1. Case Management of Suspect Avian Influenza A (H5N1) Virus Infection in Humans Part 1: Background information on clinical features of human infection with avian influenza A (H5N1) viruses May, 2007

2. Learning Objectives Recognize clinical features of avian Influenza A (H5N1) virus infection in humans Understand how information about the patient before onset of illness can help you suspect H5N1 virus infection

3. Part 1 Session Outline Clinical features Epidemiological Context –Exposure

4. Illness Scenario Alex sick for three days –Fever –Headache –Cough –Shortness of breath –Muscle aches –Watery diarrhea No one else sick Works at poultry farm and handles poultry Question: Is avian Influenza A (H5N1) the most likely cause of Alex’s symptoms?

5. Clinical Features

6. General Information Human influenza Avian Influenza A (H5N1) Affected Age Groups All ages affected Highest attack rate in children <5 years Most complications in elderly >65 years and persons with chronic medical conditions Children of all ages Healthy young adults Highest CFR in adolescents. Estimated Incubation Period Mean: 2 days Range: 1 – 4 days Mean: 2 – 5 days ≤7 days

7. Signs and Symptoms Avian Influenza A (H5N1) Type of infectionLower respiratory SymptomsFever, Cough, Headache Shortness of breath, difficulty breathing Diarrhea in some cases Hospitalized PatientsPneumonia Hypoxia requiring oxygen and respiratory failure requiring intubation and mechanical ventilation Acute Respiratory Distress Syndrome (ARDS)

8. Laboratory Findings Commonly associated with human infection with avian influenza A (H5N1) viruses: –Drop in white blood cell count (leukopenia) Drop in lymphocytes, a kind of white blood cells (lymphopenia) –Mild to moderate drop in blood platelet count –Increased aminotransferases (liver enzymes)

9. Unusual Clinical Manifestations and Outcomes Knowledge of avian influenza A (H5N1) virus infection in humans is still evolving Unusual symptoms –Southern Vietnam – encephalitis and diarrhea –Fever and diarrhea can be the only early signs and symptoms before pneumonia occurs later with H5N1 virus infection

10. Complications Seasonal Influenza Ear infections, sinusitis Bronchitis, bronchiolitis Pneumonia –viral or secondary bacterial Exacerbation of chronic conditions Muscle inflammation Neurologic Disease –Seizures –Encephalopathy and encephalitis –Reye syndrome H5N1 Virus Infection in Humans Most cases develop pneumonia Acute Respiratory Distress Syndrome (ARDS) Multiorgan failure Encephalitis Cytokine storm

11. Alex Question: Do you think Alex has signs and symptoms of H5N1? Why or why not?

12. Epidemiological Context

13. Exposure to Avian Influenza (H5N1) Virus 1.Infected poultry, particularly coming in contact with respiratory secretions 2.Infected wild or pet birds 3.Other infected animals (e.g., pigs, cats, dogs) 4.Wild bird feces, poultry manure and litter containing high concentrations of virus 5.Fecally contaminated surfaces

14. H5N1 Virus Exposures Continued 6.Under- or uncooked poultry meat or eggs from infected birds 7.Contaminated vehicles, equipment, clothing, and footwear at affected sites, such as poultry farms with outbreaks 8.Contaminated air space (e.g., a barn, hen-house, or the air space proximal to barn exhaust fans) 9.Bodies of water with infected bird carcasses 10. Close contact with (within 3 feet of) confirmed human cases

15. Local Customs - Unique Exposures Cock fighting Swan defeathering Playing with dead chickens Duck blood pudding, local customs Hunting practices

16. Alex Question: Do you think Alex could have been exposed to highly pathogenic avian influenza A (H5N1) virus?

17. Using All of The Information

18. Alex’s Situation 24 year old Alex sick for three days –Fever –Headache –Cough –Shortness of breath –Muscle aches –Watery diarrhea No one else sick Alex works on poultry farm where he handles poultry

19. Alex Question: Would you suspect avian influenza A (H5N1) virus infection? Why or why not?

20. Part 1 Summary Individuals with avian influenza A (H5N1) virus infection may have non- specific lower respiratory symptoms, or (rarely) none at all Ask about recent exposure and contact with humans or animals that may have had avian influenza A (H5N1) virus infection

21. Case Management of Suspect Avian Influenza A (H5N1) Virus Infection in Humans Part 2: Case Management of Suspected Human Cases of Avian Influenza A (H5N1) Virus Infection

22. Learning Objectives Testing available for diagnosing –Clinical specimens Current treatment options Infection control measures

23. Part 2 Session Overview Laboratory Testing Treating Suspected Patients Infection Control in the Healthcare Setting

24. Laboratory Testing

25. Diagnostics Avian Influenza A (H5N1) Virus –Specimens for testing Influenza A Imaging

26. Avian Influenza A (H5N1) Virus Laboratory Tests RT-PCR –Detects viral RNA –Diagnose H5N1 in humans –BSL-2 conditions –Results within hours Viral culture –Only in enhanced BSL-3 laboratory –Results in 2-10 days Serologic Testing –Rise in H5N1 specific antibodies –Testing only in enhanced BSL-3 laboratory

27. Clinical Specimens for Detecting Avian Influenza A (H5N1) Lower Respiratory Tract* –Broncheoalveolar lavage fluid –Endotracheal aspirate –Pleural fluid –Sputum Upper Respiratory Tract –Oropharyngeal swabs* –Nasal Swab Collect multiple specimens from the same suspect H5N1 patient on different days for RT- PCR testing * Preferred specimens

28. Clinical Specimens for Testing Serology –Acute and convalescent serum specimens Acute collected within 1 week of symptom onset Convalescent collected 2-4 weeks after symptom onset –Other infections or concurrent illness Collect all possible specimens, serial collection

29. Clinical Specimens for Testing Autopsy Specimens –Eight blocks or fixed-tissue specimens from each of the following sites Central (hilar) lung with segmental bronchi Right and left primary bronchi Trachea (proximal and distal) Pulmonary parenchyma from both right and left lung –Major organs Myocardium (right and left ventricle) CNS (cerebral cortex, basal ganglia, pons, medulla, and cerebellum) Organ with significant gross or microscopic pathology)

30. Rapid Influenza Diagnostic Tests NOT RECOMMENDED TO DETECT AND DIAGNOSE H5N1 VIRUS INFECTION –Many commercial kits available –Results in 15-30 minutes –Low sensitivity (FALSE NEGATIVES LIKELY) –Positive result cannot differentiate seasonal influenza A from avian influenza A (H5N1) virus infection –Negative result does not rule out avian influenza A (H5N1) virus infection as diagnosis

31. Laboratory Diagnostics CDC’s influenza laboratory is nation’s influenza reference laboratory Capable of performing additional tests –Immunohistochemical testing on autopsy specimens CDC’s Emergency Response Hotline –770.488.7100

32. Imaging Chest X-ray changes of pneumonia are common in the lungs of H5N1 patients Non-specific changes Diffuse or patchy infiltrates Fluid in the space surrounding the lungs Cavities forming in the lung tissue BBC News. http://bbb.co.uk Saturday, 3 December 2005

33. Avian Influenza A (H5N1) Virus Patient’s Chest X-Rays Chest x-ray of a patient with avian influenza A (H5N1) virus infection, shown by day of illness Day 5 Day 7 Day 10 Tran Tinh Hien, Nguyen Thanh Liem, Nguyen Thi Dung, et al. New England Journal of Medicine. 18 March, 2004. vol. 350 no. 12. pp 1179-1188.

34. Treating Suspected Cases

35. Treatment Options Antivirals Supportive care

36. Neuraminidase Inhibitors Two drugs available –Oseltamivir (Tamiflu®) and Zanamivir (Relenza ®) –Should be given as soon as possible –Effective for treatment and prevention –Used for seasonal influenza and infection with avian influenza A (H5N1) viruses

37. Oseltamivir Dosage for seasonal influenza Adults: 75 mg twice a day for 5 days Children: <1 year, not recommended If < 15 kg: the dose should be 30 mg twice a day for 5 days If >15 kg to <23 kg: the dose should be 45 mg twice a day for 5 days If >23 kg to <40 kg: the dose should be 60 mg twice a day for 5 days If >40 kg: the dose should be 75 mg twice a day for 5 days

38. Oseltamivir Treatment for H5N1 patients Best dosage for H5N1 patients unknown –Consider longer treatment (7 to 10 days) OR –Higher doses (150 mg) –Begin as soon as possible Dosage for prevention –Once daily for 7 to 10 days after last exposure Side Effects –Nausea and vomiting –Skin rash –Neurological problems

39. Oseltamivir Effectiveness in seasonal influenza –Reduces influenza symptoms by 1 day –Reduces some complications of influenza Cautions- Consider Risk versus Benefits –People with kidney disease (adjust dose) –Pregnant or nursing females Contraindication –<1 year of age –Hypersensitivity to any component of product Resistance –Detected in some H5N1 patients

40. Zanamivir Inhaled by mouth via special device May be used for treatment of influenza >7 years of age Treatment dosage –Once in morning and night, 5 days Side effects –Wheezing, and breathing problems

41. Zanamivir Effectiveness in seasonal influenza –Reduces influenza symptoms by one day –Reduces lower respiratory tract complications Consider Risk vs. Benefit –People with chronic respiratory disease –Pregnant or nursing females Resistance –Very rare in human cases of avian influenza A (H5N1) virus infections –Active against Oseltamivir resistant H5N1 viruses

42. Other Treatments? Amantadine and Rimantadine –Some H5N1 viruses are resistant Corticosteroids –Not recommended –Only for worsening sepsis with adrenal insufficiency

43. Treating Children Different Oseltamivir dosage –Based on child’s weight –Not approved in children <1 year No aspirin for children <18 years of age –Use Acetaminophen or Ibuprofen Children potentially infectious for longer periods than adults –If child cannot remain hospitalized, educate family about infection control –Source: WHO Writing Group, Emerging Infectious Diseases, Vol. 12, No. 1, January 2006.

44. Antibiotics Broad-spectrum –Do not use as a prophylactic –Give empiric therapy for suspected bacterial pneumonia Secondary bacterial infection therapy –Treat with intravenous antibiotics as recommended

45. Supportive Care Hospital care for suspected or confirmed avian influenza A (H5N1) cases should include: Isolating the patient Supplemental oxygen and ventilation Intensive care support for organ failure

46. Infection Control in Health Care Setting

47. Infection Control Measures Patients hospitalized for clinical monitoring, diagnostic testing, and antiviral therapy Droplet/airborne precautions –Isolation –N95 respirators or more protective Eye protection (within 3 feet) –Goggles or face shields

48. Infection Control Measures Standard Precautions –Hand washing before and after contact with patient or potentially contaminated items Contact Precautions –Gloves and gown worn –Dedicated equipment used CDC recommendations http://www.cdc.gov/flu/avian/professional/infec t-control.htm http://www.cdc.gov/flu/avian/professional/infec t-control.htm

49. Managing Corpses No known risk of transmission from dead bodies Autopsy procedures could result in transmission –Use appropriate protective equipment You should know –Where corpses may be sent for disposal –Cultural or religious beliefs to respect when handling corpses

50. Part 2 Summary 1.Important appropriate clinical specimens are collected and tested 2.Begin treatment with neuraminidase inhibitor (oseltamivir) immediately! Do not wait!

51. Case Management of Suspect Avian Influenza A (H5N1) Virus Infection in Humans Part 3: Public Health Action

52. Learning Objectives Understand case management from public health perspective Recognize opportunities for public health authorities to effectively communicate avian influenza A (H5N1) information

53. Part 3 Session Overview 1.Collect Case Information Classify case according to case definition for surveillance 2.Facilitate specimen collection and laboratory testing 3.Information on avian influenza A (H5N1) illness 4.Infection control measures in the home 5.Active case follow up 6.Identify close contacts and recommend antiviral chemoprophylaxis (oseltamivir) 7.Enhance surveillance

54. Pandemic Influenza Plan Know your role and responsibilities as outlined in your health department’s plan Identify key collaborators before and during investigation

55. Collecting Case Information

56. Case Information Name and contact Information Unique Identifier Occupation (address) Demographic Symptoms Test Results Treatment Outcome Travel history Potential exposures Close contacts Name of person reporting Healthcare facility name and location Patient information:

57. Updated Interim Guidance for Laboratory Testing of Persons with Suspected Infection with Avian Influenza A (H5N1) Virus in the United States Testing for avian influenza A (H5N1) virus infection is recommended for a patient who has an illness that: requires hospitalization or is fatal; AND has or had a documented temperature of ≥100.4° F; AND has radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternate diagnosis has not been established; AND has at least one of the following potential exposures within 10 days of symptom onset:

58. A) History of travel to a country with influenza H5N1 documented in poultry, wild birds, and/or humans, AND had at least one of the following potential exposures during travel: direct contact with (e.g., touching) sick or dead domestic poultry; direct contact with surfaces contaminated with poultry feces; consumption of raw or incompletely cooked poultry or poultry products; direct contact with sick or dead wild birds suspected or confirmed to have influenza H5N1; close contact (approach within 1 meter [approx. 3 feet]) of a person who was hospitalized or died due to a severe unexplained respiratory illness;

59. B) Close contact (approach within 1 meter [approx. 3 feet]) of an ill patient who was confirmed or suspected to have H5N1; or C) Worked with live influenza H5N1 virus in a laboratory.

60. Case by Case Considerations! Mild or atypical disease (hospitalized or ambulatory) with one of the exposures listed above Severe or fatal respiratory disease whose epidemiological information is uncertain, unavailable, or otherwise suspicious but does not meet the criteria above

61. Proposed Influenza Division/CDC Case Definitions Confirmed Suspect Report under investigation Non-case To be used for reporting purposes A separate CDC Health Alert Network was released that includes criteria for who should be tested for Influenza A (H5N1)

62. Confirmed Case (symptoms, exposure, laboratory confirmation) –Documented temperature >38 C (>100.4 F) and one of the following: cough, sore throat, and/or respiratory distress AND –One of the following exposures within 10 days of onset Direct exposure to sick or dead domestic poultry Direct exposure to surfaces contaminated with poultry feces Consumption of raw or partially cooked poultry or poultry products Close contact (within 3 feet) of an ill patient with confirmed or suspected avian influenza A (H5N1) infection Works with live HPAI (H5N1) virus in a laboratory AND… Proposed Influenza Division/CDC Case Definitions

63. Confirmed Case (Continued) –Positive for avian influenza A (H5N1) virus by one of the following methods Isolation of H5N1 from viral culture Positive RT-PCR for H5N1 4 fold rise in H5N1 specific antibody titer by microneutralization assay in paired sera Positive IFA for H5 antigen using H5N1 monoclonal antibodies Proposed Influenza Division/CDC Case Definitions

64. Suspect Case –Documented temperature >38 C (>100.4 F) and one of the following: cough, sore throat, and/or respiratory distress AND –One of the following exposures within 10 days of onset Direct exposure to sick or dead domestic poultry Direct exposure to surfaces contaminated with poultry feces Consumption of raw or partially cooked poultry or poultry products Close contact (within 3 feet) of an ill patient with confirmed or suspected avian influenza A (H5N1) virus infection Works with live HPAI (H5N1) virus in a laboratory –Laboratory test for avian influenza A (H5N1) is pending, inadequate or unavailable Proposed Influenza Division/CDC Case Definitions

65. Report Under Investigation –Additional information needed on clinical and exposure information Not a Case –Negative avian influenza A (H5N1) virus testing result from a sensitive laboratory testing method using adequate and appropriately timed clinical specimens Proposed Influenza Division/CDC Case Definitions

66. Reporting Report through normal channels Information shared with WHO— probable and confirmed cases according to WHO case definition Help determine pandemic phase in US Local PH State PH CDC

67. Facilitate Specimen Collection and Laboratory Testing

68. Specimen Collection Best specimens –Lower respiratory tract Broncheoalveolar lavage fluid Endotracheal aspirate Pleural fluid –Upper respiratory tract Oropharyngeal swabs Have supplies stocked for timely collection of appropriate specimens

69. Laboratory Testing Be familiar with testing available in your area Know which laboratories can perform which tests Know tests available at CDC

70. Provide Information on Avian Influenza A (H5N1) Illness

71. Avian Influenza A (H5N1) Virus Infection Emerging disease with evolving knowledge Empathy with public concerns Provide consistent and up to date literature to healthcare providers –Appropriate reading level –Translation for non-English speaking community members Information such as clinical features, exposure, and treatment options

72. Educate on Infection Control Measures in the Home

73. Infection Control Measures Give consistent and up to date literature to healthcare providers Hand washing –Soap and water for 15-20 seconds –Alcohol based sanitizer, >60% alcohol Limit close contact with patient CDC Guidance on Community Mask Use During a Pandemic. www.pandemicflu.gov www.pandemicflu.gov

74. Infection Control Measures Seek medical care if condition worsens Stay home for 24 hours after symptoms resolve CDC’s recommendation for in- home isolation –http://www.cdc.gov/ncidod/sars/guid ance/i/pdf/i.pdfhttp://www.cdc.gov/ncidod/sars/guid ance/i/pdf/i.pdf

75. Conduct Active Case Follow Up

76. Active Follow Up Reasons for follow up –Specimens for testing –Timely notification of results –Monitor delivery of antiviral therapy –Secure antivirals if shortage –Note unusual clinical presentations or complications Follow up by telephone –Patient –Healthcare provider (when available) –Surrogate (e.g. spouse)

77. Identify Close Contacts

78. Definition of Close Contacts The definition of close contact is household and other contacts in work, school, and community settings who had close unprotected (i.e., not wearing PPE) contact in the 1 day before through 14 days after the case patient’s symptom onset. Examples of close contact (within 1 meter) with a person include providing care, speaking with, or touching. * http://www.who.int/csr/resources/publications/influ enza/WHO_CDS_EPR_GIP_2006_4r1.pdf * Depending on the specific circumstances suspect or confirmed cases that have completed isolation for at least 7 days, and who are no longer symptomatic, may not be considered a source of exposure to others.

79. Identifying Close Contacts List of contacts from patient’s case report form Close contact = within 3 feet or 1 meter –Sharing utensils, close conversation, direct contact Follow Up –Characterize exposure –Identify signs and symptoms Those with symptoms treated as potential case of infection with avian Influenza A (H5N1) virus

80. Recommendations to Contacts No symptoms Post-exposure prophylaxis for close contacts of a strongly suspected or confirmed human case of avian influenza A (H5N1) virus infection –WHO “high” and “moderate” risk categories, poultry depopulators, and responders who have been on infected premises should receive post exposure prophylaxis

81. Instruction to Contacts No symptoms (continued) Self monitor for 10 days after last exposure –Fever, respiratory symptoms, diarrhea, and/or conjunctivitis –Seek medical care if symptoms present –Notify public health authorities Follow infection control measures in the home

82. Enhance Surveillance

83. Enhance Surveillance during an Animal or Human Outbreak of Avian Influenza A (H5N1) Virus Infections Active case finding among occupationally exposed Sensitization of community to report illness Expand SARI and/or ILI surveillance to local hospitals, private practice etc... –Screening in hospitals Training on procedures and reporting Door-to-door community surveillance Telephone hotlines for reporting

84. Part 3 Summary Public health authorities serve as protectors of their community’s health Important that public health authorities provide clear and consistent messages to patients and contacts Case management also means identifying contacts

85. Glossary Avian Influenza A Viruses Influenza A viruses that cause infection of wild birds and poultry. Contraindication A specific circumstance when the use of a certain treatment could be harmful. Seasonal Influenza Expected rise in influenza occurrence among humans living in temperate climates; occurs during the winter season with strains of human influenza viruses that have minor changes from season to season.

86. References and Resources CDC Guidance for State and Local Health Departments for Conducting Investigations of Human Illness Associated with Domestic Highly pathogenic Avian Influenza Outbreaks in Animals (Draft). Preliminary clinical and epidemiological description of influenza A (H5N1) in Viet Nam. 12 February 2004. http://www.who.int/csr/disease/avian_influenza/guidelines/vietnamclinical/en/in dex.html http://www.who.int/csr/disease/avian_influenza/guidelines/vietnamclinical/en/in dex.html Tran Tinh Hien, et al. Avian Influenza A (H5N1) in 10 Patients in Vietnam. N Engl J Med March 18, 2004: 350(12), p 1179-1181. WHO interim guidelines on clinical management of humans infected by influenza A(H5N1), 2 March 2004. http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage/en/in dex.html http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage/en/in dex.html WHO pandemic influenza draft protocol for rapid response and containment. Updated draft 30 May 2006. http://www.who.int/csr/disease/avian_influenza/guidelines/protocolfinal30_05_0 6a.pdf http://www.who.int/csr/disease/avian_influenza/guidelines/protocolfinal30_05_0 6a.pdf