Research ArticleSystematic Review

A Systematic Review of Clinical Decision Rules for the Diagnosis of Influenza

Mark H. Ebell and Anna Afonso
The Annals of Family Medicine January 2011, 9 (1) 69-77; DOI: https://doi.org/10.1370/afm.1192

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Figures

Tables

  • Table 1.

    Results From a Previous Systematic Review of the History and Physical Examination for the Diagnosis of Influenza

    Likelihood Ratio for Influenza
    Clinical FindingPositiveNegative
    Note: Data from Ebell et al.2
    Rigors7.20.9
    Sweating2.90.6
    Being confined to bed2.50.5
    Inability to cope with daily activities2.30.4
    Fever (subjective)1.70.5
    Absence of systemic symptoms1.50.4
    Headache1.30.6
    Cough1.30.4
    Myalgia1.30.6
    Nasal congestion1.20.7
    Chills1.10.7
    Sore throat1.10.9
    Sputum1.10.9
  • Table 2.

    Characteristics of Included Studies

    Study and YearPopulation and Season(s)NInfluenza Prevalence, %CountryReference StandardComment
    DIF=direct immunofluorescence; ED = emergency department; ELISA = enzyme-linked immunosorbent assay; ILI = influenza-like illness; NPV = negative predictive value; PCR = polymerase chain reaction; RSV = respiratory syncytial virus; RTI = respiratory tract infection.
    Govaert et al,13 1998Average-risk, unvaccinated primary care patients older than 60 y with ILI during 1991–1992 flu season1,838 (logistic regression); 1,791 (heuristics)6.6NetherlandsIncrease in antibody titerAny symptoms reported during study period were included; part of randomized trial of vaccination.
    Carrat et al,23 1999Primary care patients older than 1 y with ILI, RTI syndrome, and/or fever >38°C without signs of other infections during 1995–1996 flu season60026FranceDIF and ELISA; if disagreement, further testing with PCR and cultureSeparate models created for H1N1 and H3N2 subtypes, and for all influenza.
    Monto et al,11 2000Adolescent or older with fever and ≥2 other symptoms (headache, myalgia, cough, or sore throat) during fall or winter of 1994–19983,74466North America, Europe, southern hemisphereCulture or increase in antibody titer (in some studies PCR or immunofluorescence)High prevalence of influenza. Data from 6 randomized trials of zanamivir vs placebo.
    Boivin et al,12 2000Patients with ILI (fever ≥37.8°C and ≥2 other symptoms) seeking care at an outpatient clinic during 1998–1999 flu season10079CanadaPCR and culture–
    van Elden et al,10 2001Primary care patients with fever (≥38°C), ≥1 constitutional symptom (malaise, headache, myalgia, chills), and ≥1 respiratory symptom (coryza, sneeze, cough, sore throat, hoarseness) seeking care within 48 hr of onset during 1997–1998 flu season8151NetherlandsPCR and cultureOnly PCR results were used for model development.
    Zambon et al,19 2001Persons aged 12 y or older seen within 48 hr of onset of ILI as part of a multicenter international clinical trial of an influenza drug1,03377 (any test positive);
 67 (all 3 tests positive)Europe, North AmericaPCR, culture, or increase in antibody titerReference standard was abnormal finding on all 3 tests.
    Walsh et al,21 2002Inpatients older than age 65 y or with underlying cardiopulmonary conditions with a respiratory diagnosis during 1999–2000 flu season33218United StatesCulture, rapid antigen test, increase in antibody titer, or PCRA model with 2 variables (temperature >38°C and absence of dyspnea) reportedly did not discriminate well; results not reported by authors.
    Friedman and Attia,20 2004Children (0–17 y) seen in the ED with suspected ILI (fever and coryza, cough, headache, sore throat, or muscle aches) during 2002 flu season12835United StatesCulture–
    Senn et al,7 2005Persons with ILI seeking care at an outpatient clinic during 1999–2000 flu season20152SwitzerlandCultureCutoff for logistic model presumably probability of influenza >50%.
    Stein et al,8 2005Consecutive adults with RTI in past 3 wk with cough, sinus pain, congestion/ rhinorrhea, sore throat, or fever seen in the ED during 2002 flu season25821United StatesPCRValidated previously developed fever and cough rule.11
    Ohmit and Monto,24 2006Study 1 (zanamivir): children aged 5–12 y with fever and duration of illness <36 hr during flu season
 Study 2 (oseltamivir): children aged 1–12 y with fever and cough or nasal symptoms, and duration <48 hr during flu seasonStudy 1: 468
 Study 2 (1–4 y): 255
 Study 2 (5–12 y): 221Study 1: 74
 Study 2: 67United StatesCulture and/or 4-fold increase in antibody titer (or PCR in zanamivir trial only)Validated previously developed fever and cough rule.11 RSV infection excluded. Unable to calculate sensitivity, specificity, NPV from data for fever and cough rule.
    van den Dool et al,22 2008Adult inpatients in the general medicine, pulmonology, and infectious disease wards of a tertiary care hospital during 2006–2007 flu season2648.7NetherlandsPCRIncluded all patients regardless of symptoms; validated previously developed fever and cough rule.11
  • Table 3.

    Quality Assessment of Included Studies Based on the QUADAS Tool for Studies of Diagnostic Accuracy27

    CriterionGovaert et al,13 1998Carrat et al,23 1999Monto et al,11 2000Boivin et al12, 2000van Elden, et al,10 2001Zambon et al,19 2001Walsh et al, 21 2002Friedman and Attia,20 2004Senn et al,7 2005Stein et al,8 2005Ohmit and Monto,24 2006van den Dool et al,22 2008
    N=no; NA=not applicable; QUADAS=Quality Assessment of Diagnostic Accuracy; U=unknown; Y=yes.
    a Participants were classified as being representative of patients who will receive the test in practice if they were undifferentiated outpatients with symptoms of respiratory tract infection. Participants were classified as not being representative if they were a subset of inpatients.
    b No temperature cutoff was given for definition of fever.
    c Although not explicitly stated, it is unlikely that diagnostic laboratories verifying the presence of influenza had access to the clinical data of each patient.
    1. Was the spectrum of participants representative of the patients who will receive the test in practice?
    YaY aYaYaY aYaNaYaY aYaYaNa
    2. Were selection criteria clearly described?
    YYYYYYYYYYUY
    3. Was the reference standard likely to classify the target condition correctly?
    YYYYYYYYYYYY
    4. Was the period between performance of the reference standard and the index test short enough to be reasonably sure that the target condition did not change between the 2 tests?
    YYYYYYYYYYYY
    5. Did the whole sample or a random selection of the sample receive verification using the reference standard?
    YYYYYYYYYYYY
    6. Did participants receive the same reference standard regardless of the index test result?
    YYYYYYYYYYYY
    7. Was the reference standard independent of the index test?
    YYYYYYYYYYYY
    8. Was the execution of the index test described in sufficient detail to permit its replication?
    YbYYYYYYYYYYY
    9. Were the index test results interpreted without knowledge of the results of the reference test?
    YYYYYYYYYYYY
    10. Were the reference standard results interpreted without knowledge of the results of the index test?
    UcUcUcUcUcUcUcUcUcUcUcUc
    11. Were the same clinical data available when the test results were interpreted as would be available when the test is used in practice?
    UUUUUUUUUUUU
    12. Were uninterpretable, indeterminate, or intermediate test results reported?
    UYYYYYYUYYUY
    13. Were withdrawals from the study explained?
    NANANANANANANANANANANANA
  • Table 4.

    Multivariate Models, Point Scores, and Symptom Combinations Reported by Included Studies

    StudyModelAccuracy
    AUC = area under the receiver operating characteristic curve; CI = confidence interval; LR+ = positive likelihood ratio, LR− = negative likelihood ratio; NPV = negative predictive value; OR = odds ratio; PPV = positive predictive value.
    Govaert et al,13 1998Variable: ORNot reported
        Cough: 5.25
        Fever: 2.18
        Vaccinated: 0.56
        Constant: 0.041
    Govaert et al,13 1998Symptom count (fever, cough, acute onset, malaise, rigors or chills, myalgia, headache, sore throat)Not reported other than data shown
    Score (n): % influenza
        0 (1,155): 3.2
        1–2 (145): 6.2
        ≤3 (491): 15
    Carrat et al,23 1999Variable: ORGoodness of fit: P=.98
    All influenza
        Temperature >38.2°C: 2.45
        Rhinorrhea: 1.83
    Temperature >38.9°C, respiratory signs, and stiffness or myalgia
 Temperature >37.7°C and cough or sore throat
 Any 3 of temperature >37.7°C, cough, chills, moderate/severe fatigue, cervical or dorsal pain, pharyngitis, and another case at patient’s homePPV: 40%; NPV: 80%
 PPV: 30%; NPV: 86%
 PPV: 27%; NPV: 91%
    Monto et al,11 2000Variable: OR (95% CI)Accuracy of multivariate model not reported
        Fever >37.7°C: 3.26 (2.75–3.87)
        Cough: 2.85 (2.21–3.68)
        Nasal congestion: 1.98 (1.54–2.54)
        Age ≥55 y: 1.60 (1.18–2.16)
        Weakness: 1.54 (1.07–2.22)
        Onset >36 hr: 1.53 (1.24–1.90)
        Loss of appetite: 1.43 (1.10–1.86)
        Sex, male: 1.27 (1.08–1.50)
        Sore throat: 0.72 (0.57–0.91)
    Boivin et al,12 2000Variable: OR (95% CI)PPV: 87%; NPV: 39%
        Cough: 6.68 (1.4–34.1)
        Temperature ≥38°C: 3.06 (1.35–8.02)
    van Elden et al,10 2001Period of increased influenza activity, cough, headache at onset, feverishness at onset, and not vaccinated
 During an outbreak, abrupt onset (<5 days), temperature >38°C, and at least 1 of cough, coryza, headache, retrosternal pain, or myalgia
 At least 4 of sudden onset, contact with influenza, fever, cough, chills, malaise, myalgia, or hyperemic mucous membranes of the nose and throat (≥6 required if not in outbreak)PPV: 75%; NPV: 80%
 PPV: 52%
 PPV: 54%; NPV: 85%
    Senn et al,7 2005Week of consultation (49–50 vs ≥51), duration of symptoms (≤48 hr vs >48 hr), temperature >37.8°C, and coughAUC=0.74
 Sensitivity: 80%; specificity: 59%
 LR+: 1.95; LR−: 0.34
 PPV: 67%; NPV: 73%
 LR+/LR−=5.7
    Ohmit and Monto,24 2006Study 1, zanamivir—variable: OR (95% CI)Accuracy not reported; only variables significant at P <.05 level included
        Age, y: 1.11 (1.00–1.23)
        Fever: 2.67 (1.66–4.30)
        Cough: 5.19 (2.66–10.10)
        Myalgia: 0.61 (0.38–0.99)
        Sore throat: 0.41 (0.24–0.70)
    Study 2, oseltamivir (age 1–4 y)—variable: OR (95% CI)
        Myalgia: 2.32 (1.22–4.39)
    Study 2, oseltamivir (age 5–12 y)—variable: OR (95% CI)
        Cough: 10.94 (2.90–40.80)
        Headache: 2.24 (1.15–4.37)
  • Table 5.

    Accuracy of Simple Heuristics for the Clinical Diagnosis of Influenza

    Rule and StudyaHeuristicSensitivity, %Specificity, %PPV, %NPV, %LR+LR−LR+/ LR−
    ILI=influenza-like illness; LR− = negative likelihood ratio; LR+ = positive likelihood ratio; NPV = negative predictive value; PPV = positive predictive value; RTI=respiratory tract infection.
    a Study population and prevalence of influenza are shown in Table 2.
    b Odds ratio in logistic regression model was 6.7 for cough and 3.1 for temperature greater than 38°C.
    c Odds ratio in logistic regression model was 7.2 for cough, 4.3 for headache, and 3.9 for pharyngitis.
    Fever and cough rule
    Stein et al,8 2005Fever (≥37.8°C) and cough409258845.10.77.3
    Govaert et al,13 1998Fever (>38°C) and cough309426955.00.746.8
    Boivin et al,12 2000bFever (≥37.8°C) and cough785587391.70.44.3
    Monto et al,11 2000Fever (≥37.8°C) and cough646779491.940.543.6
    van den Dool et al,22 2008Fever (>38.3°C) and cough429026954.20.646.5
    Fever, cough, and acute onset rule
    Stein et al,8 2005Fever (≥37.8°C), cough, and duration ≤48 hr758965936.50.321.7
    Walsh et al,21 2002Fever (≥38°C), cough, and duration <7 days787347912.90.39.7
    Govaert et al,13 1998Fever (>38°C), cough, and acute onset279530955.90.767.8
    Monto et al,11 2000Fever (≥37.8°C), cough, and acute onset636877511.950.543.6
    Cough, headache, and pharyngitis rule
    Friedman and Attia,20 2004cCough, headache, and pharyngitis807877813.70.2614.2

Additional Files

  • The Article in Brief

    A Systematic Review of Clinical Decision Rules for the Diagnosis of Influenza

    Mark H. Ebell , and colleagues

    Background Clinical decision rules to accurately identify patients at low, moderate, or high risk of influenza could help doctors determine appropriate treatment and avoid unnecessary tests. The goal of this analysis of previous research is to identify and evaluate the accuracy and validity of existing clinical decision rules for the diagnosis of influenza.

    What This Study Found This systematic review of 12 articles regarding clinical decision rules for the diagnosis of influenza found that, although influenza is a common cause of illness and death, studies about diagnosing this infection are largely small, use varied inclusion criteria and reference standards, and do not report their results in a way that would be helpful to clinicians. No study prospectively evaluated a clinical score or multivariate model for diagnosing influenza. Rather, the studies validated only simple clinical heuristics, such as �fever and cough� and �fever, cough, and acute onset,� and even then, the sensitivity and specificity varied considerably, and it was not possible to calculate summary measures of accuracy for these rules.

    Implications

    • Future research is needed to validate multivariate models for the diagnosis of influenza, as well as point scores that are easier for clinicians to use at the point of care.
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