Bedside Diagnosis of Influenzavirus Infections in Hospitalized Children.pdf

2002;110;83PediatricsHolland, Haijing Li and Kathryn M. Edwards

Katherine A. Poehling, Marie R. Griffin, Robert S. Dittus, Yi-Wei Tang, KathyBedside Diagnosis of Influenzavirus Infections in Hospitalized Children

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Bedside Diagnosis of Influenzavirus Infections in Hospitalized Children

Katherine A. Poehling, MD, MPH*; Marie R. Griffin, MD, MPH; Robert S. Dittus, MD, MPH;Yi-Wei Tang MD, PhD; Kathy Holland, BS*; Haijing Li, BSc; and Kathryn M. Edwards, MD*

ABSTRACT. Objective. For preventing nosocomialinfluenza infections and to facilitate prompt antiviraltherapy, an accessible, rapid diagnostic method for influ-enzavirus is needed. We evaluated the performance of alateral-flow immunoassay (QuickVue Influenza Test)completed at the bedside of hospitalized children duringthe influenza season.

Methods. All children who were evaluated at a largeteaching hospital during the 1999 to 2000 influenza sea-son were eligible if they were 1) younger than 19 yearsand hospitalized with respiratory symptoms or 2)younger than 3 years and hospitalized with fever. Eachstudy child had 2 nasal swabs obtained1 for influen-zavirus culture and polymerase chain reaction (PCR) andthe other for the QuickVue Influenza Test. The perfor-mance of the rapid diagnostic test was compared with theresults of culture or PCR for influenza A or B.

Results. Of 303 eligible children, 233 (77%) were en-rolled. In this population, 19 children had culture- and/orPCR-confirmed influenza A infection, prevalence of 8%.The QuickVue Influenza Test had a sensitivity of 74%,specificity of 98%, positive predictive value of 74%, andnegative predictive value of 98%.

Conclusions. Among children hospitalized with fe-ver/respiratory symptoms during the influenza season,negative bedside QuickVue Influenza Tests indicatedvery low likelihood of influenza infection, whereas pos-itive tests greatly increased the probability of influenza-associated illness. Pediatrics 2002;110:8388; influenzavi-rus, diagnosis, rapid test, polymerase chain reaction,children.

ABBREVIATIONS. RSV, respiratory syncytial virus; PCR, poly-merase chain reaction.

Influenzavirus has a significant impact on the pe-diatric population, with school-aged childrenhaving the highest infection rates.1,2 Retrospec-tive cohort studies in healthy children younger than15 years indicate that annual influenza-attributablerates of hospitalizations are 4 to 104 per 10 000 chil-dren, outpatient visits are 6 to 15 per 100 children,

and antibiotic prescriptions are 3 to 9 per 100 chil-dren.3,4 Although the youngest children experiencethe majority of influenza-related hospitalizations, allage groups have excess outpatient visits.3 In addi-tion, children with high-risk conditions have higherrates of hospitalization,5 outpatient visits, and anti-biotics prescriptions than age-matched childrenwithout high-risk conditions.6,7 Thus, influenza in-fections increase health care utilization for all pedi-atric age groups.

Influenzavirus often circulates concurrently withrespiratory syncytial virus (RSV), the most commoncause of respiratory illnesses in young children.814Although distinct clinical syndromes are attributedto influenzavirus and RSV, there can be considerableoverlap in their manifestations. Before admittingyoung children during winter months, most pediat-ric hospitals routinely use rapid diagnostic testingfor RSV to facilitate policies that minimize nosoco-mial infections.15 In contrast, many pediatric hospi-tals do not routinely perform rapid diagnostic testsfor influenzavirus. Rapid influenza tests not onlywould help to minimize nosocomial influenzavirusinfections during the winter16 but also would pro-vide physicians the opportunity to use targeted an-tiviral therapy, which is reported to be effective ifinitiated within 48 hours of the onset of symp-toms.1723

The purpose of this prospective study was to com-pare the performance of a rapid diagnostic test(QuickVue Influenza Test; Quidel Corp, San Diego,CA) completed at the bedside of hospitalized chil-dren to viral culture and/or polymerase chain reac-tion (PCR) for influenzavirus.

METHODS

Study PopulationAll children who were admitted to Vanderbilt Childrens Hos-

pital between January 10 and February 15, 2000, were eligible ifthey were 1) younger than 19 years and hospitalized with respi-ratory symptoms or 2) younger than 3 years and hospitalized withfever. Eligible children had 1) a primary admission diagnosis of anacute respiratory illness characterized by rhinorrhea, sore throat,cough, shortness of breath, or apnea or 2) a primary admissiondiagnosis consistent with a febrile illness and a temperature of100.4F. Broad inclusion criteria were chosen such that all chil-dren who were hospitalized with symptoms potentially related toinfluenza infections were eligible.

Each calendar day, potential subjects were identified by a re-view of all admission logs to pediatric inpatient services. A re-search team member approached eligible children and their par-ents for consent within 24 hours of admission. Discharge logs werereviewed to verify that all eligible patients had been identified.This study was reviewed and approved by the Vanderbilt Uni-versity Institutional Review Board.

From the Departments of *Pediatrics, Medicine, Preventive Medicine, andPathology, Vanderbilt University Medical Center, Nashville, Tennessee;and Quality Scholars Program, Veterans Affairs Tennessee Valley Health-care System, Nashville, Tennessee.This work was presented at the Options for the Control of Influenza, Crete,Greece, September 2000 and at the Pediatric Academies Societies meeting,Baltimore, MD, April 29, 2001.Received for publication Nov 2, 2001; accepted Feb 20, 2002.Reprint requests to (K.A.P.) Vanderbilt Childrens Hospital, Division ofGeneral Pediatrics, D-5028 Medical Center East, Nashville, TN 37232-8555.E-mail: [email protected] (ISSN 0031 4005). Copyright 2002 by the American Acad-emy of Pediatrics.

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Study Design

OverviewThis prospective, cross-sectional study enrolled children who

were hospitalized with fever or respiratory illnesses as discussedabove. The childs medical history was obtained by a standardizedquestionnaire administered to the parent/guardian. From eachchild, 2 nasal swabs of the turbinates were obtained1 for influ-enzavirus culture and PCR and the other for the rapid diagnostictest. The rapid test results were compared with that of culture andPCR for influenzavirus.

Study PeriodThe local influenza season, which was defined as the weeks that

influenzavirus was identified in at least 2 viral cultures at Vander-bilt University Hospitals virology laboratory or the VanderbiltVaccine Evaluation Clinics research laboratory, spanned fromDecember 5, 1999, to March 5, 2000. The study began on January10, after the rapid diagnostic kits became available, and ended onFebruary 15, after the peak influenza season.

QuestionnaireA questionnaire was developed by a group of experts, pre-

tested, and modified for item clarification. The questionnaire,which was administered to parents, obtained information regard-ing the childs medical history, including symptoms associatedwith the acute illness precipitating this hospitalization. Symptomsincluded fever, cough, rhinorrhea, dyspnea, and other. Number ofsymptom days was coded as 3 or fewer days or more than 3 daysbecause positive cultures in children who are infected with influ-enzavirus are most likely during the first 3 symptom days.24

Parents were queried to determine which children had high-risk conditions for which influenza immunization was explicitlyrecommended in the 2000 Red Book. They included 1) asthma orother chronic pulmonary diseases, 2) hemodynamically significantcardiac disease, 3) immunosuppressive disorder or therapy, 4)human immunodeficiency virus infection, 5) sickle cell anemiaand other hemoglobinopathies, 6) diseases requiring long-termaspirin therapy, 7) chronic renal dysfunction, and 8) chronic met-abolic disease.23 Children with 1 or more high-risk conditionswere coded as high risk, and all others were coded as low risk.

Influenzavirus Determination

Criterion StandardInfluenza infection was defined as any sample with 1) a posi-

tive culture for influenzavirus or 2) 2 consecutive positive PCRsfor influenza A or B.

CultureOne nasal specimen was collected on a Dacron applicator,

transported in refrigerated Hanks balanced salt solution withantibiotics and 0.5% gelatin, and cultured on 2 test tubes of rhesusmonkey kidney cells. Cells were observed for cytopathic effect andtested for hemadsorption with 0.1% guinea pig red blood cells 5and 10 days after inoculation. Hemadsorbing agents were testedby indirect fluorescent antibody to differentiate between influen-

zavirus and parainfluenza virus and by hemagglutination inhibi-tion assay to determine influenzavirus serotype.

PCRThe remaining nasal specimen from the Dacron applicator was

stored in a 70C freezer until PCR. Nucleic acids from 100 L offrozen nasal washes were extracted with RNAzol B (Leedo Labo-ratories, Inc, Houston, TX) according to the manufacturers in-structions. Colorimetric microtiter plate reverse transcriptasePCR systems were performed for influenza A and B viral RNAdetection as described previously.25 Each PCR assay was per-formed on freshly extracted RNA. A degenerate primer set(FluA01: 5-CTT CTR ACC GAR GTC GAA ACG-3 (RA and G)and FluA02: 5-GAC AAA GCG TCT ACG CTG CAG-3) and a5-biotinylated capture probe (5-TCC TGT CAC CTC TGA CTAAGG G-3) were designed to target influenza A virus matrix geneand to create a 234-base pair product.26 The primers and probesfor influenza B virus hemagglutinin gene were described previ-ously.27 The test sensitivity is approximately 0.01 plaque-formingunits per milliliter for both of these PCR assays, which weredeveloped and validated at Vanderbilt University Medical Centerunder the 1988 Clinical Laboratory Improvement Amendmentsregulation.

Rapid Diagnostic TestA second nasal specimen was collected on the QuickVue Influ-

enza Test applicator and then mixed with a prepackaged extrac-tion solution in a test tube. Next, the test strip was inserted intothis test tube and read 10 minutes later. Each researcher wastrained to perform and interpret the rapid diagnostic test at thebedside according to the manufacturers instructions. A blue lineindicated a valid test. A red line of equal or less intensity than theblue line but visible in dim light was interpreted as positive. Theabsence of a red line or the presence of a faint red line only visiblewith bright light was interpreted as negative. The laboratorytechnician who performed the culture and PCR was masked to therapid diagnostic test results.

Statistical AnalysisThe primary outcome, the performance of the QuickVue Influ-

enza Test, was calculated by comparing its results with those ofthe criterion standard. The secondary outcome was the perfor-mance of the rapid test in a subset of children hypothesized tohave high titers of influenzavirus in the nose: 1) children in theirfirst influenza season or 2) those with symptoms for 4 days.Demographic characteristics were compared using Fishers exacttest or 2 analysis. Gender and race (white, nonwhite) were di-chotomous variables. Age was classified as younger than 6months, 6 months to younger than 5 years, and 5 years to 18 years.Stata, Version 6.0 (Stata, College Station, TX) was used for allanalyses.

RESULTSOf 625 children hospitalized during the study pe-

riod, 303 (48%) had qualifying admission criteria ofrespiratory symptoms and/or fever (Fig 1). Of 303qualifying children, 233 (77%) were enrolled and hadboth nasal samples obtained. Reasons that childrenwere not enrolled in the study were 1) failure toidentify a child within 24 hours of admission (8%), 2)child or parent declined to participate (8%), and 3)unable to contact a parent (5%). Six children (2%) inwhom responses to the questionnaire were obtainedbut permission to obtain nasal specimens was deniedwere enrolled. All 6 of these children had had a rapiddiagnostic test for influenzavirus performed by thehospital laboratory before enrollment; none of thesechildren was included in the analysis. Study childrenwere more frequently male and were predominantlywhite, and 43% were between the ages of 6 monthsand 5 years (Table 1). Of the study population, 124(53%) had high-risk conditions; the most common

Fig 1. Identification of study population.

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were asthma (32%), congenital heart disease (11%),malignancy (3%), and cystic fibrosis (2%).

Of 233 enrolled children, 222 (95%) had respiratorysymptoms, 163 (73%) of which also had fever. Theiradmission diagnoses included apnea, asthma exacer-bation, bronchiolitis, cystic fibrosis exacerbation,croup, pharyngitis with dehydration, pneumonia,and respiratory distress or failure. Cough waspresent in most (91%) of these children, dyspnea orapnea in 198 (89%), and rhinorrhea in 172 (72%).

Of 11 children enrolled with fever alone, 9 (82%)were younger than 1 month. Temperatures in theseneonates ranged from 100.6F to 103.8F with anaverage of 101.8F. Eight neonates (89%) were admit-ted with the diagnosis of febrile neonate withoutlocalizing signs and 1 with a perirectal abscess. The 2other children with fever and without respiratorysymptoms were hospitalized with the diagnoses ofsepsis and fever status-post surgical procedure, re-spectively.

Nineteen study children (8%) had influenza infec-tions as determined by positive culture or 2 consec-utive positive PCRs for influenzavirus from 1 nasalspecimen (Table 2). Eleven (58%) had positive cul-tures, all influenza A (H3N2), and 18 (95%) had 2positive PCRs. Influenza B was not detected in anyparticipant by culture or PCR. One child had a pos-itive influenza culture and negative PCR. Of childreninfected with influenza A, 14 (74%) had positiverapid diagnostic tests. Of the 19 children with influ-enza infections, only 2 (11%) were diagnosed by arapid diagnostic test performed by the hospital lab-oratory in the outpatient or inpatient setting beforeenrollment. The seasonal occurrence of eligible chil-dren and the number of positive tests for influenza-virus followed similar epidemic curves, although lo-cal virology surveillance data for the 1999 to 2000season indicates that influenzavirus and RSV hadsimilar peaks and epidemic curves. Admission diag-noses for these 19 children were febrile neonate (5),bronchiolitis (2), croup (1), apnea (1), pneumonia (1),asthma exacerbation (2), fever and neutropenia (2),seizures and febrile illness (2), fever status-post sur-gical procedure (1), fever and sickle cell anemia (1),and fever of unknown origin (1).

The QuickVue Influenza Test had a sensitivity of74% and a specificity of 98%. The positive and neg-ative predictive values were 74% and 98%, respec-tively (Table 3). The positive and negative likelihoodratios, measures of the discriminatory power, were31.5 and 0.26, respectively.

We tested the hypothesis that the QuickVue Influ-enza Test would be more sensitive among children

with the highest viral titers: those experiencing theirfirst influenza season and those with a short durationof symptoms, defined as 4 days. The sensitivity ofthe rapid diagnostic test was 100% for both sub-groups, and the specificity was 98% and 97%, respec-tively (Table 3).

DISCUSSIONIn this prospective study, influenza A infections

were identified in 8% of children who were 1)younger than 19 years and hospitalized with respi-ratory symptoms or 2) younger than 3 years andhospitalized with fever. Influenza infections wereidentified by positive culture and/or 2 consecutivePCRs for influenza A or B. In this study, the Quick-Vue Influenza Test had a sensitivity and specificityof 74% and 98%, respectively. Subgroup analysis ofchildren who likely had the highest viral loads indi-cated that the sensitivity of the rapid diagnostic testincreased to 100% in children who were youngerthan 6 months of age and those with symptoms for4 days.

We used a combination of a specific test (culture)and a sensitive test (PCR) as our criterion standard.To minimize false-positive results, we required apositive result on 2 consecutive PCR assays to definea sample as PCR positive. To our knowledge, noother rapid diagnostic test for influenzavirus hasused this methodology.2831 PCR was included in theinfluenza infection definition because PCR is moresensitive than culture for influenzavirus, with anoverall reported increase in the detection rate of in-fluenzavirus by 3% to 40%.23,27,29,3238 In this study,all influenza infections were influenza A, and PCRincreased the detection of influenzavirus by 60%,from 5% detected by culture alone to 8% by cultureor PCR.

Results of this study need to be interpreted withseveral caveats. First, only influenza A was identifiedin the study samples. Because we did not detectinfluenza B in our study population, the rapid testcharacteristics for influenza B infections could not beassessed. Second, the study was conducted in thehospital setting. Rapid diagnostic tests need evalua-tion in the ambulatory setting where the viral titersor time between onset of illness and presentation toa health care provider might differ from patients inthis study. Third, we trained researchers to performthis test according to the manufacturers instructions.

TABLE 1. Characteristics of Enrolled Children

Characteristics Influenza (N 19; %)

Influenza (N 214; %)

PValue

Male gender 11 (58%) 89 (42%) .23White race 14 (74%) 155 (72%) 1.0Age (y)0.5 5 (26%) 76 (35.5%)0.55 9 (47%) 91 (42.5%)518 5 (26%) 47 (22%) .61

High-risk condition 8 (42%) 116 (54%) .35

TABLE 2. Results From Viral Culture, QuickVue InfluenzaTest (Rapid), and 2 Consecutive PCRs

Culture Rapid PCR InfluenzaInfection*

Total

8 2 1 6 5 2 20911 19 18 19 233

* Defined as either a positive viral culture or 2 consecutive positivePCRs.

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Modifying the methods by which the sample wascollected or tested may alter the performance of thisrapid diagnostic test. Fourth, using acute and conva-lescent sera as the criterion standard could poten-tially identify other children with influenzavirus in-fection. However, sera were not obtained in ourstudy because some parents would not have con-sented to phlebotomy and would not have returnedfor the convalescent sample. Finally, the power todetect potentially significant characteristics associ-ated with influenza infection was limited by the factthat only 19 children had influenza infections.

The QuickVue Influenza Test can be used to diag-nose influenza infections at the bedside of childrenwith a compatible clinical syndrome during the in-fluenza season. A negative test made the diagnosis ofinfluenza infection unlikely. A positive test shouldbe interpreted as probable influenza infection only ifinfluenzavirus is circulating in the community. Dur-ing periods in which 10% to 15% of children who arehospitalized with respiratory symptoms have influ-enzavirus, 78% to 85% of children with positiverapid diagnostic tests would be expected to haveinfluenza infection. Hence, during the influenza sea-son, a positive result could assist clinicians in iden-tifying the need for respiratory isolation for influen-zavirus and possibly deciding whether to initiate

antiviral agents directed against influenzavirus. Cau-tion is warranted in interpreting positive tests duringperiods with little or no influenzavirus circulating inthe community because false-positive results wouldpredominate.

In our study population, a positive rapid diagnos-tic test for influenzavirus changed the isolation sta-tus of some children but did not change the likeli-hood of receiving antibiotic therapy. Similarly,another study reported that children who were hos-pitalized with a positive rapid diagnostic test ob-tained in the emergency department were as likely toreceive antibiotics as those with a negative rapiddiagnostic test.39 The lack of association of a positivetest and likelihood of receiving antibiotic therapy inour study may reflect either the perceived need toinitiate antibiotics in hospitalized children with feveror respiratory symptoms or that the decision to ini-tiate antibiotics was frequently made concurrentlywith the decision to admit, which was before studyenrollment. Of 7 enrolled children with a positiverapid test for influenzavirus within 48 hours of theonset of symptoms, none received antiviral therapyfor influenzavirus. Two children had a positive testwithin 24 hours (both younger than 1 month), and 5children had a positive test between 24 and 48 hours,

TABLE 4. Comparison of Rapid Influenza Tests Currently Available

FLU OIA QuickVueInfluenza

ZstatFLU Directagen FLU AB Directagen FLU A

Test technology Opticalimmunoassay

Lateral-flowimmunoassay

Viral-encodedenzyme assay

Enzyme immunoassay Enzyme immunoassay

Detects influenza A Yes Yes Yes Yes YesDetects influenza B Yes Yes Yes Yes NoDifferentiates

influenza ABNo No No Yes No

Specimen types Nasal aspirate,NPS, throatswab,sputum

Nasal aspirate,nasal wash,nasal swab

Throat swab Nasal aspirate, nasalwash, NPS/nasalswab, throat swab,BAL

Nasal aspirate, nasalwash, NPS, throatswab

Sensitivity* 83% 73% 62% 86% 88%Specificity* 76% 96% 99% 89% 97%Positive predictive

value*59% 92% 98% 73% 95%

Negative predictivevalue*

82% 85% 75% 95% 91%

Test time 15 min 10 min 20 min 15 min 15 minCLIA88 waiver No Yes Yes No No

NPS indicates nesopharyngeal swab; BAL, bronchoalveolar lavage; CLIA88, Clinical Laboratory Improvement Amendments of 1988.* Test characteristics as compared with cell culture results. NPS. Throat swab. Nasopharyngeal wash and/or NPS.

TABLE 3. QuickVue Influenza Test Characteristics of Study Population, Children Younger Than 6 Months, and Children WithSymptoms for 4 Days

N (%) Influenza*(N [%])

Sensitivity(%)

Specificity(%)

PPV(%)

NPV(%)

Study population 233 (100%) 19 (100%) 74% 98% 74% 98%Children 6 mo 81 (35%) 5 (26%) 100% 97% 71% 100%Children 6 mo 152 (65%) 14 (74%) 64% 98% 75% 96%Children with symptoms for 4 d 96 (41%) 8 (42%) 100% 97% 73% 100%Children with symptoms for 4 d 137 (59%) 11 (58%) 55% 98% 75% 96%

PPV indicates positive predictive value; NPV, negative predictive value.* Influenza infection as defined as positive culture or 2 consecutive PCRs.


2 of which only were older than 1 year (1.9 and 2.2years, respectively).

Currently, 5 rapid diagnostic tests for influenzavi-rus are available for clinical use (Table 4). FLU OIA(Thermo BioStar, Inc, Boulder, CO), QuickVue Influ-enza, and ZstatFLU (ZymeTX, Inc, Oklahoma City,OK) identify influenza A or B but do not distinguishbetween them. Only Directagen FLU AB (Directa-gen BD Diagnostic Systems, Sparks, MD) identifiesand differentiates influenza A and B. Directagen FLUA identifies influenza A only. Table 4 outlines theperformance of these tests according to the productspackage inserts4043 or the article from which thedata used in the packet insert is described.30

Additional studies are needed to confirm thesefindings, to evaluate the performance of the rapiddiagnostic test with influenza B infections, to deter-mine the results in other clinical settings, and toidentify patients with a higher likelihood of influ-enza infection in whom the test results, if positive,would be considered confirmatory. In addition, thistest should be compared with the other availablerapid diagnostic tests for influenzavirus. Ideally, allof the rapid diagnostic tests should be tested usingthe same methodology for obtaining specimens andcriterion standard for determining an influenza in-fection.

Potentially, the most important aspect of this rapidtest is that it can provide timely, accurate, and usefulinformation at the bedside. The information can beprovided in real time when the diagnostic, isolation,and therapeutic questions need to be addressed,not hours later. Because the QuickVue InfluenzaTest received a Clinical Laboratory ImprovementAmendments Waiver, the rapid diagnostic test canbe performed in clinical settings with a Certificate ofWaiver from the Centers for Medicare and MedicaidServices.44 In this study, only 2 (11%) of 19 childrenwith influenza infections were diagnosed before en-rollment. Routine use of rapid diagnostic testing forinfluenzavirus during the influenza season wouldhave increased the number of children diagnosedwith influenzavirus and changed the isolation statusof some children. Our data suggest that the Quick-Vue Influenza Test may be useful for children whoare hospitalized with febrile or respiratory illnessesduring the influenza season.

ACKNOWLEDGMENTSFunding was provided by the Quidel Corporation, a coopera-

tive agreement (#U50/CCU41398) from the Centers for DiseaseControl and Prevention, the Veterans Affairs Tennessee ValleyHealthcare System Quality Scholars Program, and an unrestrictededucational grant from the Pfizer Foundation. The Quidel Corpo-ration provided all of the QuickVue Influenza Test kits and gavean unrestricted gift, which covered the cost of half of the PCRs.

We thank Gay Waddling, RN; Ayesha Khan, MPH; Brent Fris-bee, BS; and Brian Emerson, BS, for their contributions to the datacollection and Lisa Rush for data entry.

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DRUG COMPANIES ARE DISEASE MONGERS

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2002;110;83PediatricsHolland, Haijing Li and Kathryn M. Edwards

Katherine A. Poehling, Marie R. Griffin, Robert S. Dittus, Yi-Wei Tang, KathyBedside Diagnosis of Influenzavirus Infections in Hospitalized Children

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