Accepted Manuscript Title: Urine is superior to saliva when screening for postnatal CMV infections in preterm infants Author: J. Gunkel T.F.W. Wolfs J. Nijman R. Schuurman M.A. Verboon-Maciolek L.S. de Vries J.L. Murk PII: DOI: Reference:
S1386-6532(14)00216-9 http://dx.doi.org/doi:10.1016/j.jcv.2014.06.002 JCV 3047
To appear in:
Journal of Clinical Virology
Received date: Revised date: Accepted date:
24-3-2014 21-5-2014 2-6-2014
Please cite this article as: Gunkel J, Wolfs TFW, Nijman J, Schuurman R, VerboonMaciolek MA, de Vries LS, Murk JL, Urine is superior to saliva when screening for postnatal CMV infections in preterm infants, Journal of Clinical Virology (2014), http://dx.doi.org/10.1016/j.jcv.2014.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Urine is superior to saliva when screening for postnatal CMV
2
infections in preterm infants
3
J Gunkel1, T.F.W. Wolfs2, J Nijman1, R. Schuurman3, M.A. Verboon-Maciolek1, L.S. de Vries1, J.L.
4
Murk3
ip t
1
5
1. Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands
cr
6
Postal address: Postbus 85090, 3508 AB Utrecht, The Netherlands
8
Email addresses: [email protected], [email protected]
9
us
7
2. Department of Pediatric Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
11
Postal address: Postbus 85090, 3508 AB Utrecht, The Netherlands
12
Email address: [email protected]
M
13
an
10
3. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
15
Postal address: Postbus 85500, 3508 GA Utrecht, The Netherlands
16
Email addresses: [email protected], [email protected]
te
d
14
Ac ce p
17 18
Corresponding author:
19 20 21 22 23 24 25 26 27 28 29 30 31
J. Gunkel, MD Department of Neonatology University Medical Center Utrecht Postbus 85090 3508 AB Utrecht, The Netherlands Tel. +31 – 88 – 755 49 15 Fax. +31 – 88 – 755 53 20 Mobile: +31 – 613 767 484 Email: [email protected]
Word count abstract: 241 words Word count manuscript: 1380 words
1
Page 1 of 13
Abstract
32
Background:
33
Cytomegalovirus (CMV) is the most frequently contracted virus in preterm infants. Postnatal infection
34
is mostly asymptomatic but is sometimes associated with severe disease. To diagnose an infection,
35
urine or saliva samples can be tested for CMV-DNA by real-time polymerase chain reaction (rtPCR).
36
Although the diagnostic accuracy of testing saliva samples has not been determined in preterm infants,
37
saliva is widely used because it is easier to obtain than urine.
38
Objectives
39
To determine whether screening of saliva is equivalent to urine to detect a postnatal CMV infection in
40
preterm infants.
41
Study design
42
Between 2010 and 2013 saliva and urine samples were collected from infants admitted to the Neonatal
43
Intensive Care Unit of the University Medical Center Utrecht and born with a gestational age (GA)
44
below 32 weeks. Urine samples were obtained within three weeks after birth and urine and saliva
45
samples at term equivalent age (40 weeks GA) and tested for CMV-DNA by rtPCR. Infants with a
46
congenital CMV infection were excluded.
47
Results:
48
Of 261 preterm infants included in the study, CMV-DNA was detected in urine of 47 and in saliva of
49
43 children. Of 47 infants with postnatal CMV infection, CMV was detected in 42 saliva samples
50
(sensitivity 89.4%; CI 76.9 – 96.5). Of 214 children without postnatal CMV infection, one saliva
51
sample tested positive for CMV (specificity 99.5%; CI 97.4-99.9).
52
Conclusions:
53
Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose postnatal CMV infections in
54
preterm infants.
Ac ce p
te
d
M
an
us
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ip t
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55 56
Keywords: Postnatal infection, saliva, urine, real-time polymerase chain reaction, premature infants,
57
cytomegalovirus.
2
Page 2 of 13
1. Background
59
Human cytomegalovirus (CMV) is the most commonly contracted virus in preterm infants (born
60
before 32 weeks gestational age) and is mainly acquired through CMV positive breast milk [1]. In one
61
study of CMV acquisition among preterm neonates, the mother-to-infant transmission rate among
62
CMV seropositive mothers was 37% [1]. Postnatal CMV infections (pCMV) are mostly
63
asymptomatic, however disease severity appears to be inversely related to gestational age (GA) and
64
birth weight (BW) [2–4]. pCMV induced long-term sequelae seem less common compared to
65
congenital CMV (cCMV), but neurocognitive impairment [5], changes in white matter microstructure
66
[6] and discrepancies in language and visuospatial functions detected by functional magnetic
67
resonance imaging [7] have been reported. More studies are needed to determine the burden of disease
68
of pCMV infections. Screening would allow for more clarity on short- and long-term
69
neurodevelopment. CMV infections are diagnosed by viral culture of urine samples or detection of
70
CMV-DNA by real-time polymerase chain reaction (rtPCR) [8–10]. Studies show that saliva is
71
suitable to screen infants for cCMV infections, which has the advantage of being easier to obtain than
72
urine [8,10,11]. No studies have evaluated the sensitivity and specificity of saliva to screen for pCMV
73
infections.
te
Ac ce p
74
d
M
an
us
cr
ip t
58
75
2. Objectives
76
This study was designed to assess the diagnostic value of screening saliva for CMV-DNA in preterm
77
infants for a pCMV infection. Results were compared with screening of urine, which was regarded as
78
the gold standard for cCMV infection [12].
79 80
3. Study design
81
Patient inclusion and specimen collection
82
From March 2010 until June 2013 all preterm infants with a GA
S1386-6532(14)00216-9 http://dx.doi.org/doi:10.1016/j.jcv.2014.06.002 JCV 3047
To appear in:
Journal of Clinical Virology
Received date: Revised date: Accepted date:
24-3-2014 21-5-2014 2-6-2014
Please cite this article as: Gunkel J, Wolfs TFW, Nijman J, Schuurman R, VerboonMaciolek MA, de Vries LS, Murk JL, Urine is superior to saliva when screening for postnatal CMV infections in preterm infants, Journal of Clinical Virology (2014), http://dx.doi.org/10.1016/j.jcv.2014.06.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Urine is superior to saliva when screening for postnatal CMV
2
infections in preterm infants
3
J Gunkel1, T.F.W. Wolfs2, J Nijman1, R. Schuurman3, M.A. Verboon-Maciolek1, L.S. de Vries1, J.L.
4
Murk3
ip t
1
5
1. Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands
cr
6
Postal address: Postbus 85090, 3508 AB Utrecht, The Netherlands
8
Email addresses: [email protected], [email protected]
9
us
7
2. Department of Pediatric Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands
11
Postal address: Postbus 85090, 3508 AB Utrecht, The Netherlands
12
Email address: [email protected]
M
13
an
10
3. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
15
Postal address: Postbus 85500, 3508 GA Utrecht, The Netherlands
16
Email addresses: [email protected], [email protected]
te
d
14
Ac ce p
17 18
Corresponding author:
19 20 21 22 23 24 25 26 27 28 29 30 31
J. Gunkel, MD Department of Neonatology University Medical Center Utrecht Postbus 85090 3508 AB Utrecht, The Netherlands Tel. +31 – 88 – 755 49 15 Fax. +31 – 88 – 755 53 20 Mobile: +31 – 613 767 484 Email: [email protected]
Word count abstract: 241 words Word count manuscript: 1380 words
1
Page 1 of 13
Abstract
32
Background:
33
Cytomegalovirus (CMV) is the most frequently contracted virus in preterm infants. Postnatal infection
34
is mostly asymptomatic but is sometimes associated with severe disease. To diagnose an infection,
35
urine or saliva samples can be tested for CMV-DNA by real-time polymerase chain reaction (rtPCR).
36
Although the diagnostic accuracy of testing saliva samples has not been determined in preterm infants,
37
saliva is widely used because it is easier to obtain than urine.
38
Objectives
39
To determine whether screening of saliva is equivalent to urine to detect a postnatal CMV infection in
40
preterm infants.
41
Study design
42
Between 2010 and 2013 saliva and urine samples were collected from infants admitted to the Neonatal
43
Intensive Care Unit of the University Medical Center Utrecht and born with a gestational age (GA)
44
below 32 weeks. Urine samples were obtained within three weeks after birth and urine and saliva
45
samples at term equivalent age (40 weeks GA) and tested for CMV-DNA by rtPCR. Infants with a
46
congenital CMV infection were excluded.
47
Results:
48
Of 261 preterm infants included in the study, CMV-DNA was detected in urine of 47 and in saliva of
49
43 children. Of 47 infants with postnatal CMV infection, CMV was detected in 42 saliva samples
50
(sensitivity 89.4%; CI 76.9 – 96.5). Of 214 children without postnatal CMV infection, one saliva
51
sample tested positive for CMV (specificity 99.5%; CI 97.4-99.9).
52
Conclusions:
53
Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose postnatal CMV infections in
54
preterm infants.
Ac ce p
te
d
M
an
us
cr
ip t
31
55 56
Keywords: Postnatal infection, saliva, urine, real-time polymerase chain reaction, premature infants,
57
cytomegalovirus.
2
Page 2 of 13
1. Background
59
Human cytomegalovirus (CMV) is the most commonly contracted virus in preterm infants (born
60
before 32 weeks gestational age) and is mainly acquired through CMV positive breast milk [1]. In one
61
study of CMV acquisition among preterm neonates, the mother-to-infant transmission rate among
62
CMV seropositive mothers was 37% [1]. Postnatal CMV infections (pCMV) are mostly
63
asymptomatic, however disease severity appears to be inversely related to gestational age (GA) and
64
birth weight (BW) [2–4]. pCMV induced long-term sequelae seem less common compared to
65
congenital CMV (cCMV), but neurocognitive impairment [5], changes in white matter microstructure
66
[6] and discrepancies in language and visuospatial functions detected by functional magnetic
67
resonance imaging [7] have been reported. More studies are needed to determine the burden of disease
68
of pCMV infections. Screening would allow for more clarity on short- and long-term
69
neurodevelopment. CMV infections are diagnosed by viral culture of urine samples or detection of
70
CMV-DNA by real-time polymerase chain reaction (rtPCR) [8–10]. Studies show that saliva is
71
suitable to screen infants for cCMV infections, which has the advantage of being easier to obtain than
72
urine [8,10,11]. No studies have evaluated the sensitivity and specificity of saliva to screen for pCMV
73
infections.
te
Ac ce p
74
d
M
an
us
cr
ip t
58
75
2. Objectives
76
This study was designed to assess the diagnostic value of screening saliva for CMV-DNA in preterm
77
infants for a pCMV infection. Results were compared with screening of urine, which was regarded as
78
the gold standard for cCMV infection [12].
79 80
3. Study design
81
Patient inclusion and specimen collection
82
From March 2010 until June 2013 all preterm infants with a GA
