48
Category II. Healthy children enrolled in day care centers
US-Alabama [72] Children in day care centers, maximum of one urine and Oral secretions sample per child Culture Urine 231 29
Oral secretions 241 13
US-Alabama [55] 58 children in day care centers Culture Urine 54 41
Oral secretions 47 30
Hands 44 7
US-Alabama [14] 70 children in day care centers Culture Urine 68 53
Oral secretions 29 45
US-Alabama [56] 103 children in day care studied at least once (shedding estimated from Figure 2, ref. #117) Culture Urine 198 53
Oral secretions 160 34
US-California [63] 100 children in day care centers Culture Urine 90 22
Oral secretions 100 11
63 children in infant development centers Urine 50 22
Oral secretions 62 2
US-Iowa [66] 48 children in day care centers Culture Urine 73 23
Oral secretions 80 11
US-Iowa [67] 79 children in day care centers followed for 2.5 years Culture Urine 79 27
Oral secretions 79 25
Category III. Healthy children not enrolled in day care centers
The Gambia [61] 178 infants at 6 months Culture Urine 178 40
Oral secretions 178 37
Japan [88] 38 healthy infants between 4–9 months of age Culture Urine 38 66
Oral secretions 33 64
Category IV. Adults without CMV risk factors
Brazil [74] 102 pregnant and non-pregnant women, 98% CMV seropositive Nested PCR Genital secretions 102 13
White blood cells 98 7
England [19] 402 hospitalized patients, ages 15–60+ years old Culture Urine 402 0
Oral secretions 402 0
The Gambia [61] 178 post-partum women, 88% CMV seropositive Culture Urine 840 4
Oral secretions 838 4
Breast milk 741 3
Genital secretions 178 7
The Gambia [84] 81 post-partum women, all CMV seropositive PCR Urine 73 1
Oral secretions 74 18
Genital secretions 75 32
Plasma 79 3
Colostrum 77 38
Japan [88] 107 pregnant women Culture Urine 76 0
Oral secretions 107 0
Genital secretions 153 15
Taiwan [71] 350 pregnant women in the 2nd trimester, all CMV seropositive PCR Urine 700 6
Genital secretions 440 21
Taiwan [22] 2219 CMV seropositive pregnant women, including multiple specimens from 207 women PCR Urine 2195 7
Genital secretions 600 27
US-Alabama [86] 113 healthy, post-partum women, all CMV seropositive PCR Urine 306 3
Blood 248 3
US-Alabama [73] 81 post-partum women, all CMV seropositive, over an average of 4 visits, with uninfected infants Culture Urine 76 11
Oral secretions 78 9
Genital secretions 78 13
US-Alabama [18] 659 pregnant women Culture Urine 600 5
Genital secretions 659 10
230 non-pregnant women Urine 230 3
Genital secretions 202 9
Category V. Adults with CMV risk factors
Italy [27] 29 seroconverting pregnant women, 27 husbands, 22 children Culture Urine 95 42
Oral secretions 36 14
US-Alabama [73] 142 post-partum women, all CMV seropositive, over an average of 4 visits, with infected infants Culture Urine 141 45
Oral secretions 141 27
Genital secretions 142 23
US-Alabama [54] 6 adolescent seroconverters Culture Urine 54 59
Oral secretions 58 14
Genital secretions 45 9
Blood 54 2
PCR Blood 50 32
Plasma 50 14
US-California [21] 52 homosexual men in 1980–81, all CMV seropositive, HIV status unknown Culture Urine 52 8
Semen 52 35
US-New York [100] 30 healthy homosexual men Culture Urine 30 20
Semen 30 20
US-Washington [20] 951 CMV seropositive women presenting with problems at an STD clinic Culture Urine 890 8
Oral secretions 169 2
Genital secretions 890 14
Rectal secretions 432 1
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Results from this table are not listed again in Table A2 but, if applicable, are plotted in Figure 3. They are generally single specimen (SS), single time point (ST) sample populations as defined in table A2.

Table A2.

CMV shedding prevalence according to risk group, categorized by whether single specimens (SS) or multiple specimens (MS) were used and whether they were collected at a single time point (ST) or multiple time points (MT)a

Country Demographics/Sampling Method Testing Method Specimen Type(s) Category Sample size Shedding %
Category I. Congenitally infected children
Sweden [59] 35 congenitally infected infants, ages 3 months-4 years Culture Urine SS, ST 149 84
US-Alabama [75] 38 congenitally infected infants, ages 1–4 years Culture Urine SS, ST 69 87
Category II. Healthy children enrolled in day care centers
England [98] 117 children in day nurseries over a 1-year period, 2–4 specimens per year Culture Urine SS, MT 117 27
France [65] 93 children < 1 year old in day care centers Culture Urine SS, ST 379 24
SS, MT 93 36
Italy [69] 253 children in day care centers Culture Oral secretions SS, ST 253 13
Japan [64] 54 children in day care centers PCR Oral secretions SS, ST 54 22
Mexico [77] 152 children at day care centers, sampled at 3 visits Culture Oral secretions SS, ST 127 7
SS, ST NS 5
SS, ST NS 7
SS, MT 152 11
Sweden [122] 60 children in day care centers followed 12 weeks Culture Urine SS, MT 60 27
Sweden [68] 18 children in day care centers, ages 2–3.5 years, mean follow-up of 35 weeks Culture Urine SS, ST 221 55
US-Alabama [72] Children in day care centers Culture Urine, oral secretions MS, ST 243 32
US-Alabama [97] 188 children in day care centers Culture Urine, oral secretions MS, ST 188 41
US-Alabama [14] Children in day care centers Culture Urine, oral secretions MS, ST 71 51
US-Alabama [56] 103 children in day care centers, 1–3 visits each Culture Urine, oral secretions MS, MT 103 57
US-California [63] 100 children in day care centers Culture Urine, oral secretions MS, ST 90 22
US-Iowa [66] 48 children in day care centers Culture Urine, oral secretions MS, ST 80 21
US-Iowa [67] 79 children in day care centers followed for 2.5 years Culture Urine, oral secretions MS, MT 79 35
US-Iowa [13] 219 children in day care centers at entry Culture Urine, oral secretions MS, ST 219 15
219 children in day care centers followed for 2.5–4.5 years Urine, oral secretions MS, MT 219 28
US-Virginia [11] 66 children in day care centers cultured 3 times Culture Urine SS, MT 66 24
US-Virginia [123] Children in day care centers at 2 time points Culture Urine, oral secretions MS, ST 118 44
Category III. Healthy children not enrolled in day care centers
England [62] Infants without congenital CMV Culture Urine SS, ST 983 12
The Gambia [61] 178 infants Culture Urine, oral secretions MS, ST 178 53
MS, MT 150 62
Japan [64] 61 children not in day care centers PCR Oral secretions SS, ST 61 7
Japan [88] Infants and children ages 1 month-2 years Culture Oral secretions SS, ST 290 25
Mauritius [58] 121 healthy children Culture* Urine SS, ST 121 2
Sweden [59] 50 children without congenital CMV, ages 3 months-4 years Culture Urine SS, ST 225 31
US-Alabama [57] 87 healthy infants ages 9–15 months Culture Oral secretions SS, ST 87 7
US-Alabama [56] 25 children in home care Culture Urine, oral secretions MS, ST 25 8
US-Iowa [60] 106 children in child care homes Culture Urine SS, ST 106 8
US-New York [32] 200 healthy children Culture Urine SS, ST 200 1
US-New York [30] 38 healthy migrant children Culture Urine SS, ST 38 18
Category IV. Children with medical conditions
Denmark [89] 262 hospitalized infants, not congenitally infected Culture Urine SS, ST 262 4
England [99] Hospitalized children Culture Urine, oral secretions MS, ST 1395 3
England [19] 309 hospitalized patients, ages 2 months-14 years Culture Urine, oral secretions MS, ST 309 5
Finland [31] 356 hospitalized and outpatient children > 2 months of age Culture Urine SS, ST 356 26
Mauritius [58] 30 deaf children Culture Urine SS, ST 30 50
91 mentally retarded children 91 18
Sweden [90] 661 hospitalized infants Culture Urine SS, ST 661 9
US-California [63] 63 children in infant development centers Culture Urine, oral secretions MS, ST 50 22
US-California [114] 93 infants in the intensive care unit, cultured weekly until discharge Culture Urine SS, MT 93 14
US-New York [32] 100 hospitalized children Culture Urine SS, ST 100 1
US-Texas [124] 314 hospitalized children in chronic care Culture Oral secretions, urine, genital secretions MS, ST 314 9
US-Virginia [11] 2729 hospitalized children from newborns up to 18 years old Culture Urine SS, ST 2729 5
V. Adults without CMV risk factors
Egypt [87] 50 women with recurrent abortions PCR Serum SS, ST 50 12
England [19] 402 hospitalized patients, ages 15–60+ years old Culture Urine, oral secretions MS, ST 402 0
France [91] 231 semen donors Culture Semen SS, ST 635 1
SS, MT 231 1
PCR SS, ST 551 4
SS, MT 197 3
France [93] 97 semen donors Culture Semen SS, ST 178 3
SS, MT 97 2
PCR SS, ST 178 6
SS, MT 97 5
The Gambia [61] 178 post-partum women, average prevalence in ≥1 of 3 specimen types over 6 cross-sectional visits Urine, oral secretions, breast milk MS, ST 178 12
Greece [92] 113 men at an infertility clinic Nested PCR Semen SS, ST 113 7
Italy [82] 66 women receiving routine gynecological care PCR Genital secretions SS, ST 66 73
Italy [85] 123 patients with fever of unknown origin PCR Serum SS, ST 123 9
Japan [80] 953 blood donors PCR Blood SS, ST 953 3
Japan [81] 993 healthy pregnant women, CMV serostatus undetermined, first trimester PCR Genital secretions SS, ST 993 8
Taiwan [83] 29 post-partum women, CMV serostatus undetermined PCR Serum SS, ST 29 10
Taiwan [71] 350 pregnant women at 2 time points in the 2nd trimester, all CMV seropositive PCR Urine SS, MT 350 11
Genital secretions SS, MT 220 30
Taiwan [22] 105 non-pregnant women from an infertility clinic PCR Genital secretions SS, ST 105 8
Taiwan [95] Men and women attending infertility clinic DNA hybridization Genital secretions SS, ST 246 34
Semen SS, ST 248 34
Turkey [76] 135 pregnant women, CMV serostatus undetermined, first trimester PCR Genital secretions SS, ST 135 2
US-Alabama [86] 113 healthy, post-partum women, all CMV seropositive, mean of 4.9 specimens per woman PCR Urine, blood MS, MT 113 14
Urine SS, MT 113 8
Blood SS, MT 113 6
US-Alabama [73] 81 post-partum women, all CMV seropositive, over an average of 4 visits, with uninfected infants Culture Urine, Oral secretions, genital secretions MS, MT 81 23
US-Massachusetts [94] 241 male infertility clinic attendees PCR Semen SS, ST 241 9
US-New York [70] 181 HIV-negative, CMV-seropositive urban, minority women Culture Genital secretions SS, ST 181 4
US-Ohio [121] 710 CMV seropositive adolescent pregnant women cultured at each antenatal visit Culture Urine SS, MT 710 17
US-Texas [124] 43 nurses in chronic care Culture Oral secretions, urine, genital secretions MS, ST 43 2
76 therapists in chronic care 76 3
69 neonatal nurses 69 3
US-Virginia [12] 239 CMV seropositive day care workers, average of 3.4 culture sets per woman over two years Culture Urine, oral secretions MS, ST 239 7
MS, MT 239 11
US-Washington [125] 120 critically ill immunocompetent patients, all CMV seropositive, 1954 samples, 3 samples collected per week, median of 11 samples per patient PCR Plasma SS, MT 120 33
Category VI. Adults with CMV risk factors
Italy [82] 142 women with abnormal cytology findings PCR Genital secretions SS, ST 142 63
Malawi [126] 19 KS patients and 58 first-degree family members PCR Urine, oral secretions MS, ST 77 53
US-Alabama [73] 142 post-partum women, all CMV seropositive, over an average of 4 visits, with infected infants Culture Urine, oral secretions, genital secretions MS, MT 142 56
US-Alabama [79] 52 women who were attending an STD clinic PCR Genital secretions SS, ST 52 33
US-California [21] 206 CMV seropositive homosexual men, HIV status unknown, followed for a mean of 14.3 months Culture Urine SS, MT 206 32
US-New York [100] 30 healthy homosexual men Culture Urine, semen MS, ST 30 37
US-Washington [39] 191 CMV seropositive women attending an STD clinic, most were symptomatic, mean of 2.7 follow-up visits Culture Genital secretions SS, ST 163 38
SS, MT 191 49
US-Washington [20] 951 CMV seropositive women presenting with problems at an STD clinic Culture Urine, genital secretions MS, ST 951 17
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Results from the category SS, ST were included in Figure 1. When SS, ST results were available for more than one specimen type they were listed in Table A1 rather than in this table.

From 26 studies, we identified 34 sample population prevalences measured in a single specimen type across multiple ages (Figure 2, Table A3). Among children born with congenital CMV infection (by definition 100% were shedding at birth), shedding prevalences steadily declined during the first 5 years of life (Figure 2, panel A), although it remained quite high in a few of the studies. Among children who were not congenitally infected, shedding prevalences generally peaked at 1–2 years of age and subsequently declined by the age of five (Figure 2, panels B–E), although this age pattern was less pronounced in healthy children not in day care centers (Figure 2, panel D). Results from the two studies reporting age and shedding among adolescents and adults (Table A3) [18,19] suggest that prevalence may decrease with age [18].

Figure 2.

Figure 2

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Cytomegalovirus (CMV) shedding as a function of age for different populations of children. Each line represents results from a single study (listed in Table A1 [11,13,14,19,28–32, 55,56,59,62,63,66,69,72,75,78,88–90,96–99]). Black symbols show shedding in urine, white symbols show shedding in oral secretions, and gray symbols show shedding in other specimens. Midpoints were used for ages when an age interval was reported. When age was some value and greater (e.g. ≥7 years) the previous age interval was assumed and the midpoint was taken (e.g. if the previous interval was 1 year [6–7 years], then the interval 7–8 years would be assumed, with a midpoint of 7.5 years). Because of the small age-specific sample sizes and very fine time points (i.e. 1-month), Numazaki et al.[88] was averaged using 2-month intervals

Table A3.

CMV shedding prevalence according to agea

Country Demographics/Sampling Method Testing Method Specimen Type (s) Ages Samples Shedding %
Category I. Congenitally infected children
England [78] Congenitally infected children Culture Urine 0–3 months 48 92
4–12 months 18 78
1–2 years 7 86
2–3 years 17 82
3–4 years 8 50
4–5 years 11 82
Oral secretions 0–3 months 48 92
4–12 months 18 61
1–2 years 4 25
2–3 years 13 38
3–4 years 7 0
4–5 years 11 18
Sweden [59] Congenitally infected children Culture Urine < 1 week 35 100
3 months 29 97
6 months 26 92
9 months 22 95
12 months 27 81
18 months 21 67
30 months 17 71
4 years 7 57
US-Alabama [28] Congenitally infected children Culture Urine 0–6 months 243 98
7–12 months 103 91
13–24 months 101 86
25–36 months 71 85
37–48 months 69 72
49–60 months 53 51
61–72 months 42 33
73–84 months 28 39
≥ 85 months 62 18
Oral secretions 0–6 months 131 93
7–12 months 59 73
13–24 months 71 39
25–36 months 50 38
37–48 months 42 19
49–60 months 37 16
61–72 months 27 7
73–84 months 22 0
≥ 85 months 45 4
US-Alabama [96] Asymptomatic congenitally infected children Culture Urine and/or oral secretions 2–3 years 10 90
4–6 years 8 13
US-Alabama [75] Asymptomatic congenitally infected children Culture Urine 1 year 17 88
2 years 22 91
3 years 18 89
4 years 12 75
Category II. Healthy children enrolled in day care centers
England [98] Children in day care centers, shedding at some time during the study Culture Urine < 2 years 26 46
≥ 2 years 79 25
Italy [69] Children in day care centers Culture Oral secretions 1 year 59 16
2 years 126 13
≥ 3 years 65 14
US-Alabama [72] Children in day care centers Culture Urine 0–12 months 10 50
13–24 months 53 36
25–36 months 52 33
37–48 months 52 29
> 48 months 64 16
Oral secretions 0–12 months 11 27
13–24 months 54 33
25–36 months 56 13
37–48 months 53 2
> 48 months 67 4
US-Alabama [97] Children in day care centers Culture Urine and/or oral secretions 0–12 months 10 0
13–24 months 38 37
25–36 months 35 77
37–48 months 48 46
> 48 months 57 25
US-Alabama [55] Children in day care centers Culture Urine < 12 months 9 33
13–24 months 7 71
25–30 months 8 63
31–36 months 13 23
37–48 months 18 33
Oral secretions < 12 months 7 28
13–24 months 10 80
25–30 months 10 10
31–36 months 11 9
37–48 months 9 22
Hands < 12 months 6 16
13–24 months 10 20
25–30 months 9 0
31–36 months 11 0
37–48 months 8 0
US-Alabama [14] Children in day care centers Culture Urine and/or oral secretions 0–12 months 11 9
13–24 months 18 83
25–36 months 16 63
37–48 months 13 23
49–60 months 12 58
US-Alabama [56] Children in day care centers Culture Urine and/or oral secretions 1 year 29 9
1.5 years 25 80
2 years 21 78
3 years 46 65
4 years 37 53
5 years 40 42
US-California [63] Children in day care centers and infant developmental centers Culture Urine 0–12 months 33 21
13–24 months 51 29
25–36 months 42 19
≥ 37 months 10 10
Oral secretions 0–12 months 36 13
13–24 months 64 9
25–36 months 50 2
≥ 37 months 12 0
US-Iowa [66] Children in day care centers Culture Urine and/or oral secretions 0–9 months 8 25
10–24 months 13 62
25–36 months 17 24
37–48 months 17 18
49–72 months 25 0
Urine 0–9 months 8 25
10–24 months 12 67
25–36 months 14 29
37–48 months 16 19
49–72 months 23 0
Oral secretions 0–9 months 8 25
10–24 months 13 38
25–36 months 17 6
37–48 months 17 6
49–72 months 25 0
US-Iowa [13] Children in day care centers Culture Urine and/or oral secretions < 2 years 74 22
2 years 23 35
3 years 50 12
≥ 4 years 72 3
US-Virginia [11] Children in day care centers Culture Urine 0–2 years 31 25
2–5 years 34 20
Category III. Healthy children not enrolled in day care centers
England [62] Infants not congenitally infected Culture Urine and/or oral secretions 6 weeks 253 4
3 months 249 12
8 months 247 15
1 year 234 20
Japan [88] Healthy children Culture Oral secretions 1 month 34 6
2 months 29 10
3 months 20 20
4 months 21 24
5 months 18 56
6 months 16 44
7 months 19 42
8 months 14 36
9 months 9 44
10 months 7 0
11 months 10 10
12 months 9 22
1 year 15 7
2 years 6 0
Sweden [59] Children not congenitally infected Culture Urine < 1 week 50 0
3 months 42 24
6 months 43 35
9 months 35 31
12 months 36 33
18 months 36 33
30 months 22 27
4 years 11 36
US-New York [30] Migrant worker children Culture Urine 1–4 years 14 36
4–8 years 12 17
8–13 years 12 0
Category IV. Children with medical conditions
Denmark [89] Hospitalized infants, not congenitally infected Culture Urine < 2 months 105 1
2–5 months 76 8
6–12 months 81 5
England [99] Hospitalized children Culture Urine and/or oral secretions < 3 months 508 2
3–5 months 220 3
6–11 months 207 6
1–4 years 398 4
> 4 years 62 2
England [19] Hospitalized patients Culture Urine and/or oral secretions 2–5 months 32 9
6 months - 4 years 104 10
5–9 years 101 1
10–14 years 72 0
Finland [31] Hospitalized and outpatient children Culture Urine 2 months 43 12
3 months 30 23
4 months 26 23
5–6 months 34 35
7–9 months 32 25
10–12 months 18 33
13–18 months 35 34
19–24 months 39 41
25–36 months 30 33
37–48 months 20 20
5–15 years 49 14
Sweden [90] Hospitalized infants Culture Urine ≤ 4 weeks 394 1
5–9 weeks 52 12
2–11 months 215 23
US-New York [32] Healthy children and children with chronic conditions Culture Urine 0–2 years 52 2
2–6 years 148 8
6–19 years 145 3
US-Virginia [11, 29] Hospitalized children Culture Urine Newborns 551 3
0–2 years 544 7
2–5 years 913 7
5–12 years 476 4
12–18 years 245 1
Category V. Adults without CMV risk factors
England [19] Hospitalized patients Culture Urine and/or oral secretions 15–24 years 102 0
25–34 years 100 0
35–59 years 100 0
≥ 60 years 100 0
US-Alabama [18] Pregnant women Culture Urine ≤ 14 years 38 8
15–20 years 306 6
21–25 years 123 4
26–30 years 44 0
≥ 31 years 29 0
Genital secretions ≤ 14 years 30 17
15–20 years 372 11
21–25 years 111 11
26–30 years 41 10
≥ 31 years 30 0
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Some of the results from this table are listed in previous tables without stratifying by age.

We identified 23 studies with 28 sets of sample population prevalences (Table A1) where CMV shedding was compared in more than one specimen type. Among children, CMV shedding was most commonly detected in urine specimens (Figure 3) but was also prevalent in oral secretions (median prevalence difference = 11.5%, N = 12). In adults without risk factors for CMV shedding (N = 10), genital shedding was most common (although oral secretions were often not tested) (Figure 3). Adults with risk factors for CMV infection (N = 6) most often shed virus in urine, although in two studies [20,21] shedding in other specimen types was more frequent (Figure 3). Studies comparing shedding in multiple specimen types did not include certain specimens, such as semen, blood, and rectal secretions, frequently enough to provide insights into their relative shedding frequencies. In general, however, shedding prevalences in blood were lower than prevalences in other specimen types.

Figure 3.

Figure 3

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Comparison of cytomegalovirus (CMV) shedding from different bodily fluids and locations according to risk group. Studies were only included if they measured CMV shedding in multiple specimen types. The lower panel compares shedding in different specimens (e.g. urine vs. oral secretions). Each column of letters comes from a single study (listed in Table A2 [14,18,20–22,27,28,54–56,61,63,66,67,71–74,78,84,86,88,100]). Directly above each column of letters, in the top panel, the corresponding difference is shown between shedding percentage in urine and the highest shedding percentage in another specimen

Figure 4 displays the shedding data from 18 studies and 20 sets of sample population prevalences that measured shedding in multiple specimen types and/or multiple study visits. These data demonstrate, unsurprisingly, that if shedding is assessed in multiple specimen types at multiple times it is usually more likely to be found.

Figure 4.

Figure 4

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Prevalences of cytomegalovirus (CMV) shedding in various studies that measured not only a single specimen type at a single time point but also multiple specimen types and/or multiple time points. Each column represents results from a single study (listed in Table A3 [14,20,21,39,56,61,63,65–67,71–73,77,86,91,93,100]). Multiple empty circles from a single study occur when CMV shedding was measured separately in more than one specimen type (e.g. one empty circle for shedding in urine, one empty circle for shedding in oral specimens). This figure demonstrates that CMV shedding in individuals is more prevalent if multiple specimen types and/or multiple time points are assessed

From five studies, we identified nine sets of sample population prevalences measured in a single specimen type at different times during pregnancy (Table A4). Two of these sets came from the same women followed longitudinally throughout pregnancy [22]. The other sets came from cross-sectional samples of women at different times during pregnancy. The prevalence of CMV shedding in pregnant women increased generally with advancing gestation, reaching peak prevalences in the second and third trimesters (Figure 5). Two of the studies had non-pregnant control groups. In one of them [18], shedding was less frequent in the first and second trimesters but equally frequent in the third trimester for the pregnant women compared with the non-pregnant controls. In the other study [22], shedding was more frequent in every trimester for the pregnant women compared with the non-pregnant controls.

Table A4.

CMV shedding among pregnant women according to time of gestation.

Country Testing Method Specimen Type Time of Gestation Sample Size Shedding %
Japan [88] Culture Genital secretions 1st trimester 30 0
2nd trimester 62 6
3rd trimester 61 17
Taiwan [71] PCR Urine 15 weeks 350 3
25 weeks 350 9
Genital secretions 15 weeks 220 17
25 weeks 220 24
Taiwan [22] PCR Urine (longitudinal collection) 1st trimester 207 1
2nd trimester 207 10
3rd trimester 207 13
Urine (cross-sectional collection) 1st trimester 906 4
2nd trimester 395 10
3rd trimester 273 13
Genital secretions (longitudinal collection) 1st trimester 54 13
2nd trimester 54 32
3rd trimester 54 35
Genital secretions (cross-sectional collection) 1st trimester 217 15
2nd trimester 140 40
3rd trimester 81 37
US-Alabama [18] Culture Genital secretions 1st trimester 183 2
2nd trimester 359 6
3rd trimester 317 11
US-Pennsylvania [101] Culture Genital secretions 1st trimester 43 2
2nd trimester 83 7
3rd trimester 49 12
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Figure 5.

Figure 5

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Prevalence of cytomegalovirus (CMV) shedding among pregnant women according to time of gestation. Each group of bars represents results from a single study (listed in Table A4 [18,22,49,71,88,101]). Two studies involved longitudinal specimen collection from the same women, the rest of the studies used cross-sectional specimen collection from women having various times of gestation. Where no bar is apparent, the prevalence is zero

We identified four studies (Table 1) outside of the newborn period that assessed differences in CMV viral load by specimen type. No clear differences in viral load were present for the specimen types examined. Because of differences in how viral loads were measured, it was impossible to assess whether viral loads differed according to specimen type. Studies which compared different specimen types in the newborn period (excluded from this review) have found higher viral loads in urine than in blood [23,24].

Table 1.

CMV viral load according to risk group and specimen type

Country Demographics/sampling method Testing method Specimen type(s) Sample size Viral load
The Gambia [61] Post-partum women Culture Urine 32 3.8 log10 TCID50/mL
Oral secretions 34 3.2 log10 TCID50/mL
Breast milk 21 1.4 log10 TCID50/mL
Infants at 6 months Urine 71 3.4 log10 TCID50/mL
Oral secretions 66 3.7 log10 TCID50/mL
Japan [108] Congenitally and postnatally infected newborns PCR Urine 14 Median = ~107 ge/mL
Dried umbilical cord 30 Median = ~103 ge/μg cellular DNA
US-Alabama [104] Congenitally infected newborns
Asymptomatic with hearing loss Culture Urine 4 Mean = 1.6 × 105 pfu/mL
PCR Blood 4 Mean = 8.7 × 105 ge/mL
Asymptomatic with normal hearing Culture Urine 54 Mean = 2.9 × 104 pfu/mL
PCR Blood 54 Mean = 1.1 × 104 ge/mL
Symptomatic with hearing loss Culture Urine 8 Mean = 4.9 × 105 pfu/mL
PCR Blood 8 Mean = 1.1 × 105 ge/mL
Symptomatic with normal hearing Culture Urine 10 Mean = 3.8 × 104 pfu/mL
PCR Blood 10 Mean = 6.2 × 105 ge/mL
US-Iowa [66] Children in day care centers Culture Urine 4 Mean = 1.7 × 103 pfu/mL
Oral secretions 2 Mean = 2.3 × 104 pfu/mL
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CMV, cytomegalovirus; PCR, polymerase chain reaction; TCID50, median tissue culture infectious dose; ge, genome equivalents; pfu, plaque forming units; mL, milliliter; μg, micrograms.

In general, the risk for developing SNHL among congenitally infected newborns was strongly and consistently associated with higher viral load measured at birth (Figure 6, Table A5). The six studies used different methods to determine viral load and set variable cut-offs for categorizing viral load. As such, direct comparisons of these studies may be difficult. Nevertheless, the risk for SNHL was not zero among newborns with low viral loads in most of the studies. Higher CMV viral load at birth also correlated with symptoms of congenital CMV at birth (Table 2). Although differences in mean viral load tended to be no more than 1–2 logs, they were consistent across all five studies.

Figure 6.

Figure 6

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Frequency of sensorineural hearing loss among congenitally infected children according to cytomegalovirus (CMV) viral load at birth. Each group of bars represents measurements from a single study (listed in Table A5 [102–107]). In one study, [104] viral load was measured in urine and blood, so two sets of bars are presented. Viral load categories (i.e. cut-points) varied across different studies and are not necessarily comparable (see Table A5). Those used here correspond to the categorizations chosen by the authors of the different studies. Where no bar is apparent, the prevalence is zero

Table A5.

Frequency of sensorineural hearing loss among congenitally infected children according to CMV viral load at birth

Country Testing Method Specimen Type(s) Viral Load Sample Size % with Sensorineural Hearing Loss
Belgium [107] PCR Urine < 3 log ge/mL 11 36
3.0–4.5 log ge/mL 8 38
>4.5 log ge/mL 13 77
England [106] PCR Dried blood spots Negative 10 50
2–2.5 log ge/mL 5 60
2.5–3 log ge/mL 10 80
>3 log ge/mL 9 100
Italy [105]a PCR Blood < 102 ge/105 PBMCs 4 0
102–103 ge/105 PBMCs 16 6
103–104 ge/105 PBMCs 14 50
> 104 ge/105 PBMCs 3 67
US-Alabama [104] Culture Urine < 3500 pfu/mL 26 4
3500–25000 pfu/mL 26 12
>25000 pfu/mL 24 33
PCR Blood < 3500 ge/mL 25 0
3500–25000 ge/mL 25 8
>25000 ge/mL 25 40
US-Alabama [102] Culture Urine < 5000 pfu/mL 6 0
5000–50000 pfu/mL 8 50
>50000 pfu/mL 7 71
US-Alabama, Arkansas, Texas [103] PCR Serum < 200 ge/mL 5 20b
200–5400 ge/mL 15 67b
>5400 ge/mL 9 67b
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a

All sequelae rather than sensorineural hearing loss only.

b

At 12 months follow-up.

ge, genome equivalents; pfu, plaque forming units; mL, milliliter; PBMC, peripheral blood mononuclear cells.

Table 2.

CMV viral load among congenitally infected newborns according to presence or absence of symptoms

Country Testing method Specimen type(s) Symptoms Sample size Viral load
China [109] PCR Urine Asymptomatic 25 Median = 4.50 × 103 ge/mL
Symptomatic 54 Median = 2.95 × 105 ge/mL
Italy [105] PCR Blood Asymptomatic 22 Log mean = 2.79 ge/105 PBMC
Symptomatic 17 Log mean = 3.24 ge/105 PBMC
Italy [110] Culture Blood Asymptomatic 32 Median = 0 p72 + fibroblasts/2 × 105 PBMC
Symptomatic 9 Median = 1.5 p72 + fibroblasts/2 × 105 PBMC
PCR Asymptomatic 32 Median = 30 ge/105 PBMC
Symptomatic 9 Median = 3000 ge/105 PBMC
US-Alabama [104] Culture Urine Asymptomatic 58 Mean = 3.9 × 104 pfu/mL
Symptomatic 18 Mean = 2.4 × 105 pfu/mL
PCR Blood Asymptomatic 58 Mean = 8.2 × 104 ge/mL
Symptomatic 18 Mean = 4.0 × 105 ge/mL
US-Alabama [28] Culture Urine Asymptomatic 71 Mean log TCID50 = 3.82
Symptomatic 33 Mean log TCID50 = 4.61
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CMV, cytomegalovirus; PCR, polymerase chain reaction; TCID50, median tissue culture infectious dose; ge, genome equivalents; pfu, plaque forming units; mL, milliliter; PBMC, peripheral blood mononuclear cells.

Studies of the duration of CMV shedding were carried out in limited situations with highly variable follow-up frequency and duration (Table 3). Consequently, it is not surprising that results varied widely. In general, congenitally infected infants and healthy children often shed for months or years. Among adult seroconverters, shedding typically continued for several months but had usually ceased within half a year. In several studies, shedding was intermittent among children and adults.

Table 3.

Duration of CMV shedding

Country Demographics/sampling method Testing method Specimen type(s) Shedding duration
Category I. Congenitally infected children
England [62] 25 congenitally infected infants Culture Urine, oral secretions 96% were shedding at 30 months of age
Italy [111] 14 congenitally infected infants PCR Blood 1–7 days 8–90 days 91–180 days > 180 days
100% 93% 63% 40%
US-New York [112] 20 congenitally infected children Culture Urine 100% were still shedding through at least 1 year of age
US-Ohio [113] 15 congenitally infected children Culture Urine 73% were still shedding at 4 years of age
Category II. Healthy children enrolled in day care centers
Sweden [68] 13 children in day care centers who were shedding Culture Urine Virus shedding continued throughout follow-up (6 months–1 year)
US-Iowa [67] 79 children in day care centers Culture Urine Mean duration of shedding = 13 months
Oral secretions Mean duration of shedding = 7 months
Category III. Healthy children not enrolled in day care centers
Finland [31] 39 hospitalized and outpatient children who were shedding Culture Urine 29 children always shed during a mean of 10 months follow-up, 10 children shed intermittently
Japan [88] 17 healthy children who were shedding Culture Oral secretions 15 stopped shedding within 12 months; most shed for 3–9 months.
Sweden [90] 27 children who were shedding but who were not infected congenitally Culture Urine Up to 2 years of age, 98% of samples were positive
Oral secretions Up to 2 years of age, 84% of samples were positive
US-California [114] 13 infants in ICU who were shedding Culture Urine All infants shed weekly for the duration of their hospital stay or the duration of the study (duration of follow-up not shown)
Category IV. Seroconverters
Austria [115] 48 immunocompetent adult seroconverters Culture Serum Duration of shedding less than approximately 90 days for all (estimated from Figure 1C of [115])
Italy [116] 35 IgM + or indeterminate adults, presumed seroconverters Culture Blood Up to 120 days, shedding prevalence > 50%; after 150 days, shedding prevalence = approximately 33% (estimated from Figure 5 of Ref. [116])
Italy [117] 52 immunocompetent seroconverters (including 40 pregnant women) Blood 1–30 days 31–60 days 61–90 days 91– 180 days >180 days
Culture (by specimen) 21% 0 0 0 0
(by patient) 26% 0 0 0 0
PCR (by specimen) 100% 81% 39% 17% 0
(by patient) 100% 89% 47% 27% 0
Italy [111] 32 seroconverting pregnant women PCR Blood 4–30 days 31–60 days 61–90 days 91– 180 days >180 days
100% 71% 46% 30% 8%
Italy [118] Culture Blood Mean ge/10 μL (estimated from Figure 1 of [118]) for different numbers of days after seroconversion
20 days 70 days 150 days
74 seroconverting pregnant women 45 ge 3 ge 0 ge
16 seroconverting men and 13 seroconverting non-pregnant women 42 ge 2 ge 0 ge
US-Alabama [119] 23 seroconverting post-partum women Culture Urine, oral secretions, genital secretions Median time from seroconversion to shedding = 2 weeks, range = 0–12 weeks. All shed CMV from at least one site at their subsequent visits, with follow-up as long as 3.5 years
US-California [21] 22 seroconverting homosexual men Culture Urine 27% shed at some time during follow-up, mean follow-up of 9.3 months
US-Washington [40] 36 seroconverting women seen at an STD clinic Culture Urine, genital secretions Median of shedding = 240 days for 14 women shedding from the cervix only
Median of shedding = 70 days for four women shedding in urine and cervix
Category V. Adolescents who were shedding CMV
US-Alabama [120] 18 adolescent women who were shedding Culture Primarily genital secretions Over 4 years of follow-up, 17% shed at every visit, 67% shed intermittently, and 17% never shed again
US-Ohio [121] 121 adolescent pregnant women who were shedding Culture Urine In the majority, shedding was intermittent over a period of several months.
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CMV, cytomegalovirus; PCR, polymerase chain reaction; ge, genome equivalents.

DISCUSSION

Studies of CMV shedding in various populations have provided valuable insights into the risk of acquiring CMV infection among women of reproductive age. This comprehensive analysis of CMV shedding among a variety of age groups, demographics and social settings, supports other findings that suggest that exposure to young children, especially those ages 1–2 years, poses a great risk for CMV infection [25–27]. Among young children shedding prevalences were lowest among infants less than 1-year-old. Prevalence of CMV shedding was uniformly high among 1-and 2-year-old children, whether they were enrolled in day care centers with large numbers of children or in home care. Thereafter, the prevalence of shedding declined markedly, although still continuing at relatively high levels among 3–4-year-olds. In the several studies that examined children older than five [11,19,28–32], shedding prevalences were similar to those observed in adults (5–10%). Children in day care studied at the University of Alabama at Birmingham had higher prevalences of shedding overall than children in day care studied elsewhere (Figure 1, panels B and C), which may reflect differences in the underlying study populations such as race, socioeconomic status, or mother’s serostatus. One notable difference in shedding patterns occurred among children with serious medical conditions, where in several studies the prevalence of shedding stayed at low levels throughout childhood (Figure 2, panel E), perhaps reflecting fewer opportunities for exposure.

Children ages 1–2 years may be a key transmission risk not only because of their high shedding prevalences, but because they are more mobile than younger children and are more likely than older children to spread urine or oral secretions to others because they are not yet toilet trained (e.g. still in diapers) and are more likely to drool (e.g. because of teething). Thus, caregivers who are pregnant or planning a pregnancy should make extra efforts to follow hygienic precautions with 1–2-year-olds [33,34]. Furthermore, providers in day care centers may have lower risk when caring for infants or for older children.

Among children, CMV shedding occurs most frequently in urine but is also commonly found in oral secretions. These studies support the existing consensus that pregnant women should avoid getting urine or saliva in their eyes, nose, or mouth [35–38]. Based on these data, sensible prevention activities for pregnant women would include hand washing after diaper changes or wiping a child’s nose or face and avoiding saliva when kissing young children and not sharing food, drink, utensils, or towels.

Adults typically shed CMV less frequently than children, but their prevalence of shedding is rarely zero. Furthermore, contrary to what is sometimes stated in the literature, seroconverting adults shed for many months rather than weeks. Among adults, genital secretions are a common fluid for CMV shedding, consistent with other studies that identified sexual risk factors for CMV seropositivity or seroconversion [25,39–43]. However, adults also shed CMV in oral secretions, suggesting that CMV transmission among adults can occur through kissing or oral sex. Unfortunately, it may be difficult if not impossible to assess the relative risk of these frequently co-occurring intimate behaviors. This presents a challenge for advising women on precautions to take with intimate partners during pregnancy. At a minimum, it would be prudent to limit new sex partners during pregnancy and to use a condom with new partners, even though these practices would not eliminate the risk for oral transmission. In many cases, the risk from regular partners may be less because they typically share the same CMV serostatus—for example, in one very large study in Belgium only 20% of seronegative women had a seropositive partner [26].

Among the different risk groups, children born with congenital CMV infection displayed the highest prevalences of subsequent CMV shedding (Figures 1 and 2). However, a substantial proportion of healthy children also shed CMV, reinforcing the notion that children with congenital CMV do not pose a special risk in day care or classroom settings and should not be excluded or treated differently.

Although the risk of CMV exposure for women of reproductive age may be elevated when their child attends day care, the risk is by no means eliminated for women who care for their children at home. About 20% of children in day care centers are shedding CMV, but about 10% of children not in day care centers are also shedding (Figure 2). As such, pregnant women should follow hygienic precautions whether or not their young children attend day care centers.

Studies that only measure CMV shedding in one specimen type at one point in time invariably underestimate the number of individuals who are shedders. This is because CMV shedding is frequently intermittent [44] and because CMV is shed in some specimen types more frequently than others. Thus, the shedding prevalences in the different risk groups (Figure 1) should be treated as minimum estimates of the prevalence of individuals shedding in bodily fluids. Furthermore, care must be taken when comparing shedding prevalences across studies, because some may present results from a single specimen and time point whereas others combine results from multiple specimens or time points.

Viral shedding was more common among pregnant women as gestation progressed for all five studies that have examined this phenomenon (Table A4). It is not clear why this phenomenon occurs, but because there is no apparent reason why exposure risk should increase with advancing gestation, it may be that this trend is related to a possible altered state of immunity during pregnancy [45,46], which could increase the likelihood of CMV primary infection, reactivation, or reinfection, as well as the duration of viral shedding [47–49].

Approximately from 10% to 15% of congenitally infected children who have asymptomatic infections at birth will develop disabilities within 2 years, most often SNHL [4,50]. It does not appear that CMV shedding or viral load measured after the newborn period is a strong predictor of SNHL [44,51]. In contrast, the observation that the highest viral loads at birth are consistently associated with the greatest risk for developing hearing impairments should be useful for clinical prognoses. However, the positive predictive value of high viral load for SNHL is probably only 30%–80% whereas the negative predictive value of low viral load probably ranges from 50% to 100% depending on the chosen assay cut-off (Figure 6). Nevertheless, all congenitally infected children would probably benefit from regular follow-up audiological testing, but such follow up would be especially important for children with high viral loads at birth.

The findings from CMV shedding studies tended to be consistent with serologic studies that addressed risk factors for CMV transmission [25,52]. Nonetheless, the studies we reviewed had significant differences in study design, population demographics, number of participants studied, and other factors that limited the conclusions we could draw. The majority of studies used viral culture to isolate infectious virus. However, for those studies that used PCR, there was no way to know how well the presence of viral DNA correlated with the presence of infectious virus in any given bodily fluid. Additional studies are needed in a household setting where much child- to-mother transmission is likely to occur [15,53]. Finally, studies comparing a broad selection of clinical specimens (urine, saliva, blood in children; urine, saliva, blood, genital secretions, semen in adults) at multiple time points are needed to better understand and prevent CMV transmission to pregnant women.

Acknowledgments

We thank the European Congenital Cytomegalovirus Initiative (ECCI) for proposing and encouraging this review.

Abbreviations used

MSM

men who have sex with men

SES

socioeconomic status

SNHL

sensory neural hearing loss

STD

sexually transmitted disease

Footnotes

CONFLICT OF INTEREST

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Supporting information may be found in the online version of this article.

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