Managing Influenza in Primary Care

Managing Influenza in Primary CareA Practical Guide to Clinical Diagnosis

René Snacken, Influenza Diagnosis Working Party†

Scientific Institute of Public Health – Louis Pasteur, Section Virology, Brussels, Belgium

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791. Influenza Symptoms: Diagnostic Utility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802. Differential Diagnosis of Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813. Working Party Discussion and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

3.1 Influenza Surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823.2 Clinical Diagnostic Guidelines for Influenza in Adults . . . . . . . . . . . . . . . . . . . . . . . 823.3 Scope of the Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

3.3.1 Otherwise Healthy Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Abstract Influenza remains a significant cause of worldwide morbidity and mortality.With the availability of new effective antivirals for the treatment of influenza,early diagnosis of the disease will become increasingly important for effectivedisease management.Although investigators are generally in broad agreement about the symptoms

of influenza, there are currently no agreed guidelines for the clinical diagnosis ofinfluenza during annual outbreaks. This paper outlines the recommendations ofa Working Party (comprising virologists and family practitioners) who met toconstruct criteria that could be used by primary healthcare professionals to aidearly clinical diagnosis of influenza, i.e. before the development of any compli-cations.Avirologically confirmable diagnosis of influenza is likely when an otherwise

healthy adult presents, during a known local influenza outbreak, with rapid onsetof the symptom complex of fever, feverishness or chills plus myalgia, cough ormalaise. Guidelines for the diagnosis of influenza in children, in patients withchronic diseases and in the elderly require further refinement.

PRACTICAL DISEASE MANAGEMENT Dis Manage Health Outcomes 2000 Aug; 8 (2): 79-851173-8790/00/0008-0079/$20.00/0

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The global impact of influenza virus infectionon both individuals and healthcare providers isconsiderable, with outbreaks of the disease beingresponsible for significant morbidity and approxi-mately 20 000 deaths per year in the US alone.[1]

In the UK, the frequency of influenza-associatedcomplications, such as bronchitis, pneumonia andsinusitis, is 7.6% in normally healthy adults diag-nosed with influenza by a physician; hospitalisa-tions in this patient group occur at a median of 93

†See Acknowledgements for members of the Working Party.

per 100 000 cases of influenza.[2] During winterinfluenza outbreaks, the incidence of influenza-like illness seen during family practitioner consult-ations can increase up to 5-fold, placing consider-able pressure on primary healthcare services andresources.[3] The indirect costs of influenza are alsoof significance from the societal perspective, in theform of work absenteeism and reduced productiv-ity. For example, each case of influenza leads tobetween 3 and 7 working days lost.[4] In a study ofthe cost of influenza in France during 1989, thecosts to society were FF14.3 billion [2.18 billioneuro (EUR), $US2.05 billion], most of which wereattributable to an estimate of lost work productiv-ity.[5]The mainstay of influenza control is immunisa-

tion, which is widely recommended for the elderly(14% of the total population in the US) and otherat-risk groups of patients such as patients withbronchopulmonary diseases, cardiovascular disease,liver disease and diabetes mellitus (a further 13%of the total US population).[1] However, not allthose for whom the vaccine has been recommendedreceive it, and most of the total population (>73%)remain unvaccinated and susceptible to annual out-breaks of the disease.[1] Unfortunately, the variabil-ity in the antigenic nature of the influenza virusmay occasionally lead to vaccine/circulating strainmismatch, and consequently poor immunity in vac-cinees. This may partly explain differences in vac-cine efficacy in the elderly,[1,6-8] a large proportionof the target vaccination group and a populationwho may also have an impaired immune response.In addition, although improving each year, uptakeof vaccination is variable, with levels reaching just65.5% in the ≥65 year age group and 30% in thoseaged <65 years and at high risk for influenza-related complications in the US during 1997.[1]The management of influenza could therefore

be enhanced greatly by the use of effective and welltolerated antiviral therapies during outbreaks.Older antiviral agents (such as amantadine and rim-antadine) have limited use, as they are effective onlyagainst influenza A viruses, resistance developsrapidly, and amantadine (and rimantadine) is poorly

tolerated by many patients.[9,10] Consequently, forthe majority of patients with influenza, only symp-tomatic relief and bed rest have been recom-mended. However, with the development of a newclass of influenza drugs, the neuraminidase inhib-itors such as zanamivir and oseltamivir, therapeuticoptions have improved greatly and inappropriateprophylactic use of antibiotics could possibly beavoided. Aswith all antivirals, the sooner treatmentwith these drugs is initiated following the onset ofsymptoms the more effective they are.[11] Conse-quently, it is important to develop clear guidelineson how to diagnose influenza rapidly and as accu-rately as possible, so that maximum therapeuticbenefit is obtained; to date, clinical guidelines forthe diagnosis of influenza have been lacking.AWorking Party of influenza experts and family

practitioners with an interest in influenza met inBerlin on 24 March 1999 to discuss the clinicaldiagnosis of influenza infection. The objective of themeeting was to construct a set of simple and prac-tical diagnostic guidelines and a visual checklistfor primary healthcare professionals. The guide-lines were agreed upon following discussion of in-fluenza symptoms and diagnosis within the contextof participants’ own expertise and experience. Thisarticle is the result of those discussions and pro-vides background information to support the check-list. The guidelines will be validated for sensitivityand specificity using retrospective data from influ-enza clinical trial databases, and will be submittedimmediately to the European Scientific WorkingGroup on Influenza (ESWI) for endorsement.As influenza poses a considerable burden to both

individuals and society, both in terms of morbid-ity/mortality and in healthcare costs, new diseasemanagement initiatives are needed. It is hoped thatthese guidelines for the early diagnosis of influenzamay help in the management of this infection.

1. Influenza Symptoms: Diagnostic Utility

Descriptions of ‘pestilence’and epidemics of fe-brile respiratory illness from ancient times cannotbe substantiated by modern virological techniquesas influenza, but it is likely that influenza viruses

80 Snacken et al.

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have infected humans for many centuries. Descrip-tions of outbreaks from the 12th century onwardsclearly describe influenza-like disease,[12] and in-fluenza pandemics can be identified from reportsfrom the 17th and 18th centuries.[13-15]Descriptions of the symptoms of influenza are

similar in publications from the early 1950s onwards.In 1953, Stuart-Harris[16] described the 6 most fre-quent symptoms of influenza as fever (95%), mal-aise (91%), headache (89%), cough (86%), chills(81%) and sore throat (69%).Although influenza hasno pathognomonic features, many reports describea characteristic sudden onset of symptoms, usuallystarting with fever, myalgia, headache and sorethroat.[17–21] A dry, rasping cough often appears rap-idly and other respiratory symptoms occur afterseveral days of illness. Gastrointestinal symptoms(mainly nausea and vomiting) are occasionallymentioned, but have a lower incidence in adultsand appear to be more common in children.[19,22-28]Both influenza A and B appear to cause similarsymptoms,[29,30] although not necessarily with thesame impact in all age groups. The presence of alocal influenza outbreak is also considered to be animportant parameter to aid diagnosis.[19,27,29-32]In the elderly, Govaert et al.[18] found that a

combination of rapid onset of symptoms, fever andcough gave the highest predictive value for bothsubjective and objective diagnosis of influenza (30and 44%, respectively, during the winter of 1991to 1992 in The Netherlands). The authors suggestthat the value of this combination of symptomswould improve further if used during an influenzaoutbreak. In a study of an outbreak in France dur-ing the season of 1995 to 1996 involving patients≥1 year old (mean ages varying from 28 to 39years, depending on the virological strain of influ-enza), a combination of a high temperature >38.9°C(102°F), respiratory signs and stiffness/myalgiagave a positive predictive value of 40%.[29] Theabsence of these combined symptoms was stronglypredictive of noninfluenzal infection. Illnessescaused by different influenza viruses were indistin-guishable. Nicholson et al.[33] found that, in patientsaged ≥60 years, the symptom complex of myalgia,

respiratory symptoms and feverishness/sweatsgave a positive predictive value of 33% during out-breaks. In addition,Monto et al.[32] determined thatthe best multivariate predictors were fever pluscough (p < 0.001), with a positive predictive valueof 81% and sensitivity and specificity of 63% and71%, respectively.These studies indicate that while calculating

positive predictive values for symptoms may beuseful, they are not always strongly predictive ofinfluenza virus infection and that further diagnos-tic guidelines are needed.Clinical trials on neuraminidase inhibitors in

the treatment and prevention of influenza havedemonstrated the accuracy of clinical diagnosis inthe context of a local influenza outbreak. In treat-ment trials that used a strict case definition ofinfluenza, 63 to 75% of cases had laboratory-confirmed influenza.[11,34-36] In a study of experi-mental influenza prophylaxis, the proportion of pa-tients with influenza-like illness not attributable toinfluenza was low (approximately 20%).[37] Bothtreatment and prevention studies included partici-pants only when surveillance activities identified alocal influenza outbreak.

2. Differential Diagnosis of Influenza

Another issue that may make influenza diagno-sis difficult is the similarity of symptoms withother respiratory infections, such as respiratorysyncytial virus (RSV) infections and the commoncold. One study investigating how family practi-tioners in the UK distinguish between influenzaand the common cold found that the presence of aninfluenza outbreak was the most important crite-rion used to distinguish the 2 illnesses.[31] In con-junction with the major symptoms of fever, mal-aise and myalgia, practitioners were clearly able toidentify influenza in this setting. There was lessoverall consensus regarding the symptoms of thecommon cold, although rhinorrhoea was men-tioned by 98% of respondents. In a study of rhino-virus infections in adults, Arruda et al.[38] deter-mined that the most common symptoms were sorethroat, stuffy nose, runnynose, sneezing andmalaise.

Diagnosis of Influenza in Primary Care 81


In general, compared with patients with influenza,nasal symptoms are more common in patients witha cold, they are less likely to have systemic symp-toms and documented fever is very uncommon inthe absence of bacterial complications.[31,39]Wald et al.[28] compared the clinical findings of

RSV and influenza A infection in the institu-tionalised elderly to determine if the 2 diseasescould be distinguished. Systemic symptoms, par-ticularly malaise, occurred significantly more of-ten with influenza infection (84%) compared withRSV (44%). Patients with influenza also tended tohave a higher temperature and a higher incidenceof gastrointestinal symptoms, such as nausea, vom-iting and diarrhoea. Respiratory symptoms alonewere reported more often by patients with RSV(56%) than by patients with influenza (16%). Theauthors concluded that while illnesses associatedwith influenza and RSV were similar, the presenceof constitutional symptoms improved diagnosis ininfluenza-infected patients.

3. Working Party Discussion andRecommendations

A point-of-care diagnostic test for influenzawith sufficient sensitivity and specificity for adults,ease of performance and rapid results is not cur-rently available and, because of these demandingrequirements, is unlikely to become available in thenear future. Therefore, the Working Party agreedthat it was appropriate to pursue the clinical symp-tom approach to produce guidelines for early diag-nosis in the primary care setting. It was emphasisedthat such guidelines should be practical and easy touse for both family practitioners and other physi-cians who provide primary care (e.g. geriatricians)and should be useful as guidance for other primaryhealthcare professionals (e.g. nurses, pharmacists).Moreover, these guidelines should be easily adapt-able for public education.Before discussion on symptoms commenced,

background information on the incidence of influ-enza symptoms recorded at the time of presentationduring 10 adult studies of virologically confirmed,uncomplicated influenza undertaken between 1937

and 1992 was considered by the Working Party.[20]Together, these studies indicated that the mostcommon influenza symptoms were cough (85%),malaise (80%), feverishness (80%), chills (68%),fever (65%), headache (65%), anorexia (60%), co-ryza (60%), myalgia (58%) and sore throat (50%).Sudden onset was also an important parameter, oc-curring in 70% of cases.

3.1 Influenza Surveillance

Although not routine for family practitioner use,laboratory diagnosis of influenza will continue toplay an important role in terms of surveillance andthe identification of local outbreaks.[40] Indeed,panel members of the Working Party emphasisedthe importance of high quality surveillance to ob-tain a high positive prediction of influenza illnesswhen clinical findings and symptoms are used (seealso section 1).The panel acknowledged the similarity of symp-

toms between influenza and RSV infection, andconcluded that the key aspect of differential diag-nosis would be the information regarding the ab-sence or presence of a local influenza and knownRSV outbreak. In Western countries, RSV is usu-ally present for 5 to 6 months of the year, and Flem-ing and Cross[41] noted that there was a regular pat-tern in the occurrence of RSV in the UK,which wasdetectable in early December and dropped signifi-cantly in March/April during 4 consecutive years.These data underline the importance of a rapid andintegrated influenza surveillance network.

3.2 Clinical Diagnostic Guidelines forInfluenza in Adults

In order to develop clinical diagnostic guidelinesfor influenza in otherwise healthy adults (aged <65years), the Working Party participants firstly listedall symptoms, clinical findings and other criteria ofimportance for diagnosing influenza in this patientgroup. The symptoms/criteria most often men-tioned by the Working Party were fever, myalgia,sudden onset, knowledge of a local outbreak, cough,headache, malaise and chills. These symptoms wereconsistent with those reported in the literature, in

82 Snacken et al.


particular those found to be the most common inthe previously mentioned pooled results of 10 adultstudies (see section 3). Each symptom/criterion wasdiscussed fully, to determine if it should be on thediagnostic checklist.Sudden onset was considered to be a defining

feature of the disease. Fever, or feverishness, wasacknowledged as the most important symptom ininfluenza; participants agreed that this was essen-tial for a positive diagnosis of influenza illness.Clinical fever was not defined by a specific tem-perature because patients can be apyretic, most of-ten after the use of antipyretic drugs, and as a con-sequence may present with a history of feverduring the first day of presentation with symptom-atic influenza. Feverishness/chills are an initialsymptom of influenza and develop into clinical fe-ver during the first day of symptomatic influenza.Although headache was mentioned by the ma-

jority of participants, and is an influenza symptompresent inmuch of the literature, it was decided thatheadache was too common and general to be usefulin the specific diagnosis of influenza.Cough was the respiratory symptom most often

mentioned and was added to the checklist. Therewas considerable discussion among the WorkingGroup members as to whether a respiratory symp-tom had to be present for a positive influenza diag-nosis. Indeed, many of the participants had beeninvolved in studies of influenza treatments, whichspecified the inclusion of patients with fever andat least one respiratory and one systemic symp-tom.[11,42] However, several experts pointed outthat, in their experience, respiratory symptomsapart from cough were often minimal in the earlystages of the disease. The absolute requirement fora respiratory symptom was therefore not adoptedfor an early diagnosis.Epidemiological support for the diagnosis of in-

fluenza, such as knowledge of a local outbreak orif the patient had a family member or other closecontact with influenza, was considered to be of vi-tal importance. The panel decided that the guide-lines should operate within the parameters of suchepidemiological support.

The final checklist is shown in table I. Partici-pants agreed that, in accordance with documentedliterature and clinical trial data from influenzatreatment studies, the symptoms of fever andcough are particularly useful diagnostic meas-ures.[11,42] In fact, therapeutic benefit from anti-virals has only been shown in persons with febrileinfluenza i.e. the presence of fever is particularlyimportant when considering antiviral therapy as itis a good predictor of response to treatment.When treating influenza with antivirals, these

symptoms should have been present for less than48 hours in order for the treatment to be of clinicalbenefit.The panel emphasised the importance of a phys-

ical examination of the patient when making a di-agnosis of influenza, so that other, perhaps moreserious illnesses with similar clinical manifestationsor bacterial suprainfections, are not overlooked.

3.3 Scope of the Guidelines

The guidelines outlined in section 3.2 apply tootherwise healthy adults aged <65 years. The Work-ing Group subsequently considered whether theguidelines could be equally applied to other patientpopulations, including otherwise healthy childrenand ‘at-risk’patients comprising otherwise healthyelderly and individuals with concomitant healthproblems such as those outlined in the introduc-tion. However, in view of the complicated issuesassociated with influenza symptomatology in chil-dren and those with underlying diseases, only theat-risk group comprising otherwise healthy elderlyis discussed (see section 3.3.1). Further meetings

Table I. Guidelines for the early clinical diagnosis of influenza

If there is a local outbreak of influenza or if the patient has afamily member or other close contact with influenza, apresumptive diagnosis can be made when the patient presentswith sudden onset of:• fever, feverishness/chillsplus any one of the following:• cough• myalgia (aching, stiffness)• malaise (tiredness)



of the InfluenzaDiagnosisWorkingParty are plannedto take place during 2001 in order to define diag-nostic criteria for influenza in both children andthose with concomitant health problems.

3.3.1 Otherwise Healthy ElderlyOverall, theWorking Party decided that the gen-

eral guidelines were also applicable to otherwisehealthy elderly patients. However, the followingpoints should be noted:• Vaccinated elderly patients may still developinfluenza because of a variety of reasons, includ-ing impaired immunity, faulty injection tech-nique and mismatch of vaccine strain with thatcirculating in the community.[1] Despite this, in-fluenza vaccination remains the cornerstone ofinfluenza control in this patient group, prevent-ing severe illness, complications and deaths.[1]

• Symptoms in the elderly often do not appearwith such a sudden onset as observed in youngeradults.

• A systemic response to influenza is mountedmore slowly in elderly than in younger patients,and systemic symptomsmay appear less severe.[43]In some cases, fevermay be lower or completelyabsent. Consequently, respiratory symptomsmay seem to start earlier in the disease processin the elderly compared with younger adults.

• Malaise is not an ideal indicator for influenzadiagnosis in the elderly because this populationmay often feel generally unwell, without influ-enza infection.

• Elderly patients experience chest pain with in-fluenza infection more often than youngeradults and this may be the first sign of influenza-associated complications.

4. Conclusions

The advent of new therapeutic agents for influ-enza infection with a broader spectrum of action(i.e. against influenza AandB viruses) and the abil-ity to reduce influenza-associated complicationsoffers family practitioners the potential for im-proved management of this common, yet poten-tially fatal, infection. Prompt and accurate diagno-sis provides the foundation for effective disease

management. The probability of ‘true’ influenzainfection is much increased when persons presentwith typical symptoms/criteria during a known in-fluenza outbreak or following close contact with aperson with the infection. Such symptoms/criteriainclude sudden onset of the symptom complex offever, feverishness or chills, and any one of myal-gia, cough and malaise, and form the basis of theguidelines developed by the Influenza DiagnosisWorking Party. The recommendations of this groupare intentionally simple and practical in order tofacilitate widespread use among family practition-ers and other primary healthcare professionals.They are easily adaptable into a handy referencecard for general use and public education, and aretranslatable into other languages.For the present, the guidelines apply only to oth-

erwise healthy adults (including the ambulatory el-derly). Guidelines for otherwise healthy children,patients of all ages with underlying chronic healthconditions and the institutionalised elderly awaitthe conclusions of further discussions by theWork-ing Party.

Acknowledgements

The Influenza Diagnosis Working Party: René Snacken,Brussels, Belgium; Albert Osterhaus, Rotterdam, The Neth-erlands; Andrew Rotheray, Falmouth, Cornwall, UK; AlanMiddleton, Fowey, Cornwall, UK; Fabrizio Pregliasco, Mi-lan, Italy; J. Vidal Tort, Barcelona, Spain; Alain El Sawy, StMartin d’hers, France; Loïc Boucher, Muis-Eugné, France;Jean-Marie Cohen, Paris, France; Jérôme Boussac, Car-quefou, France; Rudolf Fuchs, Hermaringen, Germany;George Leo, Berlin, Germany; Otmar Carewicz, Dossen-heim, Germany; Paul Whitsitt, Ontario, Canada. The Influ-enzaDiagnosisWorking Party is sponsored by an educationalgrant from F Hoffmann-La Roche Ltd.

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About the Author: René Snacken is responsible for the pro-gramme of influenza surveillance in the Scientific Instituteof Public Health in Belgium. He is Chairman of the Eu-ropean Scientific Working Group on Influenza (ESWI).Correspondence and offprints: Dr René Snacken, ScientificInstitute of Public Health – Louis Pasteur, Section Virology,J. Wytsman Street 14, 1050 Brussels, Belgium.



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Managing Influenza in Primary Care