Clinical manifestations and diagnosis of influenza.

Infection with influenza presents as a spectrum of disease ranging from patients who are asymptomatic to those with fulminant primary viral pneumonia, depending on host immune status and the dose of virus. There is generally an abrupt onset of symptoms after an asymptomatic incubation period of a few days. Uncomplicated influenza usually presents as tracheobronchitis with involvement of the small airways (1) (Table 1), with systemic symptoms that are usually described first by the patient in abrupt fashion and include fever, chills, cough, myalgias (involving the long muscles of the back and the extremities), malaise, headache, and anorexia. Cough that usually changes in nature from dry to productive, as well as headache and myalgia, seem to be the most prominent symptoms. (2,3) The illness usually affects cigarette smokers in a more severe fashion. (4)

Clinical Manifestations of Influenza

The systemic symptoms of influenza drive patients to seek medical attention. Other respiratory symptoms such as rhinorrhea and nasal obstruction also are present at the onset of the viral illness. Patients describe photophobia and eye pain, especially when moving the eye laterally. Tearing and burning sensations involving the eye are common. Diarrhea and abdominal pain also are reported but seem to be less common. Patient temperatures routinely increase to between 38 and 40[degrees]C, but high-grade fevers to 41[degrees]C have been associated with influenza. The fever curve peaks within 12 hours of the onset of illness and accompanies the development of systemic symptoms. Respiratory signs and symptoms usually become more intense as the patient's body temperature decreases. The duration of fever is 3 days on average but may last between 1 and 5 days. (2)

The physical examination reveals the patient to appear toxic, usually with a flushed face and moist, hot skin. The eyes are red with lacrimation, and the mucous membranes usually reveal no exudates but are hyperemic. Cervical lymph node enlargement may be present. The lung examination reveals scattered crackles or wheezes in fewer than 25% of the patients. Systemic symptoms last for 3 to 4 days, although malaise, cough, and lassitude may continue for weeks afterward. The clinical picture may differ during an outbreak, because patients may present with pharyngitis, tracheobronchitis, common cold symptoms, or other acute respiratory syndromes. Patients may present with symptoms of a systemic illness with no respiratory complaints. (2,3,5) Despite the significant abnormalities in small and large airways during acute infection with influenza, there is usually little permanent damage in the lungs, even in patients with chronic obstructive pulmonary disease. (6,7)

Infection with influenza B leads to a clinical illness similar to influenza A, although some authorities report that influenza B may be associated with a milder illness. (8,9) Influenza C, however, induces an afebrile, common cold-like illness and is a rare cause of influenza. (10) There are significant similarities in the clinical manifestations of influenza infection in adults and children, with some notable differences. Children often have a higher-grade fever that may be associated with febrile convulsions. Cervical lymph node enlargement is described more commonly in the pediatric population. In addition, croup caused by influenza is reported mainly in children, (11,12) In the elderly population, patients may present with lassitude, high fever, and confusion, with minimal respiratory signs.

Differential Diagnosis

Because the respiratory tract manifestations of influenza are not specific and may be seen in patients with other viral and bacterial respiratory pathogens, the differential diagnosis includes respiratory syncytial virus (RSV), coronaviruses, parainfluenza viruses, rhinoviruses, adenoviruses, and Myco-plasma pneumoniae, (13) During an epidemic of influenza A, patients who present with diffuse interstitial viral pneumonia are likely to have influenza infection, because it is rare to see severe forms of viral pneumonia with other respiratory viruses. This presentation may not be applicable in institutionalized elderly patients, in whom RSV can cause a similar severe disease. (14)

Diagnostic Testing for Influenza

The diagnosis of influenza can be made clinically during influenza season in appropriate settings. (15,16) Because specific treatment for influenza should be initiated fairly rapidly after the onset of symptoms, the diagnosis of influenza should be made as rapidly as possible. (17) The laboratory diagnosis of influenza ideally is made on the basis of a method that has high specificity and high sensitivity, low cost, and rapid turnover. When the prevalence of influenza is high in a community, the positive predictive value of such testing improves. The methods currently used for influenza infection diagnosis include direct immunofluorescence, enzyme-linked immunosorbent assay, viral culture, polymerase chain reaction, serologic testing, and epidemiologie diagnosis. A summary of these methods' respective sensitivities and specificities is provided in Table 2.

Direct Immunofluorescence. Direct immunofluorescence is performed with nasopharyngeal aspirates to detect viral antigen on pharyngeal columnar epithelial cells by staining them directly with fluorescent antibody. Results are obtained within a few hours, but the sensitivity and specificity are lower than they are for enzyme-linked immunosorbent assays. (18) The advantage of this technique is its low cost; the disadvantage is the need for highly skilled laboratory personnel to interpret the results. Because specimens require special processing to concentrate the epithelial cells in the aspirate, this technique is no longer widely used in clinical practice. (19)

Enzyme-linked Immunosorbent Assay. This test is simple and can be performed fairly rapidly. Free viral antigen in nasopharyngeal secretions is detected by using enzyme-conjugated antibodies specific for influenza A and B antigens. This test is highly sensitive and specific for influenza A and B compared with viral cultures. (20) The available kits that use this assay have become the predominant tools for rapid diagnosis of influenza in the clinical setting.

Viral Culture. The specimen for viral culture is obtained from nasopharyngeal aspirate or by swabbing. Secretions are inoculated into rhesus monkey kidney, cynomolgus monkey kidney, or Madin-Darby canine kidney cell culture. Within 1 to 3 days, analysis of cell cultures is performed, focusing on cytopathic changes or hemadsorption. Approximately two-thirds of the positive cultures are detected within 3 days, and by Days 5 to 7, the remaining one-third are detected. This technique has the advantages of being reproducible, high sensitivity and specificity, and availability. The time required for processing makes this technique of little use when early treatment decisions are needed. It also requires experienced staff with technical expertise, who are not available in all clinical laboratories. (15)

The time needed for viral detection can be shortened to 1 to 2 days by centrifugation of the samples directly onto cells in shell vials, followed by viral antigen detection with the use of direct immunofluorescence, enzyme-linked immunosorbent assay, or monoclonal antibodies. (21) Promising new culture techniques include the R-Mix method, which uses mixed cell cultures coupled with immunofluorescent staining. The R-Mix method is fairly rapid, with results obtained within 24 hours, and it seems to be highly sensitive. (22)

Polymerase Chain Reaction. Polymerase chain reaction, a fairly recent technique, has proved to be more sensitive and more specific than standard culture techniques. Although labor-intensive and costly, results can be obtained within a few hours. (23) If the cost decreases and technical aspects become more streamlined, this technique may become the method of choice in the diagnosis of influenza.

Serologic Testing. Serologic testing, despite being both sensitive and specific, has limited value in clinical practice because the diagnosis requires at least 20 days. This test compares acute and convalescent sera (the latter are usually obtained 10-20 days after the acute phase serum). To diagnose an infection with influenza, a fourfold or greater increase in titer is necessary. Serologic assays are used mainly for epidemiologic evaluation of influenza. (16)

Epidemiologic Diagnosis

In an influenza outbreak setting, individuals who complain of muscle ache, fever, and two respiratory symptoms probably have influenza if the virus is confirmed in that region by a local health department or the Centers for Disease Control and Prevention. (24,25) This may not be true of individuals who reside in institutions, however, because other respiratory infections such as RSV may cause a clinical picture similar to that of influenza). (22)

Table 1. Symptoms during influenza infection (a)

Symptom         Incidence       Symptom         Incidence

Sudden onset       75%      Nasal obstruction      36%
Fever              51%      Sore throat            46%
Chills             37%      Sweating               31%
Myalgia            39%      Dizziness              26%
Headache           58%      Anorexia               28%
Cough              48%

(a) References 14, 15, and 22.

Table 2. Summary of the utility of the individual testing
modalities (a)

                                         Viral
Characteristic   DIF (b)   ELISA (c)   culture (d)   PCR (e)

Specificity       90%        100%         100%        100%
Sensitivity       70%        85%          100%        100%
Assay time       Hours      Hours         Days        1 day

(a) DIF, direct immunofluorescence assay; ELISA, enzyme-linked
immunosorbent assay; PCR, polymerase chain reaction.

(b) References 18, 19.

(c) Reference 20 (most commonly used assay systems).

(d) References 15, 21.

(e) Reference 23.

References

(1.) Walsh JJ, Dietlein LF, Low FN, et al. Bronchotracheal response in human influenza type A, Asian strain, as studied by light and electron microscopic examination of brunchoscopic biopsies. Arch Intern Med 1961;108:376-388.

(2.) Nicholson KG. Clinical features of influenza. Semin Respir Infect 1992; 7:26-37.

(3.) Stuart-Harris CH. Twenty years of influenza epidemics. Am Rev Respir Dis 1961;83:54-75.

(4.) Kark JD, Lebiush M, Rannon L. Cigarette smoking as a risk factor for epidemic A(H1N1) influenza in young men. N Engl J Med 1982;307: 1042-1046.

(5.) Kilbourne ED, Loge JP. Influenza A prime: A clinical study of an epidemic caused by a new strain of virus. Ann Intern Med 1950;33:371-382.

(6.) Ledder SR, Gill PW, Peat JK. Short and long term effects on influenza A on lung function. Med J Aust 1974;2:812-814.

(7.) Smith CB, Kanner RE, Golden CA, et ah Effect of viral infections on pulmonary function in patients with chronic obstructive pulmonary diseases. J Infect Dis 1980;141:271-280.

(8.) Nigg C, Eklund CM, Wilson DE, et al. Study of an epidemic of influenza B. Am J Hyg 1942;35:265-284.

(9.) Baine WB, Luby JP, Martin SM. Severe illness with influenza B. Am J Med 1980;68:181-189.

(10.) Mogabgab WJ. Viruses associated with respiratory illnesses in adults. Ann Intern Med 1963;59:306-311.

(11.) Glezen WP, Loda FA, Clyde WA Jr, et al. Epidemiologic patterns of acute lower respiratory disease of children in a pediatric group practice. J Pediatr 1971;78:397-406.

(12.) Glezen WP, Paredes A, Taber LH. Influenza in children: Relationship to other respiratory agents. JAMA 1980;243:1345-1349.

(13.) Kim HW, Brandt CD, Arrobio JO, et al. Influenza A and B virus infection in infants and young children during the years 1957-1976. Am J Epidemiol 1979;109:464-479.

(14.) Falsey AR, Cunningham CK, Barker WH, et al. Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J Infect Dis 1995;172:389-394.

(15.) Cram P, Blitz SG, Monto A, et al. Diagnostic testing for influenza: Review of current status and implications of newer treatment options. Am J Manag Care 1999;5:1555-1563.

(16.) Newton DW, Treanor JJ, Menegus MA. Clinical and laboratory diagnosis of influenza virus infections. Am J Manag Care 2000;6(5 Suppl): S265-S275.

(17.) Hulson TD, Mold JW, Scheid D, et al. Diagnosing influenza: The value of clinical clues and laboratory tests. J Fam Pract 200l;50:1051-1056.

(18.) Daisy JA, Lief FS, Friedman HM. Rapid diagnosis of influenza A infection by direct immunofluorescence of nasopharyngeal aspirates in adults. J Clin Microbiol 1979;9:688-692.

(19.) Leonardi GP, Leib H, Birkhead GS, et al. Comparison of rapid detection methods for influenza A virus and their value in health-care management of institutionalized geriatric patients. J Clin Mierobiol 1994;32:70-74.

(20.) Waner JL, Todd SJ, Shalaby H, et al. Comparison of Directigen FLU-A with viral isolation and direct immunofluorescence for the rapid detection and identification of influenza A virus. J Clin Microbiol 1991;29: 479-482.

(21.) Espy MJ, Smith TF, Harmon MW, et al. Rapid detection of influenza virus by shell vial assay with monoclonal antibodies. J Clin Microbiol 1986;24:677-679.

(22.) St George K, Patel NM, Hartwig RA, et al. Rapid and sensitive detection of respiratory virus infections for directed antiviral treatment using R-Mix cultures. J Clin Virol 2002;24:107-115.

(23.) van Elden LJ, van Essen GA, Boucher CA, et al. Clinical diagnosis of influenza virus infection: Evaluation of diagnostic tools in general practice. Br J Gen Praet 2001;51:630-634.

(24.) Zambon M, Hays J, Webster A, et al. Diagnosis of influenza in the community: Relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza. Arch Intern Med 2001; 161:2116-122.

(25.) Hak E, Moons KG, Verheij TJ, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med 2001;161:1351-1352 (letter).

From the James H. Quillen VA Medical Center and the Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

No financial support was obtained for this manuscript. The authors of this manuscript do not have any financial, commercial, or proprietary interest in any drug, device, or equipment mentioned in this article. The views contained in this article do not necessarily reflect those of the Department of Veterans Affairs of the United States.

Reprint requests to Felix A. Sarubbi, MD, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted June 19, 2003.