swine flu

Dr. Ashish JPost GraduateDept of MicrobiologyNavodaya Medical College,Raichur

SWINE SWINE FLU VirusFLU Virus

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).

First hit soldiers in Europe during World War I, as their immune systems were weakened by war.

The mortality rate was highest between 20 to 50 year olds. There was never any vaccine developed, after about 18 months, the virus seemed to just disappear.

The final death toll was written as 40 million people worldwide.

Soldiers whose

immunity was

weakened by war.

Many of the victims who have died in Mexico have been young and otherwise healthy. society's healthiest demographic

Structure of Virion

M1 protein

helical nucleocapsid (RNA plus NP protein)

HA - hemagglutinin

polymerase complex

lipid bilayer membrane

NA - neuraminidase

100 n m

Influenza 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

3 IMPs 8 Segments of RNA Responsible for

epidemics & pandemics

Type C 1 IMP

7 Segments of RNA Causes only mild infections

Subtype Viral Structure/Carriers

http://www-ermm.cbcu.cam.ac.uk/01002460a.pdf

Humans Swine Birds Horses Seals

Type A Humans

Type C

Type B

Humans Swine

Integral Membrane Proteins (IMP)

Matrix 2 (M2)

http://www.biotech.ubc.ca/db/TEACH/BANK/PPT/flu2.ppt

•Trimeric Protein•500 copies per virion

•Tetrameric Protein•100 copies per virion

•Tetrameric Protein•10 copies per virion

Hemagglutinin

Neuraminidase

http://ubik.microbiol.washington.edu/microm-pabio445/MM_445_lec3_2002_files/MM_445_lec3_2002.ppt

1) HA binds a cell GP at a Sialic Acid Binding Site

Fusion SchematicFusion Schematic



2) Clathrin-Coated pit endocytoses virion

Low pH





3) Conformational Change: Hydrophobic binding of HA to vesicle membrane

Low pH





3) Conformational Change: Hydrophobic binding of HA to vesicle membrane

Low pH


4) RNPs are released into cytoplasm for replication and transcription (vRNA and mRNA)

Hemagglutinin (HA)

HA0 HA1

HA2

http://www.ccbb.pitt.edu/PDFFiles/150.pdf

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 tractInfluenza 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

StrainNumber

Year of Isolation

HA & NASub-strain

Antigenic Variation

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.

Antigenic Drift

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 Influenza

A public health problem each year

Usually some immunity built up from previous exposures to the same subtype

Infants and elderly most at risk

Influenza Pandemics

Appear in the human population rarely and unpredictably

Human population lacks any immunity

All age groups, including healthy young adults

Seasonal Epidemics vs. Pandemics

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 marching

on….'Patient Zero' in Swine Flu Outbreak Identified as 5-Year-Old Mexican Boy:

Edgar Hernandez

April 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

MidMarch: La Gloria,Veracruz, 60% of the town's population is sickened by a respiratory illness of unknown provenance.

Mexico

April 16 : Mexico Authorities notify the PAHO (Pan American Health Organization) of the atypical pneumonia.

Canadian labs

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.

June 11: phase 5 to phase 6.

During this time interim, the WHO was vastly criticized for not announcing

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 pigs

Reassortment in humans

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.htm

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 prominent Stuffy Nose: Common Sometimes Sneezing: Usual Sometimes Sore Throat: Common Sometimes Chest Discomfort: Mild to moderate Common:can become

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≥38KC) 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 Hospital Admission policiespolicies

Depending on phase of pandemic, admission policies Depending on phase of pandemic, admission policies vary from admitting all probable / suspected cases to vary from admitting all probable / suspected cases to only admitting those who are ill or with complications. only admitting those who are ill or with complications.

In early phases; to prevent importation or to reduce viral In early phases; to prevent importation or to reduce viral transmission in the country, all suspect influenza H1N1 transmission in the country, all suspect influenza H1N1 cases will be admitted in designated hospitals and kept cases will be admitted in designated hospitals and kept in isolation. in isolation.

In full pandemic situation, where cases go beyond In full pandemic situation, where cases go beyond capacity of health facilities to cope, a policy of capacity of health facilities to cope, a policy of surveillance & Tx. at home or the use of non-traditional surveillance & Tx. at home or the use of non-traditional health facilities may be instituted. Hospital admissions health facilities may be instituted. Hospital admissions will only be for those with respiratory distress or with will only be for those with respiratory distress or with assoc complications of influenza or those in high riskassoc complications of influenza or those in high risk groups (ie.with co-morbidities). Such admission policies groups (ie.with co-morbidities). Such admission policies will be updated as pandemic evolves. will be updated as pandemic evolves.

INVESTIGATIONS

Confirmation 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: 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 MANAGEMENT OF SUSPECTED AND SUSPECTED AND CONFIRMED CASESCONFIRMED CASES

Detailed 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 DISCHARGE OF PATIENTSPATIENTS The 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

Type of Influenza virus infection indicated for use

Influenza A Influenza AInfluenza A Influenza B

Influenza A Influenza B

Administration oral oral oral inhalation oral

Ages approved for treatment of flu

1 year 14 year 7 years 18 years

Ages approved for prevention of flu

1 year 1 year not approved not approved

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.

Neuraminidase inhibition

http://www.tamiflu.com/hcp/neuramin/neura_index.asp

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 Protective Equipment(PPE)

PERSONAL PROTECTIVE EQUIPMENT

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 MEASURES AT 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

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2. Mahy, Brian WJ. A Dictionary of Virology. 2nd Ed. San Diego: Academic Press, 1997.

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4. http://www.med.sc.edu:85/pptvir2002/INFLUENZA-2002.ppt

5. 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.

6. 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.

7. Isin, Basak, et. al. Functional Motions of Influenza Virus Hemagglutinin: A Structure-Based Analytical Approach. Biophysical Journal. Feb 2002: vol. 82, 569-581.

8. 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

9. 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.

10. 8. Feliciano D, et. al. Five-year Experience with PTFE Grafts in Vascular Wounds. American Scientist 2003, 92: 122-129.

11. Pandemics and Pandemic Scares in the 20th Century from CDC: Pandemic Influenza [Online]

12. Schoch-Spana M. Implications of Pandemic Influenza for Bioterrorism Response. Clinical Infectious Diseases 2000; 31:1409-13

13. Puskoor, Rohit et al. Invfluenza Virus Book Chapter. Not yet published.

swine flu

Health & Medicine

coated pitendocytoses

conformational

virus infection

suspected

acute febrileillness

close contact

hydrophobic

fusion schematic1