1 management of suspect cases of human infection with avian influenza a (h5n1) virus part 1:...

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Management of Suspect Cases of Human Infection with

Avian Influenza A (H5N1) Virus

Part 1: Background information on epidemiology, clinical features and

management of human cases of avian influenza A (H5N1)

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Learning Objectives

• Understand the epidemiology of human H5N1 cases

• Recognize clinical features of H5N1 in humans

• Understand current treatment recommendations

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The Epidemiology of Human H5N1 Virus Infection

T. Uyeki, CDC

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Global Epidemiology

• 318 cases reported to WHO from 12 countries that occurred since November 2003*

• Case fatality proportion: ~ 60%

• Human surveillance has focused upon severe respiratory disease

*Reported as of July 17, 2007

6Available 3 October 2006 at:

http://www.wpro.who.int/sites/csr/data/data_Maps.htm

2003



2004



2005



2003 - 06

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Epidemiology of Human H5N1 Cases

• WHO summary of 256 H5N1 cases*• Median age: 18 years (range 3 months - 75 years)

• 89% of cases were aged <40 years• Male to female ratio = 1:1• Median time to hospitalization: 4 days• Case 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)

*WHO Weekly Epidemiological Record 2007;82:41-8.

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Risk Factors for Human Infection with H5N1

Exposures in the week before illness

• Touching sick or dead poultry• Slaughtering, preparing for cooking

• Touching dead wild birds

• Having sick or dead poultry in the household

• Visiting a live poultry market

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Risk Factors for Human Infection with H5N1

Be aware of culture-specific risk factors

• Duck blood pudding

• Defeathering of swans

• Consumption of undercooked chicken

• Playing with dead chickens

• Cock Fighting

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Transmission of H5N1 Virus Infection to Humans

• Avian-to-human transmission (zoonoses)• Predominant mode of transmission• Exposure to infected poultry

• Touching sick or dead poultry (handling, slaughtering, cleaning, defeathering, preparing for cooking)

• Indirect animal-to-human transmission• Contact with surfaces contaminated with infected

poultry feces containing H5N1 virus• Ingestion of H5N1 virus-infected poultry

(undercooked meat, uncooked duck blood)• Contact with other infected animals that ate dead

poultry is theoretically possible

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Human-to-Human Transmission of

H5N1 Virus Infection • Limited, non-sustained human-to-human

transmission* • Close, prolonged unprotected contact with a sick

human H5N1 case

• Very rare, but documented

• Mostly in family members

• Hospital transmission documented

*Currently no evidence of sustained human-to-human transmission of H5N1 viruses

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Diagnosis ofHuman Infection with H5N1

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Specimens for H5N1 Testing

• H5N1 viruses primarily infect the lower respiratory tract tissue• Deep 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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• Upper respiratory tract Lower yield than lower respiratory specimens Oropharyngeal or throat swabs have higher yield

for detecting H5N1 virus than nasal or nasopharyngeal swabs

• H5N1 virus has also been detected in rectal swab, blood, and cerebrospinal fluid (CSF) specimens from fatal case Should not be the primary sources of specimens

for the diagnosis of H5N1

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

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

• Collect oropharngeal/throat, nasal, and endotracheal aspirate specimens from mechanically ventilated patients

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H5N1 Virus Testing

• Primary method: detection of H5N1 viral RNA by reverse-transcription polymerase chain reaction (RT-PCR)• Conventional RT-PCR• Real-time RT-PCR (RT-RT-PCR)• Sensitive and specific

• Isolation of H5N1 virus • Requires special Biosafety level 3 (BSL3)

conditions at WHO laboratories

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H5N1 Virus Testing

• Serological testing

• Requires acute and convalescent sera (serum obtained >21 days from onset)

• Microneutralization assay is the “gold standard” (uses live H5N1 virus)

• Available only at specialized WHO H5 Reference Laboratories (requires BSL3 conditions)

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H5N1 Virus Testing

• Rapid influenza diagnostic test

• Commercially available

• Detects human influenza A and B viruses

• Very low accuracy to detect H5N1 virus

• 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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H5N1 Virus Found in Other Human Specimens

• H5N1 virus infection of cerebrospinal fluid documented in fatal cases with seizures and coma

• H5N1 virus has been found to be present in:– rectal swab specimens and stool of fatal cases

with diarrhea– serum and plasma of fatal cases

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

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Clinical Features of Human Infection with H5N1 virus

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H5N1 Virus Infection of Humans

• Incubation period• From 2 to 7 days from exposure to poultry or a

human H5N1 case until fever onset

• Viral shedding period for H5N1 virus• Still largely unknown

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H5N1 Clinical Features

• Common signs and symptoms:• Fever ≥38C, cough, shortness of breath,

difficulty breathing

• Other findings (less common):• Sore throat, headache, muscle aches, runny

nose, diarrhea

• Clinical findings are non-specific, common, and may be similar to other respiratory disease• Critical to ask about exposures

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H5N1 Chest X-ray and Laboratory Findings

• Chest X-ray– Non-specific evidence of pneumonia on

admission – Often progresses to multi-lobar pneumonia

• 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

– Elevated aminotransferases (Liver enzymes)

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Complications of H5N1 Virus Infection

• Most common complication: pneumonia Progresses to respiratory failure

• requiring mechanical ventilation

• Acute respiratory distress syndrome (ARDS)

• Multi-organ failure Heart and kidney dysfunction

• Encephalitis has been reported

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H5N1 Influenza Severe Pneumonia - Vietnam 2004

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

DAY 5 DAY 7 DAY 10

•Fever

•Progressive respiratory disease

•Death

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H5N1 Pathogenesis

• High H5N1 viral levels are associated with abnormal inflammatory response

• Viral infection and inflammation contribute to respiratory failure and multi-organ failure– Cytokine dysregulation: Cytokine “storm”– Associated with high viral load and fatal

outcomes

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Part 1 Summary

• Most human 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 has occurred

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Part 1 Summary

• The most common signs and symptoms in H5N1 patients are:– Fever, cough, shortness of breath, difficulty breathing– However, these signs and symptoms are non-specific

and may be seen in other respiratory diseases

• Chest X-ray and laboratory findings in human H5N1 patients may include:– Pneumonia on chest X-ray– Decreased white blood cell count, decreased

lymphocyte count, and mild to moderately decreased platelet count

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Case Management of Suspected Human Infection with Avian Influenza A (H5N1) Virus

Part 2: Case Management of Suspected Avian Influenza Cases

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Learning Objectives

• Collect appropriate clinical and exposure information• Clinical data• Information from medical charts• Epidemiologic context (exposures)

• Recognize laboratory tests used for diagnosis of a suspected human H5N1 case patient• Clinical specimens• Types of laboratory tests• Imaging (chest x-rays)

• Know the treatments and interventions for suspected case-patients and their contacts• Antiviral drugs• Supportive care

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Assess Suspected Human H5N1 Case Patients

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Assess Suspected Human H5N1 Case Patients

Does the patient have H5N1?

1. Confirm and / or collect clinical history and physical exam data

2. Evaluate the epidemiologic context

3. Consider clinical, laboratory, and epidemiologic information together

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Clinical Data to Collect

• Date of illness onset

• Signs and symptoms

• Laboratory results

• Complications– Types and dates of

onset

• Clinical specimens collected for laboratory testing

• Precautions used, breaks in precautions

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Clinical Data

• Common symptoms:– Fever– Cough– Shortness of breath– Difficulty breathing

• Other symptoms that may occur:– Sore throat– Sputum (may be bloody)– Diarrhea / abdominal pain– Muscle aches– Headache– Runny nose

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Clinical Complications

• Respiratory failure– May occur 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 and

platelets

Normal lymphocytes1500 - 4000 / mm3

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

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Medical Charts Include:

• Demographic information

• Medical history

• Current medical complaint / symptom history

• Physical examination findings

• Recommended treatment

• Laboratory or other test results

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Sample Patient Chart:Clinical Information

Demographic Information Date: _____

Name __________ Age ____ Gender ___ Occupation_______Address______________________________________________________

History of IllnessChief Complaint_____________________Date of Illness Onset _________________Other Symptoms and symptom onset date:______________________________________________________________________________________________________________

Physical Exam Findings______________________________________________________________________________________________________________

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Sample Patient Chart:Clinical Information

Demographic Information Date: _Nov 1, 2006

Name _Sok Phhoung_ Age __21_ Gender:_F_ Occupation______Address___Patang village, Rattanakiri, Cambodia_____________

History of IllnessChief Complaint___Dyspnea_________Date of Illness Onset ___Oct 27, 2006______Other Symptoms and symptom onset date:

Fever – onset Oct25____________Cough – onset Oct 25___________

Physical Exam Findings_Current fever – 39.4°C, Pulse 123 beats/min___

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Epidemiologic Context

• Potential exposure to H5N1 • Occupational exposure

• Animal culler, veterinarian, health care workers• Travel or residence in area affected by H5N1

outbreaks in birds or animals • 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

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

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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) ___________________________________________

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Use All Information

• Clinical signs compatible with H5N1 virus infection

• History suggests exposure to H5N1 virus

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

• Send samples for laboratory confirmation

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Diagnostic Testing for a Suspected Human H5N1 Case

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Diagnosis of Suspect Human H5N1 Cases

• Influenza diagnostics

• General laboratory testing

• Imaging– Chest X-ray

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Diagnostics

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

• Commercial rapid diagnostic tests may be used to detect human influenza but not to detect H5N1 virus

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Clinical Specimens

• Respiratory• Collect endotracheal specimens from mechanically

ventilated patients• Collect throat and nasal swabs • Collect specimens as soon as possible• Collect multiple specimens on different days

• Blood• Useful for detection of H5N1 antibodies three week

after infection• Not useful for detection of acute infection

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

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Lab Tests for Influenza

• Rapid tests• Several types• Not specific for H5N1• Results in 15 - 30

minutes• NOT RECOMMENDED

FOR DETECTION OF H5N1 VIRUS

• Virus culture• Results in 2 - 10 days• Must be done in special

conditions at WHO H5 Reference laboratories

• PCR• Detects viral genes• Results in a few

hours• Uses respiratory

sample, serum or culture

• Can be sensitive and specific for H5N1

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Diagnosing H5N1

If:• Patient is suspect human H5N1 case• AND, the patient’s specimen is positive for

influenza A or for influenza A/H5

Then:

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

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Radiologic Imaging

Chest x-ray changes are common in H5N1 patients

• Non-specific changes

• Diffuse or patchy infiltrates

• Fluid in the space surrounding the lungs

• Cavities may form in the lung tissue • Often there is progression of pneumonia on

serial chest X-ray

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Current Antiviral Treatment for Influenza A Viruses

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Neuraminidase Inhibitors

• Two drugs are available:• Oseltamivir (Tamiflu®); Zanamivir (Relenza ®)

• Used for the treatment and prevention of human influenza A, H1 and H3 viruses

• Effectiveness against H5N1 virus infection is unknown

• WHO recommended first line antivirals for the treatment and prevention of H5N1 virus infection

• Treatment should be given as soon as possible

• May be given as prophylaxis to prevent H5N1 disease in exposed persons

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Oseltamivir• Available as a capsule or suspension administered

by mouth

• Approved in the U.S. for treatment of influenza in children aged ≥1 year

• Pediatric dosage depends on age and weight

• For treatment of human influenza (H1 or H3), administered twice a day for 5 days

• Side effects: nausea, vomiting

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Oseltamivir

• Effectiveness in human influenza (H1 or H3)• Reduces influenza symptoms by 1 day when administered

within 2 days of illness onset• Reduces lower respiratory tract complications, pneumonia,

and hospitalization

• Effectiveness for H5N1 treatment is unknown• However, currently used as first line therapy for H5N1

infections

• 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 is

low

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Zanamivir

• Orally inhaled powder – administered by mouth via special device

• Approved in the U.S. for treatment of human influenza A (H1 and H3) in patients aged 7 years and older

• Treatment dosage is one puff in the morning and one at night for 5 days

• Side effects• Wheezing, and breathing problems

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Recommended Treatment for Human Infection with H5N1

WHO recommends Oseltamivir treatment for H5N1 case patients

• Optimal dosage, duration for H5N1 unknown

• WHO recommends same dosage as seasonal influenza (capsule and oral suspension)– Pediatric dosing based upon age and weight– However, consider longer treatment (7 to 10

days), or higher doses (150 mg) on case by case basis, especially in patient with progressive disease

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A Clinician Should Suspect H5N1 Virus

Infection if a Patient Has:

• Severe acute respiratory illness

AND

• Exposure 7 days before symptoms to:– Sick poultry or wild birds– Suspect / confirmed H5N1 patient

OR

• Residence in an area with known H5N1 virus activity in poultry or other animals

Clinical management of human infection with avian influenza A(H5N1) viruses

• Oseltamivir is the primary recommended antiviral treatment. – Reducing A(H5N1) virus infection-associated mortality if used in the early

stages of the disease– Treatment with oseltamivir is also warranted at a later stage of illness.

A(H5N1) virus continues to replicate for a prolonged period • In patients with pneumonia or progressive disease, modified regimen

may be considered on a case by case basis:– two-fold higher dosage, – Longer duration,– combination therapy with amantadine or rimantadine (in countries where

A(H5N1) viruses are likely to be susceptible to adamantanes) Ideally this should be done in the context of prospective data collection.

• Corticosteroids should not be used routinely– may be considered for septic shock with suspected adrenal insufficiency

requiring vasopressors.– Prolonged or high dose corticosteroids can result in serious adverse events

including opportunistic infection.

Clinical management of human infection with

avian influenza A(H5N1) viruses- contd.• Antibiotic chemoprophylaxis should not be used.

– when pneumonia is present, antibiotic treatment is appropriate initially for community-acquired pneumonia according to published evidence-based guidelines.

– When available, the results of microbiologic studies should be used to guide antibiotic usage for suspected bacterial co-infection.

• Monitoring of oxygen saturation should be performed whenever possible at presentation and routinely during subsequent care (e.g. pulse oximetry, arterial blood gases), and supplemental oxygen should be provided to correct hypoxemia.

• Therapy for A(H5N1) virus-associated ARDS should be based upon published evidencebased guidelines for sepsis-associated ARDS, specifically including lung protective mechanical ventilation strategies.

Summary of treatment modalities for clinical management of human A(H5N1)

virus infectionModalitiesNOT Recommended

Strategies

Adamantane monotherapy When neuraminidase inhibitors are available, monotherapy with amantadine or rimantadine is not recommended. Combination therapy is consideration in areas where A(H5N1) virus is likely susceptible (see text).

Antibiotic chemoprophylaxis Not recommended

NPPV(Non-invasive positive pressure ventilation)

Generally not recommended (see text).

Systemic corticosteroids Moderate to high doses of unproven benefit and potentially harmful: not recommended;

Salicylates Avoid administration of salicylates (such as aspirin and aspirin containing products) in children and young adults (<18 years old) because of the risk of Reye Syndrome.

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Antiviral Chemoprophylaxis for Human Infections with H5N1

• Pre-exposure Persons involved in killing or disposing of

infected poultry

• Post-exposure Household and close contacts of H5N1 cases Healthcare worker with exposure without

appropriate PPE

• WHO recommends oseltamivir for chemoprophylaxis of high-risk groups

WHO. Rapid advance guidelines for pharmacological management of H5N1. 2006

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Antiviral Chemoprophylaxis for H5N1• WHO recommends antiviral chemoprohylaxis

depending on level of risk:• High risk, medium risk, or low risk

• High-risk: – Household or family members and close contacts of

a strongly suspected or confirmed H5N1 patient, including pregnant women

• WHO recommends oseltamivir for chemoprophylaxis of high-risk groups for 7-10 days after the last exposure:WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006

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Antiviral Chemoprophylaxis for H5N1

• Moderate risk: Persons handling sick animals, decontaminating

environments, without the appropriate use of PPE 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

Antiviral chemoprophylaxis may be considered in persons defined as having moderate risk

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Summary of Part 2

• Laboratory and clinical information in the patient’s medical chart can be used to look for characteristics of H5N1 virus infection• Multiple clinical samples should be collected

• Laboratory and clinical information should be examined in context of whether the person could have been exposed to H5N1

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Summary of Part 2

• Treatments and interventions for suspected case-patients include• antiviral drugs• supportive care

• Antiviral medication may be recommended as chemoprophylaxis depending on level of risk associated with exposure to H5N1 virus

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Thank you

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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.

• Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353:1374-85.

• 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.

• 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

• Summary of the second WHO consultation on clinical aspects of human infection with avian influenza A(H5N1) virus 2007. http://www.who.int/csr/disease/avian_influenza/meeting19_03_2007/en/index.html

http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf

http://www.wpro.who.int/NR/rdonlyres/EA6D9DF3-688D-43161DF5553E7B1DBCD/0/InfectionControlAIinhumansWHOInterimGuidelinesfor2b_0628.pdf



http://www.who.int/csr/disease/avian_influenza/meeting19_03_2007/en/index.html

http://www.who.int/csr/disease/avian_influenza/meeting19_03_2007/en/index.html

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