Topic Editor: Becky Box, MBBS
Review Date: 113/2012
Definition 
Influenza is an infectious disease caused by an RNA virus in the orthomyxoviridae family. There are 3 general types, named as A, B, and C . In the majority of cases, influenza is a self-limiting infection with headaches, fevers, myalgias, sore throat, and rhinorrhea. A small subset of the population develops serious disease. Antigenic shifts in the viral envelope are responsible for producing pandemics which result in significant morbidity and mortality in previously healthy individuals.
Influenza in the types A and B are most common forms, with infection due to type C being rare.
Description
- Influenza viruses are enveloped, negative stranded, segmented RNA viruses replicated through an RNA-dependent RNA polymerase of viral origin
- Influenza A viruses are further characterized by the subtype of their strongly immunogenic surface glycoproteins, the hemagglutinin (HA) and the neuraminidase (NA). Influenza A and B virus genomes comprise eight negative-sense, single-stranded viral RNA segments, while influenza C virus has a seven-segment genome
- Influenza A viruses are more virulent and are responsible for approximately 80% of Influenza outbreaks in the community. There are many subtypes of Influenza A, based on their expression of hemagglutinin & neuraminidase antigens, but only 3 HA (H1,H2,H3) and 2 NA (N1/N2) subtypes have been implicated in human epidemics
- Influenza B virus may also cause significant disease
- Influenza C virus only rarely causes human illness, which is usually mild, but rarely can be severe. It is not usually a cause of influenza outbreaks
- RNA polymerases are ‘error-prone' and with repeat transcription viruses undergo antigenic drift/shift which enables them to evade the human immune system and cause epidemics and pandemics in the general population
- Antigent drift occurs when minor errors in transcription result in amino acid substitution in the HA or NA antigens. Antigenic shift results in the formation of a new virus subtype, i.e. a different combination of HA/NA subtypes.
- The host defense against viral infection relies on immune response from previous exposure to similar viral subtypes. If the antigenic shift results in a combination that the community does not have pre-existing immunity to, this can result in an outbreak of pandemic proportions
- The 4 most recent pandemics of Human Influenza A virus included: H1N1 [1918]; H2N2 [1957]; H3N2 [1968]; H1N1 swine flu [2009]
- In the past when the new subtype of virus infected the population it replaced the preceding one. However, since 1977, H1N1 has been co-circulating with H3N2
- Transmission between persons occurs when respiratory droplets are spread during sneezing, coughing, and talking
- Symptoms are typical of the common cold, such as chills, fever, sore throat, myalgias and headache; however the abruptness of onset and severity of symptoms in Influenza is more pronounced than a common cold.
- Complications such as pneumonia, superimposed bacterial sepsis and multi-organ failure can be life-threatening
Epidemiology
Incidence/Prevalence
- Typically, Influenza outbreaks peak in winter months, between late December & early March in the northern hemisphere and between May and September in the southern hemisphere
- In tropical climates, influenza cases can occur year round
- Seasonal influenza is estimated to cause 250,000 to 500,000 deaths/year worldwide
- The annual incidence varies significantly and is dependent on the virulence of the viral strain circulating and also the underlying level of population immunity
- Incidence attack rates are much higher in areas of overcrowding and within adult institutions
- In the previous century, the 1957 H2N2 (Asian flu), and the 1968 H3N2 (Hong Kong flu) influenza pandemics each resulted in an estimated 1-4 million deaths. Between 20–50 million deaths were attributable to the 1918 H1N1 (Spanish flu) influenza pandemic
- In 2009, H1N1 influenza virus caused the only pandemic in the U.S. in more than 40 years. The first wave of H1N1 activity occurred in the spring of 2009, followed by a second, larger wave during the fall/winter flu season. Major laboratories in the U.S. tested > 400, 000 specimens for Influenza virus H1N1, 20% of which were positive
- The 2010-2011 influenza season was less severe. The most commonly reported virus was influenza A (H3N2), though influenza A (H1N1) virus and influenza B virus also circulated
- Avian influenza viruses generally do not infect humans, although a H5N1 virus subtype (highly pathogenic AI virus) was transmitted to humans in 1997 during a poultry outbreak in Hong Kong SAR, China. The virus spread to Europe and Africa after re-emerging in 2003 and 2004, and became entrenched in some poultry populations. Worldwide, 532 cases of avian influenza have been reported with 315 deaths through March 14, 2011
Age- The rate of influenza virus infection is high in all age groups , however the hospitalization rate is higher in adults > 65 and in children 5yrs of age
- Specifically, the H1N1 pandemic in 2009 disproportionately affected younger children, likely due to lack of pre-existing immunity in this population
Gender
Risk factors
Risk factors for getting influenza:
- Crowded environments during epidemics
- Institutionalized adults (e.g., those living in long-term care facilities, prisons, or college dormitories)
- Healthcare workers (unimmunized)
Risk factors for developing influenza-related complications:
- Adults
65 years of age - American Indians and Alaskan Natives
- Children 5, and especially children 2 years old
- Pregnancy
- People with disease conditions including:
- Asthma
- Blood disorders (e.g., sickle cell disease)
- Cardiac disease such as congenital heart disease, congestive heart failure, and coronary artery disease
- Chronic lung diseases [e.g., bronchiectasis, chronic obstructive pulmonary disease (COPD), cystic fibrosis]
- Endocrine disorders (e.g., diabetes mellitus)
- Immune deficiency (e.g., HIV or AIDS, cancer, chronic steroid use, immunosuppressant or chemotherapy use)
- Long-term aspirin therapy in patients >19 years of age
- Metabolic disorders (e.g., inherited metabolic disorders, mitochondrial disorders)
- Morbid obesity (body mass index [BMI] 40)
- Neurological and neurodevelopmental disorders affecting the brain , spinal cord, peripheral nerve, and muscles (e.g., cerebral palsy, epilepsy, stroke, intellectual disability, developmental delay, muscular dystrophy, or spinal cord injury)
- Pregnancy, particularly in the third trimester
- Renal and hepatic disease
Etiology
- Influenza is caused by 1 of the 3 basic types of influenza A, B, and C virus
- Influenza viruses are ‘lytic' viruses and that do not form ‘long-term' host-virus relationships consequently their survival is dependent on host to host transmission
- Transmission occurs through infectious respiratory droplets, airborne droplet nuclei, or indirect contact with contaminated objects and self-inoculation via conjunctival mucosa or the upper respiratory tract
- There are three transmembrane proteins that are contained within the viral lipid envelope, HA, NA & M2 (ion channel). HA is crucial for viral entry into the cells & NA is critical for viral spread and transmission from host to host. M2 plays an early role in infectivity
- Influenza viruses have a preference for receptors expressed on epithelial cells throughout the respiratory tract
- Viral attachment and replication to respiratory epithelial cells causes necrotizing tracheo-bronchitis which is widespread and worsens in severity as it progresses further down the tracheo-bronchial tree
- The degree of damage to the respiratory mucosa varies, from vacuolation/edema to extensive desquamation of epithelial cells, depending on both virulence of the infecting virus and the host's immune response
[Outline]
History
- The history of symptoms associated with viral Influenza are very similar to those associated with a common cold; however, fever, chills, rigors, malaise, and myalgia are more common and severe
- The diagnosis of seasonal influenza relies on the treating physician to distinguish between the severity, frequency and intensity of these symptoms
- Patients with seasonal influenza present with sudden onset of symptoms: high fever, sore throat, cough (usually dry), runny nose, headache, muscle and joint pain, and severe malaise
- Stuffy nose, sneezing and sore throat in the absence of above symptoms is more typical for the common cold
- A recent systematic review utilized both the presence of specific features and absence of others to give a greater indication of influenza over the common cold. This review showed that clinically it is helpful to use the presence of rigors, sweating & fever within 3 days of symptom onset to ‘rule-in' Influenza AND the absence 4 additional symptoms (to rule it out), i.e. no systemic symptoms, not coughing, ability to cope with daily activities and not being confined to bed)
- Patients generally recover from fever and other symptoms within a week without requiring medical attention. In high-risk groups, influenza can cause severe illness and occasionally death
- The patient may give a history of close contact with someone who has exhibited similar symptoms. The incubation period for influenza averages 2-3 days, with a range of 1-4 days
- The 2009-2010 H1N1 influenza also resulted in symptoms involving the gastrointestinal tract, such as vomiting and diarrhea, especially in the pediatric age group, which is not commonly seen with seasonal influenza
- Patients with avian influenza have an unusually aggressive clinical course, with rapid deterioration and a high fatality rate. Such cases present with Influenza-like symptoms as well as gastrointestinal symptoms, chest pain and bleeding from the gums. Encephalopathic illness and diarrhea have also been reported without apparent respiratory symptoms. Lower respiratory tract involvement may occur early in the disease with development of acute respiratory distress
Physical findings on examination
On physical examination patients may have the following findings:
- Dry cough with clear lungs
- Elderly patients may have fever, weakness, and confusion with no respiratory findings
- Fever
- Nasal discharge at the onset of illness
- Pharyngitis
- Red and watery eyes
- Rhonchi
- Tachycardia
Physical findings in patients with avian influenza:
- Fever >38 °C
- Patients with avian influenza A (H5N1) rarely have conjunctivitis
- Lower respiratory tract manifestations present early in illness. Most patients present with clinically apparent pneumonia with radiographic changes. Respiratory distress, tachypnea, and inspiratory crackles are common. Cough may be variable with bloody sputum production
- Abdominal pain (infrequent)
[Outline]
- Diagnostic tests can be valuable in identifying circulating strains of influenza for the purpose of annual vaccine preparation. Additionally, testing has been shown to reduce unnecessary use of antibiotics in pediatric patients, allowing earlier discharge from emergency departments/ward, rationalizing antiviral use and enabling cohorting of infected patients into multi-bed rooms
- Diagnostic tests however should be reserved for cases where the diagnosis will make a difference in management of patients and their close contacts. In an otherwise healthy individual, diagnosis can be made on clinical grounds without running any diagnostic tests
- Situations where test results will change management, such as resulting in the administration of antivirals includes:
- Patients that present with severe disease and are at risk of complications i.e. severe pneumonia, super-imposed bacterial infection or multi-organ failure requiring medical inpatient or intensive care support
- High risk patients i.e. Patients with difficulty handling respiratory secretions (neuromuscular disorders, cerebral palsy, dementia); History of asthma or chronic pulmonary disease; Chronic liver disease, renal disease, heart disease or long-term aspirin therapy; Adults > 65yrs or children 5yrs; Institutionalized adults; Pregnant or post-partum women
- Patients residing with persons in the above high risk groups
- Diagnostic tests include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR), and immunofluorescence assays
- Preferred respiratory samples for testing include nasopharyngeal or nasal swab, and nasal wash or aspirate, depending upon type of test used. Collect samples within the first 4 days of illness
Blood test findings
- Serologic testing: Routine testing requires paired acute and convalescent serum specimen, although testing is not generally recommended except for research and public health investigations. Limitations for this test are as follows:
- Results do not influence clinical decision-making
- Available at a limited number of public health or research laboratories
- Results for human influenza on a single serum specimen is not interpretable and is not recommended
- Complete blood count (CBC):
- Normal to mildly decreased white blood cells (WBCs). Leukocytosis may be present with secondary infection, or solely with influenza and is not specific
- Findings in patients with avian influenza often include leukopenia, (particularly lymphopenia), and mild-to-moderate thrombocytopenia
- Comprehensive panel and Creatinine Kinase:
- These tests can help distinguish between other viral infections that cause very substantial elevation of transaminases and can assess for the presence of multi-organ failure
- Creatinine kinase may be elevated in patients with myositis secondary to influenza
- Arterial blood gas (ABG) analysis: May be used in severe cases of influenza with hypoxemia or influenza complicate by a secondary pneumonia. This test is not in any way specific to influenza
Other laboratory test findings
- Viral Culture
- These are taken from nasopharyngeal samples or throat swabs and are the gold-standard diagnostic test for influenza
- Viral culture can help identify circulating strains and subtypes of influenza viruses to allow for decisions regarding influenza treatment, future vaccines, and chemoprophylaxis
- A human influenza virus test kit was developed by the CDC in 2011 to identify seasonal influenza viruses and novel influenza A viruses with pandemic potential
- Rapid influenza diagnostic tests (RIDTs)
- RIDTs are immunoassays which can identify the presence of influenza A and B viral nucleoprotein antigens in respiratory specimens
- RIDTs vary by types of influenza viruses they can detect and ability to distinguish between types. Some tests can detect only influenza A viruses; others detect both influenza A and B viruses, but do not distinguish between the two types; and some detect both influenza A and B and distinguish between the two. No tests can provide information on influenza A subtypes
- On average, RDT's have a 70% sensitivity and 90 % specificity for viral antigens. It is important to note that RIDTs fail to correctly identify a substantial number of patients who have influenza due to the lack of sensitivity
- The specificity and sensitivity of RIDTs increases in the presence of an influenza epidemic as the pre-test probability is higher
- Molecular assays:
- Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and other molecular assays can help to identify the presence of influenza viral RNA in respiratory specimens
- These tests are more expensive but often are positive in cases where the RIDT testing is negative; they are highly sensitive and specific
- Among these assays, some are able to detect and differentiate between influenza A and B viruses; other tests can identify specific influenza A virus subtypes [A(H1N1)pdm09, seasonal A (H1N1), or seasonal A (H3N2)]
- Because PCR is required, results are delayed, ranging from 3-24 hours
- Testing may be indicated for patients where the result could influence patient management
- Direct immunofluorescent tests
- May be used to detect A and B influenza types, and adapted to identify specific subtypes
- Tests are labor intensive, require specially trained laboratory personnel, and are less sensitive than culture methods
Radiographic findings
- Chest x-ray
- Can be used to help distinguish between viral pneumonia and lobar/bronchial pneumonia secondary to bacterial infection. Viral pneumonia is typically seen as peribronchial thickening & bilateral patchy interstitial infiltrates, without focal consolidation. Bacterial pneumonia is more commonly focal
- When used in combination with patient history and examination, findings consistent for influenza of mild to moderate severity can assist in the decision to withhold antibiotics and whether the patient may appropriately be managed as an outpatient with precautions
- In contrast to patients with common strains of influenza, most patients with avian influenza have clinically apparent pneumonia. Radiographic changes show diffuse, multifocal, or patchy infiltrates; interstitial infiltrates; and segmental or lobular consolidation with air bronchograms. Many such cases progress to respiratory failure with radiographic changes which include diffuse, bilateral, ground-glass infiltrates, and signs of acute respiratory distress syndrome
[Outline]
General treatment items
- Uncomplicated influenza should be diagnosed clinically and managed symptomatically, without antivirals. Patients should be advised to return for review if their symptoms worsen or do not show improvement within 72 hours
- Medications that can be used for symptom relief include antipyretics, anti-inflammatory agents and decongestants
- Aspirin or aspirin containing medications should not be used in children due to increased risk of Reye syndrome
- Indications for chemoprophylaxis with antivirals include: Health care workers; Pregnant women; Patients at risk of complications (see below)
- Indications for antiviral treatment include: Patients with severe, complicated Influenza like illness (ILI) OR laboratory confirmed Influenza that require hospitalization; Outpatients with severe complicated ILI or outpatients that are at high risk of complications
- The pneumonia severity index score
can be used to determine clinically which patients have mild/moderate versus severe Influenza pneumonia and therefore which patients warrant admission in this setting - Early antiviral treatment has been shown to shorten the duration of fever, symptoms, and hospitalization, as well as reduce the risk of complications
- Antiviral therapy is recommended for persons at increased risk for complications
- Children aged 2 years
- Adults aged 65 years
- Persons with chronic pulmonary diseases (including asthma); cardiovascular disease (except hypertension alone), renal disease, hepatic disease, hematological disease (including sickle cell disease), metabolic disorders (including diabetes mellitus); or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)
- Persons with immunodeficiency, including those caused by medications or by HIV infection
- Women who are pregnant or postpartum (within 2 weeks after delivery)
- Persons aged 19 years who are receiving long-term aspirin therapy
- American Indians/Alaska Natives
- Persons who are morbidly obese (ie, body-mass index 40)
- Residents of nursing homes and other long-term care facilities
- The decision to treat with antivirals should take into consideration patient factors (as above), the likelihood of Influenza as the etiology of the illness, and also the time from onset of symptoms
- Ideally, antivirals should be started within 48 hours of symptom onset however they may be beneficial in patients with severe, complicated, or progressive illness, and in hospitalized patients when given after 48 hours of illness onset
- Antiviral medications include Neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza), and Amandantanes, amantadine and rimantidine
- Neuraminidase inhibitors are the current first line agents for use in acute Influenza treatment. These agents block viral neuraminidase enzyme, which is required for release of virions from infected host cells for host to host transmission. They are effective against both Influenza A and B.
- Amandantanes are M2 ion channel blockers that prevent infectivity. They are only effective against Influenza A and are not routinely used due to increasing viral resistance
- Oseltamivir (oral) is used for influenza prophylaxis in patients 1 year, and for treatment of acute influenza in patients 1 year who have been symptomatic for no more than two days
- Zanamivir (oral inhalation) used for influenza prophylaxis in patients 5 years, and for treatment of influenza in patients 7 years who have been symptomatic for no more than two days
- Zanamavir should not be used in patients with underlying pulmonary disorders as it may worsen their condition
Medications indicated with specific doses
Dietary or Activity restrictions
- Advise patients to maintain adequate fluid intake
- Activity should be advanced to the level tolerated; there is no indication for bed rest
Disposition
Admission criteria
- Altered mental status
- Dehydration
- Hemodynamic instablity
- Hypoxia
- Pneumonia (substantial on CXR and PSI meeting criteria for admission)
- Secondary bacterial infection
Discharge criteria- Patients who are hemodynamically stable may be discharged with precautions
- Most patients have a short, self-limited course provided they are able to tolerate fluids and antipyretics
[Outline]
Prevention
- Influenza vaccination remains the cornerstone in preventing both illness and complications associated with the Influenza
- The prevention rate for adults & children receiving Influenza vaccination varies between 50-80% depending on how well the seasonal vaccine matches the circulating virus
- Vaccine efficacy is less clear in elderly patients which may be due to blunted immune response
- Current recommendations are for yearly vaccination for the following groups of people: all adults > 50yrs; children aged 6-59 months; patients any age with chronic medical conditions; women who will be pregnant; immune-suppressed patients, caretakers of high risk patients and health care workers
- The Trivalent Inactivated Vaccination (TIV) contains killed virus and is usually administered IM to the deltoid. Current types of TIV available in US include:
- Regular trivalent inactivated vaccine: Given intramuscularly, and approved for 6 months including healthy people, those with chronic medical conditions, and pregnant women
- High-dose trivalent inactivated vaccine: Given intramuscularly, and contains 4 times the amount of antigen as the regular TIV which is approved for 65 years
- Intradermal trivalent inactivated vaccine: Given intradermal via a single-dose, prefilled microinjection syringe, and contains less antigen than intramuscular TIV formulations. Approved for use in people 18 to 64 years of age
- Vaccination is not recommended in the following patients:
- Those with severe allergy to chicken eggs
- People who have had a severe reaction to an influenza vaccination
- Children 6 months of age
- People experiencing moderate to severe illness with a fever
- People who have a history of Guillain-Barré syndrome within 6 weeks following influenza vaccination. Risk of recurrence with subsequent vaccination is a concern, except in cases where there is a high risk of severe influenza complications
Prognosis
- Signs and symptoms of uncomplicated influenza usually resolve within 1 week, though cough and fatigue may persist
- Risk of hospitalization is highest in people 65 years, in very young children, and in those with chronic medical conditions
- Morbidity and mortality may be high in younger age groups at the time of influenza pandemics, specifically if the subtype of Influenza A has not circulated in recent years
Associated conditions
Pregnancy/Pediatric effects on condition
- Pregnant women have an increased risk for cardiopulmonary complications related to influenza infections during seasonal influenza epidemics
- Fetuses have increased risk for perinatal complications, including preterm birth, and birth defects due to hyperthermia
Synonyms/Abbreviations
Synonyms
ICD-9-CM
- 487.0 Influenza with pneumonia
- 487.1 Influenza with other respiratory manifestations
- 487.8 Influenza with other manifestations
- 488.11 Influenza due to identified novel H1N1 influenza virus with pneumonia
- 488.12 Influenza due to identified novel H1N1 influenza virus with other respiratory manifestations
- 488.19 Influenza due to identified novel H1N1 influenza virus with other manifestations
ICD-10-CM
- J09 Influenza due to certain identified influenza viruses
- J10 Influenza due to other identified influenza virus
- J11 Influenza due to unidentified influenza virus
[Outline]
