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Vaccine 24 (2006) 6785–6790

Diagnosis and treatment of influenza in primary healthcare:“You can’t manage what you can’t measure”

Available online 14 July 2006

bstract

Early, accurate diagnosis of influenza is crucial. On an individual level, it enables effective treatment using antiviral drugs or other therapies.n a societal level, it could help national and international health authorities to contain epidemics or a pandemic. Yet influenza is notoriouslyifficult to diagnose. Various tests seek to improve the accuracy and speed of diagnosis. Rapid diagnostic tests can be effective but theirccuracy is influenced by the prevalence of influenza and other factors. Ultimately, laboratory tests are needed to confirm the influenza casend to obtain other information that can be used to develop a vaccine or contain the influenza outbreak. Cell cultures are the ‘gold standard’n testing because they offer both the most accurate diagnoses and the opportunity for further study of the virus culture.

Report on the conference session:“Diagnosis and Treatment of Influenza inprimary healthcare”Chair:Dr. M. Tashiro, National Institute of InfectiousDiseases, Tokyo, JapanSpeakers:

Dr. D. Fleming, Birmingham Research Unit,Birmingham, United Kingdom: The Recogni-tion and Differential Impact of Influenza andRespiratory Synctial Virus InfectionsDr. L. Jennings, Canterbury Health Labora-tories, Christchurch, New Zealand: Diagnosisand Treatment in Primary HealthcareDr. C. Hannoun, Institut Pasteur Paris, Mon-trouge, France, ESWI Member: Is BiologicalDiagnosis of Influenza Possible in Practice?

“The case definition is not always clear, andother viruses such as Respiratory SynctualVirus (RSV) give similar symptoms.”Dr. C. Hannoun of the Institut Pasteur Paris in

“Cell cultures are ‘the gold standard’; theyare the most sensitive. It’s the best method interms of isolation because then you can dosequencing, sensitivity to drugs, and antigenicanalysis.”Dr. C. Hannoun of the Institut Pasteur Paris inMontrouge, France.“Because of availability and cost, rapid tests arenot for generalised use in epidemics or pan-demics. The sentinel networks will be first lineand where the first strains will be isolated.”

wd“stoms,” explains Dr. C. Hannoun of the Institut Pasteur Parisin Montrouge, France.

In fact, in most countries, physicians speak of “Influenza

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Dr. C. Hannoun of the Institut Pasteur Paris inMontrouge, France.

Accurate diagnosis may very well be the most criticaleapon in the anti-influenza arsenal. With early, accurateiagnosis, influenza can be treated and outbreaks contained.The case definition is not always clear, and other virusesuch as Respiratory Synctual Virus (RSV) give similar symp-

ike Illness” (ILI), a smattering of symptoms that may

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nclude a sore throat, headache, cough, fever, coryza, malaise,nd prostration. The presence of a respiratory tract infection,sthma or acute bronchitis may further confound diagnosis,s do complications such as secondary infections. To thentrained eye, ILI even may look a bit like the common cold.

Dr. Hannoun listed several reasons why diagnosis ismportant. The most obvious of these is that early detectionould provide an early warning of an impending pandemicr epidemic. Public health authorities could then step in toontain the outbreak. The WHO is even forming a rapidesponse team and building a small stockpile of antiviraledication to contain such outbreaks. Early and rapid diag-

osis of influenza also helps in determining the best coursef treatment. Influenza typically only responds to the use ofntivirals if treatment is begun within the first 2 days of thenset of symptoms. Accurate diagnosis of influenza caseslso helps scientists fight the virus. With the influenza virusamples that they receive, they can identify the viral strain,nalyse its pathogenicity, and isolate the antigens needed forreating a vaccine. Finally, accurate and early diagnosis hasconomic and institutional benefits. It can reduce the use ofther diagnostic tests, the use of antibiotics and the length ofospital stay. For hospitals and nursing homes, early diagno-is can also help prevent the spread of the virus throughouthe institution.

. Clinical versus laboratory diagnosis

Broadly speaking, there are two categories of diagno-is: clinical and laboratory. Clinical diagnoses are typicallyade by healthcare practitioners at or near the point of care,

nd typically involve either traditional diagnostic methodsr such methods augmented by the use of “rapid diagnosticests.” Laboratory diagnosis is typically conducted by scien-ists at the national or community reference laboratories using

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dvanced techniques to analyse samples collected from theeld. The purpose of clinical diagnosis is early detection and

reatment of the patient. The purpose of laboratory diagnosiss to isolate the viral strain, better understand it, and createaccines to fight it.

Although making a clinical diagnosis of influenza is diffi-ult, the acute onset of a high fever (37 ◦C or more) and coughre good predictors. To be really certain, however, any clin-cal diagnosis must be confirmed through laboratory testing.n fact, according to Dr. L. Jennings of Canterbury Healthaboratories in Christchurch, New Zealand, the positive pre-ictive value of clinical diagnosis compared to lab confirmednfluenza ranges widely. During periods of influenza activitye.g. “flu season”) the positive predictive value is between 79nd 87% whilst during periods of low influenza activity, theositive predictive value is only 44%. In other words, whennfluenza is known to be present in a community, it is a goodet that symptoms of ILI are indeed influenza. During peri-ds of low influenza activity, however, more than half of caseslinically diagnosed as influenza turn out not to be influenzafter all, once laboratory tests are conducted. One should notault primary care physicians, however, since according toennings and others several confounding factors make clin-cal diagnosis difficult. These include the circulating virustrain, use of antipyretics, duration of symptoms, age, vacci-ation status, and any underlying illness.

. Rapid diagnostic tests

Rapid diagnostic tests are seen by some as one way ofmproving the accuracy of clinical diagnosis. These testsnvolve taking samples from the patient that may be throat,ose, washings or aspirates samples. The tests are conductedt the point-of-care or near the patient and typically take only0 min or less.

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apid diagnostic test type Available products

ateral flow immunoassay • Quidel, Quick Vue Influenza• Capilla

hromatographic immunoassay • Binax NOW Flu A, B, Flu A + Bnzyme immunoassay • Directigen Flu A, A + Bptical immunoassay • BioStar Flu OIA A + Biral coded enzyme assay • ZymeTx ZstatFlu

The advantages of rapid diagnostic tests are that they pro-ide quick results (e.g. in 30 min or less), involve fairly simplerocedures, can be used in a variety of settings and can besed 24 h a day and 7 days a week. Their disadvantages arehat they provide less accurate results than laboratory meth-ds, some tests do not distinguish between type A and type Bnfections, and most tests do not identify the influenza A sub-ype. Moreover, unlike laboratory tests, these tests are purelyiagnostic: no isolate is obtained so no data are available fornfluenza vaccine strain selection.

The accuracy of rapid diagnostic tests is a highly con-entious issue. Jennings of Canterbury Health Laboratoriesas studied the accuracy of several of the tests. He exam-ned three rapid diagnostic tests and found that they had aositive predictive value for detecting the influenza A virusf 89–97%. He also found that the accuracy of the testsas influenced by their sensitivity and their specificity (what

xactly they are designed to measure), as well as the preva-ence of influenza. During periods of peak influenza activity,he tests registered high positive predictive values whilst dur-ng periods of low influenza activity, the tests registered lowositive predictive values. Jennings also conducted a largetudy of the Emergency Department of Christchurch Hos-ital. He found that when the rapid diagnostic tests had aositive predictive value doctors were more likely to dis-harge patients and refrain from ordering other tests, and inhe case of children, doctors were more likely not to admin-ster antibiotics. In other words, the accuracy of the rapidiagnostic tests had a direct impact on the course of treatment.

. Laboratory tests: the gold standard

Laboratory tests are routinely used to confirm diagnoses ofnfluenza and gather additional information. The most com-

on test types are:

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Egg cultures: the virus is cultivated in a chick embryo anddetected using HA.Cell cultures: the virus is cultivated in a cell culture. Thistakes several days but gives the most accurate reading as tothe presence or absence of the virus. Moreover, the virusis isolated and therefore available for further study.Antigen detection: using a technique called immunofluo-rescence, the antigens can be detected. This informationis useful in developing a vaccine. These tests yield resultsmore quickly than the egg or cell culture tests do, but areless sensitive. Moreover, as no virus is kept, there is nopossibility for further testing or analysis.Nucleic acid detection: this versatile test uses a techniquecalled Polymerase Chain Reaction (PCR), and besidesinfluenza A and B can also detect parainfluenza 1, 2, and 3,Respiratory Syncytial Virus, Metapneumovirus, and sev-eral other virus types.Viral genome detection: complex gene amplification tech-niques are used to determine the viral genome. This testproduces results within hours or days, and provides usefulinformation on the genetic structure of the virus, but novirus is kept for further study.

Of all the various tests, cell cultures are perhaps the mostclassical,” but also the most useful. “Cell cultures are ‘theold standard’,” says Hannoun, “they are the most sensitive.”ell cultures do, indeed, yield the most accurate results of all

he tests. Moreover, they are also useful because the virus isvailable for further study. “It’s the best method in terms ofsolation,” adds Hannoun, “because then you can do sequenc-ng, sensitivity to drugs, and antigenic analysis.”

. Which test?

With such a broad array of tests available, it is hard tolame a healthcare practitioner for feeling confused. Which

est should be used? When should it be used? When should ite used in combination with other tests? Should tests be usedt all? The speakers answered these and other questions andlicited opinions from members of the audience.

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Both Jennings and Hannoun are against the generalisedse of rapid diagnostic tests. “Because of availability andost, rapid tests are not for generalised use in epidemics orandemics,” states Hannoun, “The sentinel networks will berst line and where the first strains will be isolated.” Jen-

ings agrees, and adds that influenza surveillance shoulde used to guide the optimal use of rapid tests. “Duringeriods of low influenza activity, positive results must benterpreted with caution, and confirmed by IFA, culture or

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T-PCR,” he cautions. During periods of high influenzactivity, on the other hand, it is simply impractical to testvery individual with ILI. During such times, Jennings rec-mmends using rapid diagnostic tests only to influenceimely patient management, such as treatment using antivi-als. A physician from the United Kingdom in the audienceoncurred: “We won’t use the rapid test other than whene know that the results will change the course of our

reatment.”

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cvtreof the available data are still the sine qua non for containingepidemics or pandemics. Although accurate diagnosis maybe the most critical weapon in the anti-influenza arsenal, it isstill more art than science.

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The use of the rapid diagnostic tests also depends uponeimbursement, public health policies, and the attitudes ofealthcare practitioners. “I don’t see a doctor taking samplesnd administering the tests in my country, but I know it’sossible in some countries,” says Hannoun. “But you needeimbursement for material and physician’s time to make itossible,” he adds. According to Hannoun, a test costs $15.he cost of the tests is reimbursed in Japan and the US, butot in many other countries.

Even when the tests are used, further testing by spe-ialised labs is required to confirm the case and identify theiral subtype. Rapid diagnostic tests cannot replace well-rained, experienced physicians, and more traditional labo-atory methods such as the cell culture technique. Moreover,ffective surveillance networks and the intelligent analysis