AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Influenza virus infection, one of the most common infectious diseases among humans, is a highly contagious airborne disease that causes an acute febrile illness and results in variable degrees of systemic symptoms. These symptoms contribute to significant loss of workdays, human suffering, mortality, and significant morbidity. The 1918-1919 H1N1 type influenza pandemic killed an estimated 20-50 million persons, with 549,000 deaths in the United States alone.

Accurately diagnosing influenza A or B infection based solely on clinical criteria is difficult because of the overlapping symptoms caused by the various viruses associated with upper respiratory tract infection (URTI). In addition, several serious viruses, including adenoviruses, enteroviruses, and paramyxoviruses, may initially cause influenzalike symptoms. The early presentation of mild or moderate cases of flavivirus infections (eg, dengue) may initially mimic influenza. For example, some cases of West Nile fever acquired in New York in 1999 were clinically misdiagnosed as influenza.

Patients with influenza frequently present with various symptoms shared by many other viral infections. In the northern and southern hemispheres, these symptoms are more common in the winter months. As a result, during the winter, clinics and emergency department waiting rooms fill with patients who have influenza or other URTIs.

For supplementary information, see Medscape’s Influenza Resource Center.

Pathophysiology

Influenza results from infection with 1 of 3 basic types of influenza virus—A, B, or C—which are classified within the family Orthomyxoviridae. These single-stranded RNA viruses are structurally and biologically similar but vary antigenically.

The RNA core consists of 8 gene segments surrounded by a coat of 10 (influenza A) or 11 (influenza B) proteins. Immunologically, the most significant surface proteins include hemagglutinin and neuraminidase. The viruses are typed based on these proteins. For example, influenza A subtype H3N2 expresses hemagglutinin 3 and neuraminidase 2.

The most common prevailing influenza A subtypes that infect humans are H1N1 and H3N2. Each year, the trivalent vaccine used worldwide contains A strains from H1N1 and H3N2, along with an influenza B strain.

Influenza virus infection occurs after transfer of respiratory secretions from an infected individual to a person who is immunologically susceptible. If not neutralized by secretory antibodies, the virus invades airway and respiratory tract cells. Once within host cells, cellular dysfunction and degeneration occur, along with viral replication and release of viral progeny. Systemic symptoms result from inflammatory mediators, similar to other viruses. The incubation period of influenza ranges from 18-72 hours.

Influenza A is generally more pathogenic than influenza B. Influenza A is a zoonotic infection, and more than 100 types of influenza A infect most species of birds, pigs, horses, dogs and seals. Indeed, the 1918 pandemic that resulted in millions of human deaths worldwide is believed to have originated from a virulent strain of H1N1 from pigs or birds. Recently, scientists obtained and sequenced the 1918 H1N1 strain from a frozen corpse found in Alaska. The virus was reconstructed at the Centers for Disease Control and Prevention (CDC) laboratory in Atlanta and was found to be highly lethal when tested in mice; the virus was also found to be lethal to chicken embryos. This unique N1 neuraminidase is being studied in order to provide better insight into the N1 found in H5N1, the type responsible for avian influenza (also known as bird flu).

H5N1 bird flu

In 1997, an avian subtype of influenza A, H5N1, was first described in Hong Kong. Infection was confirmed in only 18 individuals, but 6 died. Since then, sporadic cases of H5N1 infection have continued to be described in southern China. In January 2004, an epidemic occurred among domesticated birds in Southeast Asia, initially in Vietnam. In nearly all cases of H5N1 bird flu in humans, the virus is transmitted from birds. As of April 2008, more than 381 human cases had been documented and more than 238 persons had died following H5N1 outbreaks among poultry and resulting bird-to-human transmission. Most human deaths due to bird flu have occurred in Indonesia. Sporadic outbreaks among humans have continued elsewhere, including China, Egypt, Thailand, and Cambodia.

Experts are concerned that a slight mutation could convert H5N1 to a strain that would be easily transferred from human to human. Such a strain has the potential to spread rapidly and precipitate a catastrophic worldwide pandemic. Because of this concern, efforts to develop an effective vaccine are currently underway. In addition, studies to expand the number of drugs that are effective against influenza are underway. Ribavirin has shown activity in animal models.

Other types of avian influenza

In March 1999, infection with another avian influenza subtype, H9N2, was described in 2 young children. Despite concern, no additional cases of H9N2 infection were reported. As with the H5N1 influenza, experts are concerned that a virulent strain of H9N2 influenza may mutate to allow human-to-human infection and that such a strain may possess the triad of infectivity, lethality, and transmissibility.

Viral shedding

Viral shedding occurs at the onset of symptoms or just before the onset of illness (0-24 h). Shedding continues for 5-10 days. Young children may shed virus longer, placing others at risk for contracting infection with the virus.

Frequency

United States

Influenza epidemics typically occur in winter months and vary in severity and attack rates depending on the virus subtype involved. Millions of people may develop infection during a given year. The pandemics of 1918-1919 and 1957, which resulted in higher infection rates and profound morbidity and mortality rates, demonstrate the impact of the disease.

In the United States, significant influenza activity occurred during the winter of 1999-2000 and 2003-2004. Influenza A/Fujian/411/2002 (H3N2) was the major strain involved in 2003-2004. During the 2000-2003 and 2004-2005 seasons, influenza activity was relatively low in the United States. However, the activity increased during the 2007-2008 season to the highest levels in years.

International

In tropical areas, influenza occurs throughout the year.

Mortality/Morbidity

The CDC estimates that influenza is responsible for an average of more than 20,000 deaths annually.

Sex

Women in the third trimester of pregnancy are at higher risk for complications of influenza A and B.

Age

• Elderly people are at higher risk for complications of influenza A and B.
• For more information on pediatric influenza, see the Influenza article in eMedicine’s Pediatrics: General Medicine volume.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The presentation of influenza virus infection varies; however, it usually includes many of the symptoms described below. Patients with influenza who have pre-existing immunity or who have received vaccine may have milder symptoms.

• Abrupt onset of illness is common. Many patients with influenza are able to report the time when the illness began.
• Fever may vary widely among patients, with some having low fevers (in the 100°F range) and others developing fevers as high as 104°F. Some patients report feeling feverish and a feeling of chilliness.
• Sore throat may be severe and may last 3-5 days. The sore throat may be a significant reason why patients seek medical attention.
• Myalgias are common and range from mild to severe.
• Frontal/retro-orbital headache is common and is usually severe. Ocular symptoms develop in some patients with influenza and include photophobia, burning sensations, and/or pain upon motion.
• Some patients with influenza develop rhinitis of varying severity but is generally not the chief symptom.
• Weakness and severe fatigue may prevent patients from performing their normal activities or work. In some cases, patients with influenza may find activity difficult and may require bedrest.
• Cough and other respiratory symptoms may be initially minimal but frequently progress as the infection evolves. Patients may report nonproductive cough, cough-related pleuritic chest pain, and dyspnea. In children, diarrhea may be a feature.
• Acute encephalopathy has recently been associated with influenza A virus. In a case series of 21 patients, Steininger et al described clinical, CSF, MRI, and EEG findings.¹ Clinical features included altered mental status, coma, seizures, and ataxia. Of those who underwent further testing, most had abnormal CSF, MRI, and EEG findings.

Physical

The general appearance varies among patients who present with influenza. Some patients may appear acutely ill, with some weakness and respiratory findings, while others may appear only mildly ill. Upon examination, patients may have some or all of the following findings:

• Fever may range from 100-104°F. The fever in elderly patients is not generally as severe as that in young adults.
• Tachycardia most likely results from hypoxia, fever, or both.
• Pharyngitis may be present. Even in patients who report a severely sore throat, findings vary from minimal infection to more severe inflammation.
• Eyes may be red and watery.
• Nasal discharge is absent in most patients.
• Skin may be warm-to-hot, as reflected by the temperature status. Patients who have been febrile with poor fluid intake may show signs of mild volume depletion with dry skin.
• Pulmonary findings during the physical examination may include dry cough with clear lungs or rhonchi.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acute HIV infection
Hanta pulmonary syndrome (HPS)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Findings of standard laboratory studies such as a CBC count and electrolytes assessment are nonspecific but helpful in the workup of influenza.
• Leukopenia and relative lymphopenia are typical findings in influenza.
• Thrombocytopenia may be present.
• Viral culture
• • The criterion standard for diagnosing influenza A and B is a viral culture of nasopharyngeal samples and/or throat samples.
  • Obtain samples with Dacron swabs and send the samples in appropriate viral transport media (eg, multimicrobe [M4] transport media) to the laboratory to be cultured in several lines of cells. A laboratory diagnosis of influenza is established once specific cytopathic effect is observed or hemadsorption testing findings are positive. Staining the infected cultured cell lines with fluorescent antibody confirms the diagnosis.
  • The process may require 3-7 days, long after the patient has left the clinic, office, or emergency department and well past the time when drug therapy could be efficacious.
• Direct immunofluorescent tests
• • Some laboratories offer direct immunofluorescent tests on fresh specimens, but these tests are labor-intensive and are less sensitive than culture methods.
  • These tests require specially trained laboratory personnel (people generally not available during all shifts, even in large medical centers) for interpretation.
• Serologic studies
• • In order to overcome the expensive and time-consuming obstacle of culturing, several serologic tests have become available. In reality, many of these are not bedside tests; generally, 30-60 minutes are required to perform the test's multiple steps.
  • Some rapid tests are performed best in a laboratory, not in the office or emergency department.
  • Disadvantages to performing these rapid diagnostic tests include the cost of the laboratory personnel, the cost of the test itself, and potential false-negative results for influenza A and B. Test sensitivities generally range from 60-70%.
• Office tests
• • Recently, the US Food and Drug Administration waived federal Clinical Laboratories Improvement Act (CLIA) requirements and approved 3 office tests for diagnosis.
  • Of these, the fastest is the 10-minute QuickVue bedside test, which yields a sensitivity of 70-80%.
  • Because of cost, availability, and sensitivity issues, most physicians diagnose influenza based on clinical criteria alone.

Imaging Studies

• Chest radiography: In elderly or high-risk patients with pulmonary symptoms, perform chest radiography to exclude pneumonia.
• • Early radiographic findings include no or minimal bilateral symmetrical interstitial infiltrates.
  • Later, bilateral symmetrical patch infiltrates become visible.
  • Focal infiltrates indicate superimposed bacterial pneumonia.

Other Tests

• Arterial blood gas
• • Severe hypoxemia is present in severe cases of influenza.
  • The A-a gradient may be increased (>35 mm Hg).

Procedures

Patients with physical examination findings compatible with meningitis should undergo lumbar puncture.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• As with other diseases, prevention of influenza is the most effective strategy.
• • The CDC has published recommendations for high-risk groups, including all health care personnel, who should be vaccinated.
  • Amantadine and rimantadine have been approved for many years for use against influenza A. However, beginning with the 2005-2006 season, amantadine and rimantadine were no longer recommended by the CDC because significant resistance has evolved against these two drugs.
  • Many physicians in primary care offices or the ED have not used these medications widely.
  • Disadvantages of these drugs include lack of efficacy against influenza B, potential adverse effects, and rapid development of viral resistance.
• Two newer drugs have been recently marketed for treatment of influenza A and B. These are the neuraminidase inhibitors oseltamivir and zanamivir.
• • Oseltamivir is taken orally (75 mg bid), and zanamivir is taken via an inhalation apparatus (10 mg bid for 5 d).
  • Multiple studies have demonstrated their efficacy. These agents work by inhibiting influenza virus neuraminidase, a glycoprotein spike that protrudes from the virus envelope; this spike is needed for successful cellular release of virus and transmission within the body. To be effective, these new agents must be administered within 40 hours of symptom onset.
  • Recent studies also demonstrate the efficacy of these agents in preventing influenza A and B, an exciting expansion in their use. The prophylactic dose is one half the acute treatment dose.
  • Neuraminidase inhibitors have several advantages over amantadine, including less evolution of resistance, efficacy against influenza B, fewer adverse effects, and dramatic reduction in symptoms, even in patients who have a full course of influenza.
  • In a study of 445 patients by the Management of Influenza in the Southern Hemisphere Trialists (MIST) group 1, zanamivir was administered to one half of patients and placebo to the others within 36 hours of symptom onset. Duration of the flu was reduced by 1.5 days in normal-risk groups and 2.5 days in high-risk groups. A significant decrease in the severity of illness in patients treated with zanamivir allowed them to resume normal activities much sooner.
  • A study by Treanor et al compared oseltamivir with placebo.² This analysis included patients with laboratory-based diagnoses of influenza and those with clinical diagnosis based on symptoms. The 629 patients were enrolled and randomized into 1 of 3 treatment arms: (1) standard-dose oseltamivir, (2) high-dose oseltamivir, and (3) placebo. In both oseltamivir groups, the mean illness duration was reduced from 103 to 70 hours. The symptom severity decreased in the treated group by 40%.
  • Additional studies analyzed the effect of neuraminidase inhibitors both in acute disease and in prevention.
  • • In one of these studies, 837 relatives of family members infected with influenza were treated prophylactically with either placebo or zanamivir.³ While 20% of the placebo group became ill, only 4% of the drug-treated group became ill. In addition, this study provided treatment to the index case family member, resulting in a 2.5-day reduction in illness over placebo. Recombinant DNA viral sequences were performed in this study, and no resistant influenza strains developed.
    • A novel study analyzed the effects of oseltamivir in experimentally induced influenza in humans.⁴ In a controlled laboratory environment, volunteers were inoculated intranasally with influenza A/Texas/36/91 (H1N1). One group was administered oseltamivir 26 hours before virus inoculation and another group was administered 28 hours after inoculation. In the prophylactic group, 38% of patients developed influenza, which 67% in the placebo group developed influenza. In the posttreatment group, the duration of illness was reduced from 95 to 53 hours and the severity was reduced by 50% compared with placebo.
    • Another study by Hayden et al analyzed 1559 healthy nonimmunized patients who were treated with either placebo or oseltamivir for 6 weeks.⁵ At the end of the period, 4.8% of the placebo group had laboratory-confirmed influenza, compared with only 1.2% of the oseltamivir group.
    • Ongoing studies are analyzing both treatment efficacy and the preventive effects of neuraminidase inhibitors.
• Whether to prescribe one of the newer neuraminidase inhibitors should depend on the patient, the probable type of influenza involved (A or B), and the potential benefit.
• • Advantages for prescribing these agents include significantly reducing illness severity and duration. In elderly and high-risk patients who receive these agents, the secondary complications of influenza are also decreased.
  • Disadvantages include potential adverse effects and costs. Some patients may be willing to pay $100 to have a less severe episode of the flu. Adverse effects include potential bronchospasm with inhaled zanamivir and nausea, vomiting, and headache from oseltamivir. The bronchospasm associated with zanamivir has received attention from national media. Until more data are available, physicians should not prescribe zanamivir to patients prone to bronchospasm.
  • Although oseltamivir is approved for use up to 48 hours after the initiation of symptoms, one study suggested that the most significant effect occurs when taken within 6 hours of symptom onset and only limited effects when therapy is begun more than 24 hours after symptom onset.

Consultations

Consultation with an infectious disease specialist is prudent in some cases.

Activity

Patients with influenza generally benefit from bedrest. Most patients with influenza recover in 3 days; however, malaise may be present for weeks.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antiviral agents

Drugs indicated for treatment of influenza include neuraminidase inhibitors (ie, oseltamivir and zanamivir) and amantadine and rimantadine.

Drug Category: Vaccine

Influenza A vaccine is administered each year prior to flu season. The CDC analyzes the vaccine subtypes each year and makes any necessary changes based on worldwide trends.

In April 2007, the US Food and Drug Administration (FDA) approved the first vaccine for H5N1 influenza (ie, avian influenza or bird flu). The approval was based on one multicenter, randomized, double-blinded, placebo-controlled, dose-ranging study in healthy adults aged 18-64 years. The trial investigated the safety and immunogenicity of the vaccine. A total of 103 healthy adults received a 90-mcg dose of the vaccine via IM injection, followed by another 90-mcg dose 28 days later. In addition, approximately another 300 healthy adults received the vaccine at doses lower than 90 mcg, and a total of 48 received placebo by injection. Of the various doses tested, the study showed that the 90-mcg 2-dose regimen provided the better immune response and produced levels of antibodies expected to reduce the risk of acquiring H5N1 influenza in 45% of those who received it.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Hospitalization
• • Most frequently, hospitalization is necessary when influenza exacerbates underlying chronic diseases. Some patients, especially elderly individuals, may be too weak to care for themselves alone at home.
  • On occasion, the direct pathologic effects of influenza may require hospitalization. Most commonly, this is influenza pneumonia.

Further Outpatient Care

• Patients with influenza who do not improve should return for further evaluation. Patients diagnosed with influenza should be educated about potential complications and encouraged to return for evaluation if concerned. This is especially true of patients with underlying chronic disease or those who are immunocompromised.

Deterrence/Prevention

• Influenza vaccine provides good protection against immunized strains. The vaccination becomes effective 10-14 days after administration.
• Each year in the United States, a vaccine that contains antigens from the strains most likely to cause infection during the winter flu season is produced.
• • For example, during 2001-2003, 2 strains of influenza A virus, A/Panama/2007/99 (H3N2) and A/New Caledonia/20/99 (H1N1), and 1 strain of influenza B (B/Hong Kong 330/01) comprised the vaccine.
  • During the 2003-2004 season, the vaccine contained the same A-H1N1 and B strains. However, the A-H3N2 strain selected was Moscow 10/99, similar to A-H3N2 Panama/2007/99. Instead, the predominant strain that surfaced in the United States was A-H3N2 Fujian/2007/99. The CDC believes that partial protection was still provided to individuals who received the vaccine. For the 2004-2005 and 2005-2006 seasons, similar compositions were used (eg, A/H1N1-New Caledonia/20/99, A-H3N2-Fujian/411/2002, B-Shanghai/361/2002).
  • For the 2007-2008 season, the trivalent vaccine contains the following antigenic strains: influenza A - H1N1: Solomon Islands/3/2006; influenza A - H3N2: Wisconcin/67/2005 or equivalent; and influenza B: Malaysia 2506/2004 or equivalent.
• Influenza vaccine is also available as a nasal spray (FluMist) for healthy children aged 5 years or older, adolescents, and adults aged younger than 50 years. Clinical trials are limited in scope regarding the protective effects of live vaccine. The live virus is attenuated by cold; therefore, only very limited viral replication occurs at temperatures of more than 95°F.
• Specific recommendations for individuals who should be immunized can be obtained from the CDC (see Prevention and Control of Influenza). People recommended for immunization include elderly individuals, those with certain chronic diseases, and health care workers.
• A vaccine designed to be effective against H5N1 is currently under development, and contracts to produce several million doses have been awarded.

Complications

• Primary influenza pneumonia is characterized by progressive cough, dyspnea, and cyanosis following the initial presentation on the infection. Chest radiographs show diffuse infiltrative patterns bilaterally, without consolidation, which can progress to a presentation similar to acute respiratory distress syndrome. Risks for viral pneumonia involve numerous complex host immune responses and viral virulence. Although elderly individuals, especially nursing home patients, and those with cardiovascular disease constitute the highest risk groups, do not forget that, in the 1918-1919 epidemic, many young adults died of a pneumonia that some experts believe was caused directly by the virus.
• Secondary bacterial pneumonia can occur from numerous bacteria (eg, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae).
• • The most dreaded complication is staphylococcal pneumonia, which develops 2-3 days following the initial presentation of viral pneumonia. Patients appear severely ill, with hypoxemia, an elevated WBC count, productive bloody cough, and a chest radiograph showing multiple cavitary infiltrates. Methicillin-susceptible S aureus (MSSA) and methicillin-resistant S aureus (MRSA) pneumonias have occurred following influenza pneumonia. MRSA pneumonia may be severe and difficult to treat, and deaths have occurred within 24 hours of presentation of pneumonia symptoms.
  • S pneumoniae or H influenzae pneumonia, if occurring as a complication, usually develops 2-3 weeks after the initial symptoms of influenza and can be managed as a community-acquired pneumonia, following standard antibiotic and admission/discharge guidelines. Myositis is a rare complication. This group of patients may develop frank rhabdomyolysis, with elevated creatine kinase levels and myoglobinuria.
• Myocarditis and pericarditis have been associated with influenza infections.

Prognosis

• In patients without comorbid disease, the prognosis is very good, although some patients have a prolonged recovery time and remain weak and fatigued for weeks.

Patient Education

• For excellent patient education resources, visit eMedicine's Cold and Flu Center. Also, see eMedicine's patient education article Flu in Adults.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early presentations of more serious infections may initially be misdiagnosed as influenza.
• Physicians who diagnose influenza in residents of nursing homes should notify the nursing home medical director so that preventive measures can be taken to protect other residents.
• Postinfluenza pneumonia is a serious complication and needs to be treated aggressively.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Steininger C, Popow-Kraupp T, Laferl H, et al. Acute encephalopathy associated with influenza A virus infection. Clin Infect Dis. Mar 1 2003;36(5):567-74. [Medline].
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11. Cunha BA. The Clinical Diagnosis of Severe Viral Influenza. Infection. 2008;36:92-93.
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20. Smee DF, Wong MH, Bailey KW, et al. Activities of oseltamivir and ribavirin used alone and in combination against infections in mice with recent isolates of influenza A (H1N1) and B viruses. Antivir Chem Chemother. 2006;17(4):185-92. [Medline].
21. Smith GJ, Fan XH, Wang J, et al. Emergence and predominance of an H5N1 influenza variant in China. Proc Natl Acad Sci U S A. Nov 7 2006;103(45):16936-41. [Medline].
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Article Last Updated: Sep 26, 2008