Influenza

Influenza, commonly called “the ‘Flu”, is described as "an acute viral infection in humans involving the respiratory tract. It is marked by inflammation of the nasal mucosa; the pharynx; and conjunctiva, and by headache and severe, often generalized, myalgia". It is contagious (easily passed from one person to another) and is caused by viruses of the Orthomyxoviridae family.

Classification

There are three types of influenza viruses:

• Influenza A virus. "Influenza A viruses are further classified by subtype on the basis of the two main surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). Influenza A subtypes and B viruses are further classified by strains."
  • 2009 H1N1 influenza virus
• Influenza B virus
• Influenza C virus

Hosts

Influenza in humans

In April, 2009, the 2009 H1N1 influenza virus was first isolated and is a novel H1N1 strain that was initially untypeable. The 2009 novel H1N1 influenza virus contains genes normally found in North American swine as well as two genes found in European and Asian swine and has been called a triple-reassortant of genes.

In the 2007-2008 season, the most common strains of influenza in the United States were:

• influenza A virus (H1N1) 35%
• influenza A virus (H3N2) 35%
• influenza B virus 30%

In the 1999-2000 season, the most common strains of influenza in the United States were:

• influenza A virus (H1N1) 3%
• influenza A virus (H3N2) 99%
• influenza B virus 0.6%

Equine Influenza

This is a species-specific strain that infects horses, ponies, donkeys and mules. Humans do not catch this disease but are carriers of it. It is airborne and highly contagious. Equine influenza generally does not kill its victims, and affected horses display similar symptoms to those of humans.

In 2007, a horse flu epidemic began in New South Wales, Australia. The outbreak is believed to have begun as a result of infractions of proper quarantine procedure and is expected to cost millions of dollars in lost revenue. As of September, 2007, it had spread to the Victorian border, causing the cancellation of events at the Melbourne Show, and the possibility that the Spring Carnival, including the running of the Melbourne Cup horse race, would be canceled.

Avian flu

Avian flu, also known as Bird flu or H5N1, has led to recent outbreaks.

Epidemiology

Seasonal influenza activity in the United States of America over four years. During the off season, the prevalence is < 2%. During the height of season, the prevalence may be 20-35%.

Current influenza activity can be monitored online:

• In the United States of America, the Centers for Disease Control and Prevention (CDC) maintains public statistics at http://www.cdc.gov/flu/weekly/fluactivitysurv.htm.
• Google maintains statistics based on search terms (http://www.google.org/flutrends/).
• http://healthmap.org/

The prevalence of influenza among people who have an "influenza-like illness" varies strongly with the seasons of the year. In the United States of America, the Centers for Disease Control and Prevention (CDC) maintains public statistics at http://www.cdc.gov/flu/weekly/fluactivity.htm.

• During the off season, the prevalence is < 2%
• During the height of season, the prevalence may be 20-35%.
• During local outbreaks, the prevalence may be 50-80% according to studies. Unfortunately, the CDC does not report sufficient details to determine where local outbreaks are occurring.

In addition to seasonal variations, there have been several worldwide influenza epidemics, resulting in millions of deaths.

Diagnosis

History and physical examination

Since anti-viral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. A systematic review by the Rational Clinical Examination concluded that the best findings for excluding the diagnosis of influenza are:

Most sensitive individual findings for diagnosing influenza

Finding:	Sensitivity	Specificity
Fever†	86%†	25%
Cough†	98%†	23%
Sore throat	~80%†	~30%
Nasal congestion†	70–90%†	20–40%
Absence of vaccination	83-97%	14-19%
Note: † All three findings, especially fever, were less sensitive in patients over 60 years of age.

Using the symptoms listed above, the combinations of findings below can improve diagnostic accuracy. Unfortunately, even combinations of findings are imperfect. Studies of combining symptoms have included use of recursive partitioning; however, this study combined two cohorts with different prevalences of influenza. However, Bayes Theorem can combine pretest probability with clinical findings to adequately diagnose or exclude influenza in some patients. The pretest probability has a strong seasonal variation; the current prevalence of influenza among patients in the United States receiving sentinel testing is available at the CDC. Using the CDC data, the following table shows how the likelihood of influenza varies with prevalence:

Combinations of findings for diagnosing influenza

Combinations of findings	Sensitivity	Specificity	Projected during local outbreaks (prevalence approx 66%)		Projected during influenza season (prevalence=25%)		Projected in off-season (prevalence=2%)
			PPV	NPV	PPV	NPV	PPV	NPV
Fever and cough	64% 61%	67% 80%	79% 86%	49% 49%	39% 50%	15% 14%	4% 6%	1% 1%
Fever and cough and sore throat	56	71	79	45	39	17	4	2
Fever and cough and nasal congestion	59	74	81	48	43	16	4	1
Fever and cough and acute onset	41	93	92	55	66	18	11	1

Laboratory tests

An electron tomography of the influenza virus.

Available tests are listed at the CDC website.

Clinical practice guidelines address diagnosis.

Rapid tests using for influenza antigens include immunofluorescence assays, immunoenzyme technique, and polymerase chain reaction testing. The sensitivity of these tests range from 63% to 95%.

Rapid influenza diagnostic tests (RIDT) using immunosorbent technique for influenza antigens have a sensitivity of about 50% and specificity of about 85%

The polymerase chain reaction is the most sensitive test and is as sensitive as viral culture.

Differential diagnosis

Influenza-like illness is defined as "fever (temperature of 100°F [37.8°C] or greater) and cough and/or sore throat" A study from Australia found that possible causes for influenza-like illness include respiratory syncytial virus, rhinovirus, adenovirus, parainfluenza viruses, coronaviruses, and metapneumovirus.

Other diagnoses to consider are:

• Parvovirus B19 - arthropathy is prominent
• Flaviviruses
  • Dengue fever - bonebreak fever with retro-orbital pain
  • West Nile virus - tremor is common

Treatment

The two classes of antiviral agents are neuraminidase inhibitors and M2 inhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections.

Different strains of influenza virus have differing degrees of resistance against these antivirals and it is impossible to predict what degree of resistance a future pandemic strain might have.

In the United States, the Centers for Disease Control and Prevention have issued recommendations for the use of antiviral agents. The CDC recommends oseltamivir or zanamivir.

When to treat

According to two decision analysis studies of adults, treatment may be justified in the following settings:

• Elderly patients if the probability of influenza is over 14%
• Adults if the probability of influenza is over 30%.

During local outbreaks of influenza, the prevalence will be over 50-80% and thus patients with any of the above combinations of symptoms may be treated with neuramidase inhibitors without testing. In the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.

Neuraminidase inhibitors

These drugs are effective, but modestly so, against both influenza A and B. Examples are oseltamivir (trade name Tamiflu) and zanamivir (trade name Relenza) are neuraminidase inhibitors. The Cochrane Collaboration concluded that these drugs reduce symptoms and complications. Zanamivir, which must be delivered by inhalation, may cause bronchospasm in patients with asthma.

Oseltamivir may or may not reduce the incidence of respiratory complications on one of 13 patients who take it (number needed to treat = 13). This trial only included patients up to 65 years old.

Neither of these drugs can be administered by injection. For the 2009 pandemic, the U.S. Food and Drug Administration issued an emergency authorization for the use of intravenous peramavir, which had been in Phase III clinical trials.

M2 inhibitors (adamantanes)

These drugs are sometimes effective against influenza A if given early in the infection, but are always ineffective against influenza B. Examples include the antiviral drugs amantadine and rimantadine which block a viral ion channel and prevent the virus from infecting cells.

Prevention

Barriers

N95 mask. This mask is NOT better than a regular surgical mask.

A regular surgical mask is adequate.

Vaccination

In the United States of America, the Centers for Disease Control and Prevention has maintains recommendations on who should get the influenza vaccination. Protection from infection occurs by two weeks after vaccination and lasts one year.

The quality of the research on vaccination my be reduced by conflict of interest according to the Cochrane Collaboration.

	Inactivated				Live attenuated (intranasal)
	Mammalian cells	Recombinant	Embryonated chicken eggs		Normal
	Trivalent	Trivalent	Trivalent	Quadrivalent	Quadrivalent
High dose			Fluzone high-dose. CDC lists as an option for age > 65 years old
Standard dose	Flucelvax†	FluBlok†	Needle-free jet‡	CDC lists as an option for age < 65 years old
Low dose			Fluzone intradermal‡
† For egg allergy ‡ For needle phobia

Adverse effects

Several randomized placebo-controlled trials assess adverse effects , including patients who have lung disease or are elderly .

Among health adults, vaccination may be associated with arm pain and "runny nose or sore throat during the first 7 days after vaccination".

Among patients with asthma, vaccination was associated with body aches.

Among elderly patients, the influenza vaccine may increase arm pain.

Chemoprevention

Chemoprevention (chemoprophylaxis) with neuraminidase inhibitors can prevent symptomatic influenza according to a meta-analysis by the Cochrane Collaboration.Zanamivir may cause bronchospasm in patients with asthma. Extended-duration (>4 weeks) chemoprevention may be effective as well.

Pandemics and notable outbreaks

Spanish influenza pandemic of 1918-1920

A pandemic of Spanish Influenza, involving a highly pathogenic mutation of serotype H1N1, swept across the world in the wake of the Great War (1918-20). More people are believed to have died of the flu in the year after the war then in the Great War itself. Estimates vary but it is estimated that one third of the world's population were infected and up to 50 million people perished in this pandemic (it is possibly that fatalities world wide were as high as 100 million). Some comparisons are drawn between Spanish Flu and the Black Death (Bubonic Plague) of 1347 to 1351. Estimates are that the flu killed more people in one year than plague did in four.

In the United States of America, the epidemic led to closing of schools and banning of public meetings in order to successfully reduce mortality.

Asian influenza pandemic of 1957 - 1963

A/H2N2 virus was responsible for this outbreak

Hong Kong pandemic 1968-1970

This was caused by serotype A/H3N2.