1. Investigation of Suspected Cases of Human Infection with Avian Influenza A (H5N1) Virus 1

2. 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

3. Outline Pre-investigation and response planning Gathering initial evidence Specimen collection Case finding and clusters Contract tracing Managing data Reporting and evaluation 3

4. 4 An important resource for H5N1 case investigations

5. 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 5

6. 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 6

7. Phases of a Case Investigation Pre-Investigation  Plan the Response Investigation 1.Gather epidemiologic evidence: Create case definitions, assess exposure and risk, collect clinical specimens 2.Conduct case/cluster finding, contract tracing 3.Manage and analyze data, study epidemic curves and patterns 4.Prevention and control activities Post-Investigation  Write a summary report and evaluation of performance 7

8. Pre-Investigation and Response Planning Phase 1 8

9. 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 9

10. 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 among those with other relevant occupational exposures 10 Photo: Tony Mounts, CDC

11. Additional H5N1 Triggers Poultry events: excessive deaths Rumors from informal data sources  News media  Information hotlines 11 Photo: Diane Gross, CDC

12. 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 12

13. 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

14. Rapid Response Team (RRT) Team leader Epidemiologists Medical officer Veterinary officer Laboratory scientist Communications specialist Logistician Data Manager 14 Photo: Tim Uyeki, CDC

15. Resources to Use People  Physicians 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 Other  Security  Communication devices, money 15

16. Institutional Resources Ministry of Health, and Ministry of Agriculture  Advice, guidance, additional personnel  Background 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 16

17. 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 17

18. Supplies Epidemiological Case definitions, reporting forms, questionnaires Medical Antiviral medications Laboratory Specimen collection materials, transportation containers, labels, viral transport media Personal Protective Equipment (PPE) Respirators, gloves, gown, goggles Decontamination Solution for homes or hospital rooms 18

19. Supplies, cont Electronic equipment  Cell phone  Laptop (with epidemiologic software ) Educational materials  H5N1 information brochures and posters  Simple messages, culturally appropriate  Guidelines for contacts, family members, and healthcare workers  Ccommunication materials 19

20. Stakeholders Veterinary Health Authorities Government Officials Health Care personnel Community Non-governmental organizations Laboratory 20 Centers for Disease Control and Prevention

21. 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 forms  WHO and national guidance documents  Standard protocols and procedures  Specimen collection forms 21

22. 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

23. Investigation Step 1: Gathering Initial Evidence Phase 2: Investigation 23 Centers for Disease Control and Prevention

24. Evidence From a Suspect Case Epidemiological findings Exposures Clinical evidence Laboratory evidence 24

25. 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? 25

26. H5N1 Avian Exposures Unprotected exposure to H5N1 virus-infected poultry or wild birds (ill or dead) 26 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

27. Human H5N1 Exposures Exposures to a H5N1 case  Contact (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 27 Source: Josh Mott, CDC

28. Other Possible H5N1 Exposures Exposure to other H5N1 virus- infected animals Touching or consuming an H5N1 virus infected animal (cat, dog, pig) Laboratory exposure Unprotected exposure while processing samples suspected of containing H5N1 virus Other environmental exposure Residence or visit to an area where H5N1 virus is suspected or confirmed 28 Centers for Disease Control and Prevention

29. Risk Stratification: Based on Exposures High risk exposure  Household or close family contacts Moderate risk exposure  Other exposed persons who were not wearing appropriate PPE Low risk exposure  Unexposed persons or those wearing appropriate PPE) * WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus http://www.who.int/csr/disease/avian_influenza/guidelines/pharmamanagement/en/index.html 29

30. Why Use Risk Stratification? Helps prioritize limited resources  A priori rationale for who will, and will not, receive resources Is used in WHO’s recommendations for guiding post-exposure antiviral chemoprophylaxis 30

31. 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 meat 31

32. Case Definitions “Standardizes” the investigation Clear criteria  Signs  Symptoms  Epidemiological data  Lab results Unique for every outbreak Objective measures Person, place, and time 32

33. 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

34. Person Under Investigation Person whom public health authorities have decided to investigate for possible H5N1 virus infection 34 Photo: Reuters / Amr Dalsh

35. 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 35

36. 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 36

37. Probable Case Probable 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

38. 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

39. 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 39

40. 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 case 40

41. Investigation Step 2: Case Finding, Clusters, Contract Tracing 41 Photo: Diane Gross, CDC

42. Case Finding and Clusters 42 Photo: Diane Gross, CDC

43. 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 43

44. What is Case Finding? Attempt to identify additional cases  Persons who may have been exposed to the same H5N1 source as the case  Persons with bird/animal exposures or healthcare workers caring for H5N1 patients  Persons 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

45. 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 45 Any cases meeting H5N1 or pandemic early warning trigger criteria must be referred for specimen testing and appropriate medical care!

46. 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 46

47. 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

48. How to Interview Generate list of potentially exposed contacts for each case Collect as much information as reasonably possible  Structure 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 48

49. 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 49

50. Specimen Collection Confirm the Diagnosis 50 Centers for Disease Control and Prevention

51. 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

52. 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 serum 52

53. 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) 53

54. 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 atypical 54

55. 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 controlled 55

56. Methods to Enhance Surveillance among Medical Community Conduct trainings at health care facilities in the area to r ecognize 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 56

57. 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

58. Clusters of Severe Acute Respiratory Illness 58 PHOTO: AP / Binsar Bakkara

59. 59 A Cluster May Exist When: Two or more people with moderate or severe acute respiratory illness  Unexplained by other causes  May have died from the illness  Onset within two weeks of each other AND History suggests exposure to H5N1 virus or another person with SARI

60. 60 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

61. 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. 61

62. Contact Tracing 62

63. 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 63

64. 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 illness  Antiviral chemoprophylaxis of exposed  Early treatment of ill persons  Collection of specimens for H5N1 testing  Educational information to prevent transmission 64

65. 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 65

66. 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 66

67. 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 67

68. 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 68 Centers for Disease Control and Prevention

69. 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

70. Monitoring and Managing Contacts Actively (daily) monitor contacts for signs of illness for 7 days after exposure  Encourage self-health monitoring  Instruct to report onset of fever or respiratory symptoms  Visit or phone daily to monitor for illness  Refer 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 70

71. Investigation Step 3: Managing Data 71

72. Data Management Line listing of cases, contacts Record keeping Validation and Cross-Checking 72

73. Line Listing Case # AgeSexStatusOccupationDifficult breathing Date of Onset 15MProbableChildYes7 July 255FSuspectCaretaker of case #1 Yes9 July 348MSuspectPoultry FarmerNo7 July 73 Information included: An organized way to view all cases in an investigation Demographic, Epidemiological (exposures) Clinical, Laboratory data

74. Record Keeping Where will records be kept? How will records be kept? Who is assigned to record keeping? Maintain confidentiality!! 74

75. Validation and Cross-Checking Check line lists against medical charts and interviews Validation  Ask same question in different ways  Ask same question at different times  Ensure answers are consistent  Double-entry of data 75

76. Creating an Epidemic Curve and Analyzing Data 76

77. 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 77

78. 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 78

79. 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

80. Epi Curve for Human to Human Transmission 80

81. Epi Curve for Human Cases from Single Source 81

82. 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? 82

83. Investigation Step 4: Prevention and Control Activities 83 Photo: Reuters / Bobby Yip

84. 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 84

85. Reporting and Evaluation Phase III: Post Investigation 85

86. 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. 86

87. 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 87

88. 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 88 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

89. Writing a Summary Report 89

90. 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 90

91. Content of a Summary Report Summary Introduction and Background Outbreak Description Methods and Results Discussion Lessons Learned Recommendations Acknowledgements Supporting Documentation 91

92. Evaluate Performance 92 Onset Response Detection

93. Why Evaluate the Investigation To summarize the events that occurred To learn from experience  Make recommendations for future investigations  Take lessons from what worked well  Take lessons from mistakes 93

94. 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 94

95. 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 95

96. Glossary Trigger A 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.

97. Glossary Stakeholder A person or group who is affected by, or involved in the investigation and its outcomes Risk Stratification Grouping individuals according to specific risk attributes such as degree of exposure or severity of illness Case finding The concerted effort of public health professionals to search for and identify any potential cases of disease in order to treat or contain an illness

98. Glossary Cluster An unusual grouping, or excess number of disease cases in a geographical location or point in time Case-patient Index 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

99. 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/influen za/WHO_CDS_EPR_GIP_2006_4r1.pdf http://www.who.int/csr/resources/publications/influen za/WHO_CDS_EPR_GIP_2006_4r1.pdf 99