Investigation of Suspected Cases of Human Infection with

Avian Influenza A (H5N1) Virus

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Learning Objectives

• Know when and how to prepare for the investigation of suspected human H5N1 cases

• Understand the objectives of outbreak investigation of suspected, probable, or confirmed H5N1 cases

• Understand the mechanics of an outbreak investigation of suspected, probable, or confirmed H5N1 cases

• Describe how to analyze and communicate findings from case investigations 2

Outline

• Pre-investigation and response planning

• Gathering initial evidence

• Specimen collection

• Case finding and clusters

• Contract tracing

• Managing data

• Reporting and evaluation

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4

An important

resource for H5N1

case investigations

Investigating Cases to Protect Public Health

• Confirm or exclude H5N1 virus infection

• Reduce morbidity and mortality through rapid identification, isolation, treatment, clinical management of cases and follow-up of contacts

• Reduce spread of H5N1 virus infection through identification of exposure sources and implementation of control measures

• Determine if cases or cluster of cases represent the beginning of a potential pandemic

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Investigating Cases to Gather and Disseminate Data

• Determine key epidemiological, clinical, and virologic characteristics of cases

• Enhance surveillance

• Ensure timely communication to facilitate informed decision-making

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Phases of a Case Investigation

• Pre-InvestigationPlan the Response

• Investigation1. Gather epidemiologic evidence: Create case definitions,

assess exposure and risk, collect clinical specimens 2. Conduct case/cluster finding, contract tracing3. Manage and analyze data, study epidemic curves and

patterns4. Prevention and control activities

• Post-InvestigationWrite a summary report and evaluation of performance

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Pre-Investigation and Response Planning

Phase 1

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Define: Trigger

Trigger: A series of events or occurrence of cases which initiates an epidemiologic investigation

• May be used for avian influenza Epidemiologic links to H5N1

• May be used for any emerging pandemic Early warning Clusters of severe, unknown respiratory disease

• More sensitive than standard WHO case definitions alone

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Triggers With Possible H5N1 Link

Any person that meets the WHO definition of: suspect, probable or confirmed case of human H5N1 infection

OR

SARI cases in workers in poultry industry or amongthose with other relevantoccupational exposures 10

Photo: Tony Mounts, CDCPhoto: Tony Mounts, CDC

Additional H5N1 Triggers

• Poultry events: excessive deaths

• Rumors from informal data sources News media Information hotlines

11Photo: Diane Gross, CDCPhoto: Diane Gross, CDC

Triggers Without Clear H5N1 Link

• Severe, acute, respiratory cases in health care workers who care for patients with SARI or pneumonia

• Clusters of 2 or more SARI cases in a 2 week period 2 people in a family Cases in a small geographic area Cases with social or occupational connection

• Increases in cases at a hospital compared to the same time in previous years

• Change in the epidemiology of cases

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Preliminary Data Collection

• How many suspected cases are there?

• Among those, how many would meet the WHO suspect case definition for H5N1?

• What are the signs, symptoms and clinical characteristics?

• How serious is the condition of the case(s)?

• What is the date of onset fever and other symptoms?

• What is the geographic location of these cases?

• Has this area had a recent bird or poultry H5N1 epizootic?

• Have the suspected cases had any relevant exposures, including poultry or other bird exposures, or exposure to people with SARI?

• Has any testing for seasonal influenza, avian influenza A (H5N1) or other novel influenza subtypes been undertaken?

! Consider the security situation in the area ! 13

Rapid Response Team (RRT)

• Team leader • Epidemiologists• Medical officer • Veterinary officer • Laboratory scientist• Communications

specialist• Logistician• Data Manager

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Photo: Tim Uyeki, CDC

Resources to Use

• PeoplePhysicians and nurses caring for case-patient Agricultural and animal health workers,

veterinarians, clinical and laboratory experts, support personnel

Local district, city, and provincial public health staff

• OtherSecurity Communication devices, money

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Institutional Resources

• Ministry of Health, and Ministry of AgricultureAdvice, guidance, additional personnelBackground information on organization of health care

system

• World Health Organization (WHO) Request for assistance: PPE, antiviral, personnel WHO guidelines for investigation of human

cases of avian influenza A (H5N1)

• Other Non-governmental Organizations

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Logistics and Documentation

• Proof of employment

• Information on cases already gathered

• List of important contacts or resources

• Manuals or Standard Operating Procedures (SOPs)Case management, laboratory procedures

• Local currency

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Supplies• Epidemiological

Case definitions, reporting forms, questionnaires

• MedicalAntiviral medications

• LaboratorySpecimen collection materials, transportation containers, labels,

viral transport media

• Personal Protective Equipment (PPE)Respirators, gloves, gown, goggles

• DecontaminationSolution for homes or hospital rooms

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Supplies, cont

• Electronic equipmentCell phoneLaptop (with epidemiologic software)

• Educational materialsH5N1 information brochures and postersSimple messages, culturally appropriateGuidelines for contacts, family members, and

healthcare workersCcommunication materials

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Stakeholders

• Veterinary Health Authorities

• Government Officials

• Health Care personnel

• Community

• Non-governmental organizations

• Laboratory 20

Centers for Disease Control and Prevention

Review Question #1

What are some of the logistic and planning documents you need to prepare as part of the pre-

investigation?

Answer: Many are possible. Examples include: Case reporting formsWHO and national guidance documentsStandard protocols and proceduresSpecimen collection forms

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Collaborative Investigation

• Public health investigators should work together with human, animal, and environmental health investigators Plan joint visits to affected areas

• Animal health investigators help assess appearance and health of animals and surrounding environment

• Coordinate and share test results and surveillance data 22

Investigation Step 1: Gathering Initial Evidence

Phase 2: Investigation23

Centers for Disease Control and Prevention

Evidence From a Suspect Case

• Epidemiological findings

Exposures

• Clinical evidence

• Laboratory evidence

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Key Questions to Address in H5N1 Case/Cluster Investigations

? What are the likely H5N1 virus exposure sources for the case(s)?

? Has human-to-human transmission of H5N1 virus likely to have occurred?

? Is there evidence of human-to-human H5N1 virus transmission beyond two generations?

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H5N1 Avian Exposures

• Unprotected exposure to H5N1 virus-infected poultry

or wild birds (ill or dead)

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Source: Tim Uyeki, CDC

• Consumption of raw poultry products infected or contaminated with H5N1 virus

• Visiting a live poultry market

• Contact with ducks and geese

• Unprotected contact with contaminated environment

Human H5N1 Exposures

• Exposures to a H5N1 caseContact (within one meter) with a person

(e.g. caring for, speaking with or touching) who is a suspected, probable or confirmed H5N1 case

From one day before to 14 days after the case patient’s illness onset

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Source: Josh Mott, CDC

Other Possible H5N1 Exposures

• Exposure to other H5N1 virus-infected animals

Touching or consuming an H5N1 virus infected animal (cat, dog, pig)

• Laboratory exposureUnprotected exposure while processing samples suspected of containing H5N1 virus

• Other environmental exposureResidence or visit to an area where H5N1 virus is suspected or confirmed

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Centers for Disease Control and Prevention

Risk Stratification: Based on Exposures

• High risk exposure Household or close family contacts

• Moderate risk exposureOther exposed persons who were not wearing appropriate PPE

• Low risk exposureUnexposed persons or those wearing appropriate PPE)

* WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virushttp://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.html

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Why Use Risk Stratification?

• Helps prioritize limited resourcesA priori rationale for who will, and will not,

receive resources

• Is used in WHO’s recommendations for guiding post-exposure antiviral chemoprophylaxis

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Review Question #2

Which of these are possible exposure routes for H5N1 infection in humans?

• Uncooked poultry meat

• Close contact with a suspected case

• Virus in home environment

• Occupational exposure (work with poultry, poultry products)

• Infected domestic pets

• Cooked poultry meat

Answer: All are possible exposures except cooked poultry meat31

Case Definitions• “Standardizes” the investigation

• Clear criteriaSignsSymptomsEpidemiological dataLab results

• Unique for every outbreak

• Objective measures• Person, place, and time 32

WHO Case Definitions for Human Infection

with Avian Influenza A (H5N1) Virus*

• Person under investigation

• Suspected Case

• Probable Case

• Confirmed Case

33*WHO case definitions for human infections with influenza A(H5N1) virus; 29 August 2006

Person Under Investigation

• Person whom public health authorities have decided to investigate for possible H5N1 virus infection

34Photo: Reuters / Amr Dalsh

Suspected Case

• A person presenting with unexplained acute lower respiratory illness with fever (>38°C) and cough, shortness of breath, or difficulty breathing;

AND

• Potential exposure to H5N1 virus in the 7 days prior to symptom onset

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WHO Suspected Case Exposures• Exposure to poultry or wild birds ,their

remains, or areas contaminated by their feces in area with suspected/confirmed H5N1 in the last month

• Consumption of raw or undercooked poultry products

• Close contact (within 1 meter) with a person who is a suspected, probable, or confirmed H5N1 case

• Close contact with a confirmed H5N1 infected animal other than poultry or wild birds

• Handling samples (animal or human) suspected of containing H5N1 virus in a laboratory or other setting

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Probable CaseProbable definition 1

• A person meeting the criteria for a suspected case

AND

Exhibit infiltrates or evidence of an acute pneumonia on chest radiograph plus evidence of respiratory failure (hypoxemia, severe tachypnea) OR

Have a positive laboratory confirmation of an influenza A infection but insufficient evidence for H5N1 virus infection

Probable definition 2

• A person dying of an unexplained acute respiratory illness who is considered to be epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1 case 37

Confirmed Case

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

AND

• A positive test result accepted as “confirmatory” by WHO, and was conducted in a national, regional or internationally accepted* influenza laboratory

38* Accepted by WHO

Confirmatory Test Results for H5N1 Virus Infection

• Isolation of an H5N1 virus

• Positive H5 PCR results from tests using two different PCR targets

• Fourfold or greater rise in H5N1 neutralizing antibody titer from acute serum specimen (collected 7 days or less after symptom onset) and a convalescent serum specimen (convalescent titer must be 1:80 or higher)

• An H5N1 neutralizing antibody titer of 1:80 or greater in a single serum specimen collected at day 14 or later after symptom onset and a positive result using a different serological assay

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Review Question #3

Is this case a suspect, probable, or confirmed case based on WHO definitions:

A 8 year old boy dying of an unexplained acute respiratory illness who was a neighbor of a

previously confirmed H5N1 case

Answer: probable case40

Investigation Step 2: Case Finding, Clusters, Contract Tracing

41Photo: Diane Gross, CDC

Case Finding and Clusters

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Photo: Diane Gross, CDC

Importance of Case Finding

• Identify all possible cases in a community Treat affected persons, determine exposure sources, and prevent further transmission

• May provide information about potential human-to-human transmission

Obtain information on cases related in time and location to other cases or clusters

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What is Case Finding?

• Attempt to identify additional casesPersons who may have been exposed to the same

H5N1 source as the case Persons with bird/animal exposures or healthcare

workers caring for H5N1 patientsPersons with unexplained SARI (with fever AND

either cough, difficulty breathing, or shortness of breath)

Persons who died of an unexplained acute respiratory illness

Close contacts of the case 44

Methods of Case Finding

Active: Search effort by public health workers in an area where a case has occurred

• House-to-house searches

• Visits to health care facilities

• Private practitioners

• Traditional healers

• Laboratories

Passive: Suspect cases that are reported without efforts by public health staff

• Routine surveillance

• Rumor hotlines

• Public information messages in the affected communities

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Any cases meeting H5N1 or pandemic early warning trigger criteria must be referred for specimen testing and appropriate medical care!

Whom to Interview

• Suspected, probable, confirmed H5N1 cases, other persons meeting trigger criteria

• Family members/Household contacts

• Health care providers, health workers

• Co-workers, if occupational exposures are suspected

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Type of Information to Collect

• Demographic data Age, sex, household members

• Epidemiology data Occupational, home, avian or other environmental exposures (7

days before illness onset) Contact with confirmed or suspect H5N1 cases (7 days before

illness onset) Travel history

• Clinical data Signs & symptoms, underlying conditions, physical exam, vitals, Hospital admission, treatments, laboratory results, chest x-ray

results, complications Outcome

• Laboratory results 47

How to Interview

• Generate list of potentially exposed contacts for each case

• Collect as much information as reasonably possibleStructure and unstructured components to the interviews

• Repeat critical questions for accuracy, validity, and additional details

• Understand that family members may be grieving for deceased cases

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Interview Tips

• Be friendly, but professional

• Identify yourself and your institution

• Explain purpose of interview

• Stress importance of information you will collect

• Inform respondents that all information will be kept confidential

• If appropriate, conduct the interview in private place

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Specimen Collection

Confirm the Diagnosis

50Centers for Disease Control and Prevention

Specimen Collection

• Safe and correct collection

• What samples to collect?

• What to wear for protection?

• How to transport specimens?

• Procedures for diagnosis?

Who to collect from (trigger criteria)?51

What to Collect

Collect multiple specimens from different sites on different days

• Lower respiratory tract specimens (best) Endotracheal aspirates Bronchiolalveolar lavage (BAL) Pleural fluid from chest tubes

BAL or pleural fluid should only be tested if they were collected for another purpose

• Upper respiratory tract specimens Throat swabs preferred Nasal swabs (can help detect human influenza viruses)

• Collect acute and convalescent serum52

Review Question #4

What types of information do you need solicit during an interview?

Environmental exposures Clinical symptoms Travel information Potential contacts Poultry exposure during last month

Answer: All of these EXCEPT poultry exposure in last month (should be in last 7 days before symptom onset)

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Common Challenges to Case Finding

• Even with active case finding, all cases may not be identified:

Physicians may not suspect H5N1 virus infection

Some H5N1 virus-infected persons may not seek medical care

Secrecy about poultry outbreaks to avoid culling of poultry

Presentation may be atypical54

Enhancing Surveillance

• Location• Implement in areas where H5N1 cases live or

where animal outbreaks are occurring• Active surveillance at healthcare facilities or

healers, private laboratories;• Active surveillance among health care workers,

persons exposed to birds/animals

• Duration• Minimum of 2 weeks after the last human H5N1

case is identified (2 incubation periods) • Maintain for longer periods if H5N1 poultry

outbreaks are not controlled55

Methods to Enhance Surveillance among Medical Community

• Conduct trainings at health care facilities in the area to recognize trigger events and reporting process

• Ask health care facilities in the area to report all cases of SARI for the next 2-4 weeks

• Notify pharmacists and dispensers to report increases in medications for respiratory illnesses

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Methods to Enhance Surveillance among General Community

• Expand sensitization training to key community members

• Ask village leaders, traditional healers, and religious leaders to report trigger events

• Notify teachers and school administrators to report increases in student absenteeism

• Pharmacists may also report any unusual increases in prescription practices 57

Clusters of Severe Acute Respiratory Illness

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PHOTO: AP / Binsar Bakkara

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A Cluster May Exist When:

• Two or more people with moderate or severe acute respiratory illnessUnexplained by other causesMay have died from the illnessOnset within two weeks of each other

AND

• History suggests exposure to H5N1 virus or another person with SARI

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• 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 exposures to birds, other animals, feathers, droppings, fertilizers made of fresh bird droppings, live poultry markets, contaminated environments, or laboratory specimens)

Determining Human-to-Human Transmission of H5N1 Virus

Review Question #5

If you recognize a cluster of human H5N1 cases with contact with a confirmed H5N1 case and onset within one incubation period of that case, would you

conclude that human-to-human transmission of H5N1 virus has occurred?

•Answer: No. A detailed epidemiologic investigation would need to take place to ensure that no other plausible source of infection should be of concern.

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Contact Tracing

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What is Contact Tracing?

The identification and diagnosis of persons who may have been in close contact with an infected individual

during the infectious period

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Purpose of Contact Tracing during an Influenza A(H5N1) Investigation

• Find new suspected human cases of H5N1 or other cases meeting trigger criteria

• Decrease risk of illness and interrupt further transmission through methods such as:Active surveillance for illnessAntiviral chemoprophylaxis of exposedEarly treatment of ill personsCollection of specimens for H5N1 testingEducational information to prevent transmission

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How to Identify Contacts

1. Review the case patient’s activities for the 1 day before onset of symptoms through 14 days after onset of symptoms

2. Identify all close contacts (within 1 meter) of the case

3. Identify additional individuals with exposure to birds and other animals suspected of being infected with H5N1 virus

4. Verify all information collected

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Prioritize Contact Identification

• If number of contacts is large, focus on:

Contacts of probable and laboratory confirmed H5N1 cases

Contacts with prolonged close exposures to a suspected H5N1 case

Household contacts sharing the same sleeping and eating space, persons providing bedside care

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Key Information for Contact Tracing

• Who did the case come into close contact with?

• What activities was case doing at the time?

• Where did these activities take place?

• When did case come into contact with this person?

• Other key information:

Contact information, health status

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General Guidelines for Interviewing Contacts

• Do not alarm contacts

• Communicate preventive information

• Refer symptomatic individuals to a designated healthcare facility

• Consider if Personal Protective Equipment (PPE) is necessary

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Centers for Disease Control and Prevention

Information from Contacts

• Demographic and contact information Name, Address Occupation, age, gender, relationship to the case

• Exposure History Contact with case-patient Poultry and wild bird exposure Other high-risk exposures such as contact with SARI cases

• Physical Exam and Clinical information Health status Temperature, other vital signs Presence of signs or symptoms of acute respiratory infection

(feverishness, fever, sore throat, coughing)

Hospital lab findings (such as blood work, chest xray findings) 69

Monitoring and Managing Contacts

• Actively (daily) monitor contacts for signs of illness for 7 days after exposureEncourage self-health monitoring Instruct to report onset of fever or respiratory symptomsVisit or phone daily to monitor for illnessRefer contacts with fever or respiratory illness to medical

care, isolation, treatment; obtain respiratory specimens for H5N1 testing

• MOH may request (voluntary) home quarantine of all contacts for 7 days post exposure

• Consider antiviral chemoprophylaxis, if available

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Investigation Step 3: Managing Data

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Data Management

• Line listing of cases, contacts

• Record keeping

• Validation and Cross-Checking

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Line Listing

Case #

Age Sex Status Occupation Difficult breathing

Date of Onset

1 5 M Probable Child Yes 7 July

2 55 F Suspect Caretaker of case #1

Yes 9 July

3 48 M Suspect Poultry Farmer No 7 July

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Information included:

An organized way to view all cases in an investigation

• Demographic, Epidemiological (exposures)

• Clinical, Laboratory data

Record Keeping

• Where will records be kept?

• How will records be kept?

• Who is assigned to record keeping?

• Maintain confidentiality!!74

Validation and Cross-Checking

• Check line lists against medical charts and interviews

• ValidationAsk same question in different waysAsk same question at different timesEnsure answers are consistentDouble-entry of data

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Creating an Epidemic Curve and Analyzing Data

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What is an Epidemic Curve?

An epidemic curve (‘Epi’ curve) is a graph or histogram of the number of cases of illness by the date of illness onset

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How Can an Epidemic Curve Help in an Outbreak?

Provides information on the characteristics of an outbreak

•Pattern of spread or transmission pattern

•Magnitude of epidemic

•Outliers (case outside expected time frame)

•Time trend

•Disease incubation period, possible timing of exposure

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Epidemic Curves and Transmission

• Epidemic curves have different patterns depending on transmission Infectious agent transmitted between people Infectious agent transmitted from one source to multiple

people

• Can be used to assess whether human-to-human transmission is occurring

• Patterns easier to identify with larger number of cases 79

Epi Curve for Human to Human Transmission

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Epi Curve for Human Cases from Single Source

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Key Analytic Questions

• Do data suggest greater spread of H5N1 virus among humans? Large increase in human H5N1 cases? Increase in cluster frequency, duration of illness?Cases in non-family member contacts?Mild or moderately ill cases?Absence of animal/bird exposures?Change in age distribution? Multiple generations of human-to-human transmission

suspected?

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Investigation Step 4: Prevention and Control Activities

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Photo: Reuters / Bobby Yip

Prevention and Control Activities

• Animal health and control measures Culling, disinfection,

surveillance, vaccination

• Infection control Isolation of suspected

and confirmed cases PPE, infection control

precautions

• Treatment of ill patients

• Contact tracing & contact surveillance Voluntary quarantine

of well contacts Antiviral

chemoprophylaxis

• Enhanced (active) surveillance and case finding

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Reporting and Evaluation

Phase III: Post Investigation

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Multiple Levels of Reporting

• Local Level: Who is responsible for submitting H5N1 case reports? When should this be done?

• National Level: Who needs to be updated on the investigation and receive the final report on number of H5N1 cases? Who is responsible for assuring that this occurs?

• International Level: Probable, and confirmed H5N1 cases should be reported immediately to WHO. The WHO IHR National Focal Point should be responsible for notifying WHO.

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International Health Regulations (IHR)

• Compulsory notification of any human infection with a novel subtype of influenza A

• Under IHR (2005) all probable and confirmed H5N1 cases in humans must be immediately reported to WHO

• Compliance with these standards is required to strengthen early detection, reporting, and response

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How and When to Report

Use standard reporting forms

• Case/Lab specimen based forms, line-lists, weekly and monthly reporting forms, contacts follow-up forms

• Immediate reporting of cases/clusters to next levels

Share information

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Local Health Department

District Epidemiology

Offices

National /Ministry of Health

Feedback (all levels)

Case Reporting site

Local Laboratories &

Agencies

District Animal / Agriculture

Offices

National Agencies /Ministry

of Agriculture

Writing a Summary Report

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Why communicate the findings?

• A document for action Control and prevention measures

• To share new insights

• To obtain national and international resources

• Documents the investigation

• To assist other nations districts or countries with investigation

• Inform the public

• Help prevent future outbreaks

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Content of a Summary Report

• Summary

• Introduction and Background

• Outbreak Description

• Methods and Results

• Discussion

• Lessons Learned

• Recommendations

• Acknowledgements

• Supporting Documentation91

Evaluate Performance

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Onset ResponseDetection

Why Evaluate the Investigation

• To summarize the events that occurred

• To learn from experienceMake recommendations for future investigations Take lessons from what worked wellTake lessons from mistakes

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What to Evaluate

• Timeliness of response Detection Response time Control measures Communication

• Completeness of the investigation Case finding Data collection Analysis

• Accuracy of the data

• Inter-agency coordination

• Lessons for better practice in the future

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Case Investigation Summary

• Be aware of epidemiologic triggers• Prepare investigation logistics and supplies in advance• Investigation begins with gathering clinical, epidemiologic,

and laboratory information• If warranted, conduct active case finding, cluster

investigation, and contact tracing activities• Initiate prevention and control measures at any time it is

necessary• Maintain a system for collecting, managing, storing,

analyzing, and reporting data• After the response is concluded, evaluate the investigation

performance

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Glossary

TriggerA series of events or cases which initiate an epidemiologic investigation. Diseases have different and specific triggers. For example, a single suspect case of human H5N1 is a sufficient trigger for avian flu investigation. However, multiple cases of gastrointestinal disease would be required to trigger a salmonella investigation.

Rapid response team (RRT)A multi-disciplinary group of investigators and medical scientists who are quickly mobilized in response to a disease outbreak or adverse health event. Teams can consist of epidemiologists, medical providers, veterinarians, laboratory and communication specialists, data managers, infection control nurses, etc.

Glossary

StakeholderA person or group who is affected by, or involved in the investigation and its outcomes

Risk StratificationGrouping individuals according to specific risk attributes such as degree of exposure or severity of illness

Case findingThe concerted effort of public health professionals to search for and identify any potential cases of disease in order to treat or contain an illness

Glossary

Cluster

An unusual grouping, or excess number of disease cases in a geographical location or point in time

Case-patientIndex case, or patient who initiated the investigation

Line listing

A way to organize and present important information that is collected about each potential case or contact

References

• WHO Guidelines for the Investigation of Human Cases of Avian Influenza A (H5N1), Jan 2007. Accessed from:

http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_2006_4r1.pdf

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