Asia 1829 Spread to Indonesia by January 1831 Russia 1830 Spread throughout Russian and westward between 1830 and 1831 By November 1831, the influenza outbreak reached America Epidemics prevalent until 1851
M1 protein unnderlies the lipid bilayer, is the most abundant protein. Genome organized in 7 or 8 segments. 3 integral membrane proteins that coordinate fusion are NA, HA, and M2 (not shown) NP protein important for subtyping NS protein, not shown, important for virulence.
A and B are similar, C is much different—both in terms of protein composition and virality.
Because of A’s ability to infect numerous carriers, it is the most dangerous subtype, and will be focus of presentation. Dangerous outbreaks are often the result of genetic reassortment, which relies on cross infection of one host with more than one strain of the virus, followed by transmission from one species to humans. This can’t happen with B, so there are less outbreaks.
HA and NA are the most important proteins for determining the exact strain (NP does the subtype, and then these two do the strain) They frequently mutate in the antigen recognition domain, and account for IV’s ability to evade the immune system
HA1- Uses Sialic-acid-containing receptors on host cell glycoproteins. This receptor binding event is followed by endocytosis. HA2 Decrease in pH in endosome enables HA to undergo a confomational change that enables HA to fuse with the endosomal membrane
Example of how a virus uses the host cell’s machinery for proliferation. Host cell enzyme cleaves the precursor.
On the other end of fusion, the viral budding process, NA plays critical role. Elysha will discuss NA inhibitors later, they prevent the cleavage of virion sform a host cell and can effectively limit infection if taken early on. Viral resistance is a big problme here.
Elysha will discuss the potential for using a highly conserved domain of this protein for vaccine development later.
Elysha and Ayesha will refer to outbreaks using this system, especially the type an dstrain.
Process involves combining strains in an intermediate host (so it’s mostly A). This is where the big outbreaks stem from.
Unusual combination of genetic material from pigs, birds & humans which have re-assorted human-to-human transmission occurs through respiratory droplets generated from sneeze or cough Affects all age groups Vaccines for human seasonal flu can not protect humans against the novel virus
Virions are usually roughly spherical and about 200nm in diameter. The envelope contains rigid &quot;spikes&quot; of haemagglutinin and neuraminidase which form a characteristic halo of projections around negatively stained virus particles. .
Children can have additional gastro-intestinal symptoms, such as nausea, vomiting, and diarrhea, but these symptoms are uncommon in adults. The period when an infected person is contagious depends on the age of the person. Adults may be contagious from one day prior to becoming sick and for three to seven days after they first develop symptoms. Some children may be contagious for longer than a week.
Outbreaks are likely to occur among individuals living together in settings such as nursing homes or among people who gather together indoors during the winter months.
clinical specimens such as nasopharyngeal swab, throat swab, nasal swab, wash or aspirate, and tracheal aspirate (for intubated patients) are to be obtained. The sample should be collected by a trained physician / microbiologist preferably before administration of the anti-viral drug AND PREFEREBLY WITHIN FIRST4-5 DAYS OF ILLNESS.
Serum samples also can be tested for influenza antibody to diagnose recent infections. Two samples should be collected per person: one sample within the first week of illness and a second sample 2-4 weeks later. If antibody levels increase from the first to the second sample, influenza infection likely occurred. Because of the length of time needed for a diagnosis of influenza by serologic testing, other diagnostic testing should be used if a more rapid diagnosis is needed. http://www.austehc.unimelb.edu.au/guides/burn/photos.htm VACCINES
Correct procedure for applying PPE in the following order: Follow thorough hand wash Wear the coverall. Wear the goggles/ shoe cover/and head cover in that order. Wear face mask N95 Wear gloves The masks should be changed after every six to eight hours.
Key Concepts: Some search engines work better for specific types of searches. While Yahoo will take your keyword and sort information into categories, a search engine like Hotbot will bring up the ten “hottest” (or most popular) sites for your keyword. While Hotbot might be useful for assessing the popularity of web sites in a cultural analysis paper, Yahoo might offer a more comprehensive listing of sites.
SWINE FLUVirus Dr. Ashish J Post Graduate Dept of Microbiology Navodaya Medical College, Raichur
Koen-1919- Swine flu isolated. Smith Andrew and Laidlow-1933 Francis and Magill-1940 Taylor -1949
20th Century Outbreaks 1918 Spanish Flu 1957 Asian Flu 1968 Hong Kong flu 1976 Swine Flu scare 1977 Russian Flu scare 1997 Avian Flu scare
1918 - Spanish Flu (originated in birds). SoldiersFirst hit soldiers in Europe during World whoseWar I, as their immune systems were immunityweakened by war. was weakenedThe mortality rate was highest between by war.20 to 50 year olds.There was never any vaccinedeveloped, after about 18 months, thevirus seemed to just disappear. Many of theThe final death toll was written as 40 victims who havemillion people worldwide. died in Mexico have been young and otherwise healthy. societys healthiest demographic
Structure of Virion HA - hemagglutinin NA - neuraminidase helical nucleocapsid (RNA plus NP protein) 100 n m lipid bilayer membrane polymerase complex M1 proteinInfluenza virions are SMALL. The average eukaryotic cell diameter is 10,000 nm (10 microns), which is 100 times bigger than the influenza virion diameter. http://www.med.sc.edu:85/pptvir2002/INFLUENZA-2002.ppt
Influenza Subtypes Types A & B Type C 3 1 IMP IMPs 8 Segments of RNA 7 Segments of RNA Responsible for Causes only mild infections epidemics & pandemics
Subtype Viral Structure/CarriersType A Type B Humans Humans Swine Birds Horses Seals Type C Humans Swine http://www-ermm.cbcu.cam.ac.uk/01002460a.pdf
Integral Membrane Proteins (IMP) Hemagglutinin •Trimeric Protein •500 copies per virion Neuraminidase •Tetrameric Protein •100 copies per virion Matrix 2 (M2) •Tetrameric Protein •10 copies per virion http://www.biotech.ubc.ca/db/TEACH/BANK/PPT/flu2.ppt
Fusion Schematic 1) HA binds a cell GP at a Sialic Acid Binding Site http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt
Fusion Schematic 1) HA binds a cell GP at a Sialic Acid Binding Site Low pH 2) Clathrin-Coated pit endocytoses virion http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt
Fusion Schematic 1) HA binds a cell GP at a Sialic Acid Binding Site 3) Conformational Change: Hydrophobic binding of HA to vesicle membrane Low pH 2) Clathrin-Coated pit endocytoses virion http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt
Fusion Schematic 1) HA binds a cell GP at a Sialic Acid Binding Site 3) Conformational Change: Hydrophobic binding of HA to vesicle membrane Low pH 2) Clathrin-Coated pit endocytoses virion 4) RNPs are released into cytoplasm for replication and transcription (vRNA and mRNA) http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt
HA Cleavage Specific cleavage site is a basic sequence of AAs. Cleaving enzyme can determine pathogenicity of virus. If the enzyme is ubiquitous in cells, then those cells can make virulent influenza. Humans: Argenine is present at cleavage site Cleaving enzyme is a tryptase called Clara Only produced in Clara cells, which are only found in upper respiratory tract Influenza infection is confined to this region of the body
Neuraminidase IMP: HA binds sialic receptors, NA releases virus or progeny virus from receptor Roles in viral entry/exit: Help virion navigate mucusal lining of respitory tract Release progeny virion from surface of host cell Newest Class of drugs: Neuraminidase Inhibitors
Matrix 2 IMP: Homotetrameric Single pass transmembrane protein Roles in last 2 steps of entry process Facilitates membrane fusion in endosome Low pH in endosome activates M2 to open ion channel. Hydrogens enter virus and activate HA to undergo conformational change that results in membrane fusion with endosome As a consequence, RNPs are released into cytoplasm http://www.northwestern.edu/neurobiology/faculty/pinto2/pinto_flu.pdf
Nomenclature 3 Subtypes, coupled with variance of the antigenicity of surface proteins (HA & NA) and the long history of influenza epidemics necessitate a nomenclature system to catalogue each strain. A/Moscow/21/99/H3N2 Subtype NP & MI Geographic Origin Strain Number Year of Isolation HA & NA Sub-strain
Antigenic VariationAntigenic Drift Minor changes in the antigenic character Mutation rate highest for type A, lowest for type C Most meaningful mutations occur in HA1 protein When 2 virions infect a cell, there are 256 possible combinations of RNA for offspring. http://www.biotech.ubc.ca/db/TEACH/BANK/PPT/flu2.ppt
Antigenic Shift Phylogenic evolution that accounts for emergence of new strains of virus Immunologically distinct, novel H/N combinations Genetic reassortment between circulating human and animal strains is responsible for shifts Segmented genome facilitates reassortment Only been observed in type A, since it infects many species
Seasonal Epidemics vs. Pandemics Seasonal Influenza Influenza Pandemics A public health Appear in the human problem each year population rarely and unpredictably Usually some immunity built up from Human population previous exposures to lacks any immunity the same subtype Infantsand elderly All age groups, most at risk including healthy young adults
A H1N1 :new virus Illness was first recognised in 1930. The 2009 H1N1 virus is a hybrid of swine, avian and human strains Influenza A (H1N1)
He says ice- cream made him feel better, and Thank God has now recovered full health. But the rest of the planet has a quick – paced pandemic marchingPatient Zero in Swine Flu Outbreak on….Identified as 5-Year-Old Mexican Boy: Edgar Hernandez
MexicoMidMarch: La Gloria,Veracruz, 60% of the towns population is sickened by a respiratory illness of unknown provenance.April 16 : Mexico Authorities notify the PAHO (Pan American Health Organization) of the atypical pneumonia. Canadian labsApril 23 : S-OIV (swine origin influenza virus) confirmed, same strain detected in two California children as in Mexico. PAHO informed of Mexico cluster of S-OIV
WHO April 24: 2009 H1N1 first disease outbreak notice. April 25: WHO Director General declares a formal “Public health emergency of international concern” April 27: “containment of the outbreak is not feasible” pandemic alert raised from phase 3 to phase 4. April 29: phase 4 to phase 5. During this time interim, the WHO was vastly criticized for not announcing phase 6 June 11: phase 5 to phase 6.
Phase 1 – animal to animal transmission.Phase 2 – an animal influenza virus is capable of human infection.Phase 3 - small outbreaks among close populations but not through human to human contact. Phase 4 - Human to human transmission Phase 5 - spread across two countries or more in one of the WHO regions (continents). Phase 6 – spread across two countries or more in one of the WHO regions plus spread to another WHO region.
Viral Re-assortment Reassortment in humansReassortment in pigs Pandemic Influenza Virus
Pigs a Mixing vessel Pigs can catch human and avian or bird flu. When flu viruses from different species infect pigs, they can mix inside the pig and new, mixed viruses can emerge. Doctortvrao’s ‘e’ learning series
Where virus act in the body? The influenza virus is a upper respiratory tract infection Although called a respiratory disease, it affects the whole body, making you feel sick all over. http://www.nlm.nih.gov/medlineplus/ency/imagepages/17237.ht
Transmission from person-to-person by: Tiny droplets that come from a person’s mouth and nose when they cough and sneeze. Touching objects contaminated with particles from an infected person’s nose and throat. http://www.lungusa.org/diseases/c&f02/influenza.html#what
Symptoms Symptoms begin 1-4 days after infection. You can spread the flu before your symptoms start and 3-4 days after your symptoms appear. The following symptoms of the flu can vary depending a person’s age and overall health: Sudden onset of chills and fever (101 – 103 degrees F) Sore throat, dry cough Fatigue, malaise Terrible muscle aches, headaches Diarrhea Dizziness
Is it a cold or the flu? Symptoms Cold Flu Fever: Rare Characteristic,high (102 –104 °F),lasts 3 –4 days Headache: Rare Prominent General Aches: Pains Slight Usual Often severe Fatigue: Quite mild Can last up to 2 –3 weeks Extreme Exhaustion: Never Early and prominen Stuffy Nose: Common Sometimes Sneezing: Usual Sometimes Sore Throat: Common Sometimes Chest Discomfort: Mild to moderate Common:can becom hacking cough severe
Risk Factors Older age group >65 yr pregnancy chronic lung disease (eg., COPD, cystic fibrosis,asthma) congestive heart failure renal failure immunosuppression (due to underlying disease or therapy) haematological abnormalities (anemia, haemaglobinopathies) Diabetes mellitus Chronic hepatic disease socially unable to cope (i.e., without personal support at home ).
Suspected Case : Person with acute febrile ̊ illness(fever≥38C) with onset # within 7 days of close contact with a person who is a confirmed case of swine influenza A, or # within 7 days of travel to areas where there are one or more swine influenza cases, or # resides in a community where there are one or more confirmed swine influenza cases.
Probable case : A person with an acute febrile respiratory illness who : # is positive for influenza A, but unsubtypable for H1 and H3 by influenza RT-PCR or reagents used to detect seasonal influenza virus infection or, # is positive for influenza A by an influenza rapid test or an IF assay plus meets criteria for a suspected case, or # individual with a clinically compatible illness who is considered to be epidemiologically linked to a probable case.
Confirmed case: person with an acute febrile illness with laboratory confirmed swine influenza A(H1N1) virus infection at WHO approved laboratories by one or more of the following: Real Time PCR Viral Culture Four Fold rise in virus specific neutralising antibodies.
Close Contact : is defined within 6 feet of an ill person who is a confirmed, probable or suspected case of influenza A (H1N1) virus infection during the infectious period. Acute respiratory Illness : is defined as illness of recent onset with at least two of the following: Rhinorrhea or nasal congestion Sore throat Cough(with/without fever).
Complications – “Superinfection” A bacterial “superinfection” can develop when the influenza virus infects the lungs. The result? The bacteria that live in the nose and throat can descend to the lungs and cause bacterial pneumonia. Who is most at risk? People over 50, infants, those with suppressed immune function or chronic diseases. Other complications include bronchitis, sinusitis and ear infections.http://www.ecureme.com/atlas/version2001/atlas.asp
Complications in children: Reye’s syndrome CNS and liver and children exhibit symptoms of drowsiness, persistent vomiting and change in personality.
Transmission Limited data indicate that transmission is similarly as in other influenza viruses. Spread is 1° from person to person through large-particle respiratory droplets. This requires close contact between source & recipient, as droplets do not remain suspended in air & travel only short distances (<1m ). Contact with respiratory-droplet contaminated surfaces is another possible source of transmission. As data from influenza viruses H1A1 are limited, potential for ocular, conjunctival, or GI infection is unknown. Being a novel influenza A virus, transmission from infected persons to close contacts maybe common. All respiratory secretions & bodily fluids (diarrheal stool) of H1N1 cases should be considered infectious.
Facilities Needed Proper screening and triage facilities Proper holding areas Proper examination rooms Changing areas
Hospital Admission policies Depending on phase of pandemic, admission policies vary from admitting all probable / suspected cases to only admitting those who are ill or with complications. In early phases; to prevent importation or to reduce viral transmission in the country, all suspect influenza H1N1 cases will be admitted in designated hospitals and kept in isolation. In full pandemic situation, where cases go beyond capacity of health facilities to cope, a policy of surveillance & Tx. at home or the use of non-traditional health facilities may be instituted. Hospital admissions will only be for those with respiratory distress or with assoc complications of influenza or those in high risk groups (ie.with co-morbidities). Such admission policies will be updated as pandemic evolves.
INVESTIGATIONSConfirmation of influenza A(H1N1) infection is through: Real time RT PCR or Isolation of the virus in culture or Four-fold rise in virus specific neutralizing antibodies.
Diagnosis: Rapid influenza tests, and serum samples can be used to confirm infection by the influenza virus since the symptoms of the flu are similar to the symptoms caused by other infections. Serology test to be done include Complement fixation test. HAI
MANAGEMENT OF SUSPECTED AND CONFIRMED CASESDetailed history obtained: clinical, travel and contact history including occurrence of respiratory disease in contact patients during the last 10 days Clinical workup should follow measures stated in Syndromic Approach Protocol for acute respiratory syndromes Virology samples sent to Virology Unit, IMR Bacteriology samples are processed in respective hospitals All specimens should be transported in accordance to Guidelines of Transport of Infectious Material. In event of death, post-mortem should be performed in accordance with Guidelines For Post-Mortems Involving Unknown/Uncertain Infectious Agents Dead bodies handled as per Guidelines on Handling of Bodies with HIV/AIDS
DISCHARGE OF PATIENTSThe patients can be discharged with the following criteria: Suspected cases: When PCR results are negative (IMR) If patient is still unwell, he can be transferred out of isolation ward Probable & Confirmed cases: At least 7 days from onset of illness and Completed at least 5 days of antiviral therapy and Well / asymptomatic If the patient has fulfilled the first 2 criteria but is still recovering, he can be transferred out of isolation ward
Surveillance The global surveillance network determines which strains of the influenza virus will make-up the vaccine.
Surveillance Cont’d: After both parties agree, the vaccine is manufactured from inactivated viruses.
I already have the flu…Now what? Increase liquid intake like water, juice, and soups. Get plenty of rest for the 7 to 10 days during which the symptoms may persist. Take anti-fever drugs to relieve the fever. Anti-viral drugs have recently been designed to treat the flu. If patients begin taking these drugs within 48 hours after their symptoms begin, the drugs may reduce the length of the illness by about 1 to 2 days.
Anti-viral drugs: General background All anti-viral drugs inhibit viral replication but they act in different ways to achieve this. Drugs that are effective against influenza A viruses: amantadine and rimantadine. Drugs that are effective against influenza A viruses and influenza B viruses: zanamivir and oseltamivir. Amantadine Rimantadine Zanamivir Oseltamivir Influenza A Influenza AType of Influenza virus Influenza A Influenza A Influenza B Influenza Binfection indicated for useAdministration oral oral oral inhalation oralAges approved for treatment 1 year 14 year 7 years 18 yearsof fluAges approved for 1 year 1 year not approved not approvedprevention of flu http://wdhfs.state.wy.us/epiid/fluvac.htm
Zanamivir and Oseltamivir These drugs are neuraminidase inhibitors. They prevent the NA proteins on the surface of the IV from removing sialic acid from sialic acid- containing receptors. Viral budding and downstream replication of IV are inhibited when sialic acid remains on the virion membrane and host cell. The emerging IV’s stick to the cell plasma membrane or other viruses since the sialic acid is still on the surface of the cell and the virion.
Standard Operating Procedures Reinforce standard infection control precautions i.e. all those entering the room must use high efficiency masks, gowns, goggles, gloves, cap and shoe cover. Restrict number of visitors and provide them with PPE. Provide antiviral prophylaxis to health care personnel managing the case and ask them to monitor their own health twice a day. Dispose waste properly by placing it in sealed impermeable bags labeled as Bio- Hazard.
PERSONAL PROTECTIVEEQUIPMENT Remove PPE in the following order:• Remove gown (place in rubbish bin).• Remove gloves (peel from hand and discard into rubbish bin).• Use alcohol-based hand-rub or wash hands with soap and water.• Remove cap and face shield • Remove mask - by grasping elastic behind ears – do not touch front of mask• Use alcohol-based hand-rub or wash hands with soap and water.• Leave the room.• Once outside room use alcohol hand-rub again or wash hands with soap and water.
HAND HYGIENE Hands should be washed frequently with soap and water / alcohol based hand rubs/ antiseptic hand wash and thoroughly dried preferably using disposable tissue/ paper/ towel. After contact with respiratory secretions or such contaminated surfaces. Any activity that involves hand to face contact such as eating/ normal grooming / smoking etc.
CHEMO PROPHYLAXIS It is indicated for : All close contacts of suspected, probable and confirmed cases. Close contacts include household /social contacts, family members, workplace or school contacts, fellow travelers etc. All health care personnel coming in contact with suspected, probable or confirmed cases
CHEMO PROPHYLAXIS Oseltamivir is the drug of choice. Prophylaxis should be provided till 10 days after last exposure (maximum period of 6 weeks)For weight <15kg 30 mg OD 15-23kg 45 mg OD 24-<40kg 60 mg OD >40kg 75 mg OD For infants: < 3 months not recommended unless situation judged critical due to limited data on use in this age group 3-5 months 20 mg OD 6-11 months 25 mg OD
ADVERSE REACTION Oseltamivir is generally well tolerated, gastrointestinal side effects (transient nausea, vomiting) may increase with increasing doses, particularly above 300 mg/day. Occasionally it may cause bronchitis, insomnia and vertigo. Less commonly angina, pseudo membranous colitis and peritonsillar abscess have also been reported. There have been rare reports of anaphylaxis and skin rashes. There is no recommendation for dose reduction in patients with hepatic disease. Zanamivir causes severe bronchoconstriction
MONITORING The suspected cases should be constantly monitored for clinical / radiological evidence of lower respiratory tract infection hypoxia and shock. Look for Pulse ,Blood Pressure, Temperature and Resp. rate Oxygen saturation level of consciousness Rhonchi and basal rales. Input/output charting
SUPPORTIVE THERAPY Patients with signs of tachypnea, dyspnea, respiratory distress and oxygen saturation less than 90 per cent should be supplemented with oxygen therapy. Patients with severe pneumonia and acute respiratory failure (SpO2 < 90% and PaO2 <60 mmHg with oxygen therapy) must be supported with mechanical ventilation. If the laboratory reports are negative, the patient would be discharged after giving full course of oseltamivir. Even if the test results are negative, all cases with strong epidemiological criteria need to be followed up. Low dose corticosteroids (Hydrocortisone 200-400 mg/ day) may be useful in persisting septic shock (SBP < 90).
Vaccine Vaccines are available to be given to pigs to prevent swine influenza. Vaccination most effective measure for reducing impact of influenza. Vaccine recommended for people most at risk. Two types of vaccines TIV LAIV.
INFECTION CONTROL MEASURESAT HOME Get plenty of sleep, be physically active,manage your stress, drink plenty of fluids , and eat nutritious food. Persons & their household members should be told frequent hand washing with soap and water ; use alcohol based hand gel. When the patient is within 6 feet of other family member, he should wear a face mask/ handkerchief / tissues. Sweeping and dusting to be done with wet cloth. Small amount of disinfectant may be mixed in water . ( absolute alcohol ) If any family member develop any symptom, report to health authorities. Precautions to continue during the period of infectivity
ALGORITHM FOR MANAGEMENT OF PATIENT WITH H1N1 A INFLUENZADOES THE PATIENT HAVE TWO OF THE FOLLOWING SYMPTOMS? |RHINORRHEA/NASAL CONGESTION, SORE THROAT, COUGH(WITH/WITHOUT FEVER(≥38C) | ________ |_________________________ | | YES NO | |HAS THE ILLNESS STARTED LOOK FOR OTHER ILLNESSWITHIN 7 DAYS OF CLOSE CONTACT |WITH A CONFIRMED SWINE INFLUENZA |CASE/TRAVEL TO AFFECTED AREAS/ OR RESIDENCE |IN AN AFFECTED AREA | |____________________________________NO | YES | ADMIT THE PATIENTCOHORT IN A WELL VENTILATED WARD WITH BEDS KEPT 1MTR APARTSEND NASOPHARYNGEAL/THROAT SWAB FOR RTPCR/VIRAL CULTURESEND PAIRED SERA SAMPLESTART TAMIFLU(75 mg BD for 5 days)MONITOR VITALS/SaO2 FOR COMPLICATIONS | | SEE RESULTS OF VIRUS SPECIFIC INVESTIGATIONS | |POSITIVE NEGATIVE | | | |COMPLETE THE COURSE COMPLETE THE COURSEAND D/S AFTER 7 DAYS AND D/S.THE SYMPTOMS HAVESUBSIDED/MONITOR FORCOMPLICATIONS
Conclusion Outbreak caused by novel influenza 2009 A(H1N1). Rapidly spreading across the globe. Antigenically distinct to other seasonal flu. Higher transmissibility as compared to circulating seasonal flu Diagnosis PCR. Treatment is Oseltamivir and Zanamivir.
References CDC manual for treatment of swine flu WHO manual of Swine flu FDA approved treatment for swine flu NIV manual of swine flu Emergence of novel influenza virus H1N1, V Ravi, IJMM. 2009 vol3 Emergence of Swine flu- Dr. T. R Rao Medical daily internet reference Harrison manual of internal medicine Jawertz text book of medical microbiology Ananthnarayan text book of medical microbiology Topley and wilson textbook of medical microbiology
References • Burnett, Chiu, and Garcea. Structural Biology of Viruses. Oxford: Oxford University Press, 1997. • Mahy, Brian WJ. A Dictionary of Virology. 2nd Ed. San Diego: Academic Press, 1997. • Fields, Barnard N. et al. Fields Virology vol 1. 3rd Ed. Philadelphia: Lippincott-Raven, 1996. • http://www.med.sc.edu:85/pptvir2002/INFLUENZA-2002.ppt • Structure and Genome Organization of Influenza Viruses. Expert Reviews in Molecular Medicine. Available: http://www-ermm.cbcu.cam.ac.uk/01002460a.pdf. Cambridge University Press, 2001. • Antler, Christine, Boyler, Erin. Who Knew? The Flu and You! From: Biotechnology Laboratory, University of British Columbia. Available Online: http://www.biotech.ubc.ca/db/TEACH/BANK/PPT/flu2.ppt. No date. • Isin, Basak, et. al. Functional Motions of Influenza Virus Hemagglutinin: A Structure-Based Analytical Approach. Biophysical Journal. Feb 2002: vol. 82, 569-581. • Lagunoff, Michael. Viral Replication. Lecture notes from April 9, 2002 for Microbiology/Pathology 445. University of Washington. Available Online: http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt • Pinto, Lawrence. The M2 Ion Channel Protein of Influenza Virus A. Detailed Research Summary from Northwestern University. Available Online: http://www.northwestern.edu/neurobiology/faculty/pinto2/pinto_flu.pdf. • 8. Feliciano D, et. al. Five-year Experience with PTFE Grafts in Vascular Wounds. American Scientist 2003, 92: 122-129. • Pandemics and Pandemic Scares in the 20th Century from CDC: Pandemic Influenza [Online] • Schoch-Spana M. Implications of Pandemic Influenza for Bioterrorism Response. Clinical Infectious Diseases 2000; 31:1409-13 • Puskoor, Rohit et al. Invfluenza Virus Book Chapter. Not yet published.