Management of Suspect Cases of Human Infection with

Avian Influenza A (H5N1) Virus

1

Outline

• Part 1: Background and epidemiology of avian influenza A

(H5N1) virus infection in humansHuman H5N1 clustersClinical features of human infection with H5N1 virus

• Part 2:Assessing case patients: Collecting clinical and

epidemiologic informationSpecimen collection and diagnosticsTreatment

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Management of Suspect Cases of Human Infection with

Avian Influenza A (H5N1) Virus

Part 1: Epidemiology and Clinical Features

Part 1: Learning Objectives

• Understand the epidemiology of known human H5N1 cases and risk factors

• Importance of clusters

• Recognize clinical features of H5N1 in humans

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Epidemiology of Influenza A(H5N1) Virus Infection of Humans

5Photo: T. Uyeki, CDC

Global Epidemiology

• 409 cases have been reported to WHO from 15 countries*

• Case fatality proportion = 256/409: ~ 63%

• Human surveillance has focused upon severe respiratory disease (pneumonia)

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*Reported as of March 2, 2009

Progression of Human Cases

World Health Organization, Western Pacific Regional OfficeCommunicable Disease Surveillance and Response

Human Avian Influenza A (H5N1) Cases by Onset Date and Country(as of 23 November 2009)

As of 23 March 2009, total of 412 cases were reported officially to WHO* Cases missing onset date are excluded: 1 Viet Nam, 13 Indonesia, 3 Azerbaijan, 20 Egypt, 1 Turkey, 1 Iraq, 1 Nigeria ** CFR Trend: computed based on cumulative dead & total number of cases

WHO Summary of H5N1 cases

• Epidemiologic summary of H5N1*Median age: 18 years (range 3 months - 75 years)90% of cases were aged <40 yearsMale to female ratio = 1:1Median time to hospitalization: 4 daysCase fatality proportion: ~60%Highest case fatality: 10-19 years (76%)Lowest case fatality: ≥50 years (40%)Median time to death: 9 days (range 2 – 31 days)

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*Update: WHO-confirmed human cases of avian influenza A(H5N1) infection,November 2003–May 2008. Weekly Epidemiological Record, NO. 46, 14 November, 2008WHO Avian Influenza http://www.who.int/csr/disease/avian_influenza/en/

Review Question 1

Which two countries have reported the most cases Influenza A (H5N1) to WHO to date?

a. Indonesia and Vietnam

b. Egypt and Thailand

c. China and Cambodia

d. India and China

Answer: a. Indonesia and Vietnam

Review Question 2

What age group has the highest reported case fatality rate from H5N1 virus infection?

a. 0-9 years old

b. 10-19 years old

c. 20-29 years old

d. > 50 years old

Answer: 10 – 19 years old

Risk Factors: Exposures in the Week

Before Illness

• Touching sick or dead poultrySlaughtering, preparing for cooking

• Touching dead wild birds

• Having sick or dead poultry in the household

• Visiting a live poultry market12

Photo: AP/ Bikas Das

Risk Factors:

Culture-Specific Risk

• Eating uncooked duck blood

• Defeathering of swans

• Playing with dead chickens

• Contact with roosters used in cock fighting

13

Photo: TIME Magazine / John Stanmeyer

Avian to Human Transmission of H5N1

• Primary mode of transmission is avian-to-human (zoonotic):Exposure to infected poultryPreparing or consuming uncooked or undercooked H5N1

virus-infected poultry or poultry products

• Indirect transmission may occur through: Inhalation of aerosolized H5N1 virus infected materialContact with surfaces contaminated with infected poultry

feces Contact with infected animals that ate dead poultry

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Human-to-Human Transmission of H5N1 Virus Infection

• Probable but limited, non-sustained* human-to-human transmission

Very rare, but documented

Occurred during close, prolonged, unprotected contact with a human H5N1 case

Mostly in family members

Transmission in hospital setting reported

15*Currently, no evidence of sustained human-to-human H5N1 virus transmission

Human Influenza A(H5N1) Case Clusters

Occurrence of H5N1 Clusters

• >25% of all cases have occurred in clusters

• Clusters are 2 or more H5N1 cases that are epidemiologically-linked Occurred in several countries

Hong Kong (2003)Thailand (2004)Indonesia (2006)

Human Case Cluster, Hong Kong 2003

• Family of five Hong Kong residents visited Fujian Province, southern China in late January 2003

• 7-year old girl developed pneumonia and died, was buried, but not tested

• Four survivors returned to Hong Kong

• Father and son were hospitalized with pneumonia; both confirmed with H5N1, father died

• No direct link between cases and avian flu infection in poultry was found

Human Case Cluster, Thailand 2004

• 11-year old girl who lived in a rural village with her aunt where poultry deaths occurred Mother lived near Bangkok (no poultry exposure)

• The girl developed fever and lower respiratory tract disease, hospitalized with pneumonia Mother and aunt traveled to hospital to provide care

• The girl died 24 hours later

• Mother and aunt became sick, were confirmed with H5N1 virus infection; mother died

• Probable human-to-human transmission of H5N1 virus from girl to her mother and aunt

Human Case Cluster, Indonesia 2006

• A large H5N1 family cluster occurred in North Sumatra 1 probable + 7 confirmed H5N1 cases7 deaths H5N1 virus was isolated from 7 cases Index case was likely infected by contact with

sick/dead chickensLimited human-to-human-to-human transmission

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Interpretation of Case Clusters

• Cases with similar illness onset datesSame exposure source, similar incubation

period?

• Cases with illness onset separated in timeSimilar exposure source, different incubation

periods?Different exposure sources? Limited human-to-human transmission?

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Significance of Case Clusters

• Increase in number and size of clusters, or increase in number of mild cases can indicate:That H5N1 viruses are spreading to more peoplePossible increased adaptability of H5N1 viruses to humans

• Signal for:An increased pandemic threat and a change in WHO

Pandemic Alert Period PhasesThe beginning of a pandemicEarly containment measures

• Documented exposure to a confirmed, probable, or suspected human H5N1 case,

AND

• The time interval between contact with a suspected, probable, or confirmed H5N1 case and illness onset is 7 days or less,

AND

• No other sources of H5N1 exposures Such as: birds, other animals, feathers, droppings, fertilizers made of fresh bird droppings, live poultry markets, contaminated environments, or laboratory specimens

Assessing for Possible Human-to- Human H5N1 Virus Transmission

H5N1 Cluster Summary

• ~25% of confirmed H5N1 cases have occurred in clusters worldwide Mostly among blood related family members Most cluster cases had contact with sick birds

• Evidence of limited, non-sustained, human-to-human contact has occurred

• Clinically mild pediatric H5N1 cases identified during investigations of severely ill index cases

• Changes in size, number or epidemiology of clusters could signal important viral changes/adaptability, or pandemic

• Epidemiologic evidence that H5N1 virus can be transmitted from patients to healthcare workers

Review Question 3

If you recognize a cluster of human H5N1 cases, what would cause you to suspect that human-to-human transmission of H5N1 virus has occurred?

a. Documented exposure to a confirmed, probable, or suspected human H5N1 case

b. The time interval between contact with a suspected, probable, or confirmed H5N1 case and illness onset is 7 days or less

c. No other apparent source of H5N1 exposure

d. 3 or more cases are reported

e. H5N1 is isolated from common environment of cases

Answer:

a,b, and c

Clinical Features of Human Infection with H5N1 Virus

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H5N1 Viral Infection in Humans

• Incubation periodGenerally from 2 to 7 days

• Viral shedding period for H5N1 virusStill largely unknownMay be 2 weeks or longer

Longer for children and immune compromised

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H5N1 Clinical Manifestations

• Common signs and symptoms:Fever ≥38C, 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 diseasesCritical to ask about H5N1 exposures

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Possible Complications of H5N1 Infection

• Most common: pneumoniaMay progresses to respiratory failure

May requires mechanical ventilation

Acute respiratory distress syndrome (ARDS)

• Gastrointestinal disease

• Multi-organ failureHeart and kidney dysfunction

• Neurologic symptomsEncephalitis, seizures, altered mental status,

progression to coma 29

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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”)

Review Question 4

What clinical signs and symptoms are pathognomonic (distinguishing) for Influenza A (H5N1) infection?

a. Fever

b. Cough

c. Shortness of breath

d. Sore throat

e. Pneumonia

f. Gastrointestinal symptoms

g. None of the above

Answer: g. These symptoms may typically occur, but they are non-specific and similar to other acute respiratory diseases.

Part 1 Summary: Epidemiology

• Most human H5N1 cases have been healthy children and young adults

• Epidemiology and exposure sources critical to suspecting a case

• Most H5N1 cases had direct contact with sick or dead poultry or birds in the week prior to illness onset

• Limited, non-sustained human-to-human transmission of H5N1 virus is rare, but has occurred 32

Part 1 Summary: Clinical Manifestation

• Signs and symptoms of H5N1 infection are non-specific and are observed in other respiratory diseases:Fever, cough, shortness of breath, difficulty

breathing

• Pneumonia

• Peripheral blood changes may occur but are non-specific

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Management of Suspect Cases of Human Infection with Avian

Influenza A (H5N1) Virus

Part 2: Diagnosis, Management, and Treatment

Part 2: Overview

• Clinically assessing suspected patients: Collecting clinical and epidemiologic information

• Diagnostic and laboratory tests

• Current recommendations for clinical treatment

Part 2: Learning Objectives

• Identify important sources of clinical and epidemiologic information

• Recognize laboratory tests used for identification of new casesClinical specimen collection, diagnostic and laboratory tests

• Know the treatments and interventions for suspected case-patients and their contacts

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Part 2: Learning Objectives, cont

• Know what pharmaceutical treatments are available for seasonal and pandemic influenza

• Understand the difference in the recommendations between seasonal vs. pandemic flu treatment

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Assessing Suspected H5N1 Patients

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Assessing Suspected H5N1 Patients

Does the patient have findings consistent with H5N1 virus infection?

1. Collect clinical history and data on clinical findings

2. Evaluate epidemiological data

3. Consider clinical, laboratory, and epidemiologic information together

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Clinical Data to Collect

• Date of illness onset

• Signs and symptoms

• Routine laboratory results

• ComplicationsType and date of onset

• Clinical specimens collected for H5N1 testing

• Precautions used, breaks in precautions

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Clinical Data

• Common signs and symptoms:FeverCoughShortness of breathDifficulty breathing

• Other signs and symptoms that may occur:Sore throatSputum production (may be bloody)Diarrhea / abdominal painMuscle achesHeadacheRunny nose 41

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

• Abnormal lab values Low lymphocytes: <1500 / mm3 Low platelets: < 150,000 / mm3

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Normal lymphocyte count1500 - 4000 / mm3

Normal platelet count 150,000 - 400,000 / mm3

Medical Charts Include:

• Demographic information

• Medical history

• Illness signs and symptoms

• Physical examination findings

• Treatment

• Laboratory testing results

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Epidemiologic Context

Potential exposure to H5N1

• Occupational exposure Animal culler, veterinarian, health care workers

• Residence or travel in area affected by H5N1 outbreaks in birds or animals (e.g., poultry market)

• Direct contact with dead or diseased birds or other animals in affected area

• Close contact with a person with H5N1 virus infection, unexplained moderate or severe acute respiratory illness

44Warning! Even if NO reports of ill poultry in a location, there could be disease in that area, especially if poultry influenza vaccines are used or reporting is poor

Sample Patient Chart:Exposure History

Contact with ill people? (If yes, date and name, relationship to patient) ___________________________________________ ___________________________________________

Contact with diseased poultry (Live or dead)? (If yes, date and location) ___________________________________________ ___________________________________________

Recent travel? (If yes, date and location) ___________________________________________ ___________________________________________

Other close patient contacts (Household members, close coworkers) ___________________________________________

Are any of these contacts ill?

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Review Question 5

What are the critical pieces of epidemiologic information that must be collected from a patient with illness that is clinically

compatible with Influenza A (H5N1) infection?

Answer: Occupational exposure - Animal culler, veterinarian, health care

workers Residence or travel in area affected by H5N1 outbreaks in birds or

animals (e.g., poultry market) Direct contact with dead or diseased birds or other animals in affected

area Close contact with a person with H5N1 virus infection, unexplained

moderate or severe acute respiratory illness

Use All Information

• Clinical signs compatible with H5N1 virus infection

• History suggests exposure to H5N1 virus 7 days prior to symptom onset

• Are there multiple cases or respiratory deaths in the same family or in contacts?

• Send samples for laboratory confirmation47

Specimen Collection and Diagnostics

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Diagnostic and Laboratory TestingSuspected Human H5N1 Case

• Clinical specimen collection

• Diagnostic tests Laboratory testing

• ImagingChest X-ray

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Clinical Specimens: Lower Respiratory Tract

• H5N1 viruses primarily infect lower respiratory tract tissueDeep lung tissues

• Best specimens for detecting H5N1 viruses:Lower respiratory tract

Endotracheal aspirates from intubated, mechanically ventilated patients

Bronchioalveolar lavage (BAL)

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Other Clinical Specimens for H5N1 Testing

• Upper respiratory tract has worse virus yield than lower respiratory tractThroat swabs better for detecting H5N1 virus than other

upper respiratory tract locationsUse for ambulatory patients

• H5N1 virus has also been detected* in:Rectal swab and stool Blood serum and plasmaCerebrospinal fluid (CSF) specimens* These clinical specimens should not be the primary

sources used for H5N1 diagnosis

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Collecting Specimens for H5N1 Testing

• All respiratory secretions and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus!

• Collect specimens from different respiratory sites from the same patient on multiple days

• Collect oropharyngeal and nasal/nasopharyngeal swabs from both ventilated and non- ventilated patients

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Collecting Specimens, cont.

• Respiratory Collect endotracheal specimens from mechanically ventilated

patients Collect throat and nasal swabs from all patients Collect specimens as soon as possible

• Blood May be useful for detection of H5N1 antibodies three weeks

after infection Not useful for rapid detection of H5N1 virus infection for rapid

detection of outbreaks Need to collect paired sample: acute and convalescent

• Rectal swab or diarrheal stool• Not primary specimen for confirming H5N1 virus infection

Review Question 6

What are the optimal specimens to collect from a non-ambulatory suspected case of Influenza

A(H5N1) infection?

Answer: Lower respiratory tract; endotracheal aspirates from intubated, mechanically ventilated patients

Review Question 7

What are the optimal specimens to collect from an ambulatory suspected case of Influenza

A(H5N1) infection?

Answer: Throat swabs

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

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Tests on Respiratory Samples

• Reverse-transcription polymerase chain reaction (RT-PCR)Primary method of confirming H5N1 virus infectionHighly sensitive and specific

• Virus Isolation “Gold standard”Requires BSL-3 laboratoryAllows for characterization of the virus

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Other Tests

• Serological methodsRequire acute and convalescent sera (serum

obtained >21 days from onset)

• ImmunoflorescenceRequires H5 monoclonal antibodyCan be difficult to interpret

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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

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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

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

62Hien TT et al., New England J Med 2004;350:1179-1188

DAY 5 DAY 7 DAY 10

•Fever

•Progressive pulmonary disease

•Death

Severe H5N1 Pneumonia - Vietnam 2004

Review Question 8

What is the most sensitive and specific laboratory test for confirmation of influenza A (H5N1)

infection in humans?a. Real-time PCR

b. Rapid influenza test

c. Chest X-ray

d. Serology

Answer: a. Real-Time RT-PCR

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A Clinician Should Suspect H5N1 Virus Infection:

• Severe acute respiratory illness

AND

• Exposure 7 days before symptom onsets to:Sick poultry or wild birdsSuspect , 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

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

65* Every country should have access to at least one laboratory capable of H5N1 virus detection by RT-PCR

Clinical Treatment for Seasonal and Pandemic Influenza

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Treatment for Influenza Viruses

• Neuraminidase InhibitorsOseltamivirZanamivir

• 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

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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

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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 cells70

Oseltamivir for Seasonal Influenza

• Capsule or suspension administered by mouth

• Approved in the U.S. for treatment of seasonal influenza in children aged ≥1 yearPediatric 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 onsetReduces lower respiratory tract complications,

pneumonia, and hospitalization

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H1N1 Oseltamivir Resistance• Seasonal H1N1 resistance

observed EU in 2008 Prevalence varies: 0-60+%

• H1N1 resistance elsewhere 8% in the U.S. None reported elsewhere

• Implications for avian influenza H5N1 Need to know more about why

H1N1 resistance occurred Theoretically viruses could

swap genes, but evidence does not support this possibility

European Center for Disease Prevention and Control

Oseltamivir: Considerations

• PrecautionsPeople with kidney disease (reduce dose)Pregnant or nursing femalesReports of delirium in pediatric patients (mostly

from Japan)

• Resistance Can develop with treatment, but frequency of

resistance to oseltamivir is low

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Oseltamivir for H5N1 Infection

Effectiveness for H5N1 treatment is unknown

However is first line therapy for H5N1 infections

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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 daysPediatric dosing based upon age and weightConsider longer treatment, and higher doses (150 mg) on

case by case basis, especially in patient with progressive disease

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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

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Treatment of Children

• Different oseltamivir dosageBased on child’s weightNot approved in children <1 year old

• No aspirin for children <18 years of ageRisk of Reye’s syndrome with aspirinUse paracetemol or ibuprofen

• Children potentially infectious for longer periods than adults after illness onset

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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 nightfor 5 days

• Side effects Wheezing, and breathing problems

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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

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Zanamirvir: Considerations

• Not recommended forPeople with chronic respiratory disease Pregnant or nursing females

• ResistanceVery low for human influenza A (H1 and H3)

viruses

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Zanamirvir for H5N1 Infection

Effectiveness for H5N1 treatment is unknownUsed as second line therapy for H5N1 infections

when virus is resistant to oseltamivir

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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) virusesResistance develops rapidly influenza A viruses

• Adverse effects include gastrointestinal and neurological symptoms

• NOT recommend for H5N1 treatment82

Review Question 9

According to WHO, what drug is the first-line for treatment of Influenza A (H5N1) infection? a. Oseltamivir, 75 mg twice per day, 7-10 daysb. Zanamirvir, 75 mg twice per day, 7-10 daysc. Amandatine, 75 mg twice per day, 7-10 daysd. Rimantadine, 75 mg twice per day, 7-10 days

Answer: a.

• Consider longer treatment, and higher doses (150 mg) on case by case basis

• Pediatric dosing is based on age and weight

Other Treatments

84

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

85

Recommended Treatment with Antibiotics

• Antibiotic prophylaxis should be avoided

• When pneumonia is present:Antibiotic treatment is appropriateTreat according to published evidence-based

guidelines

86

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

87

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 forHousehold and close contacts of suspected or confirmed

H5N1 casesHealthcare worker with exposure without appropriate PPE

to suspected or confirmed H5N1 patients

• Treatment depends on level of riskWHO recommends oseltamivir

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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

89WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006

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 90

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 animalsHandlers of sick animals or decontaminating environments while

using appropriate PPE91

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 OxygenMechanical ventilation for respiratory failure in the

intensive care unit

• For the health care provider, PPE and not prophylaxis is the first line of defense!

92

Summary

• Oseltamivir is first line therapy for treatment and prevention of H5N1 virus infectionChemoprophylaxis is recommended depending on

level of risk (low, moderate, high)

• Treatment with antibiotics should be avoided

93

Part 2 Summary: Epidemiology and Diagnosis

• Collect clinical and epidemiologic data from multiple sources

• Identify and collect appropriate specimens for diagnostic testing Lower respiratory tract Multiple respiratory samples should be collected for H5N1 testing

• Diagnostic Tests: Real-time reverse-transcription polymerase chain reaction (RT-RT-

PCR) is the most sensitive and timely method for confirming H5N1.

Rapid influenza tests are not sensitive for detecting H5N194

Part 2 Summary: Clinical Management and Treatment

• Consider all evidence together (epidemiologic, clinical and diagnostic)

• Treatments and interventions for suspected H5N1 patients includeAntiviral treatment with oseltamivirOxygen and mechanical ventilationSupportive care

95

Glossary

• Case fatality proportion:• The proportion (percentage) of all the cases of disease who died within a specific

time period. Also know as the case fatality rate

• Incubation period • The period of time between the exposure to a virus or disease causing pathogen and

when the actual infection or disease onset begins.

• Viral shedding • process that occurs when a virus is present in bodily secretions and can thereby be

transmitted to another persons.

• Encephalitis• Inflammation in the brain usually caused by a virus (viral encephalitis).

• Pathogenesis• The origination and development of a disease or the mechanism through which the

disease causes illness96

Glossary

• Cytokine dysregulation (“cytokine storm”)• A complicated and uncontrolled immune response caused by severe

infections. This exaggerated and damaging immune response can lead to organ damage, multi-organ failure, and death. Symptoms include: hypotension, tachycardia, dyspnea, fever, ischemia, or insufficient tissue perfusion (especially involving the major organs), uncontrollable hemorrhage, and multisystem organ failure (caused primarily by hypoxia, tissue acidosis, and severe metabolism dysregulation

• Lower respiratory tract:• Portion of the respiratory system that refers to the Trachea, Primary bonchi

and lungs

• Upper respiratory tract • Portion of the respiratory system that refers to the nasal cavity, pharynx

and larynx97

Glossary• Sensitive• Used to describe a test that is “accurate” or “sensitive” to cases of true disease The

proportion of specimens that are infected with the Influenza A(H5N1) virus that test positive based on diagnostic criteria.

• Specificity• Proportion of true negatives among specimens that are not infected with Influenza

A(H5N1) virus.

• False negatives• A case that tests negative for disease although they are actually infected  • False positive• A person who tests positive for disease but are not actually infected

• Biosafety Level 3 (BSL3)• The level of biocontainment and safety practices for facilities that work on potentially

dangerous agents (biological or environmental). Level three is applicable for agents which cause serious or potentially lethal disease (e.g., anthrax, SARS, Typhus, etc). 98

References and Resources

• WHO. Update: WHO-confirmed human cases of avian influenza A(H5N1) infection, 25 November 2003 – 24 November 2006. Weekly Epidemiological Record 2007;82:41-48.

• Recommendations and laboratory procedures for detection of avian influenza A(H5N1) virus in specimens from suspected human cases, August 2007. http://www.who.int/csr/disease/avian_influenza/guidelines/RecAIlabtestsAug07.pdf

• WHO. WHO Rapid Advice Guidelines for pharmacological management of human infection with avian influenza A (H5N1) virus. 2006 http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf

• WHO. Avian influenza, including influenza A (H5N1), in humans: WHO interim infection control guideline for health care facilities. 24 April 2006. http://www.wpro.who.int/NR/rdonlyres/EA6D9DF3-688D-43161DF5553E7B1DBCD/0/InfectionControlAIinhumansWHOInterimGuidelinesfor2b_0628.pdf

• Clinical management of human infection with avian influenza A (H5N1) virus. 15 August 2007. http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf

• Risk of Influenza A (H5N1) Infection among Health Care Workers Exposed to Patients with Influenza A (H5N1), Hong Kong

• Carolyn Buxton Bridges, Katz JM, Seto WH, Chan PKS, Tsang D, Ho W, Mak KH, Lim W, Tam JS, Clarke M, Williams SG, Mounts AW, Bresee JS, Conn LA, Rowe T, Hu‐Primmer J, Abernathy RA, Lu X, Cox NJ, and Fukuda K. The Journal of Infectious Diseases 2000 181:1, 344-348

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