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R. Phillip Dellinger, MD, FCCM, Section EditorConcise Definitive Review
Influenza
John H. Beigel, MD
I
nfluenza is a major concern forintensivists in all communities inthe United States. Although thereis considerable concern whetheror not the country will be ready for apandemic influenza, even seasonal influ-enza poses a major challenge to hospitals.This concise review summarizes currentknowledge about influenza.
SEASONAL INFLUENZA
Seasonal influenza, the influenza dis-ease that occurs on a yearly basis, causesmore than 200,000 hospitalizations and41,000 deaths in the United States every year and is the seventh leading cause of death in the United States (1). Despitethis, 38% of unimmunized individualsfeel they are not at risk for influenza andits related complications (2). Althoughthis may be easy to attribute to the per-ceptions of the lay public, physicians’attitudes are not much better; only 35%to 40% of healthcare workers are vacci-nated annually; 40% of physicians believethat influenza is a benign disease thatdoes not require treatment; and 29% be-lieve that antiviral therapy decreasesmortality, an efficacy that has never beenshown in clinical trials (3, 4). Intensivistsneed to recognize the importance of sea-sonal influenza as a cause of severe mor-bidity and mortality, and be well versedon diagnosis, complications, therapy, andinfection control measures associated with this disease.
Virus.
Influenza viruses are membersof Orthomyxoviridae family of viruses,and are negative strand RNA viruses (5).Influenza viruses can be classified as A, B,or C. Influenza A is found in humans,other mammals, and birds, and is theonly influenza virus which has histori-cally caused pandemics. Types B and C, while previously thought found only inhumans have been isolated from sealsand pigs, respectively (6–8). Influenza Aand B are more common than type C, andcause more severe disease. Influenza C isa significant cause of respiratory infec-tions in children younger than 6 yrs of age (9). The majority of humans acquireprotective antibodies to influenza C earlyin life and do not subsequently developclinical disease (10).Influenza A can be further classifiedbased on surface glycoproteins: hemag-glutinin and neuraminidase. The viralhemagglutinin binds to host cell sialicacid conjugated glycoproteins (11). Thisattachment is necessary for viral entryinto the cell. The configuration of thesialic acid conjugated glycoproteins var-ies from species to species, and may serveto limit transfer of viruses across species(12). Neuraminidase is important for vi-ral release and propagation (13). Thenaming convention signifies which of these proteins is on a given virus. Thus,the standard nomenclature is Influenza AH
 x
N
 x
(the x is the number correspondingto the specific type of hemagglutinin andneuraminidase). The nomenclature is rel-evant to clinicians because changes inhemagglutinin antigens, and to a lesserextent neuraminidase antigens, signal vi-ruses that population may have little orno prior immunity to. When major anti-genic shifts occur, patients unimmunizedagainst the new strain may develop par-ticularly severe disease. Wild aquatic birds are the naturalreservoir of influenza A viruses. Thereare 16 types of hemagglutinin (H1–H16)and nine types of neuraminidase (N1–N9)and all have been found circulatingin wild and domestic birds (14).Three types of hemagglutinin (H1–H3)and two neuraminidase (N1–N2) areknown to have caused widespread diseasein humans (H1N1, H2N2, H3N2). Onlytwo of these viruses (H1N1 and H3N2)are currently circulating as seasonal in-fluenza. H2N2 has not circulated in hu-mans since 1968.
From the National Institute of Allergy and Infec-tious Diseases, National Institute of Health, Be-thesda, MD.This research was supported, in part, by the In-tramural Program of the NIH, National Allergy andInfectious Diseases Institute and Critical Care MedicineDepartment, Clinical Center, National Institutes ofHealth.The author is involved in scientific collaborationswith Roche, Biocryst, and Omrix.For information regarding this article, E-mail: jbeigel@niaid.nih.govCopyright © 2008 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e318180b039
Objective: 
Influenza is a major concern for intensivists in allcommunities in the U.S. While there is considerable concernwhether or not the country will be ready for a pandemic influenza,even seasonal influenza poses a major challenge to hospitals. Theobjective of this review is to summarize current knowledge ofinfluenza with emphasis on the issues that intensivist will en-counter.
Setting: 
Intensive care unit in a 450-bed, tertiary care, teachinghospital.
Methods: 
Source data were obtained from a PubMed search ofthe medical literature. PubMed “related articles” search strate-gies were likewise employed frequently.
Summary and Conclusions: 
Seasonal influenza causes morethan 200,000 hospitalizations and 41,000 deaths in the U.S. everyyear, and is the seventh leading cause of death in the U.S. Despitethis impact there is a shortcoming in knowledge of influenza amongmany health care workers, and a paucity of clinical data and studiesto guide therapy. Intensivists need to recognize the importance ofseasonal influenza as a cause of severe morbidity and mortality. Thisreview summarizes current knowledge of the diagnosis, complica-tions, therapy, and infection control measures associated with influ-enza. (Crit Care Med 2008; 36:2660–2666)K 
EY
W
ORDS
: influenza; avian flu; pandemic; pneumonia; compli-cations; treatment
2660 Crit Care Med 2008 Vol. 36, No. 9
 
 AVIAN INFLUENZA
It has been recognized in the last de-cade that other influenza A viruses thatcirculate in birds are able to infect hu-mans. Currently Avian influenza is anepisodic zoonotic disease. Most humancases have been associated with concur-rent outbreaks of influenza in domesticand wild birds (15). Although individualcases and small clusters have occurred, widespread circulation of the virus in anyhuman population has not yet occurred.Sporadic human cases of H5N1 haveoccurred over the last several years, ashave outbreaks of H7N3, H7N7, H9N2,and H10N7. These later viruses havecaused relatively few human cases. Genereassortment of these viruses with otheranimal or human influenza viruses couldproduce more virulent and transmissible viruses. Most experts predict that a majorreassortment will eventually occur. Basedon previous pandemics, the virus wouldlikely be a reassortment virus using avianand human influenza genes, and producea transmissible, virulent virus against which humans have little or no preexist-ing immunity. When this will occur isimpossible to predict, but most scientiststhink that this will occur within severaldecades of the last major antigenic shift(1977). Thus, since such an outbreak hasnot occurred in 30 yrs, there is greatconcern that a global pandemic could beimminent.
EPIDEMIOLOGY
The epidemiology of influenza variesdepending on locale. In North Americaand other northern climates, influenzaactivity is generally seasonal: activity in-creases during the cooler months andpeaks from December to March. There islarge variation in this activity, however,and peaks may occur as early as Octoberand as late as May (16). In the UnitedStates, influenza rarely occurs betweenMay and September, unless the virus wasacquired outside the United States.For locations that are more proximateto the equator, the influenza season be-comes prolonged to the point of multi-phasic or year round disease, and is in-fluenced by other climate patterns suchas rainy season (17–19).
Transmission.
Human influenza at-tachesandinvadestheepithelialcellsoftheupper respiratory tract. Viral replication inthese epithelial cells lead to proinflamma-tory cytokines, and necrosis of ciliated epi-thelial cells (20, 21). This combination of events may cause coughing. When humans exhale or talk, smallrespiratory droplets are generated on aroutine basis, but these are generally lessthan 1
m (22). With a cough, largerdroplets (
5
m) are generated. The sizeof the droplet dictates the distance thatthe droplet can be carried by air currents(airborne vs. droplet spread): smallerdroplets remain airborne longer, andthus spread further. Although rigorous data are lacking,influenza is thought primarily transmit-ted from person to person by large drop-lets (
5
m) that are generated wheninfected persons cough or sneeze (23).These large droplets settle on the muco-sal surfaces of the upper respiratorytracts of susceptible persons. Given thesize and weight of these droplets, trans-mission primarily occurs in those whoare near the infected person (within 3feet).Coughs also generate smaller dropletnuclei, which theoretically can be spreadlonger distances by air currents (air-borne). Several epidemiologic investiga-tions have invoked airborne transmissionof influenza, but this is relatively rare(24). Finally, contact transmission mayplay a role. Infected individuals will oftentouch mucous membranes before directinterpersonal contact (e.g., hand shak-ing) or indirect contact such as touchingcommon surfaces. Influenza virus hasbeen detected on over 50% of the fomitestested in homes and day care centers dur-ing influenza season (25). Uninfected in-dividuals touch these surfaces or engagein interpersonal contact, then touch theirmucous membranes, thereby depositinginfectious virus on their mucous mem-branes. Whether the route of exposure orinfectious dose influences the incubationperiod or clinical manifestations is not well studied.
 Infection Control.
If patients with in-fluenza are admitted to the hospital, es-pecially early in the clinical course whilethey are actively shedding virus, theyshould be isolated with “droplet precau-tions.” The Center for Disease Controland Prevention defines this as placing thepatients in private rooms (or cohortingpatients with influenza) and having per-sonnel entering the room or within 3 feetof a person use a surgical or proceduremask and standard precautions (i.e., hand washing, gloving, and gowning whensoiling with the patient’s respiratory se-cretions is likely) (26). If the patientneeds to be transported from the room,the patient should wear a surgical mask,if possible, to minimize the dispersal of droplets. Certain droplet generating pro-cedures such as intubation have beenshown to increase the risk of transmis-sion to the healthcare workers in other viral respiratory infections such as severeacute respiratory syndrome (27). There isno demonstrated added value of placingpatients with influenza in rooms for air-borne infection isolation (i.e., negative-pressure rooms), using N95 respirators,or personal air-powered respirators (26).If a highly virulent form of influenza wereto circulate widely, however, such addedprecautions might well be prudent if themagnitude of the outbreak made suchmeasures feasible.
Clinical Features.
The incubation pe-riod for influenza is usually 1–2 days, butcan be up to 4 days. The classic clinicalsymptoms of influenza are fever, myalgia,sore throat, and nonproductive cough.However, only about 50% of infected per-sons present with these classic symp-toms. The fever is usually 101°–102°F,and often occurs with an abrupt onset. Additional symptoms may include rhi-norrhea, headache, nausea, and diarrhea.In most patients, these symptoms andfever last 2 to 3 days. Although most influenza is associated with a mild acute self-limited illness,more severe manifestations can occur.Influenza infections can present as a typ-ical community acquired pneumonia with fever, cough, bilateral interstitial in-filtrates, hypoxemia, and leucopenia. Inseveral series, influenza is the etiology of 5% to 10% of community-acquired pneu-monias (CAPs) (28–30). The incidence isslightly higher in pediatric series (12%)and immunosuppressed populations(11%) (31, 32). More severe disease isgenerally seen in young children, personsaged
65 yrs, and persons of any age with underlying health conditions (33).In one series comparing influenza upperrespiratory infection and pneumonia,those with pneumonia were older (63 vs.51 yrs old), and more likely to havechronic respiratory disease (41% vs. 6%)(34). Bilateral diffuse interstitial/alveolarinfiltrates were seen as the most commonradiographic abnormality (52%), fol-lowed by right lower lobe consolidation(35%).Primary influenza pneumonias are dif-ficult to distinguish from other viral, bac-terial, or atypical pneumonias based onclinical radiologic, or laboratory alone. In
2661Crit Care Med 2008 Vol. 36, No. 9
 
one series, 9% of people hospitalized withcommunity acquired pneumonia had adual infection with both a respiratory vi-rus and bacterial pathogen, and an addi-tional 9% had only a respiratory virusisolated, with influenza the most com-mon (33).There are no clinical criteria that candifferentiate influenza or other viralpneumonias from bacterial pneumonias.Cough and expectoration occur less com-monly in viral pneumonias, but produc-tive cough is still present in more than50% of cases (33).Patients with more severe disease shed virus longer than uncomplicated influ-enza, with a median duration of viralshedding of 4 days compared with 1–2days in less severe disease (35). Immuno-suppressed patients can shed influenzafor months (36).
 Diagnosis.
In the community, thetriad of fever, respiratory symptoms(cough, sore throat, or nasal symptoms),and constitutional symptoms (headache,mailase, myalgia, sweats/chills or fatigue)had a sensitivity of 60% if influenza isknown to be present in the community(37). However, to guide isolation policyand therapy, definitive diagnosis of influ-enza as the causative organism is often warranted. Virus replication begins within 6 hrsof infection, and continues at least con-tinues 24 hrs before the onset of symp-toms (38). The duration of shedding de-pends on the severity of illness and age(35, 37, 39), but generally virus can beisolated from throat and nasopharyngealswabs obtained within 2 days of onset of illness. In adults, viral shedding contin-ues for 1–3 days after onset of symptoms.Children can shed virus for 10 days ormore (39).There are several modalities to docu-ment influenza infection. These includedirect viral detection (antigen tests, poly-merase chain reaction [PCR], immuno-fluorescence, and culture), or serologictests. The choice among these tests isdependant on the use and answerssought.Rapid tests of respiratory secretions:Direct testing of sputum and nasal washes for influenza antigen permits arapid diagnosis in a variety of settings.There are commercially available rapidantigen testing kits. These vary by theircomplexity, storage conditions, and re-porting metrics, but the test characteris-tics (sensitivity and specificity) are largelysimilar. Generally, these tests are veryspecific (95–100%), but sensitivity ismodest, especially in adults (50–70%)(40–42). Higher sensitivity is reported inchildren compared with adults (43).Immunofluorescence microscopy of respiratory specimens to detect influenzaantigens increases the sensitivity (80%)compared with rapid antigen kits withsimilar specificity (40). Immunofluores-cence microscopy involves deposition of respiratory epithelial cells from a pelletedsample onto a slide, followed by staining with specific antibodies directly conju-gated to a fluorescent dye (direct fluores-cent antibody) or staining with an anti-body to the viruses and a secondconjugated antibody directed at the first(immunofluorescent antibody) (44). Be-cause of time and expense, few laborato-ries do this type of test.Culture is the gold standard for diag-nosis. It is performed by inoculation of cell cultures that support viral replica-tion, and takes a minimum of 48 hrs todemonstrate viral growth, with additionaltime for specific viral identification. Cul-tures are helpful in defining the etiologyof local outbreaks, and may demonstrateother pathogens. Clinicians need to becognizant, however, that the presence of influenzadoesnotprecludeconcurrentinfec-tion with another pathogen, especially pneu-mococcus or staphylococcus. In research set-tings, drug susceptibility testing of influenzaisolates can be done.Nucleic acid testing (PCR) is gaining widespread use due to the versatility while maintaining high sensitivity andspecificity. PCR has a sensitivity andspecificity approaching 100%, and some-times the sensitivity may exceed cultures(45). These tests will not only establish adiagnosis of influenza, but will providestrain specific information that may beuseful for epidemiologic and therapeuticpurposes. Multiplex PCR platforms allowsimultaneous testing for multiple patho-gens (46, 47). Some of these platformsallow simultaneous testing of multiple viral, bacterial, mycobacterial, and fungalagents. Newer techniques such as PCR with electrospray ionization mass spec-trometry may have future clinical appli-cations but currently are still for researchpurposes (48).Serologic testing for IgM or IgG anti-bodies can be performed to confirm adiagnosis, but such testing is rarely help-ful in the intensive care unit setting be-cause 7–21 days are required to docu-ment seroconversion or rising titers(Table 1).
Complications.
Influenza deaths canresult from pneumonia (either primaryor secondary bacterial pneumonia), orfrom exacerbations of cardiopulmonaryconditions. When overall influenza at-tributable mortality is examined by com-paring deaths above seasonal baseline in years of high influenza versus low influ-enza activity, influenza and influenzapneumonia account for only 15% of theattributable excess mortality, whereaschronic obstructive pulmonary diseasehas been the cause of death in 14% andischemic heart disease has been the causein a staggering 23% (49).There are several well-described extrapulmonary complications of influenza. Although many of these complicationsoccur in subjects known to have influ-enza, others will present for medical caredue in patients not recognizing or seek-ing medical care for primary influenzainfection. The most frequent complica-tion of influenza is secondary bacterialpneumonia. Causative agents are classi-cally
Staphylococcus aureus
, but also
 Streptococcus pneumoniae
,
Haemophi-lus influenzae
, and other Gram-negativebacilli.
Table 1.
Diagnostic testsTime to Result Advantages DisadvantagesRapid antigen
30 mins Fast, not technically difficult,point of care testingMarginal sensitivity especiallyin adults, does notdistinguish subtypes of influenzaImmunofluorescence 1–4 hrs Fast and versatile Not widely available, requirestechnical expertiseNucleic acid testing 4–24 hrs Very sensitive, subtypes virus,detects other respiratorypathogensRequires technical expertiseCulture 24 hrs–5 days Very sensitive, detects otherrespiratory virusesSlow results Antibody testing Several weeks Highly specific and sensitive Labor intensive, slow results
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