Avian Influenza A (H5N1) Virus

Infection in Humans

Dr . Didin Retno SpPD

 Influenza A viruses have 16 H
subtypes and 9 N subtypes.
• In poultry, the viruses can mutate, usually
within a few months, from then low
pathogenic avian influenza (LPAI) form into
the highly pathogenic form (HPAI).
• Only viruses of the H5 and H7 subtypes are
known to cause the highly pathogenic (HPAI)
form of the disease.
 Influenza A HA and NA Subtypes
H1 N1
H2 N2
H3 N3
H4 N4
H5 N5
H6 N6
H7 N7
H8 N8
H9 N9
H10
H11
H12
H13
H14
H15, H16
Progression of Human Cases
 Research regions, bird migration routes, and phylogeny of the clade 2.3.2 HPAI H5N1 virus
samples based on the sequences of the HA gene.

Huaiyu Tian et al. PNAS 2015;112:172-177

©2015 by National Academy of Sciences

Risk Factors: Exposures in the
Week Before Illness
• Touching sick or dead poultry
– Slaughtering, preparing for cooking

• Touching dead wild birds

Photo: AP/ Bikas Das

• Having sick or dead poultry in the household

• Visiting a live poultry market

9
 Risk Factors:
Culture-Specific Risk

• Eating uncooked duck blood

• Defeathering of swans

• Playing with dead chickens

Photo: TIME Magazine / John Stanmeyer

• Contact with roosters used in cock fighting

10
 Current Criteria for Suspected Case
H5N1
Unexplained acute lower respiratory illness with documented fever >38°C
with cough, shortness of breath, or difficulty breathing, and 1 or more of
the following exposures within 7 days of symptom onset:

•Close contact with a person who is a suspected, probable, or confirmed

H5N1 case.
•Exposure to poultry, or their remains, or environments contaminated
with their feces in an area with active H5N1 infections in humans or
animals.
•Consumption of raw or undercooked poultry products in an area with
active H5N1 infections in humans or animals.
•Close contact with a confirmed H5N1-infected animal other than birds
(eg, cat or pig).
•Handling samples (animals or human) suspected of containing H5N1
virus in a laboratory or other setting.
 Current Criteria for Probable Case
H5N1

A person dying of an unexplained acute respiratory illness who is

considered to be epidemiologically linked to a probable or confirmed
H5N1 case

OR

A person meeting the criteria for a suspected case and 1 of the following
criteria:
Evidence of an acute pneumonia on chest radiograph plus evidence of
respiratory failure.
Positive laboratory confirmation of influenza A infection but not
confirmed as H5N1 infection.
 Current Criteria for Confirmed Case
H5N1

• A person meeting the criteria for a suspected or probable case

AND

• One of the following positive results conducted in a national,

regional, or international influenza laboratory whose H5N1 test results are
accepted by WHO as confirmatory:
Isolation of H5N1 virus.
Positive H5 PCR results from 2 different PCR targets.
A 4-fold or greater rise in neutralization antibody titer for H5N1.
A microneutralization antibody titer for H5N1 of 1:80 or greater in
a single serum specimen collected at day 14 or later post symptom
onset
 H5N1 Viral Infection in Humans

• Incubation period
– Generally from 2 to 7 days

• Viral shedding period for H5N1 virus

– Still largely unknown
– May be 2 weeks or longer
• Longer for children and immune compromised

14
 H5N1 Clinical Manifestations
• Common signs and symptoms:
– Fever ≥38C, cough, shortness of breath,
difficulty breathing

• Other findings (less common):

– Sore throat, headache, muscle aches,
diarrhea

• Clinical findings are non-specific, and

are similar to other common acute
respiratory diseases
– Critical to ask about H5N1 exposures 15
 Possible Complications of
H5N1 Infection
• Most common: pneumonia
– May progresses to respiratory failure
• May requires mechanical ventilation
– Acute respiratory distress syndrome (ARDS)

• Gastrointestinal disease
• Multi-organ failure
– Heart and kidney dysfunction

• Neurologic symptoms
– Encephalitis, seizures, altered mental status,
progression to coma 16
 H5N1 Pathogenesis
• High H5N1 viral levels are associated with an
abnormal inflammatory response

• Other blood changes

 Decreased white blood cell count
 Low lymphocyte count
 Mild to moderately decreased platelet count

• Infection and inflammation contribute to

respiratory failure and multi-organ failure
 Cytokine dysregulation (cytokine “storm”)

17
 Clinical Complications
• Respiratory failure
– Complication from pneumonia within a few days to 2
weeks after illness onset

• Acute Respiratory Distress Syndrome

• Multiple organ failure
– Renal dysfunction
– Cardiac dysfunction
Normal lymphocyte count
• Abnormal lab values 1500 - 4000 / mm3
– Low lymphocytes: <1500 / mm3
Normal platelet count
– Low platelets: < 150,000 / mm3
150,000 - 400,000 / mm3

18
 Diagnosis
Tests on respiratory samples (most common):
• PCR-based techniques
• Virus isolation
• Immunofluorescence
• Rapid antigen detection (Flu A or B)

Tests on serum:
• Measurement of specific antibodies
• PCR-based techniques

Other tools:
• Chest X-Ray
Tests on Respiratory Samples
• Reverse-transcription polymerase chain
reaction (RT-PCR)
 Primary method of confirming H5N1 virus
infection
 Highly sensitive and specific

• Virus Isolation
 “Gold standard”
 Requires BSL-3 laboratory
 Allows for characterization of the virus
20
 Other Tests
• Serological methods
Require acute and convalescent sera
(serum obtained >21 days from onset)

• Immunoflorescence
Requires H5 monoclonal antibody
Can be difficult to interpret

21
 Rapid Influenza Test
• Commercially available
• Results in 15 - 30 minutes
• Detect human influenza A and B viruses
• Very low accuracy to detect H5N1 virus and
seasonal influenza
 Not sensitive or specific for detecting H5N1 virus
 May result in false negatives and false positives
• NOT RECOMMENDED for DETECTION of
H5N1 virus
22
 Other Diagnostic Tools
Peripheral blood
• Decrease in the white blood cell
count (WBC)
Decrease in lymphocyte count (one type of
white blood cell)
• Mild to moderate decrease in the
blood platelet count

23
 Imaging
Radiologic Imaging (X-ray)
• Non-specific evidence of pneumonia on
admission
• Often progresses to bilateral, multi-lobar
pneumonia
• Diffuse or patchy infiltrates
• Fluid in the space surrounding the lungs
• Cavities may form in the lung tissue
 Severe H5N1 Pneumonia - Vietnam
2004

DAY 5 DAY 7 DAY 10

•Fever
•Progressive pulmonary disease
•Death

25
Hien TT et al., New England J Med 2004;350:1179-1188
 A Clinician Should Suspect
H5N1 Virus Infection:
• Severe acute respiratory illness
AND
• Exposure 7 days before symptom onsets
to:
 Sick poultry or wild birds
 Suspect , probable, confirmed H5N1 case
OR
• Residence in an area with known H5N1
virus infections of poultry or other animals
OR
• Occupational risk factors, or reported
cases of severe respiratory illness among
close contacts and household members
26
 Diagnostic Tests

If
• Patient is suspected human H5N1 case or
meets other trigger criteria (link to trigger
criteria)

Then
• Patient’s specimen should be sent to a WHO
H5 Reference Laboratory* for further
influenza testing and confirmation

* Every country should have access to at least one laboratory capable of

H5N1 virus detection by RT-PCR 27
 Clinical Treatment for
Seasonal and Pandemic
Influenza

28
 Treatment for Influenza
Viruses
• Neuraminidase Inhibitors
– Oseltamivir
– Zanamivir

• Other Treatments

• Chemoprophylaxis

• Clinical Management
Top image located at: http://www.biota.com.au/?page=1021001&subpage=1021019. Bottom image located at: http://www.free-rx-
drugstore.com/gb/.
Antivirals

30
 Antivirals
• Used for the treatment and prevention of
seasonal influenza A and B virus infections
• Effectiveness against H5N1 virus infection is
unknown
• WHO recommended first line therapy for
treatment and prevention of H5N1 virus
infection
• Treatment should be given as soon as possible
• May be given as chemoprophylaxis to prevent
H5N1 disease in exposed persons

31
 Neuraminidase Inhibitors
• Two drugs available:
– Oseltamivir (Tamiflu ®); Zanamivir (Relenza ®)

• Inhibit the Neuraminidase enzyme which

provides the bond between infected cell and
new virus particles
• Prevents the release of new virus particles
from the infected cell
• Virus particles cannot go on to infect other
cells
32
 Oseltamivir for Seasonal
Influenza
• Capsule or suspension administered by
mouth
• Approved in the U.S. for treatment of
seasonal influenza in children aged ≥1 year
– Pediatric dosage depends on age and weight
• Administered twice a day for 5 days
• Side effects: nausea, vomiting
• Effectiveness
– Reduces influenza symptoms by 1 day when
administered within 2 days of illness onset
– Reduces lower respiratory tract
complications, pneumonia, and
hospitalization
33
 Oseltamivir: Considerations
• Precautions
– People with kidney disease (reduce dose)
– Pregnant or nursing females
– Reports of delirium in pediatric patients
(mostly from Japan)

• Resistance
– Can develop with treatment, but frequency
of resistance to oseltamivir is low

34
Oseltamivir for H5N1 Infection

Effectiveness for H5N1 treatment is

unknown

– However is first line therapy for H5N1

infections

35
Recommended Treatment for
Human H5N1 Infection
WHO recommends Oseltamivir treatment
• Optimal dosage, duration for H5N1 unknown

• WHO recommends similar dosage to

seasonal influenza (capsule and oral
suspension)
75 mg twice per day, 7-10 days
– Pediatric dosing based upon age and weight
– Consider longer treatment, and higher doses (150
mg) on case by case basis, especially in patient
with progressive disease 36
 OseltamivirTreatment for
Human H5N1 Infection
• Should be started as early as possible in
suspected H5N1 patients

• Warranted even with late presentation

• Resistance has been reported during

treatment of a small number of H5N1 patients

Zanamivir can treat oseltamivir resistant

viruses
37
 Treatment of Children

• Different oseltamivir dosage

– Based on child’s weight
– Not approved in children <1 year old

• No aspirin for children <18 years of age

– Risk of Reye’s syndrome with aspirin
– Use paracetemol or ibuprofen

• Children potentially infectious for longer

periods than adults after illness onset

38
 Zanamivir
• Orally inhaled powder – administered by
mouth via special device
• Approved in the U.S. for treatment of
seasonal influenza in patients aged 7
years and older and for
chemoprophylaxis in persons older than
5 years of age
• Treatment dosage for seasonal influenza
is one puff in the morning and one at
night
for 5 days
• Side effects
– Wheezing, and breathing problems
39
 Zanamivir: Effectiveness

• Effectiveness in seasonal influenza

– Can reduce influenza symptoms by 1 day if
administered within 48 hours
– Reduces lower respiratory tract
complications
– Oseltamivir-resistant influenza A(H1N1)
viruses remain sensitive to zanamivir

40
 Zanamirvir: Considerations

• Not recommended for

– People with chronic respiratory disease
– Pregnant or nursing females

• Resistance
– Very low for human influenza A (H1 and
H3) viruses

41
Zanamirvir for H5N1 Infection

Effectiveness for H5N1 treatment is

unknown
– Used as second line therapy for H5N1
infections when virus is resistant to
oseltamivir

42
 Adamantanes
Amantadine and Rimantadine
• Chemically related, orally administered drugs
• Reduce viral replication of Influenza A
viruses
• No activity against Influenza B viruses
• High frequency of resistance among
circulating human influenza A (H3) viruses
– Resistance develops rapidly influenza A viruses
• Adverse effects include gastrointestinal and
neurological symptoms
• NOT recommend for H5N1 treatment
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Other Treatments

44
 Corticosteroids

• No proven effectiveness on clinical H5N1

infection

• Risk of side effects, including

opportunistic infections

• May be considered on case by case basis

for persistent septic shock with adrenal
insufficiency
45
 Recommended Treatment
with Antibiotics

• Antibiotic prophylaxis should be

avoided

• When pneumonia is present:

– Antibiotic treatment is appropriate
– Treat according to published evidence-
based guidelines
46
 Treatment for the
Acute Respiratory Distress Syndrome
(ARDS)
• Therapy for H5N1 virus infection associated
ARDS should be based upon published
guidelines for ARDS

Lung protective mechanical ventilation with

low tidal volume

47
 WHO Recommnedations:
Antiviral Chemoprophylaxis for
Human Infections with H5N1 Virus
• Pre-exposure prophylaxis may be considered
for
– Those involved in culling or disposing of infected
poultry

• Post-exposure prophylaxis should be

considered for
– Household and close contacts of suspected or
confirmed H5N1 cases
– Healthcare worker with exposure without
appropriate PPE to suspected or confirmed H5N1
patients 48
WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006
 Antiviral Chemoprophylaxis:
High Risk
WHO recommends Oseltamivir for
chemoprophylaxis of high-risk groups:
75 mg / day for 7-10 days after the last known
exposure

High-risk:
Household or family members and close contacts,
including pregnant women, of a strongly
suspected or confirmed H5N1 patient
WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006 49
Chemoprophylaxis: Moderate
Risk
Antiviral chemoprophylaxis may be considered in
persons defined by WHO as having moderate risk
Moderate Risk:
– Persons handling sick animals, decontaminating
environments, without the appropriate use of PPE or
without using PPE 100% of the time
– Unprotected and very close direct exposure to sick or
dead animals infected with H5N1 virus or birds
implicated in human cases
– Healthcare workers in close contact with strongly
suspected or confirmed H5N1 patients (performing
intubation, tracheal suctioning, delivering nebulized
drugs, handling body fluids) without the appropriate
use of PPE
50
Chemoprophylaxis: Low Risk
Antiviral chemoprophylaxis is generally not recommended for low
risk persons

Low Risk:
– Healthcare workers not in close contact with a strongly
suspected or confirmed H5N1 patient and having no direct
contact with infectious material
– Healthcare workers in contact with H5N1 cases wearing
appropriate PPE
– Culling of non-infected or likely non-infected animals
– Handlers of sick animals or decontaminating environments
while using appropriate PPE

51
 Clinical Management
• Infection control:
– Isolate patient
– Implement infection control precautions
– All bodily fluids, secretions, clinical specimens should
be considered potentially infectious
– Proper personal protective equipment (PPE) for
caregivers
• Supportive care:
– Supplemental Oxygen
– Mechanical ventilation for respiratory failure in
the intensive care unit
• For the health care provider, PPE and not
prophylaxis is the first line of defense! 52