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Diagnosis of Influenza in the Community
Relationship of Clinical Diagnosis to Confirmed Virological, Serologic, or Molecular Detection of Influenza
Maria Zambon, PhD;
John Hays, PhD;
Alison Webster, MD;
Robert Newman, MSc;
Oliver Keene, MA, MSc
Arch Intern Med. 2001;161:2116-2122.
ABSTRACT
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Background Successful treatment of influenza depends on an accurate diagnosis of
the illness and prompt intervention. However, there is a lack of data comparing
clinical diagnosis vs laboratory diagnostic techniques.
Objective To compare the clinical diagnosis of community cases of influenza with
various laboratory diagnostic techniques including multiplex, reverse transcription
polymerase chain reaction.
Methods Clinical diagnosis, viral isolation, hemagglutinin inhibition serology,
and multiplex, reverse transcription polymerase chain reaction were used to
diagnose influenza in patients enrolled in international phase 3 studies designed
to investigate the efficacy and safety of an anti-influenza drug (inhaled
zanamivir). Patients clinically diagnosed with influenza were enrolled at
centers across North America and Europe.
Results A total of 791 (77%) of 1033 patients with laboratory results from all
3 methods were confirmed positive for influenza by 1 or more test results.
For 692 patients (67%), the results of all 3 tests agreed. Total symptom scores
at baseline showed a significant association toward greater severity of symptoms
with an increasing number of positive test results (P<.001).
An increasing number of positive test results also showed a significant correlation
with a longer time to alleviation of symptoms of influenza in the placebo
group (P = .001).
Conclusions During a time when influenza was known to be circulating and clinical
diagnostic criteria were applied, diagnosis of influenza in these trials was
accurate in approximately 77% of adults on clinical grounds alone. This highlights
the need for primary care physicians to be alerted to circulating influenza
and to be aware that presentation with cough and fever provide the most predictive
symptoms.
INTRODUCTION
SUCCESSFUL treatment of influenza depends on an accurate clinical diagnosis
of the illness and prompt intervention. The onset of symptoms is normally
rapid, with prominent systemic features including fever, cough, chills, myalgia,
headache, malaise, and sore throat.1 Other
respiratory diseases, such as respiratory syncyctial virus, which frequently
circulate in the community at the same time as influenza, may present with
similar clinical symptoms.2 Although laboratory
tests do not provide results quickly enough to direct therapy, confirmation
of the clinical diagnosis can provide valuable and accurate information of
when influenza is circulating for surveillance purposes.
Viral isolation and hemagglutination inhibition serologic testing are
conventional methods for influenza virus diagnosis. Although polymerase chain
reaction (PCR) is widely used in clinical diagnostic laboratories for the
diagnosis of other viral infections, it has not been extensively used for
the diagnosis of respiratory tract infections. Molecular diagnosis of influenza
by reverse transcription PCR (RT-PCR) provides improved sensitivity and specificity,
allows accurate detection, and facilitates the subtyping of influenza.3 Multiplex RT-PCR is a more recently established technique
and has the added advantage of allowing identification of several infectious
agents (eg, influenza subtypes A/H1N1, A/H3N2, and B, and respiratory syncytial
virus) in 1 sample and in 1 reaction.3-4
However, there is a lack of data comparing RT-PCR, culture, or serologic testing
in confirming the clinical diagnosis of influenza in a community-based sampling
of cases of influenza. Laboratory diagnosis is usually performed on a few
hospitalized patients and is rarely used to confirm cases of influenza seen
in the community. Near-patient tests for influenza that can be performed in
the physician's office and yield results in 10 to 30 minutes represent a significant
diagnostic development. However, these will also require evaluation in clinical
practice against traditional laboratory methods to determine sensitivity and
specificity, and it will be important to determine which laboratory test should
be used as a "gold standard" for the diagnosis of influenza.
Two international phase 3, double-blind, randomized, placebo-controlled,
parallel-group studies (NAIA3002 and NAIB3002 described elsewhere5-7) were designed to investigate
the efficacy and safety of an inhaled anti-influenza drug in the treatment
of symptomatic influenza type A and type B viral infections. The trials used
a common study protocol and provided a unique opportunity to examine the relationship
between clinically diagnosed influenza and laboratory confirmation using different
diagnostic test results for patients initially seen within 48 hours of the
onset of illness in the community when influenza was known to be circulating.
PATIENTS, MATERIALS, AND METHODS
PATIENTS
Male or female patients, aged at least 12 years, initially seen within
48 hours of the onset of influenzalike illness were enrolled in the studies.
Symptoms were defined as the presence of fever (temperature  37.8°C,
unless the patient was 65 years, in which case, fever was defined as 0.2°C
[temperature 37.2°C]) and at least 2 of the following 4 symptoms:
headache, myalgia, sore throat, and cough. All participants were required
to give written informed consent.
All investigators had access to local and national influenza surveillance
data and recruitment began only when influenza was confirmed to be circulating
locally. The site was activated if more than 2 positive samples were reported
in a 7-day period. The exclusion criteria were as described previously.6 Patients who had received influenza vaccine for the
current season could be recruited in the study if confirmed as positive for
influenza (IP) before the first study treatment by a rapid diagnostic test.
CLINICAL ASSESSMENTS
Global assessment of symptoms was made by the investigator at baseline
on day 1 (first treatment visit, before study drug administration) using a
4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Patients
recorded the presence and severity of the following 9 symptoms at baseline:
headache, sore throat, feverishness, myalgia, cough, nasal symptoms, weakness,
loss of appetite, and overall illness score, using the same 4-point scale.
Patients also measured their baseline temperature using a tympanic thermometer
before study treatment.
Patients continued to record the presence and severity of their symptoms
and to take their temperature for 14 days or, if symptoms persisted, for 28
days. Alleviation of the main clinical symptoms was defined as follows: no
fever (temperature <37.8°C), feverishness recorded as none, and a score
of 0 or 1 (mild) for headache, myalgia, cough, and sore throat, all maintained
for a further 24 hours. The incidence of influenza-related complications and
associated antibiotic agent use was recorded throughout the studies.
LABORATORY ASSESSMENTS
Samples for diagnostic virologic testing, including nasal wash, nasal
swabs, nasopharyngeal aspirates, throat swabs, and blood (serum) samples,
were taken before treatment. Virus culture was performed using local isolation
protocols, which involved inoculation of the clinical specimen onto either
primary monkey kidney cells or Madin-Darby canine kidney cells, and was performed
at a central laboratory for North American studies and in local laboratories
in European countries. An aliquot of the same sample was stored at -70°C
for subsequent PCR analysis. Influenza antibody titers at baseline and at
day 28 were measured by hemagglutination inhibition serologic testing; assays
were performed at the National Institute for Biological Standards and Control
(Hertford, England) for both studies, according to standard protocols.8 Patients were considered to have shown seroconversion
if the convalescent antibody titers were increased at least 4-fold compared
with baseline.
Influenza diagnosis that included subtyping by multiplex RT-PCR was
performed at the Public Health Laboratory Service, London, England, for both
studies according to previously published methods.3
Stringent quality control procedures were used to ensure the accuracy, reproducibility,
and quality of diagnosis.
STATISTICAL ANALYSIS
The intention-to-treat (ITT) population was defined as all randomized
patients, whether or not the study drug was taken or the patient completed
the study. Patients were considered to be IP if a positive result was obtained
by culture or PCR assay, or if seroconversion was demonstrated by hemagglutination
inhibition. All analyses included patients who had negative results on all
3 tests as positive on 0 tests.
Total symptom scores at baseline were calculated first as the sum of
the 5 principal symptoms (ie, headache, sore throat, feverishness, myalgia,
and cough) and second as the sum of all 9 symptoms (ie, headache, sore throat,
feverishness, myalgia, cough, nasal symptoms, weakness, loss of appetite,
and overall influenza assessment). Scores were expressed as a percentage of
the maximum achievable score. Analysis of variance (ANOVA) was used to test
for a statistically significant association between the total symptom scores
and the number of positive test results. The presence of an association between
the severity of each individual symptom on the original 4-point scale and
the number of positive test results were assessed using the Mantel-Haenszel
test. The ANOVA was also applied to test the relationship between baseline
temperature and the number of positive test results.
Data on time to alleviation of symptoms of influenza, incidence of complications,
and antibiotic agent use for complications was analyzed for the patients randomized
to placebo. The presence of an association with the number of positive test
results was assessed using the Mantel-Haenszel test.
RESULTS
A total of 1133 patients were enrolled in the European and North American
studies. Baseline patient characteristics were similar in the ITT population
and the population with results from culture, serologic testing, and PCR (Table 1). Data from all 3 methods were
available for 1033 patients (91%). These patients, whether they were treated
with placebo or zanamivir, were included in the analysis of baseline diagnostic
tests. A total of 791 evaluable patients (77%) clinically diagnosed with influenza
were confirmed as IP with 1 or more tests. A total of 242 patients (23%) did
not have a positive result in any laboratory diagnostic test and were categorized
as influenza negative. Of the 100 patients with missing test results, 77 were
missing for the day 28 serology only, 6 for serology and PCR, 12 for PCR only,
and 5 for culture only.
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Table 1. Patient Characteristics (ITT Population)*
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Overall, in the 13 countries involved, 579 patients (56%) were positive
by culture, 629 patients (61%) were positive by serology, and 730 patients
(71%) were positive by PCR. Some variation in the positivity rates achieved
by laboratory diagnosis was noted from country to country (Table 2).
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Table 2. Laboratory Diagnosis Results by Country
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For 692 (67%) of the 1033 patients with results from all 3 methods,
the results of all 3 tests agreed. In 341 patients (33%), there was a discrepancy
in the results of 1 test compared with the other 2 tests (Figure 1). Of the 791 IP patients, 450 patients (57%) were positive
by all 3 methods. Where only 2 test results were positive (247 patients [31%]),
serology and PCR gave the highest additional confirmation (126 patients [16%]),
followed by culture and PCR (109 patients [14%]), and culture and serology
(12 patients [2%]). A further 8 patients (1%) positive by culture, 45 patients
(6%) positive by PCR, and 41 patients (5%) positive by serology were unconfirmed
by any other test. However, in 29 (64%) of the cases with unconfirmed PCR
results, the samples showed a serologic rise to the same subtype as detected
by PCR, but the increase in antibody titers did not reach 4-fold, suggesting
that these individuals had influenza infection but did not meet the scoring
criteria for serologic positivity. In contrast, only 38 (16%) of 242 patients
negative in all 3 methods showed any rise in antibody titers.
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Concordance of results in patients with positive test results from
all 3 diagnostic tests—serology (ie, nasal wash, nasal swabs, nasopharyngeal
aspirates, throat swabs, and blood samples), virus culture (ie, inoculation
of the clinical specimen onto either primary monkey kidney cells or Madin-Darby
canine kidney cells), and multiplex reverse transcription polymerase chain
reaction (RT-PCR).
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If culture and serology together are considered a gold standard for
diagnosis of influenza, with a positive result on either test being considered
evidence of influenza infection, then the sensitivity and specificity of diagnosis
using RT-PCR was 92% and 84%, respectively.
Total symptom scores at baseline showed a significant association toward
greater severity of symptoms with an increasing number of positive test results
analyzed by ANOVA (P<.001; Table 3 and Table 4).
Baseline temperature and the severity of cough, feverishness, nasal symptoms,
loss of appetite (all P<.001), and weakness (P = .01) individually showed a statistically significant
positive correlation with the number of positive test results. Sore throat
showed a statistically significant negative correlation with the number of
positive test results (P = .01) suggesting that severity
of this symptom was greater in patients who tested negative for influenza.
Analysis of the 100 patients who did not have results from all 3 laboratory
tests indicated that 55 had a positive result in 1 or more of their remaining
tests. Comparison of those who had positive results on 2 tests with those
who had negative test results indicates a rise in temperature and an increase
or identical symptom score. Therefore, we conclude that there is no evidence
of bias by the exclusion of patients with missing test results.
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Table 3. Baseline Individual Symptoms*
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Table 4. Baseline Total Symptoms*
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The influenza vaccine components for the study year were A/Wuhan/359/95(H3N2),
A/Bayern/7/95(H1N1), and B/Beijing/184/93; whereas, the predominant circulating
influenza strains were a mixture of A/Wuhan/359/95 and A/Sydney/5/97, a significant
H3N2 drift variant from A/Wuhan/359/95. Of the 114 patients vaccinated for
the season (with data from all 3 tests), confirmation of influenza was obtained
in 92 patients (81%). The remaining 22 patients (19%) were found to be negative
by all 3 laboratory diagnostic tests. No difference in severity of symptoms
was seen between the vaccinated and nonvaccinated patients. Patients in the
younger (12-16 years) and older (65 years) age groups were more likely
to be positive by all 3 tests than patients in the middle-age (17-64 years)
group (Table 5).
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Table 5. Test Results by Age Group*
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Of 783 patients were IP who had subtype information available, 765 had
influenza type A (731 H3N2; 34 H1N1), and 18 had influenza type B. It was
impossible to draw conclusions about the association of clinical scores or
laboratory results with different subtypes because of the overwhelming predominance
of H3N2 circulation. Concordance in the subtype of influenza identified by
the different diagnostic tests was good. In 1 patient, PCR indicated influenza
type B, whereas, serologic testing indicated type A. In 2 influenza A–positive
patients, PCR indicated H3N2 and serologic testing indicated H1N1 infection.
The reasons for the discrepancies of influenza subtype identified in 3 patients
are unclear.
The natural course of influenza in these studies was followed by analyzing
the time to alleviation of symptoms, incidence of complications (upper and
lower respiratory tract, cardiovascular, and other complications of influenza
as defined by the patient's physician), and antibiotic agent use in the patients
randomized to placebo (Table 6).
There was no evidence of an association between the incidence of complications
or antibiotic use for complications and the number of positive test results
in patients who were IP and were receiving placebo. However, a statistically
significant association with longer time to alleviation of symptoms was found
with an increasing number of positive test results (P
= .001).
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Table 6. Follow-up in Patients Receiving Placebo*
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COMMENT
The 2 international phase 3 clinical trials conducted with anti-influenza
drugs provide a large set of clinical data allowing investigation of the relationship
between clinical and laboratory diagnosis using a common clinical protocol.
Of the patients who were clinically diagnosed with influenza, 77% were confirmed
as IP by 1 or more laboratory test results. We can conclude that, during a
time when influenza was known to be circulating and clinical diagnostic criteria
were applied, diagnosis of influenza in these trials was accurate in approximately
77% of adults on clinical grounds alone. Other recent phase 2 and 3 trials
for sialidase inhibitors, which did not include the use of RT-PCR for diagnosis,
have shown that 59.6% of the 71% of patients initially seen with influenzalike
illness had laboratory-confirmed influenza at a time when influenza was circulating.9-12 Enrollment
criteria were similar for all studies, apart from documented fever which was
not required in the Southern Hemisphere phase 3 trial9
or the European phase 2 trial.12 Our results
show that baseline temperature and the severity of cough and fever showed
a significant positive correlation with the number of positive test results
and sore throat showed a significant negative correlation (Table 3, Table 4, and Table 5). This agrees with Monto et al13 who conclude that sore throat is a negative predictor
of influenza and suggested that fever and cough are the best predictors of
influenza.
In general, concordance between laboratory tests was reasonable, with
692 patients (67%) with results from all 3 tests having the same result in
all tests. This may reflect the different sensitivity of the 3 diagnostic
tests. As predicted from the findings of previous studies,3, 14-18
PCR was the most sensitive diagnostic test; 92% of the patients who were IP
were positive by PCR, compared with 80% of the patients who were IP and were
positive by serologic testing, and 74% of the patients were IP and were positive
by viral culture. Similar numbers of individuals were diagnosed with influenza
infection using serologic criteria in both the placebo-treated and the drug-treated
groups (data not shown), which supports the previous conclusion that zanamivir
treatment does not interfere with the serologic response to influenza antigens.19
Neither culture nor serologic testing alone can be considered a gold
standard for influenza diagnosis, mainly because each lacks sensitivity, and
as shown here, is not universally in agreement, although both have been widely
used as methods of diagnosing influenza in the past. While serology is a cheap
and reliable diagnostic test,20 the requirement
for paired samples limits the use of serology in the management of influenza
and limits its usefulness as a diagnostic tool; most patients for whom diagnostic
test results were incomplete were those failing to present for a day 28 serology
test. Viral culture is well established and will continue to be a standard
laboratory test in the diagnosis of influenza,21
although the drawbacks of length of procedure and requirement for infectious
virus make it less useful for immediate patient management. In our studies
culture testing missed 26% of IP cases identified by serologic testing or
PCR. The sensitivity of RT-PCR against combined culture and serologic testing
indicates that it should be considered the most sensitive test for diagnosis
of influenza. In almost two thirds of cases where PCR was the only positive
test result, there was also some serologic evidence of influenza infection,
suggesting that these were not false-positive PCR results. In summary, we
suggest that RT-PCR could be considered the gold standard for diagnosis of
influenza, although further work is required to understand the relationship
of RT-PCR detection of influenza with presentation later in the course of
an influenzalike illness, as these results refer to presentation
in the first 48 hours of an influenzalike illness. Several rapid tests for
the detection of influenza in a "near-patient setting" have appeared in the
marketplace in the last few years.22-23
There are limited data on the sensitivity, specificity, and value for money
of such tests and their place in the management of influenza in the community
remains uncertain. However, the evaluation of such tests will require knowledge
of their predictive value against other well-validated laboratory tests for
influenza at a time when influenza is circulating and consideration of performance
at different stages of the natural history of influenza exists.
Variation between countries was observed in the proportion of positive
results obtained from the 3 laboratory tests. In particular, results from
viral culture showed marked variation between countries, possibly reflecting
the fact that this test was performed at several different individual study
centers and that local difficulties in transportation of the samples might
have occurred. Although PCR and serology were performed centrally, variation
in positive laboratory results between countries was seen. Another contributing
factor to the variation observed is that few patients were recruited at some
centers, such as in Holland and Spain; this was inevitable, because outbreaks
of influenza are unpredictable and can vary in severity and prevalence.
Analysis of the total symptom scores and the laboratory diagnostic test
results showed that the number of positive test results correlated with the
severity of symptoms at baseline. It is considered that increased severity
of illness is likely to be related to increased viral load, although this
was not formally evaluated in this study. If this hypothesis is correct then
the likelihood of detecting virus by several different laboratory methods
may correlate with viral load and may be related to the nature of the immune
response, and, hence, with severity and duration of illness.
The length of illness recorded in the patients receiving placebo was
positively correlated with the number of positive diagnostic test results.
The criteria used to calculate the alleviation of the clinical symptoms of
influenza in these studies are a conservative measure of recovery from influenza.
The high incidence of complications and antibiotic agent use for complications
in patients whose test results were negative for all 3 tests suggests that
while the influenzalike illness is shorter, the risk of developing complications
in these patients is similar to that for influenza.
The subtype of influenza may be related to the severity of the illness.
Influenza type A subtype H3N2 infection is believed to be more severe than
subtype H1N1 infection24 and influenza type
A infection is generally thought to be more severe than influenza type B infection.
Although in phase 2 and 3 clinical trials of zanamivir-treated patients with
both subtypes have similar length and severity of disease, there were insufficient
data on H1N1 and influenza type B available to compare clinical indicators
of severity following infection with different subtypes.
Of 114 patients in these trials with results from all 3 methods who
had received the influenza vaccine in the current season and were clinically
diagnosed with influenza, 92 were confirmed as IP with 1 or more laboratory
diagnostic tests. In the year in which this study was conducted (1997-1998),
the vaccine strain for influenza type A H3N2 was A/Wuhan/359/95, and circulating
strains included a mixture of A/Sydney/5/97, a drift variant of influenza
type A H3N2, as well as A/Wuhan/359/95. The effectiveness of influenza vaccines
is 65% to 85% in years where there is a good match between vaccine and circulating
strains.25 This study was not designed to investigate
the difference in influenza illness severity between vaccinated and unvaccinated
individuals, and it incorporates data from a few patients in a single influenza
season. Nevertheless, of the vaccinated patients included in these trials,
80% had IP illness as severe as that recorded in nonvaccinated patients; therefore,
vaccination status should not automatically exclude the diagnosis of influenza.
CONCLUSIONS
There is good correlation between clinical diagnosis carried out by
general practitioners in the community and laboratory-confirmed diagnosis
at times when influenza is circulating. This highlights the need for primary
care physicians to be alerted to circulating influenza and to be aware that
presentation with cough and fever provide the most predictive symptoms. This
will allow accurate clinical diagnosis of influenza to be made with confidence.
AUTHOR INFORMATION
Accepted for publication February 22, 2001.
We thank Carol Sadler, BSc, and Paul Laidler, MSc, for excellent technical
assistance, Ezzie Hutchinson for help in preparation of the manuscript, and
Karen Barrett, BSc, for programming assistance.
Corresponding author: Maria Zambon, PhD, Influenza Unit, Enteric
and Respiratory Virus Laboratory, Central Public Health Laboratory, 61 Colindale
Ave, Colindale, London NW9 5HT, England (e-mail: mzambon{at}phls.nhs.uk).
From the Influenza Unit, Enteric and Respiratory Virus Laboratory,
Central Public Health Laboratory, London (Drs Zambon and Hays); Glaxo Wellcome
Research and Development, Greenford (Dr Webster and Mr Keene); and the National
Institute for Biological Standards and Control, South Mimms (Dr Newman), England.
Dr Zambon was a consultant to Glaxo Wellcome Inc between 1997 and 1999. Dr
Webster and Mr Keene are employees with benefits (ie, pension, equity, and
stock options) with GlaxoSmithKline.
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Arch Pediatr Adolesc Med 2004;158:391-394.
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Management of Influenza in Adults Older than 65 Years of Age: Cost-Effectiveness of Rapid Testing and Antiviral Therapy
Rothberg et al.
ANN INTERN MED 2003;139:321-329.
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Accuracy of Screening for Inhalational Anthrax after a Bioterrorist Attack
Hupert et al.
ANN INTERN MED 2003;139:337-345.
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Comparison of the Directigen Flu A+B Test, the QuickVue Influenza Test, and Clinical Case Definition to Viral Culture and Reverse Transcription-PCR for Rapid Diagnosis of Influenza Virus Infection
Ruest et al.
J. Clin. Microbiol. 2003;41:3487-3493.
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