Clinical Signs and Symptoms of Influenza

NOTE: The text below is taken directly from Prevention & Control of Influenza - Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2007 Jul 13;56(RR06):1-54. Also available as PDF (720K).

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Hospitalizations & Deaths from Influenza
Table 1: Month of Peak Influenza Activity
Table 2: Estimated Rates of Influenza-associated Hospitalization

Influenza viruses are spread from person to person primarily through large-particle respiratory droplet transmission (e.g., when an infected person coughs or sneezes near a susceptible person) (14). Transmission via large-particle droplets requires close contact between source and recipient persons, because droplets do not remain suspended in the air and generally travel only a short distance (1 meter or less) through the air. Contact with respiratory-droplet contaminated surfaces is another possible source of transmission. Airborne transmission (via small-particle residue [5μm or less] of evaporated droplets that might remain suspended in the air for long periods of time) also is thought to be possible, although data supporting airborne transmission are limited. The typical incubation period for influenza is 1–4 days (average: 2 days). Adults can be infectious from the day before symptoms begin through approximately 5 days after illness onset. Young children also might shed virus several days before illness onset, and children can be infectious for 10 days or more after onset of symptoms. Severely immuno-compromised persons can shed virus for weeks or months.

Uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis). Among children, otitis media, nausea, and vomiting also are commonly reported with influenza illness. Uncomplicated influenza illness typically resolves after 3–7 days for the majority of persons, although cough and malaise can persist for >2 weeks. However, influenza virus infections can cause primary influenza viral pneumonia; exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease); lead to secondary bacterial pneumonia, sinusitis, or otitis; or contribute to coinfections with other viral or bacterial pathogens. Young children with influenza virus infection might have initial symptoms mimicking bacterial sepsis with high fevers, and febrile seizures have been reported in 6%–20% of children hospitalized with influenza virus infection. Population- based studies among hospitalized children with laboratory- confirmed influenza have demonstrated that although the majority of hospitalizations are brief (2 days or less), 4%–11% of children hospitalized with laboratory-confirmed influenza required treatment in the intensive care unit, and 3% required mechanical ventilation. Among 1,308 hospitalized children in one study, 80% were aged <5 years, and 27% were aged <6 months. Influenza virus infection also has been uncommonly associated with encephalopathy, transverse myelitis, myositis, myocarditis, pericarditis, and Reye syndrome.

Respiratory illnesses caused by influenza virus infection are difficult to distinguish from illnesses caused by other respiratory pathogens on the basis of signs and symptoms alone. Sensitivity and predictive value of clinical definitions can vary, depending on the degree of circulation of other respiratory pathogens and the level of influenza activity. Among generally healthy older adolescents and adults living in areas with confirmed influenza virus circulation, estimates of the positive predictive value of a simple clinical definition of influenza (cough and fever) for laboratory-confirmed influenza infection have varied (range: 79%–88%).

Young children are less likely to report typical influenza symptoms (e.g., fever and cough). In studies conducted among children aged 5–12 years, the positive predictive value of fever and cough together was 71%–83%, compared with 64% among children aged <5 years. In one large, population-based surveillance study in which all children with fever or symptoms of acute respiratory tract infection were tested for influenza, 70% of hospitalized children aged <6 months with laboratory-confirmed influenza were reported to have fever and cough, compared with 91% of hospitalized children aged 6 months–5 years. Among children with laboratory-confirmed influenza infections, only 28% of those hospitalized and 17% of those treated as outpatients had a discharge diagnosis of influenza. A study of older nonhospitalized patients determined that the presence of fever, cough, and acute onset had a positive predictive value of only 30% for influenza. Among hospitalized older patients with chronic cardiopulmonary disease, a combination of fever, cough, and illness of <7 days was 53% predictive for confirmed influenza infection. The absence of symptoms of influenza-like illness (ILI) does not effectively rule out influenza; among hospitalized adults with laboratory-confirmed infection, only 51% had typical ILI symptoms of fever plus cough or sore throat. A study of vaccinated older persons with chronic lung disease reported that cough was not predictive of laboratory-confirmed influenza virus infection, although having both fever or feverishness and myalgia had a positive predictive value of 41%. These results highlight the challenges of identifying influenza illness in the absence of laboratory confirmation and indicate that the diagnosis of influenza should be considered in any patient with respiratory symptoms or fever during influenza season.

Hospitalizations and Deaths from Influenza

In the United States, annual epidemics of influenza typically occur during the fall or winter months, but the peak of influenza activity can occur as late as April or May (Table 1). Influenza-related hospitalizations or deaths can result from the direct effects of influenza virus infection or from complications due to underlying cardiopulmonary conditions and other chronic diseases. Studies that have measured rates of a clinical outcome without a laboratory confirmation of influenza virus infection (e.g., respiratory illness requiring hospitalization during influenza season) to assess the effect of influenza can be difficult to interpret because of circulation of other respiratory pathogens (e.g., respiratory syncytial virus) during the same time as influenza viruses.

During seasonal influenza epidemics from 1979–1980 through 2000–2001, the estimated annual overall number of influenza-associated hospitalizations in the United States ranged from approximately 55,000 to 431,000 per epidemic (mean: 226,000); the estimated annual number of deaths attributed to influenza ranged from 8,000 to 68,000 per epidemic (mean: 34,000). Since the 1968 influenza A (H3N2) virus pandemic, the number of influenza-associated hospitalizations typically has been greater during seasonal influenza epidemics caused by type A (H3N2) viruses than during seasons in which other influenza virus types or subtypes have predominated. In the United States, the number of influenza-associated deaths has increased since 1990. This increase has been attributed in part to the substantial increase in the number of persons aged 65 years and older, who are at increased risk for death from influenza complications. In one study, an average of approximately 19,000 influenza-associated pulmonary and circulatory deaths per influenza season occurred during 1976–1990, compared with an average of approximately 36,000 deaths per season during 1990–1999. In addition, influenza A (H3N2) viruses, which have been associated with higher mortality, predominated in 90% of influenza seasons during 1990–1999, compared with 57% of seasons during 1976–1990.

Influenza viruses cause disease among persons in all age groups. Rates of infection are highest among children, but the risks for complications, hospitalizations, and deaths from influenza are higher among persons aged 65 years and older, young children, and persons of any age who have medical conditions that place them at increased risk for complications from influenza. Estimated rates of influenza-associated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics (Table 2). During 1990–1999, estimated rates of influenza-associated pulmonary and circulatory deaths per 100,000 persons were 0.4–0.6 among persons aged 0–49 years, 7.5 among persons aged 50–64 years, and 98.3 among persons aged 65 years and older.

Table 1. Month of peak influenza activity* during 31 influenza seasons —United States, 1976-2006
	Month
	Nov	Dec	Jan	Feb	Mar	Apr	May
No. (%) of years with peak influenza activity	1 (3)	4 (13)	6 (19)	14 (45)	4 (13)	1 (3)	1 (3)
* The peak month of activity was defined as the month with the greatest percentage of respiratory specimens testing positive for influenza virus. Laboratory data were provided by the U.S. World Health Organization Collaborating Laboratory (CDC, National Center for Immunization and Respiratory Diseases unpublished data, 1976–2006).

Table 2. Estimated rates of influenza-associated hospitalization, by age group and risk group for selected studies—United States
Study years	Population	Age group	Hospitalizations/ 100,000 persons with high-risk conditions	Hospitalizations/ 100,000 persons without high-risk conditions
1973-1993*†§	Tennessee Medicaid	0-11 mos	1,900	496-1,038
		1-2 yrs	800	186
		3-4 yrs	320	86
		5-14 yrs	92	41
1992-1997§¶	Two health maintenance organizations	0-23 mos		144-187
		2-4 yrs		0-25
		5-17 yrs		8-12
1968-1969 1970-1971 1972-1973**††	Health maintenance organization	15-44 yrs	56-110	23-25
		45-64 yrs	392-635	13-23
		65 yrs and older	399-518	—
1969-1995††§§ 1969-1995††§§	Discharge Data	<65 yrs	—	20-42¶¶***
1969-1995††§§ 1969-1995††§§	Discharge Data	65 yrs and older	—	125-228***
1979-2001C	National Hospital Discharge Data	all ages	—	88§§§
1996-2000¶¶¶	Three health maintenance organizations	18-49 yrs	40	5
		50-64 yrs	123	18
		65 yrs and older	556	87
2000-2001****††††	Two counties	<1 yr	—	170
		1 yr		50
		2-<5 yrs		20
2001-2004††††§§§§	Large children's hospital	6 mos and younger		253
		6-11 mos		113
		1-<2 yrs		96
		2-<3 yrs		36
2000-2004††††¶¶¶¶¶	Three counties	6 mos and younger		240
		6-23 mos		60
		24-59 mos		20
2003-2004††††*****	9 states	6 mos and younger	311	118
1994-2000†††††	Health maintenance organization	6-23 mos	213	51
1994-2000†††††	Health maintenance organization	2-4 yrs	142	32
2000-2004††††§§§§§	Large children's hospital	0-23 mos		416
		2-4 yrs		70
		5-11 yrs		19
		12-17 yrs		18
* Sources: Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. Effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225–31. Neuzil KM, Wright PF, Mitchel EF Jr, Griffin MR. Burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000;137:856–64 † Outcomes were for acute cardiac or pulmonary conditions. The low estimate is for infants aged 6–11 months, and the high estimate is for infants aged 0–5 months. § Source: Izurieta HA, Thompson WW, Kramarz P, Mitchel EF Jr, Griffin MR. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med 2000;342:232–9. ¶ Outcomes were for acute pulmonary conditions. Influenza-attributable hospitalization rates for children at high risk were not included in this study. Source: Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980;112:798–811. †† Outcomes were limited to hospitalizations in which either pneumonia or influenza was listed as the first condition on discharge records or included anywhere in the list of discharge diagnoses. §§ Source: Simonsen L, Fukuda K, Schonberger LB, Cox NJ. Impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831–7. ¶¶ Persons at high risk and not at high risk for influenza-related complications are combined. * The low estimate is the average during influenza A (H1N1) or influenza B-predominate seasons, and the high estimate is the average during influenza A (H3N2)-predominate seasons. ††† Source: Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004;292:1333–40. §§§ Outcomes were for rate of primary respiratory and circulatory hospitalizations. Rate for all ages of persons, both with and without high-risk conditions. ¶¶¶ Source: Mullooly JP, Bridges CB, Thompson WW, et al. Influenza- and RSV-associated hospitalizations among adults. Vaccine 2006;25:846–55. ** Source: Iwane MK, Edwards KM, Szilagyi PG, et al. Population-based surveillance for hospitalizations associated with respiratory syncytial viirus, influenza virus, and parainfluenza viruses among young children. Pediatrics 2006;113:1758–64. †††† Laboratory-confirmed influenza virus infection. §§§§ Source: Ampofo K, Gesteland PH, Bender J, et al. Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics 2006;118:2409–17. ¶¶¶¶ Source: Poehling KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of influenza in young children. N Engl J Med 2006;355:31–40. *** Source: Schrag SJ, Shay DK, Gershman K, et al. Multistate surveillance for laboratory-confirmed, influenza-associated hospitalizations in children, 2003–2004. Pediatr Infect Dis J 2006;25:395–400. ††††† Source : O’Brien MA, Uyeki TM, Shay DK, et al. Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics 2004;113:585–93. §§§§§ Source: Coffin SE, Zaoutis TE, Rosenquist AB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with community-acquired influenza. Pediatrics 2007;119:740–8.