Clinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns Prognostic Birth Cohort Study

7/29/2019 Clinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns Prognostic Birth Cohort Study

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DOI: 10.1542/peds.2010-0581; originally published online December 27, 2010;2011;127;35Pediatrics

Kimpen, Gerard H. A. Visser and Maroeska M. RoversMichiel L. Houben, Louis Bont, Berry Wilbrink, Mirjam E. Belderbos, Jan L. L.

Birth Cohort StudyClinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns: Prognostic

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Clinical Prediction Rule for RSV Bronchiolitis in

Healthy Newborns: Prognostic Birth Cohort Study

WHATS KNOWN ON THIS SUBJECT: Hospitalized respiratorysyncytial virus (RSV) lower respiratory tract infection (LRTI) can

be predicted by using host and environmental factors. The impact

of outpatient-treated RSV LRTI includes increased number of

physician visits, drug prescriptions, and parents missed work

days.

WHAT THIS STUDY ADDS: A simple prediction rule can identify

infants at risk of outpatient-treated RSV LRTI. The absolute risks

of RSV LRTI range from 3% for children with the lowest prediction

rule score to 32% for children with all predictive factors.

abstract +OBJECTIVE: Our goal was to determine predictors of respiratory syn-

cytial virus (RSV) lower respiratory tract infection (LRTI) among

healthy newborns.

METHODS: In this prospective birth cohort study, 298 healthy term

newborns born in 2 large hospitals in the Netherlands were monitored

throughout the first year of life. Parents kept daily logs and collected

nose/throat swabs during respiratory tract infections. The primary

outcome was RSV LRTI, which was defined on the basis of the combina-tion of positive RSV polymerase chain reaction results and acute

wheeze or moderate/severe cough.

RESULTS: Of the 298 children, 42 (14%) developed RSV LRTI. Indepen-

dent predictors for RSV LRTI were day care attendance and/or siblings,

high parental education level, birth weight of4 kg, and birth in April

to September. The area under the receiver operating characteristic

curve was 0.72 (95% confidence interval: 0.640.80). We derived a

clinical prediction rule; possible scores ranged from 0 to 5 points. The

absolute risk of RSV LRTI was 3% for children with scores of2(20%of

all children) and 32% for children with all 4 factors (scores of 5; 8% of

all children). Furthermore, 62% of the children with RSV LRTI experi-enced wheezing during the first year of life, compared with 36% of the

children without RSV LRTI.

CONCLUSIONS: A simple clinical prediction rule identifies healthy new-

borns at risk of RSV LRTI. Physicians can differentiate between children

with high and low risks of RSV LRTI and subsequently can target pre-

ventive and monitoring strategies toward children at high risk.

Pediatrics2011;127:3541

AUTHORS: Michiel L. Houben, MD,a Louis Bont, MD, PhD,a

Berry Wilbrink, PhD,b Mirjam E. Belderbos, MD,a Jan L. L.

Kimpen, MD, PhD,a Gerard H. A. Visser, MD, PhD,c and

Maroeska M. Rovers, PhDd

aDepartment of Pediatrics, Wilhelmina Childrens Hospital,cDepartment of Obstetrics and Gynecology, anddJulius Center

for Health Sciences and Primary Care, University Medical Center

Utrecht, Utrecht, Netherlands; andbLaboratory of Infectious

Diseases and Perinatal Screening, National Institute of Public

Health and the Environment, Bilthoven, Netherlands

KEY WORDS

birth cohort study, respiratory syncytial virus, lower respiratory

tract infection, health-related quality of life, postbronchiolitis

wheeze, risk stratification

ABBREVIATIONS

AUCarea under the curve

GPgeneral practitioner

HRQoLhealth-related quality of life

LRTIlower respiratory tract infection

ORodds ratio

PCRpolymerase chain reaction

ROCreceiver operating characteristic

RSVrespiratory syncytial virus

www.pediatrics.org/cgi/doi/10.1542/peds.2010-0581

doi:10.1542/peds.2010-0581

Accepted for publication Oct 8, 2010

Address correspondence to Louis Bont, MD, PhD, University

Medical Center Utrecht, Department of Pediatrics, Lundlaan 6,

3584 EA Utrecht, Netherlands. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2011 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: Dr Bont received research funding and

speakers fees from Abbott International; the other authors have

indicated they have no financial relationships relevant to this

article to disclose.

ARTICLES

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The proportion of all children in their

first year of life with medically at-

tended respiratory syncytial virus

(RSV) infections in the United States is

estimated to be 44%.1 The majority of

these children (95%) are treated as

outpatients by general practitioners(GPs) or at the emergency depart-

ment.1 Therefore, from a socioeco-

nomic point of view, outpatient-treated

RSV infections have a large impact, in-

cluding emergency department and of-

fice visits, drug prescriptions, and par-

ents missed work days.2 Moreover,

RSV lower respiratory tract infection

(LRTI) is associated with subsequent

recurrent wheeze for 40% of pa-

tients, leading to reduced health-related quality of life (HRQoL).35

Identifying newborns who will develop

RSV LRTI is important, because simple

lifestyle changes, such as intensified

hand hygiene, can prevent RSV infec-

tions.69 In addition, current and future

medical preventive measures may be

used to target individuals at high

risk.10,11 Known risk factors for the oc-

currence of RSV LRTI are preterm

birth, young age, male gender, heartand lung disease, Down syndrome, ab-

sence or short duration of breastfeed-

ing, presence of siblings, day care at-

tendance, and exposure to tobacco

smoke.1220

To date, clinical prediction models for

RSV have been developed only with re-

spect to hospitalization among pre-

term infants.2123 A clinical prediction

model for outpatient-treated RSV LRTI

among term children does not yet ex-ist. Therefore, the objective of this

study was to develop a clinical predic-

tion rule to identify healthy term new-

borns at high risk of RSV LRTI in the

first year of life.

METHODS

Population

Two large urban hospitals (University

Medical Center Utrecht and Diakones-

senhuis [Netherlands]) participated in

this prospective birth cohort study.

Children who were born after 37

weeks of gestation (term) after an un-

complicated pregnancy were eligible

to participate. Newborns with major

congenital anomalies and newbornswhose parents had limited Dutch lan-

guage skills were excluded. Between

January 2006 and December 2008,

1080 newborns were eligible and the

parents of 341 (32%) agreed to partic-

ipate and gave written informed con-

sent. The most frequent reason for

nonparticipation was reluctance of

parents to perform daily follow-up

measurements according to the study

protocol. Baseline characteristics ofnonparticipating children and their

parents were similar to the character-

istics of participating subjects (data

not shown). Of the 341 included chil-

dren, 298 (87%) had no missing values.

The study protocol was approved by

the institutional review boards of the 2

participating hospitals.

Predictive Factors

The presence or absence of risk fac-

tors for RSV LRTI was assessed by us-

ing data from the hospital delivery files

(gender, gestational age, birth weight,

and month of birth) or from standard-

ized questionnaires completed at 1

month and 1 year of age. Gestational

age was dichotomized by using an ar-

bitrary cutoff value of 40.0 weeks. Birth

weight was dichotomized by using an

arbitrary cutoff value of 4 kg.24 Breast-

feeding was defined as being given

mothers milk exclusively (without ad-

ditional formula feeding) beyond the

age of 1 month. Parental atopy was de-

fined as the presence of any atopic di-

agnosis (asthma, eczema, or hay fe-

ver) made by a physician for 1 or both

parents. Exposure to maternal tobacco

smoke was defined as maternal smok-

ing of1 cigarette per day at the age

of 1 month. Day care attendance was

defined as attendance of any day care

during any period in the first year of

life. The presence of siblings in the

household of the child was defined as

1 sibling younger than 18 years liv-

ing 3 days per week in the same

house. A composite variable of day

care and/or siblings was created tolimit the number of potential predic-

tive factors, because of the relatively

small sample size. Parental education

level was dichotomized by using the ar-

bitrary cutoff level of a bachelors de-

gree for1 parent. Because maternal

anti-RSV antibodies may protect in-

fants against RSV disease in the com-

munity in their first months of life,

being born within 6 months before

the start of the RSV season (Aprilthrough September) was used as a

potentially predictive variable.25

Outcomes

The primary outcome was RSV LRTI,

which was defined as the presence of

an LRTI and the presence of RSV RNA.

Parents were instructed to record

daily respiratory symptoms, including

wheeze and cough, in a log.26 Episodes

in the log were defined to represent anLRTI by using strict predefined criteria,

that is, moderate or severe cough or

wheeze of any severity lasting for 2

days. A nose/throat swab sample was

obtained by the parents at the start of

every respiratory episode and subse-

quently was sent to the researchers in

a single vial containing 2 mL of viral

transport medium. The samples were

frozen at 80C until polymerase

chain reaction (PCR) assays were per-formed. The presence of RSV A or B RNA

was determined by using real-time

PCR assays.27

A secondary outcome was GP-attended

RSV infection, which was defined as

the occurrence of a respiratory epi-

sode with GP attendance and the pres-

ence of RSV RNA. To study the burden of

RSV LRTI episodes, we also examined

wheezing during the first year of life

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and HRQoL (measured with the TNO-AZL

Preschool Children Quality of Life ques-

tionnaire [TAPQoL]) for children with

and without RSV LRTI (secondary out-

comes).2830 Data on wheezing during

the first year of life were derived from

the logs.

Statistical Analyses

The association between each prog-

nostic factor and the presence or ab-

sence of RSV LRTI was examined with

univariate logistic regression analy-

ses. Predictors that were associated

with the outcome in univariate analy-

ses (P .15) were included in multi-

variate logistic regression analyses.

The model was reduced through exclu-sion of predictors with P values of

.10. The predictive accuracy of the

model was estimated on the basis of

its reliability (goodness of fit) by using

Hosmer-Lemeshow tests.31,32 The mod-

els ability to discriminate between

children with and without RSV LRTI was

estimated as the area under the curve

(AUC) for the receiver operating char-

acteristic (ROC) curve for the model.

The ROC curve is a plot of the true-positive rate (sensitivity) versus the

false-positive rate (1 specificity)

evaluated at consecutive cutoff points

for the predicted probability. The AUC

provides a quantitative summary of

the discriminative ability of a predic-

tive model. A useless predictive model,

such as a coin flip, would yield an AUC

of 0.5. When the AUC is 1.0, the model

discriminates perfectly between sub-

jects who do and subjects who do notdevelop a prognostic outcome.33

Prediction models derived with multi-

variate regression analyses are known

for overestimated regression coeffi-

cients, which result in too-extreme

predictions when applied in new cas-

es.33 Therefore, we validated our mod-

els internally with bootstrapping tech-

niques in which the entire modeling

process was repeated with each boot-

strap sample. This yielded a shrinkage

factor for the regression coefficients

and the ROC AUC.33

To obtain a prediction rule that is eas-

ily applicable in clinical practice, the

adjusted regression coefficients of the

model were divided by the lowest coef-

ficient and rounded to the nearest in-

teger. Scores for each individual pa-

tient were obtained by assigning

points for each variable and adding

the results. Patients were classified

according to their risk scores and the

number of children developing or not

developing RSV LRTI, and correspond-

ing positive and negative predictive

values were calculated.

To test the robustness of the model,

sensitivity analyses were conducted by

using the alternative outcome of GP-

attended RSV infection and by using al-

ternative predictive factors (eg, day

care and siblings as separate vari-

ables and duration of breastfeeding,

intensity of maternal smoking, and du-

ration of day care attendance as con-

tinuous variables). The clinical rele-

vance of the model was studied by

comparing the proportions of children

with wheeze each month, respiratory

symptoms, and HRQoL between chil-

dren with and children without RSV

LRTI in the first year of life. All analyses

were performed with SPSS 15 (SPSS

Inc, Chicago, IL).

RESULTS

Of the 298 participating children, 42

(14%) developed RSV LRTIs during

their first year of life. One child devel-

oped 2 separate RSV LRTIs within the

same season. The median age at the

time of RSV LRTI was 6 months (inter-

quartile range: 48 months) (Fig 1).

Twenty children (48%) were boys. Of

the 42 children with RSV LRTI, 27 (64%)

visited a GPand 3 (2, 6, and 8 monthsof

age) were hospitalized. Although RSV A(25 of 42 cases) and RSV B (17 of 42

cases) were detected separately in

PCR assays, the clinical outcomes of

children with LRTI attributable to RSV A

and RSV B were comparable (data not

shown).

Results of univariate and multivariate

logistic regression analyses are pre-

sented in Table 1. The final reduced re-

gression model included 4 indepen-

FIGURE 1Distributions of month of birth for children with (A) and without (B) RSV LRTI(s) and of month of RSVLRTI(s) (C).

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dent predictive variables, that is, day

care attendance and/or the presence

of siblings (odds ratio [OR]: 5.8), high

parental education level (OR: 2.8), birth

weight of4 kg(OR: 2.2), and month of

birth between April and September

(OR: 2.2) (Table 1). The goodness-of-fit

test indicated an acceptable fit of the

final prognostic model (P .91), and

the AUC was 0.72 (95% confidence in-

terval: 0.64 0.80). The shrunk AUC

was 0.70 (shrinkage factor: 0.97). The

sensitivity analyses with the alterna-

tive outcome of GP-attended RSV

infection and with alternative pre-

dictive factors yielded similar

prognostic models with identical dis-

criminating abilities (ROC AUC values

of 0.72 and 0.71, respectively).

By using the regression coefficients of

the final predictive model, the proba-

bility of developing a RSV LRTI can be

estimated for each child by using the

formula given in Table 1. For example,

a child who is born in July (1 point),

attends day care (2 points), has a birth

weight of 4.2 kg (1 point), and has par-

ents who are not highly educated (0

points) has a total score of 1 2

1 0 4 points, which corresponds

to a probability of developing a RSV

LRTI of 23%. Table 2 shows the number

of children in the cohort with and with-out RSV LRTI across different catego-

ries of risk scores. Figure 2 shows that

children with the lowest scores (02

points; 20% of all children) had an ab-

solute risk of 3% for developing RSV

LRTI, whereas children with all risk fac-

tors (8% of all children) had an abso-lute risk of 32% (risk ratio: 9.6).

Furthermore, 62% of the children with

RSV LRTI experienced wheezing during

the first year of life, compared with

36% of the children without RSV LRTI

(risk ratio: 1.72; P .003) (Fig 3). Ex-

clusion of the episodes that defined

the RSV LRTI group gave similar results

(59% vs 36%; risk ratio: 1.65; P .005).

Children with RSV LRTI used more re-spiratory drugs at the age of 1 year,

although this finding was not signifi-

cant (15% vs 8%), and more often vis-

ited a physician because of respiratory

problems, compared with children

without RSV LRTI (48% vs 30%; P .03).

The HRQoL was lower for children with

RSV LRTI with respect to 5 of the 10

domains (lungs, stomach, appetite,

anxiety, and problem behavior), com-

TABLE 1 Univariable and Multivariable Analyses of Predictors of RSV LRTI

Characteristic n(%) Univariate Analyses Multivariate Analyses

(Final Model)

Points

for

RuleRSV LRTI

(N 42)

No RSV LRTI

(N 256)

OR (95% CI) P OR (95% CI) P

Child

Breastfeeding 22 (52) 140 (55) 0.91 (0.471.8) 0.78

Male 20 (48) 138 (54) 0.78 (0.401.5) 0.45

Gestational age 4042 wk 28 (67) 128 (50) 2.00 (1.014.0) 0.05

Birth weight 4 kg 16 (38) 52 (20) 2.41 (1.24.8) 0.01 2.24 (1.14.6) 0.03 1

Environment

Parental atopy 24 (57) 143 (56) 1.05 (0.552.0) 0.88

Maternal smoking 2 (5) 24 (9) 0.48 (0.112.1) 0.33

Born in April to September 28 (67) 132 (52) 1.88 (0.953.7) 0.07 2.17 (1.14.4) 0.03 1

Day care or siblings 41 (98) 214 (84) 8.05 (1.160.1) 0.02 5.80 (0.7644.4) 0.09 2

High parental education level 38 (91) 186 (73) 3.58 (1.210.4) 0.01 2.79 (0.948.3) 0.07 1

Hosmer-Lemeshow 2 2.74 0.91

ROC AUC 0.72 (0.640.80) 5

CI indicates confidence interval. The prediction rule was as follows: score (2 for day care attendance and/or siblings) (1 for high parental education level) (1 for birth weight of4

kg) (1 for birth in April to September). All variables were dichotomous (0 or 1), and scores ranged from 0 through 5.

TABLE 2 Performance of Different Thresholds for Prediction Rule for RSV LRTI (N 298)

Threshold True-Positive

Results

(N 42), %

True-Negative

Results

(N 256), %

Positive Predictive

Value, %

Negative Predictive

Value, %

3 40 (95) 58 (23) 16.8 96.7

4 33 (79) 148 (58) 23.4 94.3

5 8 (19) 239 (93) 32.0 87.5

The prediction rule was as follows: score (2 for day care attendance and/or siblings) (1 for high parental education

level) (1 for birth weight of4 kg) (1 for birth in April to September). All variables were dichotomous (0 or 1), and

scores ranged from 0 through 5.

FIGURE 2Absolute risk to develop RSV LRTI for children

with different prediction rule scores. Scores of

0, 1, or 2 points (pooled), n 60; score of 3

points, n 97; score of 4 points, n 116; score

of 5 points, n 25 were compared by using 2

test, P .001.

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pared with children without RSV LRTI

(Supplemental Figure 4).

DISCUSSION

We developed a simple prediction rule

that identifies healthy newborns at

high risk of RSV LRTI in the first year of

life. Independent predictors for RSV

LRTI were day care attendance and/or

the presence of siblings, high parental

education levels, birth weight of 4kg, and month of birth between April

and September.

Our prognostic study differs from oth-

ers with respect to the domain and

outcome studied.21,22 We focused on

nonhospitalized RSV LRTI among

healthy term infants, whereas others

studied hospitalized RSV in premature

infants. This may explain the small dif-

ferences in predictive factors. The

strongest predictor in our study (day

care attendance and/or the presence

of siblings) is in agreement with the

findings of other studies.2123 High

birth weight may be associated with

delayed parturition and an altered

immunologic phenotype.21,34,35 Birth

within 6 months before the start of the

RSV season is a longer window than

usually found.16,21,23 However, it is

consistent with the median age of 6months for RSV LRTI in the commu-

nity and/or at GPs in our cohort study

and in studies by others.1 Highly ed-

ucated parents might be more care-

ful or might seek earlier medical ad-

vice if their child develops a

respiratory infection.36,37 However,

parental education levels also may

be associated with other environ-

mental factors.

To our knowledge, this is the first study

that attempts to predict the risk of

nonhospitalized RSV LRTI for healthy

newborns by using molecular detec-

tion of RSV. Some of our findings de-

serve additional discussion. First, only

341 of the 1080 eligible newborns par-ticipated in our study, which might

have resulted in selection bias. Com-

parison of the baseline clinical and de-

mographic characteristics between

participants and nonparticipants,

however, showed no differences.

Therefore, we think that our results

are generalizable to all healthy new-

borns. Second, because of the design

of our study, elective cesarean deliver-

ies were overrepresented in this co-hort (16% vs 6% in the Netherlands).38

Mode of delivery, however, was not as-

sociated with RSV LRTI. Therefore, we

assume that the results are generaliz-

able to other modes of delivery. Third,

the possibility of misclassification at-

tributable to parental noncompliance

with recording of respiratory symp-

toms and collection of nose/throat

swabs cannot be completely ruled out.

However, associations between paren-tal compliance and any potential risk

factor seem unlikely. Fourth, because

missing values usually do not occur at

random, exclusion of participants with

missing values (complete case analy-

sis) might have resulted in biased es-

timates.39,40 Therefore, we used impu-

tation to address the missing values,

including missing values for the out-

come, which yielded results similar to

those of the presented complete caseanalysis. Fifth, for a number of vari-

ables, we used arbitrary cutoff values

and/or definitions, mostly in favor of a

simple prediction rule or as a result of

study design. Accessory analyses with

alternative cutoff values yielded a sim-

ilar prediction model. Similarly, use of

continuous variables (eg, for duration

of breastfeeding and number of ciga-

rettes smoked per day) did not change

FIGURE 3Proportions of children with wheezing during the first year of life, for children with and without RSV

LRTI in the first year of life. A, Proportion of children with wheezing in each calendar month. Fishers

exact test: November, P .001; December, P .01. Exclusion of the episodes that defined the RSV LRTI

group yielded similar results (November, P .01). B, Cumulative proportion of children with wheezing

in each month of life. Fishers exact test or 2test: all P .01, except for month 1 (not significant) and

month 5 (P .02). Exclusion of the episodes that defined the RSV LRTI group yielded similar results;

all P .01, except for month 1 (not significant), month 5 (P .05), month 6 (P .05), and month

7 (P .01).

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the final model. Therefore, we think

that our prediction rule is robust.

The clinical implications of our finding

include the use of the prediction rule

by primary care pediatricians, who

care for the majority of children at risk

of and/or with RSV LRTI.1 The incidence

of medically attended RSV infections

among children younger than 1 year is

extremely high (44%), and the inci-

dence is highest for the group 6 to 12

months of age (24%).1 Children classi-

fied as being at high risk could be mon-

itored more closely and lifestyle

changes that reduce exposure could

be applied.69 When novel preventive

treatment options become available,

these could be used for targeted high-

risk populations.4143 Finally, the model

may be used in randomized clinical tri-

als when future RSV vaccines become

available for healthy term infants.44

CONCLUSIONS

The risk of RSV LRTI was 10 times higher

for children who attended day care, had

older siblings, had high parental educa-tional levels, had birth weights of4 kg,

and were born between April and Sep-

tember, compared with childrenwithout

these factors. Clinicians can use these

features to differentiate between chil-

dren with high and low risks of RSV LRTI

and subsequently can target preventive

and monitoring strategies to children at

high risk.

ACKNOWLEDGMENTS

This study was funded by a fellowship

award from the European Society for

Paediatric Infectious Diseases (to Dr

Houben), the Wilhelmina Childrens

Hospital Research Fund (grant

2004.02), the Catharijne Stichting, and

the Dutch Asthma Foundation (grant

3.2.07.001). The funders had no role in

study design, data collection or analy-

sis, the decision to publish, or prepa-ration of the manuscript.

We acknowledge Eltje Bloemen, re-

search nurse, for her participation in

data collection; Jojanneke Dekkers,

laboratory technician, for technical as-

sistance with real-time PCR assays;

Projka Piravalieva-Nikolova, labora-

tory assistant, and Arthur Gottenkieny,

laboratory technician, for technical

support; and Hilda Kessel, gynecolo-

gist, and Wouter de Waal, pediatrician,

for their assistance with recruitment

of participants.

REFERENCES

1. Hall CB, Weinberg GA, Iwane MK, et al. The

burden of respiratory syncytial virus infec-

tion in young children. N Engl J Med. 2009;

360(6):588 598

2. Bourgeois FT, Valim C, McAdam AJ, Mandl KD.

Relative impact of influenza and respiratory

syncytial virus in young children. Pediatrics.

2009;124(6).Available at: www.pediatrics.org/cgi/content/full/124/6/e1072

3. Stein RT, Sherrill D, Morgan WJ, et al. Respi-

ratorysyncytial virus in earlylifeand risk of

wheeze and allergy by age 13 years. Lancet.

1999;354(9178):541545

4. Bont L, Steijn M, Van Aalderen WM, et al.

Seasonality of long term wheezing follow-

ing respiratory syncytial virus lower respi-

ratory tract infection. Thorax. 2004;59(6):

512516

5. Bont L, Steijn M, Van Aalderen WM, Kimpen

JL. Impact of wheezing after respiratory

syncytial virus infection on health-relatedquality of life. Pediatr Infect Dis J. 2004;

23(5):414417

6. Contreras PA, Sami IR, Darnell ME, Ottolini

MG, Prince GA. Inactivation of respiratory

syncytial virus by generic hand dishwash-

ing detergents and antibacterial hand

soaps. Infect Control Hosp Epidemiol. 1999;

20(1):5758

7. Forbes M. Strategies for preventing respi-

ratory syncytial virus. Am J Health Syst

Pharm. 2008;65(23 suppl 8):S13S19

8. Jafri HS. Treatment of respiratory syncytial

virus: antiviral therapies. Pediatr Infect Dis

J. 2003;22(2 suppl):S89 S92

9. van de Pol AC, Rossen JW, Wolfs TF, et al.

Transmission of respiratory syncytial vi-

rus at the paediatric intensive-care unit:

a prospective study using real-time PCR.

Clin Microbiol Infect. 2010;16(5):488 490

10. IMpact-RSV Study Group. Palivizumab, a hu-manized respiratory syncytial virus mono-

clonal antibody, reduces hospitalization

from respiratory syncytial virus infection in

high-risk infants. Pediatrics. 1998;102(3):

531537

11. Ramilo O. Evolution of prophylaxis: MoAb,

siRNA, vaccine, and small molecules. Paedi-

atr Respir Rev. 2009;10(suppl 1):2325

12. Bloemers BLP, van Furth AM, Weijerman ME,

et al.Downsyndrome: a novel risk factorfor

respiratory syncytial virus bronchiolitis: a

prospective birth-cohort study. Pediatrics.

2007;120(4). Available at: www.pediatrics.org/cgi/content/full/120/4/e1076

13. Simoes EA. Environmental and demo-

graphic risk factors for respiratory syncy-

tial virus lower respiratory tract disease. J

Pediatr. 2003;143(5 suppl):S118S126

14. Doering G, Gusenleitner W, Belohradsky BH,

Burdach S, Resch B, Liese JG. The risk of

respiratory syncytial virus-related hospital-

izations in preterm infants of 29 to 35

weeks gestational age. Pediatr Infect Dis J.

2006;25(12):11881190

15. Feltes TF, Cabalka AK, Meissner HC, et al.

Palivizumab prophylaxis reduces hospital-

ization due to respiratory syncytial virus in

young children with hemodynamically sig-

nificant congenital heart disease. J Pediatr.

2003;143(4):532540

16. Hall CB. Respiratory syncytial virus and

parainfluenza virus. N Engl J Med. 2001;

344(25):1917192817. Holberg CJ, Wright AL, Martinez FD, Ray CG,

Taussig LM, Lebowitz MD. Risk factors for

respiratory syncytial virus-associated

lower respiratory illnesses in the first year

of life. Am J Epidemiol. 1991;133(11):

11351151

18. Nachman SA, Navaie-Waliser M, Qureshi MZ.

Rehospitalization with respiratory syncytial

virus after neonatal intensive care unit

discharge: a 3-year follow-up. Pediatrics.

1997;100(6). Available at: www.pediatrics.

org/cgi/content/full/100/6/e8

19. Shay DK, Holman RC, Newman RD, Liu LL,

Stout JW, Anderson LJ. Bronchiolitis-

associated hospitalizations among US chil-

dren, 19801996. JAMA. 1999;282(15):

14401446

20. Stevens TP, Sinkin RA, Hall CB, Maniscalco

WM, McConnochie KM. Respiratory syncytial

virus and premature infants born at 32

weeks gestation or earlier: hospitalization

and economic implications of prophylaxis.

Arch Pediatr Adolesc Med. 2000;154(1):

5561

21. Simes EA, Carbonell-Estrany X, Fullarton

JR, et al. A predictive model for respiratory

http://www.pediatrics.org/cgi/content/full/124/6/e1072http://www.pediatrics.org/cgi/content/full/124/6/e1072http://www.pediatrics.org/cgi/content/full/120/4/e1076http://www.pediatrics.org/cgi/content/full/120/4/e1076http://www.pediatrics.org/cgi/content/full/100/6/e8http://www.pediatrics.org/cgi/content/full/100/6/e8http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/http://pediatrics.aappublications.org/http://www.pediatrics.org/cgi/content/full/100/6/e8http://www.pediatrics.org/cgi/content/full/100/6/e8http://www.pediatrics.org/cgi/content/full/120/4/e1076http://www.pediatrics.org/cgi/content/full/120/4/e1076http://www.pediatrics.org/cgi/content/full/124/6/e1072http://www.pediatrics.org/cgi/content/full/124/6/e1072


8/9

syncytial virus (RSV) hospitalisation of pre-

mature infants born at 3335 weeks of ges-

tational age, based on data from the Span-

ish FLIP study. Respir Res. 2008;9(1):78

22. Rietveld E, Vergouwe Y, Steyerberg EW,

Huysman MW, de Groot R, Moll HA. Hospital-

ization for respiratory syncytial virus infec-

tion in young children: development of aclinical prediction rule. Pediatr Infect Dis J.

2006;25(3):201207

23. Law BJ, Langley JM, Allen U, et al. The Pedi-

atric Investigators Collaborative Network

on Infections in Canada study of predictors

of hospitalization for respiratory syncytial

virus infection for infants born at 33

through 35 completed weeks of gestation.

Pediatr Infect Dis J. 2004;23(9):806 814

24. Landon MB, Spong CY, Thom E, et al. A mul-

ticenter, randomized trial of treatment for

mild gestational diabetes. N Engl J Med.

2009;361(14):1339 134825. Ochola R, Sande C, Fegan G, et al. The level and

duration of RSV-specific maternal IgG in infants

in Kilifi, Kenya.PLoS One. 2009;4(12):e8088

26. Ermers MJ, Rovers MM, van Woensel JB,

Kimpen JL, Bont LJ. The effect of high dose

inhaled corticosteroids on wheeze in in-

fants after respiratory syncytial virus

infection: randomised double blind placebo

controlled trial. BMJ. 2009;338:b897

27. van der Zalm MM, van Ewijk BE, Wilbrink B,

Uiterwaal CS, Wolfs TF, van der Ent CK. Re-

spiratory pathogens in children with and

without respiratory symptoms. J Pediatr.2009;154(3):396 400

28. Brunekreef B, Groot B, Rijcken B, Hoek G,

Steenbekkers A, de Boer A. Reproducibility

of childhood respiratory symptom ques-

tions. Eur Respir J. 1992;5(8):930935

29. Fekkes M, Theunissen NC, Brugman E, et al.

Development and psychometric evaluation

of theTAPQOL: a health-related quality of life

instrument for 15-year-old children. Qual

Life Res. 2000;9(8):961972

30. TheunissenNC, VeenS, FekkesM, etal. Qualityoflifein preschoolchildren bornpreterm.DevMed

Child Neurol. 2001;43(7):460 465

31. Royston P, Moons KG, Altman DG, Vergouwe

Y. Prognosis and prognostic research: de-

velopinga prognostic model. BMJ. 2009;338:

b604

32. Altman DG, Vergouwe Y, Royston P, Moons

KG. Prognosis and prognostic research: val-

idating a prognostic model. BMJ. 2009;338:

b605

33. Harrell FE Jr, Lee KL, Mark DB. Multivariable

prognostic models: issues in developing

models, evaluating assumptions and ade-

quacy, and measuring and reducing errors.

Stat Med. 1996;15(4):361387

34. AtgboJM, GrissaO, Yessoufou A, et al.Mod-

ulation of adipokines and cytokines in ges-

tational diabetes and macrosomia. J Clin

Endocrinol Metab. 2006;91(10):41374143

35. Moore TR. A comparison of amniotic fluid

fetal pulmonary phospholipids in normal

and diabetic pregnancy. Am J Obstet Gy-

necol. 2002;186(4):641 650

36. Saunders NR, Tennis O, Jacobson S, Gans M,

Dick PT. Parents responses to symptoms of

respiratory tract infection in their children.

CMAJ. 2003;168(1):2530

37. de Jong BM, van der Ent CK, van der Zalm

MM, et al. Respiratory symptoms in young

infancy: child, parent and physician related

determinants of drug prescription in pri-

mary care. Pharmacoepidemiol Drug Saf.

2009;18(7):610 618

38. Zwart JJ, Richters JM, Ory F, de Vries JI,

Bloemenkamp KW, van Roosmalen J. Severe

maternal morbidity during pregnancy, de-

livery and puerperium in the Netherlands: a

nationwide population-based study of371,000 pregnancies. BJOG. 2008;115(7):

842 850

39. Sterne JA, White IR, Carlin JB, et al. Multiple

imputation for missing data in epidemiolog-

ical and clinical research: potential and pit-

falls. BMJ. 2009;338:b2393

40. Greenland S, Finkle WD. A critical look at

methods for handling missing covariates in

epidemiologic regression analyses. Am J

Epidemiol. 1995;142(12):12551264

41. Olszewska W, Openshaw P. Emerging drugs

for respiratory syncytial virus infection. Ex-

pert Opin Emerg Drugs. 2009;14(2):207217

42. DeVincenzo J, Cehelsky JE, Alvarez R, et al.

Evaluation of the safety, tolerability and

pharmacokinetics of ALN-RSV01, a novel

RNAi antiviral therapeutic directed against

respiratory syncytial virus (RSV). Antiviral

Res. 2008;77(3):225231

43. DeVincenzo J, Lambkin-Williams R, Wilkin-

son T, et al. A randomized, double-blind,

placebo-controlled study of an RNAi-based

therapy directed against respiratory syncy-

tial virus. Proc Natl Acad Sci U S A. 2010;

107(19):8800 8805

44. Empey KM, Peebles RS Jr, Kolls JK. Pharma-

cologic advances in the treatment and pre-

vention of respiratory syncytial virus. Clin

Infect Dis. 2010;50(9):12581267

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DOI: 10.1542/peds.2010-0581; originally published online December 27, 2010;2011;127;35Pediatrics

Kimpen, Gerard H. A. Visser and Maroeska M. RoversMichiel L. Houben, Louis Bont, Berry Wilbrink, Mirjam E. Belderbos, Jan L. L.

Birth Cohort StudyClinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns: Prognostic

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