Chapter 11:Influenza and antibiotic resistance

Influenza

Influenza is an infectious disease of birds and mammals caused by a RNA virus.

The most common symptoms are chills, fever, runny nose, sore throat, muscle pains, headache, coughing, weakness/fatigue and general discomfort.

Although it is often confused with other flu-like illnesses, especially the common cold, the flu is a more severe disease caused by a different type of virus.

Influenza may produce nausea and vomiting, particularly in children, but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as "stomach flu" or "24-hour flu”.

Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus. Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact with contaminated surfaces.

Influenza types

Influenzavirus A: Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

H1N1, which caused Spanish Flu in 1918, and Swine Flu in 2009 H2N2, which caused Asian Flu in 1957 H3N2, which caused Hong Kong Flu in 1968 H5N1, which caused Bird Flu in 2004

Three influenza types

Influenzavirus B: Influenza B almost exclusively infects humans and is less common than influenza A. Influenza B mutates at a rate 2–3 times slower than type A and consequently is less genetically diverse, with only one serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age.

Influenzavirus C: Influenza C infects humans, dogs and pigs, sometimes causing both severe illness and local epidemics. However, influenza C is less common than the other types and usually only causes mild disease in children.

Serotyping

Serotyping = Microorganisms, viruses, or cells are classified together based on their cell surface antigens, allowing the epidemiologic classification of organisms to the sub-species level.

Influenza A hosts

The native host of influenza A viruses (subtypes: H1-H16, N1-N9) is wild waterfowl such as duck, which is the origin of all the influenza A viruses on earth.

The virus originally had low pathogenicity but acquired high pathogenicity over time by transmission to and propagation among domestic fowl chicken on land.

Influenza viruses mutate easily, acquiring high pathogenicity and expanding their host range.

H5N1, H7N7, H7N9 viruses have been transmitted from chicken to humans and H9N2 virus from quail to humans, but these viruses are not transmitted efficiently among humans.

Neuraminidase and hemagglutinin

Hemagglutinin

Influenza hemagglutinin (HA) is a glycoprotein found on the surface of the influenza viruses.

It is responsible for binding the virus to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.

It is also responsible for the fusion of the viral envelope with the endosome membrane, after the pH has been reduced.

The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro.

Neuraminidase

Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids.

Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread of influenza infection.

The viral neuraminidases are frequently used as antigenic determinants found on the surface of the Influenza virus.

Some variants of the influenza neuraminidase confer more virulence to the virus than others.

Tamiflu bound to neuraminidase

Seasonal influenza virus is controlled by vaccines

Typically:H1N1H3N2B-strain

The flu vaccines either contain inactivated (killed) influenza virus, or weakened live virus that cannot cause influenza.

The killed vaccine is injected, while the live vaccine is given as a nasal spray.

Both types of vaccine are usually produced by growing the virus in chicken eggs

Antivirals: Adamantanes

Amantadine (a specific type of adamantane) is an antiviral drug, which blocks the M2 H+ ion channel protein, which is associated with viral replication.

Due to resistance, Amantadine is no longer recommended for treatment of influenza A infection. In the ’08/’09 flu season, it was found that 100% of seasonal H3N2 and 2009 pandemic flu samples tested had resistance to adamantanes.

Not to be confused with Adam Ant (Goody Two Shoes)

Antivirals: Neuraminindiase inhibitors

Oseltamivir, marketed under the trade name Tamiflu, is an antiviral that slows the spread of influenza A and influenza B (flu) virus between cells in the body by stopping the virus from chemically cutting ties with its host cell.

The drug is taken orally in capsules or as a suspension.

Oseltamivir is a prodrug, a (relatively) inactive chemical, which is converted into its active form by metabolic process after it is taken into the body.

It was the first orally active neuraminidase inhibitor commercially developed.

The role of antivirals

Flu vaccines are only about 70-90% effective, and it takes about 6 months to prepare a new vaccine.

Thus, prophylactic antivirals

But this can exacerbate antiviral resistance

Detecting antiviral resistance is more difficult than antibacterial resistance

Method 1: Human or animal cells are grown in culture, and then infected with virus with or without an antiviral drug. The drug concentration needed to reduce viral yield by 50% (IC50) is then determined.

Method 2: In vitro neuraminidase activity assay.

Method 3: Genotyping for known antiviral resistance mutations.

Antiviral resistance within seasonal influenza

In 2002-03, seasonal flu strains began to display adamantane resistance in Asia, perhaps stimulated by treatment of domestic birds. Further, it was added to over-the-counter cold remedies in Russia and China.

By 2005-06, amantidine resistance was extensive in the United States.

Resistance was so widespread by 2008, that it was no longer recommended for treatment.

Resistance to neuraminidase inhibitors is also appearing, even though these drugs have not been used extensively in domestic birds. In 2007-08, approximately 15% of H1N1 isolates were resistant to Tamiflu.

There is wide geographical variability within resistance corresponding to proliferation of the various influenza strains.

Pandemic influenza

Killed 40 million people worldwide, including more than 500,000 in the United States.

Pandemic influenza: what to expect

Most important is the 6-month lag between virus emergence and vaccine availability.

Second, obtaining and distributing the vaccine will be difficult.

To combat the outbreak before the vaccine becomes available, stockpiled antivirals can be used prophylactically. That is, antivirals limit infection by susceptible influenza virus if used early in the infection. However, when the body reacts to the virus with flu-like symptoms, the viral load is already high and drugs are presumed to have little impact.

In fact, with highly lethal viral strains, the uncontrollable health problems come from a massive inflammatory response from the body, meaning waiting for symptoms before administering drugs is ineffective.

Antiviral resistance occurs quickly, and thus it is likely that the widespread use of current drugs to combat a pandemic will lead to their ineffectiveness in subsequent outbreaks.

Neuraminidase resistance tends to emerge from point mutations

Neuraminidase resistance tends to emerge from point mutations

In this example, the R292K mutation reducing binding affinity of three related antiviral drugs (including Tamiflu).

Bacterial pneumonia and the flu

Bacterial pneumonia is an inflammatory condition of the lung affecting primarily the microscopic air sacs known as alveoli. It is caused by Legionella pneumophilia and staphylococcus aureus bacteria.

Battling the flu can tax your immune system and increase the chances that you'll develop pneumonia.

In fact, in the 1918-19 pandemic, most deaths appear to have been due to the follow-up bacterial pneumonia.

To help prevent other infectious organisms from gaining a foothold in the lungs, drink lots of liquids. Avoid taking antihistamines, which can dry and thicken secretions in the respiratory tract. Also, try to avoid smoking and drinking excessive alcohol, which can interfere with the body's natural mechanisms that flush out invading organisms.

However, if you give antibacterials for pneumonia prophylactically, it will further exacerbate antibiotic resistance.