The document provides an overview of the history of influenza pandemics, including details on the 1918 Spanish Flu pandemic that killed an estimated 50 million people globally. It discusses the H1N1 influenza virus and 2009 H1N1 pandemic, symptoms of H1N1 infection, and guidelines for testing and diagnosing suspected cases of H1N1. The document also reviews pathogenesis of H1N1 and strategies for prevention and treatment of influenza.

1. H1N1 INFLUENZA
09/09/2017

2. HISTORY
 Pandemics from as early as 412 BC
 Term “influenza” first used in 1357 BC, , Italian word meaning
“influence” of the stars on the disease.
 First convincing record of a pandemic in 1580; began in Russia and
spread to Europe and Africa. killing 8,000 people in Rome; several
Spanish cities wiped out.
 Pandemics sporadic throughout the 17th and 18th centuries

3. PANDEMICS OF INFLUENZA
3
H1N1
H2N2
1889
Russian
influenza
H2N2
H2N2
1957
Asian
influenza
H2N2
H3N2
1968
Hong Kong
influenza
H3N2
H3N8
1900
Old Hong
Kong influenza
H3N8
1918
Spanish
influenza
H1N1
1915 1925 1955 1965 1975 1985 1995 2005
1895 1905 2010 2015
2009
Pandemic
influenza
H1N1
Reproduced and adapted (2009) with permission of Dr Masato Tashiro, Director, Center for Influenza Virus Research,
National Institute of Infectious Diseases (NIID), Japan.
Animated slide: Press space bar
H1N1
Pandemic
H1N1

4. 1918 Pandemic: "the greatest medical holocaust in
history"
• “Spanish flu” 1918 A(H1N1)
• An estimated 50 million deaths globally…
• 20-40% of total world’s population was
thought to be infected
• Killed more number of people in 25 weeks
than HIV-AIDS killed in 25 years…
• Killed 7 times the number of people killed
in world war I.

5. 1918, INFLUENZA
PANDEMIC
 Second and third waves of infection, in
1918-1919 and 1919-1920.
 Death toll to at least 50 million
 Probably infected over 1/3 humans alive at
the time, case mortality rate of ~
5%(normal mortality rate for seasonal flu is
0.1 – 0.3%)
 Seemed to affect mainly young adults

6. HISTORY
 Charles Nicolle and
Charles Lebailly in France proposed
in 1918 : causative agent of the
Spanish Flu was a virus, based on
properties of infectious extracts from
diseased patients
 1931, Robert Shope (USA) managed
to recreate swine influenza by
intranasal administration of
filtered secretions from infected
pigs.
 Patrick Laidlaw (UK) at NIMR, in
1933, isolated a virus from humans
infected with influenza from an
epidemic then raging.
Their serotype was named
“influenza A”, and it was later typed
as H1N1

7.  Frank Macfarlane Burnet (Australia) in
1936 showed that it was possible to do
“pox assays” for influenza virus on the
chorio-allantoic membranes of
fertilized chicken eggs.
 This led directly to the
development of the first influenza
A vaccine – a killed virus
preparation made in eggs – by
Thomas Francis in the USA in 1943
with support from the U.S. Army
 The Army was deeply involved in
this research due to its experience
of influenza in WWI, when
thousands of troops were killed by
the virus in a matter of months.
Historic picture on the wall in the routine
influenza isolation laboratory at the NICD,
Johannesberg.

8. OVERVIEW OF THE SEMINAR
 What is influenza & What makes it dangerous?
 Bird flu, swine flu, seasonal flu…How do these differ?
 Bird flu in brief
 Pandemics : phases & how it occurs.
 Pathogenesis of H1N1
 Clinical features, Complications
 Diagnosis and treatment
 Preventive measures
 Immunization

9. INFLUENZA
• Enveloped, ss RNA virus
• Orthomyxoviridae
• Eight segmented genome
• Mutations occur frequently and unpredictably
• Point mutations in the HA gene cause minor antigenic
changes to HA, causes seasonal epidemics (antigenic
drift).
• Genetic re-assortment causes emergence of a novel
human influenza A virus , responsible for the
pandemic(antigenic shift).
NELSON 20TH ed

10.  Type A
 moderate to severe illness
 all age groups
 humans and other animals
– birds,pigs,horses etc.,
 Type B
 milder disease
 primarily affects children
 humans only
 Type C
 rarely reported in humans
 no epidemics
 Classified on the basis of
Haemagglutinin (HA) and
neuraminidase (NA)
 18 subtypes of HA and 11
subtypes of NA are known to
exist.
 Human diseases caused by
-3 subtypes of HA (1-3) and 2
subtypes of NA (1-2).
-HA 5, 7, 9 and NA 7 can also
infect humans

11. NAMING THE VIRUS

12. SWINE FLU IN PIGS
 Three main influenza A virus : H1N1, H1N2, and H3N2
 Spread among pigs mostly through close contact & contaminated
objects
 Signs in pigs: fever, depression, coughing (barking), discharge from
the nose or eyes, sneezing, breathing difficulties, eye redness or
inflammation, and going off feed. Some pigs, however, may show no
signs of illness at all.
 H1N1 and H3N2 endemic among pig population occur in colder
weather months (late fall and winter)
 Specific swine influenza vaccines available for pigs.

13. AVIAN INFLUENZA
 H5N1, cause minor illness among poultry birds
 mutate to a highly pathogenic form that could kill chickens within
48 hours ( mortality ~ 100%)
 First highly pathogenic form in 1997; suddenly became highly and
widely visible towards the end of 2003.
Documented ability to pass directly from birds to humans
2.Once in humans, causes severe disease with very high mortality
3. Potential to ignite a severe pandemic

14. H5N1 TRANSMISSION
 Human cases – winter & spring, seasonality in poultry.
 Direct contact with live or recently dead poultry- most important
risk factor for infection.
 Source – direct handling of infected poultry, slaughtering,
consumption, close contact.
 Human infections are rare by avian influenza because:
Avian viruses prefer
αlpha 2,3
linkages (GIT)
Human viruses prefer
αlpha 2,6
linkages
(Respiratory Tract)

16. WHO ON AVIAN INFLUENZA
 WHO network laboratories developed a prototype virus, for use as
the “seed” for vaccine production, and made it available to
manufacturers in April 2004.
 Inadequate vaccine supplies and the uncertain role of antiviral drugs
 Non medical intervention takes a precedence
“The virus is now firmly entrenched in the poultry populations in Asia
No high-risk group, defined by occupation, exists for the targeting of protective
measures
The health threat for this group has been compounded by the increasing
tendency of human cases to occur in the absence of reported outbreaks in
poultry”

17. INDIAN BIRD FLU
 Outbreak of bird flu (Avian Influenza sub-type H5N1) first reported on 18th
October, 2016 among wild birds in National Zoological Park, Delhi.
 samples of wild/ migratory birds from Delhi, Madhya Pradesh, Kerala, Punjab
and Haryana have been tested positive for Avian Influenza H5N1 at National
Institute of High Security Animal Diseases (NIHSAD), Bhopal, Madhya
Pradesh.
 The Department of Animal Husbandry, Dairying and Fisheries, Government of
India took all necessary precautions to control the outbreaks of bird flu.
 Advisories were issued and Teams of Experts were deputed to the affected
areas to assist in control and containment measure.
 The concerned State Governments have carried out such operations as per
‘Action Plan on Preparedness, Control and Containment of Avian Influenza’.
 As informed by Department of Animal Husbandry, Dairying and Fisheries,
the situation is under control.

18. PANDEMIC
 A pandemic is an epidemic occurring on a scale which crosses
international boundaries, usually affecting a large number of people.
 it must also be infectious.
 Notable pandemics in history
 Plague of Athens, 430 BC
 Antonine Plague, 165–180 AD
 Black Death, 1347 to 1453
 Cholera: 19th century
 Tuberculosis: 20th -21st century
 HIV: 21st century

19. WHO’s Definition of an Influenza
Pandemic
“An influenza pandemic occurs when a new influenza
virus appears against which the human population has
no immunity; resulting in several, simultaneous
epidemics worldwide with enormous numbers of
deaths and illness.”

21. H1N1 INFLUENZA
 A/H1N1/2009
 The novel H1N1 swine flu
virus was thus the product
of re-assortment of human
virus, avian virus, North
American swine and
Eurasian swine virus.

23. SEASONAL INFLUENZA PANDEMIC INFLUENZA
• Circulate and cause disease in humans
every year.
• Occur seasonally in the winter months, in
rainy season in tropics
• Spreading from person-to person through
sneezing, coughing, or touching
contaminated surfaces.
• Increased risk for severe disease
 Pregnant women
 <5, >65 yrs
 Immunocompromised people,
 chronic medical conditions.
• Influenza virus not previously circulating
among humans
• Emerge, circulate and cause large outbreaks
outside of the normal influenza season.
• Proportion of persons infected quite large.
• Spread across many nations.

24. Bird Flu (H5N1) Swine Flu (H1N1)
Rarely infects humans Human infections are
common
High Mortality (>50%) Less Mortality (<1%)
Human – human
extremely rare.
Widespread transmission
occurs.

28. INDIAN SCENARIO
42592
1786
22186
2990
265
1094
0
10000
20000
30000
40000
50000
2015 2016 2017
deaths
cases

29. INDIAN SCENARIO-2017
Total no. of case 22,186
Highest no. of cases Maharashtra- 4245
Goa- 3029
Tamil Nadu- 2994
Karnataka-2956
Delhi- 1416
Kerala- 1374
Rajasthan- 651
Swine flu related deaths 1094
Deaths in August 342
Highest no. of deaths Maharashtra- 437
Goa- 269
Rajasthan-69

30. PATHOPHYSIOLOGY

31. SIGNS AND SYMPTOMS

32. TYPICAL ILLNESS

33. PANDEMIC H1N1 INFECTION IS
CHARACTERIZED BY RESPIRATORY &
GASTROINTESTINAL SYMPTOMS!
1.N=879 cases reported by 28 EU/EEA countries, as of 17 June 2009. 2. Due to reporting limitations, ‘Other’ represents systemic symptoms
ECDC Surveillance Report, Analysis of Influenza A(H1N1)v individual case reports in EU and EEA countries, Update 17 June 2009.
Symptoms reported for confirmed cases of pandemic H1N1 cases in EU and EEA countries
While many symptoms of pandemic H1N1 infection are shared with seasonal influenza,
approximately 21% of pandemic influenza patients report gastrointestinal symptoms,
which are atypical of seasonal infections
Symptoms unique to
pandemic H1N1 2009
Symptoms common to
seasonal and pandemic
influenza
Fever or history of fever
Dry cough
Other (various)
Headache
Sore throat
Muscle pain
Runny nose
Joint pain
Sneezing
Productive cough
Nausea
Shortness of breath
Diarrhea
Vomiting
Conjunctivitis
Nose bleed
Altered consciousness
60%
50%
40%
30%
20%
10%
0% 80%
70%
Proportion of symptoms reported (%)

35. PREDICTORS OF MORTALITY

36.  A person with acute febrile respiratory illness (fever
≥ 380 C)
 Onset within 7 days of close contact with a person
who is a confirmed case of H1N1 virus infection, or
 Within 7 days of travel to areas where there are one or
more confirmed H1N1 cases, or
 Resides in a community where there are one or more
confirmed swine influenza cases.
Suspected case (H1N1)

37. PROBABLE CASE
A person with an acute febrile respiratory illness who:
 Is positive for influenza A, but unsubtypable for H1 and H3 by
RT-PCR or reagents used to detect seasonal influenza virus
infection, or
 Is positive for influenza A by an influenza rapid test or an
influenza immunofluorescence assay (IFA) plus meets criteria
for a suspected case, or
 Individual with a clinically compatible illness who died of an
unexplained acute respiratory illness who is considered to be
epidemiologically linked to a probable or confirmed case.

38. CONFIRMED CASE
A person with an acute febrile respiratory illness
with laboratory confirmed H1N1 virus infection
at WHO approved
laboratories by one or more of:
 Real Time PCR
 Viral culture
 Four-fold rise in H1N1 virus specific neutralizing
antibodies

39. WHO NEEDS TESTING?
CATEGORY SYMPTOMS Testing for
H1N1
A Mild fever + cough / sore throat with/ without body ache,
headache, diarrhoea and vomiting
No testing
required
B Cat A symptoms + high grade fever & severe sore throat.
Mild illness with predisposing risk factors. Pregnant women;
Persons >65 yrs; with lung heart , liver ,kidney diseases, blood
disorders, diabetes, neurological disorders, cancer HIV/AIDS, on
long term cortisone therapy.
No testing
required
C •Breathlessness, chest pain, drowsiness, fall in blood pressure,
cyanosis, sputum mixed with blood
•Children with severe disease manifested by red flag signs
(Somnolence, high persistent fever, inability to feed well,
convulsions, shortness of breath, difficulty in breathing
• Worsening of underlying chronic conditions
Required

40. LAB TESTS
 Direct detection – microscopy
 Antigen detection
 Nucleic acid analysis
 Isolation of virus – cell culture
 Serologic tests

41. SAMPLE TO BE
COLLECTED
 Respiratory specimens: Bronchoalveolar lavage,
tracheal aspirates, nasopharyngeal or oropharyngeal
aspirates as washes, and nasopharyngeal or
oropharyngeal swabs.
 Swab specimens should be collected only on swabs
with a synthetic tip (such as polyester or Dacron) and
aluminium or plastic shaft.
 Swabs with cotton and wooden shafts are not
recommended.
 Specimens collected with swabs made of calcium
alginate are acceptable.

42. WHEN TO COLLECT
RESPIRATORY
SPECIMENS?
 As soon as possible after symptoms begin
 Before antiviral medications are administered
 Even if symptoms began more than one week
ago
 Multiple specimens on multiple days could be
collected if you have access to patient

43. THROAT SWAB
 Highest yield in detecting H1N1
 The patient should try to resist gagging and closing the mouth while
the swab touches the back of the throat near the tonsils

44. NASAL / NASOPHARYNGEAL
SWAB
 Insert dry swab into nostril and back to nasopharynx.
 Leave in place for a few seconds
 Slowly remove swab while slightly rotating it
 Use a different swab for the other nostril
 Put the tip of the swab in the vial containing VTM
 Nasal Swab is collected from the anterior turbinate.

45. TRANSPORT OF SAMPLES
 specimens kept at 4 0 C in viral transport media until transported for
testing.
 Transported to designated laboratories within 24 hours.
 If can’t be transported; stored at -70 0 C.
 Transported on dry ice in triple packaging

46. DIRECT DETECTION
 Not used routinely.
 Done by electron microscopy.
 Immune EM being most sensitive.
 Requires large number of virus (>10⁵ - 10⁶/ml) for successful
detection.

47. RAPID INFLUENZA
DIAGNOSTIC TEST
 Detect influenza viral nucleoprotein antigen.
 results within 30 minutes or less.
 Commercially available RIDTs can either:
 detect and distinguish between influenza A and B viruses;
 detect both influenza A and B but not distinguish between
influenza A and B viruses; or detect only influenza A viruses.
 Sensitivities ~ 50-70%
 Specificities ~90-95%
 Positive predictive value more during influenza season.

48. IMMUNOFLUORESCENCE (DFA/ IFA)
• Staining of cells from the sample, followed by bioconjugation of
antibodies to the fluorescent dye.
• Can distinguish between influenza A and B viruses
• Sensitivity ~ 70% and 100%
• Specificity ~ 80% to 100%

49. VIRUS CULTURE
 Monkey kidney cells, Madin darby canine kidney (MDCK) cells and
A549 cells used to detect influenza viruses.
 cause cytopathology, which is different according to the cell type
used.
 10-14 days to get the result
 Delays initiation of antiviral therapy or infection control methods

50. RT-PCR
 RNA extracted from the influenza sample is
purified and transcribed using the
oligonucleotides specific to the target
sequence, producing cDNA
 Sensitivity:77%
 Specificity: 96%

52. TREATMENT GUIDELINES
CATEGOR
Y
SYMPTOMS Testing for
H1N1
Drug treatment
A Mild fever + cough / sore throat with/ without
body ache, headache, diarrhoea and vomiting
No testing
required
No need of
treatment
B Cat A symptoms + high grade fever & severe sore
throat.
Mild illness with predisposing risk factors. Pregnant
women; Persons >65 yrs; with lung heart , liver
,kidney diseases, blood disorders, diabetes,
neurological disorders, cancer HIV/AIDS, on long
term cortisone therapy.
No testing
required
oseltamivir
C •Breathlessness, chest pain, drowsiness, fall in blood
pressure, cyanosis, sputum mixed with blood
•Children with severe disease manifested by red
flag signs (Somnolence, high, persistent fever,
inability to feed well, convulsions, shortness of
breath, difficulty in breathing
• Worsening of underlying chronic conditions
Required oseltamivir

53. MANAGEMENT
 Early implementation of infection
control
 Minimize nosocomial/household
spread of disease
 Prompt treatment to prevent severe
illness and death
 Early identification and follow-up of
persons at risk
 Avoid crowding of patients together,
promote distance between patients
 Hand hygiene
GENERAL PRINCIPLES SUPPORTIVE MEASURES
• Rest and adequate hydration
• Antipyretics: Paracetamol or
ibuprofen
• Aspirin contraindicated
• Supportive oxygen therapy, if
required mechanical ventilation.
• Noninvasive ventilation
• Use of filters on expiratory ports of
the ventilator circuit/high-flow
oxygen masks

54. PHARMACOLOGICAL
AGENTS
 Neuraminidase inhibitors
Oseltamavir, Zanamivir, Peramivir, Laninamivir
 M2 protein inhibitors
Amantadine, Rimantadine

55. MECHANISM OF ACTION

56. OSELTAMIVIR
 Neuraminidase inhibitor (Oseltamivir phosphate)
 Bioavailability 80%, absorption not affected by food/altered gastric pH
 Elimination primarily by renal excretion(80%), feces(20%)
• Shorten the duration of uncomplicated influenza when administered
early (< 48 hours after illness onset).

57. OSELTAMIVIR
 30 mg, 45 mg, 75 mg capsules
 Oral suspension 12 mg/1ml
 Rs 100/capsule
 Produced by Hetero , Cipla, Ranbaxy
 Not available in medical shops

58. OSELTAMIVIR
Age based:
 14 days -1 year: 3 mg/kg/dose, twice daily
 For <14 days: 3 mg/kg/dose once daily

59. ADVERSE REACTIONS
 In children : vomiting, abdominal pain, epistaxis, bronchitis, otitis
media, dermatitis and conjunctivitis
 Neuro-psychiatiric illness in children and adolescents
 Adults: gastrointestinal side effects , bronchitis, insomnia and vertigo,
angina, pseudo membranous colitis and peritonsillar abscess
Clinical pharmacokinetics of the prodrug; Oseltamivir and its active metabolite; Clinical pharmacokinetics. 1999

60.  Pregnancy- same dose and duration, Category C
 In renal failure – with CrCl <30ml/min, decrease dose
by 50%. In patients with ESRD oseltamivir is not
recommended
 No dose adjustment required for mild to moderate
hepatic impairment
Clinical pharmacokinetics of the prodrug; Oseltamivir and its active metabolite; Clinical pharmacokinetics. 1999

61. RESISTANCE
 His275Tyr mutation–high level resistance to oseltamivir, esp. in those on
prolonged therapy and immunosuppression.
 As per WHO ; resistance to Oseltamivir is rare.

62. ZANAMIVIR
 MOA- Neuraminidase inhibitor
 Mode of administration- inhaled/iv
 Bioavailability- 14-17% of inhaled dose is systemically absorbed
 No dose modification in renal impairment
 Approved by US-FDA for treatment in patients >7yrs of age similar to
indications of oseltamivir
 Dosage:
 Treatment :10mg(2 puffs) BD x 5days

63. PERAMIVIR
 Approved by US-FDA in 2014
 MOA- neuraminidase inhibitor
 Dose 600mg iv infusion over 15min
 Not approved in <18 years

66. TIME OF DISCHARGE ?

67. ROLE OF STEROIDS
Corticosteroids have no beneficial effects in treating patients with
influenza A

68. SUPPORTIVE
MANAGEMENT
 Adequate hydration oral/IV fluids.
 Paracetamol/Ibuprofen –fever/myalgia/headache.
 Sore throat- steam inhalation/lozenges/decongestants.
 Oxygen supplementation - If SpO2<90%/PaO2<60mmHg.
 If unable to maintain saturation- ventilation, Invasive(preferred)/non
invasive. Use HEPA filters on expiratory ports of ventilator to limit spread
of aerosols
 Use antibiotics according to local clinical guidelines if suspected to be
having CAP. For mechanically ventilated patients- prophylactic antibiotics
to prevent VAP .

70. ANTIBIOTICS
 Patients with clinical syndrome compatible with
pneumonia with or without suspected influenza infection
should receive initial empirical antibiotic cover .
 If necrotizing pneumonia, sepsis , rapid onset of
respiratory distress, leukopenia should be started on
anti staphylococcal cover.
 Empirical cover for health care associated pneumonia
should include cover for MRSA and resistant gram
negative organism
JAMA 2013 , 309(3)275-
282

71. PROPHYLAXIS
 Frequent hand wash, cough etiquettes, maintaining
arms length distance from others.
 Contact surfaces disinfected by wiping, with sodium
hypochlorite solution or with household bleach (5%)
solution.
 Masks, tissue papers disposed of in dustbins.
 Utensils used by the case should not be used by
others without washing.
 Use triple layered surgical masks or N 95 masks

72. PERSONAL PROTECTION
EQUIPMENTS
1. Gloves (nonsterile)
2. Mask (high‐efficiency mask) / Three layered surgical
mask,
3. Long‐sleeved cuffed gown
4. Protective eyewear (goggles/visors/face shields),
5. Cap
6. Plastic apron if splashing of blood, body fluids,
excretions and secretions is anticipated

73. CHEMOPROPHYLAXIS
• Close contacts: household/
social contacts, family
members, workplace or
school contacts, fellow
travelers and all health care
personnel coming in
contact with suspected,
probable or confirmed
cases.
• Oseltamivir is drug of
choice
• Prophylaxis - till 10 days after
last exposure (maximum
period of 6 weeks)
• By 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 critical
• 3-5 months 20 mg OD
• 6-11 months 25 mg OD

74. INFLUENZA VACCINES
 The antigenic composition - revised twice annually to the
antigenic characteristics of circulating influenza viruses by
WHO’s GISRS to ensure optimal vaccine efficacy against
prevailing strains in both the northern and southern
hemispheres
 Hence the vaccine should be used every year.

75. INFLUENZA VACCINES
• Trivalent
• Made from strains of influenza A (H1N1,H3N2) and influenza B.
Inactivated Killed Vaccine
• > 6months of age
• Intramuscular route
• Adult dosage : single 0.5 ml
injection
• 6 months to 8 years: two doses
with 4 weeks apart
• Immunity develops in 2 weeks
• No contraindication for
pregnancy and systemic diseases.
• Protective efficacy of 50–80%.
Live Attenuated Vaccine
• Indicated for all healthy persons
2–49 years
• Contraindicated in pregnancy
and systemic diseases.
• Intranasal route
• Immunity in 7–10 days.
• To be given on an annual basis
• Protective efficacy of around
90%

77. WHO NEEDS
VACCINATION?
 Pregnant women
 People who live with or care for children < 6 months of age
 Children and young people between the ages of 6 months and
24 years
 Health care workers and emergency medical service providers .
 25 and 64 years of age who have chronic medical disorders or
compromised immune systems.

78. CONTRAINDICATIONS TO
VACCINE
 Severe allergy to egg.
 Severe reaction to an influenza vaccination
 Children < 6 months of age
 People who have a moderate-to-severe illness with a
fever
 History of Guillain–Barré Syndrome

79. APC EXPERIENCE-2017
Tested positive: 67
Expired: 12
LAMA: 7

80. TAKE HOME MESSAGE
 Suspicion of H1N1 : clinical + epidemiological
features
 Strict precautions to prevent transmission
 Hand hygiene : simple and effective
 Starting oseltamivir early based on clinical suspicion +
categorization can prevent complications
 Annual vaccination is recommended amongst high
risk population

81. THANK YOU!