Medical Resources :: Common Diseases :: Infectious Diseases & Parasites :: Influenza

• Influenza remains the most important cause of wintertime respiratory morbidity throughout the world
• Widespread epidemics occur annually, with significant mortality from pulmonary complications
• An epidemic was first described by Hippocrates in 412 BC
• 32 pandemics have occurred since 1580.

• Influenza A first isolated in ferrets in 1933, B in 1939, and C in 1950
• First cultured in eggs in 1936
• Inactivated vaccines developed in the 1940s
• "Influenza" derived from 15th century Italian, blaming the epidemic on the influence of the planets

Microbiology

• Are medium sized enveloped RNA viruses in the Orthomyxoviridae family
• Three major antigenic types: A, B, C
• Epidemic disease caused by types A and B; C typically causes a localized outbreak in children and young adults

Influenza A proteins

• 10 total, 8 structural and 2 only found in infected cells
• Of the 8 structural proteins, 5 are internal. 3 are membrane proteins, and the 2 important ones are hemagluttinin and neuraminidase.

Hemagluttinin

• There are 15 different subtypes, but only 3 (H1, H2, and H3) widely affect humans
• Named after its ability to agglutinate erythrocytes
• Responsible for viral attachment, penetration and cell membrane fusion, all essential for infection

Neuraminidase

• Only 2 subtypes associated with human illnesses, there are 9 total
• Far fewer found on the viral envelope
• Its function is still not well understood; but it appears to be important in viral release by preventing self-agglutination by the virus' own hemagglutinin

Nomenclature

Each year, viruses are named by the influenza type, geographic site of isolation, strain number, and year of isolation, followed by the antigenic description.
The primary 1999-2000 strains were:

• A/Sydney/05/97 (H3N2) (90%)
• B/Beijing/184/93-like (10%)
• A/Beijing/262/95 (H1N1) (<1%)
• All of these are represented in the current influenza vaccine

• Antigenic drift is the minor change that regularly occurs within an influenza subtype, i.e. A/USSR/77 (H1N1) to A/Brazil/78 (H1N1)
• Antigenic shift is the major change that sporadically occurs in the H and/or N antigens, i.e. H1N1 to H3N2. This usually leads to a pandemic and has only been observed with influenza A

Recorded Influenza Pandemics

1729	Russia	?
1732	Russia	?
1781	Russia/China	?
1830	Russia	?
1833	Russia	?
1889	Russia/Asia	H2
1899	?	H3
1918	USA/France	H1N1 (Spanish)
1957	China	H2N2 (Asian)
1968	China	H3N2 (H.K.)
1977	China	H1N1 (Swine)

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The 1918 Pandemic

• Called "Spanish" flu because of a high incidence in Spain
• Swept across the US in March/April 1918. 20 - 30% of the population was affected.
• The worst epidemic in history with 20 million dead and 25% of the population affected in less than a year.
• Overall mortality was 2.5% versus the usual <0.1%
• Over 550,000 Americans died, mostly young adults from pulmonary complications. This represented 0.5% of the population, and was 10x the number of Americans killed in WW I.
• No part of the world was spared - even affected Alaska and Samoa, where mortality was about 25%
• 31 years since the last pandemic; the longest interval this century was 39 years (1918 - 1957), the shortest was 11 years (1957-1968).
• H3N2 has been predominant for 31 years, H1N1 has been present for 22 years but only to a trivial extent

Epidemiology

• Mainland China appears to be the source of influenza outbreaks annually
• One reason is that the viruses can be isolated in China year round, and spread both east and west, but primarily to Russia and Europe before the Americas.
• The two major reservoirs for influenza A are humans and water fowl.
• However, there is no spread of avian viruses within human populations and vice versa.
• So, what is responsible for antigenic drift and shift?
• Swine have low barriers to infection by either human or avian influenza viruses
• Swine appear to be the vessel for the genetic reassortment of the 8 influenza A genes. This can lead both minor and major variations in the hemagluttinin and neuraminidase spikes.
• Again, in China, water fowl, humans and pigs live in close proximity, facilitating the above

Epidemics

• Epidemics are virtually exclusive to winter months (Dec - Apr) in the Northern hemisphere.
• In the Southern hemisphere, outbreaks occur from May to September and help plan the components of the vaccine for that winter
• During an epidemic, up to 20% of the local population may be affected, but this can be sporadic and/or higher (i.e. the elderly and children)
• During an epidemic, other influenzas (A, B, C) and other viruses (i.e. RSV) can be prevalent as well
• One study found that children under 5 had a hospitalization rate of 42.7 per 100,000

Pathophysiology

• The virus is acquired by inhalation of large droplets produced by coughing or sneezing.
• The virus invades columnar epithelial cells of the respiratory tract, with peak replication 1 -3 days after infection.
• Necrosis, edema and inflammation rapidly occur and can spread to the bronchioles and alveoli
• The epithelium begins to recover with 3 to 5 days, but may take up to 14 to regain normal cilia function and mucus production.
• Viral shedding usually last 6 - 8 days in adults but up to 2 weeks in young children.

Clinical Presentation

• In neonates, it can mimic bacterial sepsis and commonly cause apnea.
• Up to 50% of those less than 3 have a concomitant AOM
• In children less than 5, the most common presentation is a febrile URI
• Croup can be caused by influenza and tends to be have more severe airway compromise, with higher fevers and more tenacious secretions
• Similarly, bronchiolitis caused by influenza can be differentiated by the higher fevers (>39° C)
• The high fevers can also lead to febrile convulsions
• Other common symptoms are a dry, hacking cough that peaks after 3 - 4 days, but can persist as the patient improves, sore throat without exudative pharyngitis, and eye discomfort
• Gastroenteritis from influenza is much more common in pediatrics
• Bronchopneumonia may occur, either from the virus or from bacterial superinfection

More Unusual Complications

• Myocarditis
• Encephalitis
• Rhabodomyolysis
• Myositis
• Toxic Shock syndrome
• Renal failure
• Reye syndrome (with ASA usage)

Diagnosis

• WBC usually normal, children often show a relative neutrophilia
• CXR usually nonspecific
• Viral culture remains the gold standard but takes several days
• Influenza A DFA is specific but not very sensitive
• Acute and convalescent sera can be done for influenza A only

Treatment

• Only two agents are currently indicated for treatment/prophylaxis of influenza in children
• Amantadine and rimantadine block the third envelope protein (M2) and are effective against influenza A alone.
• Must be given within 36-48 hours of onset of illness, only 70-90% effective
• Amantadine is approved for both treatment and prophylaxis in children > 1 year old.
• The dose is 5 mg/kg/day, up to 150 mg/day if less than 10, 200 mg/day if >= 10 years. 1 or 2 doses/day
• Side effects include insomnia, dizziness, difficulty concentrating, loss of appetite
• Rimantadine is only FDA approved for prophylaxis; however many infectious experts feel it is also appropriate for treatment in children
• Dose is the same as amantadine, side effects are less common
• Drug resistance can occur with both

Indications for therapy

• Patients with underlying conditions that put them at higher risk for severe or complicated influenza infection
• Patients with severe influenza
• Patients in special environmental/social situations

Neuraminidase blockers

• Zanamavir (Relenza, Glaxo Wellcome) and oseltamavir (Tamiflu, Hoffman- La Roche) selectively inhibit the neuraminidase of both influenza A and B.
• Relenza is an intranasal spray, while Tamiflu is a pill for ingestion.
• Relenza is approved for >12, Tamiflu for >18 but this is likely to change by 2000-2001 influenza season. Roche is also planning a suspension.
• Relenza is given via 2 intranasal puffs bid x 5 d. Tamiflu
• Like amantadine/rimantadine, they must be started within 36 - 48 hours of onset of symptoms to gain any benefit
• It is important to still consider other etiologies or sources of infection in patients on these medications.

Prevention

• Every expert still considers this the primary means of avoiding and minimizing potential influenza complications.
• The current vaccine is a formalin inactivated whole or split product trivalent virus product. Split virus is recommended for those < 13 y.o., because of decreased local and febrile reactions, despite the better immune response with whole virus
• The vaccine is safe, immunogenic and has minimal side effects.
• Studies have shown that patients who receive a placebo vaccine vs. influenza vaccine show no differences with regard to fever, cough, coryza, fatigue, malaise, myalgia, headache, or nausea. The only statistically significant difference was arm soreness.

Who should be immunized?

• Children 6 months and older with:
• Asthma or chronic pulmonary diseases
• Hemodynamically significant heart disease
• Immunosuppressive therapies or illnesses
• Hemoglobinopathies, i.e. SCC
• Rheumatologic conditions requiring long term aspirin therapy (i.e. Kawasaki, RF)

Consider immunization for:

• Diabetes
• Chronic renal disease
• Chronic metabolic disease
• Household contacts of high risk patients
• Pregnancy beyond 14 weeks
• Otitis prone children

Future Vaccines

• Live attenuated vaccines have been created by using a master cold-adapted donor A with multiple mutations making reversion to virulence unlikely. This is reassorted with the desired current wild type strains
• These vaccines are then given intranasally and have already been tested in children between 6 - 18 months with promising results.
• Other advantages include eliminating egg usage (avoiding potential allergic reactions) and theoretically faster vaccine development - instead of trying to grow sufficient virus to be deactivated, you could start with a small amount, cross it with the master strain and then rapidly clone

Issues for the Future

• China reservoir likely to persist for many years.
• Cases of H5N1 and H9N2 have occurred in humans in China, with some mortality. H4 is also most frequent in Chinese poultry.