INFLUENZA

INFLUENZA VIRUS

ORTHOMYXOVIRUSES

M1 protein

helical nucleocapsid (RNA plus NP protein)

HA - hemagglutinin

polymerase complex

lipid bilayer membrane

NA - neuraminidase

type A, B, C : NP, M1 protein sub-types: HA or NA protein

Influenza Virus

A/Fujian/411/2002 (H3N2)

NeuraminidaseHemagglutinin

Type of nuclearmaterial

Virustype

Geographicorigin

Strainnumber

Year of isolation

Virus subtype

• Drift Minor change, same subtype Point mutations in gene

May result in epidemic

• Example:– In 1997, A/Wuhan/359/95 (H3N2) virus was

dominant– A/Sydney/5/97 (H3N2) appeared in late 1997 and

became the dominant virus in 1998

Influenza Antigenic Changes

• Shift Major change, new subtypeExchange of gene segmentMay result in pandemic

• Example:– H2N2 circulated from 1957-1967– H3N2 appeared in 1968 and completely

replaced H2N2

Influenza Antigenic Changes

Pathogenesis and Pathology • Influenza virus can spread from person-to-

person by the aerosol route.

• The major site of infection is the ciliated columnar epithelial cells.

• The first alteration is the disappearance of the elongated form of these cells which become round and swollen, the nucleus shrinks and fragments.

• Vacuolization of the cytoplasm may occur and cilia are lost.

• Edema and inflammation follow with desquamation of the ciliated and mucous-producing epithelial cells down to a one-cell thick basal layer.

• Submucosal edema and hyperemia occur with an infiltration by neutrophils and mononuclear cells.

• The extent of virus induced cellular destruction is the prime factor in determining the occurrence, diversity and duration of clinical illness.

• Reparative and destructive processes may be present simultaneously and complete resolution (repair) of the epithelial necrosis probably takes up to a month.

NORMAL TRACHEAL MUCOSA

3 DAYS POST-INFECTION 7 DAYS POST-INFECTION

• Influenza virus induces pathological changes throughout the entire respiratory tract.

• Occasionally, it causes interstitial pneumonia sometimes with marked accumulation of lung hemorrhage and edema.

• Although it could be primary viral, most cases of pneumonia associated with influenza are caused by bacteria.

• Recovery is associated with interferon production and the development of cellular immunity.

• Recovery precedes antibody production.

• Antibodies to HA, NA, NP and M proteins are produced.

• Viremia is rare

Clinical Features• The incubation period ranges from 1 to 4 days with an

average of 2 days but in children it may reach 7 days.

• The typical uncomplicated influenza syndrome is a febrile illness of sudden onset characterized by tracheobronchitis with the additional involvement of small airways.

• Most adults do not display the classic syndrome and it is uncommon in children and is not seen in infants.

SYMPTOMS• FEVER• HEADACHE• MYALGIA• COUGH• RHINITIS• OCULAR SYMPTOMS

• Manifestations are related to:

• Common cold: Sneezing, nasal obstruction, nasal discharge.• Upper respiratory illness: Nasal obstruction,

discharge, sore throat.• Pharyngitis: Sore throat and erythema

• Laryngitis: Hoarseness

• Tracheobronchitis: Cough

• Children tend to have higher fever and febrile convulsions may take place.

• They also have a higher incidence of

gastrointestinal manifestations.

• Infections in neonates can be life threatening. • Otitis media, croup and myositis are more

frequent in children.

CLINICAL FINDINGS

• SEVERITY– VERY YOUNG– ELDERLY– IMMUNOCOMPROMISED– HEART OR LUNG

DISEASE

Persons at High Risk• All persons 50 years of age or older

• Persons >6 months of age with chronic illness

• Residents of long-term care facilities

• Pregnant women (2nd and 3rd trimesters)

• Children 6 months to 18 years receiving chronic aspirin therapy

• Children 6-23 months of age

High risk due to Chronic Medical Conditions

• Pulmonary (e.g. COPD, asthma)

• Cardiovascular (e.g. CHF)

• Metabolic (e.g. diabetes)

• Renal (e.g. chronic renal failure)

• Hemoglobinopathies (e.g. sickle cell)

• Immunosuppression (e.g. HIV)

PULMONARY COMPLICATIONS• CROUP (YOUNG CHILDREN)

• PRIMARY INFLUENZA VIRUS PNEUMONIA

• SECONDARY BACTERIAL INFECTION– Streptococcus pneumoniae– Staphlyococcus aureus– Hemophilus influenzae

• Fatality is 10-12% but staphylococcal pneumonia may be fatal in 42% of cases.

NON-PULMONARY COMPLICATIONS

• myositis (rare, > in children, > with type B)• cardiac complications• recent studies report encephalopathy• liver and CNS

– Reye’s syndrome• peripheral nervous system

– Guillian-Barré syndrome

Reye’s syndrome• liver - fatty deposits• brain - edema• vomiting, lethargy, coma• Fatality ranges from 22 to 42%.• risk factors

– youth– certain viral infections (influenza, chicken pox)– aspirin

• In summary:• Uncomplicated Influenza - Fever, Myalgia, headache Dry cough, nasal

discharge and Ocular symptoms

• Pulmonary complications - Croup and Pneumonia • Nonpulmonary complications - Myositis, Cardiac complications, Reye’s

syndrome, and Guillain Barré syndrome

TYPE A++++yesyesyesshift, driftyessensitivesensitive2

severity of illnessanimal reservoirhuman pandemicshuman epidemicsantigenic changessegmented genomeamantadine, rimantidineZanamivir, Oseltamivirsurface glycoproteins

TYPE B++nonoyesdriftyesno effectsensitive2

TYPE C+nonono (sporadic)Drift?yesno effectno effect(1)

Diagnosis• Viral Isolation: PMK, MDCK• Antigen Detection: IF• Molecular Methods: Rt -PCR• Serology: Hemagglutination inhibition.

• Original antigenic sin.

TREATMENT - DRUGS• RIMANTADINE (M2)

• type A only, needs to be given early

• AMANTADINE (M2)• type A only, needs to be given early

• ZANAMIVIR (NA)• types A and B, needs to be given early

• OSELTAMIVIR (NA)• types A and B, needs to be given early

OTHER TREATMENT

• REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6 months -18 years)

• BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

EPIDEMIOLOGY

Epidemiology

• Influenza is an Italian word reflecting an old belief that the illness was caused by the “influence” of atmospheric factors (stars).

• The viral etiology of the disease was first proven in 1933 in Ferrets by Sir Christopher Andrewes and coworkers.

The Story of Influenza: Historically Speaking

• Influenza is NOT a new illness

• Influenza can be traced as far back as 400 BC

• In Hippocrates’ Of the Epidemics, he describes a cough outbreak that occurred in 412 BC in modern-day Turkey at the turn of the autumn season

412 BC Outbreak• Actual disease that affected the camp is still under

debate – but is theoretically influenza

• High communicable rate and autumn season onset are notable characteristics of influenza

• Death and funerals were a daily spectacle

• Miasma rising from bodies was fatal to the sick and the sick were fatal to the healthy

• Outbreaks were documented in the 18th and 19th century infecting about 70% of the population in some cities

• Human influenza infection spreads by: – Close contact (<6 feet) with a sick person

who is coughing or sneezing, or

– Touching a surface contaminated by their respiratory secretions and getting the virus into mouth, nose or eyes. (WASH YOUR HANDS!)

Survival of Influenza in the Inanimate Environment and on Skin

 • 24 – 48 hours on hard, non porous surfaces• 8 – 12 hours on cloth, paper, and tissue• 5 minutes on hand• in water 22ºc → 4 days, 0ºc → 30 days• at 60ºc for 30 mins• inactivated by 70% alcohol and by Chlorine

The 3 Influenza Scenarios

• Seasonal flu

• Avian flu

• Pandemic flu