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Influenza, or the flu, is one of the most common infectious diseases in the world. It is responsible for epidemics and has a wide range of symptoms, ranging from a mild upper respiratory tract infection to death, depending on the patient’s immune status.
Seasonal variations of the virus have been responsible for more deadly strains such as the Spanish flu, swine flu, and avian flu. As well, the symptoms of the disease commonly overlap with other viruses such as adenovirus and parainfluenza virus.
The influenza virus is responsible for a significant number of infectious diseases around the world. Severe illness from the virus has been reported to affect up to 5 million people annually and influenza is responsible for approximately 500,000 deaths per year.
In the United States, the influenza virus is estimated to be responsible for at least 3,000 deaths per year. However, this figure is based on statistical modeling, as influenza is not a reportable disease.
The H1N1 influenza strain, which is responsible for the swine flu, hit the United States in 2009, where it was responsible for approximately 500 deaths. The avian flu virus was responsible for 375 deaths worldwide. Although these strains of the influenza virus are more fatal compared with the more common strains of influenza, fortunately they are less likely to spread and so far the number of reported cases seems to be low.
Certain groups of people are known to be at an increased risk of mortality and morbidity from the influenza virus. These groups include those older than 65 years, those younger than 18 years of age, and the immunocompromised.
Three main types of influenza are responsible for human disease: type A, B, and C. Type A is the most pathogenic, while type C is the least virulent (see table).
|Characteristics||Influenza A||Influenza B||Influenza C|
|Natural host range||Humans, swine, equine, birds, marine mammals||Humans only||Humans and swine|
|Epidemiology||Antigenic shift and drift||Antigenic drift only||Antigenic drift only|
|Clinical manifestations||May cause large epidemics with significant mortality in young persons||No pandemics; confined to older adults and the immunocompromised||Mild disease without seasonality|
The influenza virus comprises 8 different genome segments composed of RNA. Two virulence proteins are hemagglutinin (H) and the neuraminidase (N). There are 18 subtypes of hemagglutinin (H1- H18) and 11 subtypes of neuraminidase (N1-N11). The type of hemagglutinin and neuraminidase is part of the naming convention for different types of influenza virus. Hemagglutinin is responsible for the binding of the virus to the respiratory epithelium, while the neuraminidase is implicated in the spread of the virus to other cells.
The influenza virus genome is constantly in a state of flux. Its RNA-dependent RNA polymerase does not check for errors during transcription, unlike DNA polymerases. Thus, the chance of transcription errors increases, and as a result, different strains and variants of the same virus occur. These mutations are the result of genetic drift, the slow change of the virus due to mutations over the course of years. Additionally, whole-genome segments can be swapped out during infection. A bird-type influenza virus and a human-type influenza virus can both infect an animal, usually a pig. If this occurs at the same time, it is possible for the 2 viruses to infect the same cell at the same time, resulting in a shuffling of their genome segments and a new and potentially deadly virus. This is called a genetic shift, a rapid and potentially lethal change in the viruses genome.
Transmission to humans can happen from direct contact with infected animals, such as in swine and avian flu, or from human-to-human contact. Human-to-human spread is airborne and the virus usually spreads via aerosols when an infected patient coughs or sneezes.
Once a person is infected with the virus, the prodrome period can last anywhere from 1 day to 1 week. An infected person is contagious about 1 day before symptoms become evident. Once the virus enters a new host, respiratory epithelium dysfunction occurs and inflammatory mediators are released. As a result, systemic features of influenza virus infection ensue.
In most cases of influenza virus infection, symptoms begin suddenly.
Symptoms of influenza include cough, fever, sore throat, body aches, headaches, weakness, and red watery eyes. Nasal discharge is also a common finding in patients with influenza virus infection (see image).
Most patients seek medical attention because of a severe sore throat, which can last up to 5 days. These symptoms are usually milder in people who have received the annual influenza vaccine.
Physical examination confirms the presence of fever, tachycardia, and pharyngitis. The eyes can be red and watery. Patients can have a normal chest examination, but in a few cases, wheezes can be heard, usually focal. Patients feel fatigured.
Patients can also be dehydrated due to fever and the inability to drink fluids due to sore throat.
Patients with influenza can develop primary influenza pneumonia. These patients usually progress to severe cough, develop dyspnea and become cyanotic. Pregnant women, patients older than 65 years, and those with cardiovascular disease are at risk of developing primary influenza pneumonia.
Additionally, patients with influenza are at risk of developing secondary bacterial pneumonia. The most commonly implicated pathogens are Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Patients with secondary bacterial pneumonia appear severely ill, have a productive cough, develop leukocytosis, and have lung infiltrates on chest x-rays.
Avian flu carries the highest risk of progression to adult respiratory distress syndrome and is responsible for a significant number of hospitalizations related to influenza.
While laboratory investigations do not provide any specific findings for the diagnosis of influenza, certain patterns have been identified. Patients usually have leukopenia and lymphopenia unless they develop secondary bacterial pneumonia. Patients can also have hypoxemia.
Rapid diagnostic tests of influenza are available and show good accuracy but somewhat limited sensitivity. The QuickVue Influenza A+B test can provide a confirmatory result in 10 minutes, for example, while the Zstat Flu test takes 20 minutes to showathe result. As these tests can become less accurate because of the viruses’ frequent genetic changes, their specificity should be checked annually.
The Alere I Influenza A and B test was approved in 2017 by the FDA. The test is based on accurate molecular testing. Results can be confirmed within 15 minutes and the test is believed to be more reliable compared with other currently available rapid diagnostic tests.
While these tests are helpful for clinical decisions, viral cultures and reverse-transcriptase polymerase chain reaction testing are the standard criterion for the confirmation of the diagnosis of influenza infection. Viral cultures yield results in approximately 1 week, which makes them useless from a clinical point of view because any drug intervention should be started before results are available.
Recently, a reverse-transcriptase polymerase chain reaction test was approved for the detection of influenza virus infection. This test can differentiate between influenza type A and B viruses, can classify type A viruses by subtypes based on the H and N genes, and is able to detect the highly pathogenic avian virus (H5N1).
The inflammatory response to influenza virus infection is different from bacterial pneumonia. Therefore, some have advocated the use of a testing panel that is based on interleukin 10 to distinguish between influenza and other viral or bacterial pneumonia. Influenza was found to be associated with a significantly higher interleukin-10 blood concentration compared with other etiologies of pneumonia and patients had an average of 88.69 pg/mL IL-10.
Imaging studies are needed in patients presenting with symptoms of possible complications or in high-risk populations such as the elderly. Chest X-rays can show multiple and diffuse infiltrates, a picture consistent with adult respiratory distress syndrome. Patients with diffuse lung infiltrate consistent with adult respiratory distress syndrome should be screened for possible avian influenza virus infection.
The current understanding of genetic shift and drift in the influenza virus allows us to anticipate the most likely epidemic strain this season. Vaccination becomes a possibility and is therefore been recommended for all those aged 6 months or older. Annual vaccination against influenza virus not only prevents the disease in most patients but can also alleviate the symptoms of influenza if a person develops the disease that year.
Patients with established disease usually benefit from bed rest. Patients may also benefit from antiviral therapy, but only if it is started within the first 48 hours of symptom onset (within the first 24 hours is recommended). Oseltamivir, peramivir, and zanamivir inhibit the activity of neuraminidase, which is responsible for the virus spread from 1 cell to another.
These antivirals can help by alleviating symptoms, preventing complications in patients at risk, making the disease duration shorter, and decreasing mortality in more severe strains such as avian influenza. Current recommendations are to use antivirals for up to 6 days after the onset of the symptoms in people with confirmed avian influenza infection hoping to lower mortality.
These treatments carry higher costs and significant adverse effects’ profile. Thus, the decision to prescribe them should be based on the individual case. Accordingly, antiviral therapy should be used only in a select population of patients who are severely ill, require hospitalization, and are at risk of complications, and in any patient who presents with symptoms that began less than 48 hours before presentation.