Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza A (H5N1) Virus In this session we will talk about the “management of suspect cases of human infection with avian influenza A H5N1 virus”

Outline Part 1: Background and epidemiology of avian influenza A (H5N1) virus infection in humans Human H5N1 clusters Clinical features of human infection with H5N1 virus Part 2: Assessing case patients: Collecting clinical and epidemiologic information Specimen collection and diagnostics Treatment This session will be organized into two parts. Part 1 focuses on background information and the epidemiology of H5N1 infections of humans, discusses human clusters of H5N1 virus infection, and clinical features of human infection with H5N1 virus. Part 2 will walk you through the process of assessing case patients for potential infection with H5N1 virus and collecting clinical and epidemiological information, and will cover specimen collection and diagnostics for case identification. And finally, we will discuss treatment options and recommendations

Part 1: Epidemiology and Clinical Features Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza A (H5N1) Virus Let’s begin with Part 1: Epidemiology and Clinical Features of Human H5N1 virus infection. Part 1: Epidemiology and Clinical Features 3 3

Part 1: Learning Objectives Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 1: Learning Objectives Understand the epidemiology of known human H5N1 cases and risk factors Importance of clusters Recognize clinical features of H5N1 in humans By the end of this section of the presentation, you should: Have a good understanding of the epidemiology of the known cases of human Influenza A (H5N1) virus infection, the geographic and age distribution of human cases. This includes learning about risk factors for H5N1 virus infection and known and suspected ways in which H5N1 viruses are transmitted from animals to humans, and between humans. Secondly, you should be able to understand the importance and significance of case clusters Lastly, you will be able to recognize the clinical features of avian influenza A (H5N1) virus infection in humans.

Epidemiology of Influenza A(H5N1) Virus Infection of Humans Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Epidemiology of Influenza A(H5N1) Virus Infection of Humans We will begin by discussing the epidemiology of human Influenza A(H5N1) cases. Photo: T. Uyeki, CDC

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Global Epidemiology 409 cases have been reported to WHO from 15 countries* Case fatality proportion = 256/409: ~ 63% Human surveillance has focused upon severe respiratory disease (pneumonia) As of March 2, 2009, 409 cases have been reported to WHO from 15 countries. Of these reported cases, 256 have died making the case fatality proportion (sometimes called the case fatality “rate”) approximately 63%. However surveillance for human H5N1 cases has been focused on identifying severe respiratory disease such as pneumonia so milder cases may not have been reported. *Reported as of March 2, 2009

Progression of Human Cases These next few slides show the progression of human influenza A(H5N1) cases from 2003 through 2007. As we go through the slides and progression of years, the newly affected areas are circled in yellow. Now let’s start with 2003. First Click: The first diagnosed cases of H5N1 in humans were in Vietnam (three cases) and China (1 case). Second click: The following year, 2004, saw a much broader spread of the virus across Vietnam (29 more cases) and into Thailand (17 cases) Third click: As you can see here, by 2005, more cases were found in China (8 additional cases), as well as south into Cambodia (4 cases), and Indonesia (9 cases). There were 61 new cases in Vietnam. Fourth click: In 2006, the virus spread west and more cases were confirmed as far away as Egypt (18 cases), Djibouti (1 case), Iraq (3 cases), Turkey (12 cases), and Azerbaijan (8 cases). Incident cases continued to appear in Cambodia, China, Indonesia, and Thailand. Fifth click: By 2007 a case was identified on the west coast of Africa in Nigeria, as well as deeper into Asia, in Lao (2 cases) . Sixth click: This final map shows both the morbidity and mortality of known H5N1 human cases across the African, European and Asian continents, from 2003 through June of 2008. Here you can see although the burden of disease was wide-spread - there were large concentrations of cases in Indonesia (135 cases) and Vietnam (106 cases).

Human Avian Influenza A (H5N1) Cases by Onset Date and Country (as of 23 November 2009) This slide shows the epidemic curve of human H5N1 cases from November 2003 to late October 2007. Each color represents a different country and it’s relative proportion of confirmed human H5N1 cases reported to WHO. The line shown in red dots represents the case fatality proportion at each point in time, most recently between 60 and 70%, as we have seen. The first wave of cases occurred in late 2003 to early 2004. The second wave of cases occurred in the middle of 2004. As you can see from the prevailing pink and green colors these two initial waves of H5N1 cases occurred predominantly in Vietnam and Thailand with a few cases in Cambodia and China. As you can also see, during the third wave of cases, which started in late 2005; human H5N1 cases were reported in several new countries. H5N1 virus infection also spread to domestic poultry and wild birds in many countries throughout Asia, Europe, the Middle East, and Africa during this time. You can see the diverse number of affected countries from the number of varying colors represented, although the largest number of cases have been reported from Indonesia (yellow). Perhaps you have noticed the apparent peaks of H5N1 cases. These occurred at the end of each year and beginning of the next year, suggesting seasonal trends. However, human cases have been detected year-round. As of 23 March 2009, total of 412 cases were reported officially to WHO * Cases missing onset date are excluded: 1 Viet Nam, 13 Indonesia, 3 Azerbaijan, 20 Egypt, 1 Turkey, 1 Iraq, 1 Nigeria ** CFR Trend: computed based on cumulative dead & total number of cases

WHO Summary of H5N1 cases Epidemiologic summary of H5N1* Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 WHO Summary of H5N1 cases Epidemiologic summary of H5N1* Median age: 18 years (range 3 months - 75 years) 90% 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) As of March 2, 2009, there have been 409 confirmed cases of avian influenza infection in humans. For a subset of these cases the clinical and epidemiologic characteristics were summarized by WHO at the end of 2007: The median age of human H5N1 cases was 18 years with a range of range of 3 months to 75 years. There was an equal ratio of male to female cases. The vast majority of the cases were <40 years old and the largest proportion of cases occurred in children aged 10-19 years old and young adults aged 20-29. To date, the worldwide case fatality proportion has been approximately 60% The highest case fatality proportion, was observed in children 10-19 years, approximately 76% And the lowest case fatality proportion was among adults aged ≥50 years, approximately 40% The median time from onset of symptoms to death was approximately 9 days, with a range of 2 to 31 days The median time from onset of symptoms to hospitalization was 4 days. Epidemiologic evidence that H5N1 virus can be transmitted from patients to health care workers *Update: WHO-confirmed human cases of avian influenza A(H5N1) infection, November 2003–May 2008. Weekly Epidemiological Record, NO. 46, 14 November, 2008 WHO Avian Influenza http://www.who.int/csr/disease/avian_influenza/en/

Review Question 1 Which two countries have reported the most cases Influenza A (H5N1) to WHO to date? a. Indonesia and Vietnam b. Egypt and Thailand c. China and Cambodia d. India and China Answer: a. Indonesia and Vietnam Before we move on, let’s review some of the information we’ve just covered. Which two countries have reported the most Influenza A (H5N1) cases to WHO to date? a. Indonesia and Vietnam b. Egypt and Thailand c. China and Cambodia d. India and China Answer: Indonesia and Vietnam

Review Question 2 What age group has the highest reported case fatality rate from H5N1 virus infection? a. 0-9 years old b. 10-19 years old c. 20-29 years old d. > 50 years old Answer: 10 – 19 years old What age group has the highest reported case fatality rate from H5N1 virus infection? a. 0-9 years old b. 10-19 years old c. 20-29 years old d. > 50 years old Answer: 10-19 years old

Risk Factors: Exposures in the Week Before Illness Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Risk Factors: 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 Photo: AP/ Bikas Das Risk factors for human infection with H5N1 virus include the following exposures in the week before onset of illness: Touching sick or dead infected poultry, including activities such as slaughtering or preparing poultry for cooking. Touching dead wild birds. Having sick or dead poultry in the household Visiting a live poultry market

Risk Factors: Culture-Specific Risk Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Risk Factors: Culture-Specific Risk Eating uncooked duck blood Defeathering of swans Playing with dead chickens Contact with roosters used in cock fighting Its important to remember that there may be culture-specific risk factors for exposure that may not have been observed previously. For example: Eating uncooked duck blood De-feathering dead swans (taking the feathers off of dead wild swans was believed to be the risk factor for H5N1 virus infection in Azerbaijan) Playing with dead chickens Contact with roosters used in cock fighting Whenever investigating an outbreak in a new context it is important to remember that we may come across mechanisms of exposure that have not previously been observed. Photo: TIME Magazine / John Stanmeyer

Avian to Human Transmission of H5N1 Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Avian to Human Transmission of H5N1 Primary mode of transmission is avian-to-human (zoonotic): Exposure to infected poultry Preparing or consuming uncooked or undercooked H5N1 virus-infected poultry or poultry products Indirect transmission may occur through: Inhalation of aerosolized H5N1 virus infected material Contact with surfaces contaminated with infected poultry feces Contact with infected animals that ate dead poultry Because H5N1 virus infection is primarily a zoonotic disease, avian to human transmission has been the predominant mode of H5N1 virus transmission to humans. As discussed in the previous two slides, the primary risk factor for transmission of H5N1 viruses to humans is touching sick or dead infected poultry or preparing or consuming uncooked or undercooked poultry or poultry products infected with H5N1 virus. Indirect avian-to-human transmission of H5N1 viruses may theoretically occur through the following: Inhalation of aerosolized H5N1 virus-infected debris (e.g. while visiting a live poultry market) Contact with surfaces that are contaminated with poultry feces containing H5N1 virus Contact with other infected animals (cat, dog) that ate dead poultry is also theoretically possible

Human-to-Human Transmission of H5N1 Virus Infection Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Human-to-Human Transmission of H5N1 Virus Infection Probable but limited, non-sustained* human-to-human transmission Very rare, but documented Occurred during close, prolonged, unprotected contact with a human H5N1 case Mostly in family members Transmission in hospital setting reported Probable but limited, non-sustained human-to-human transmission of H5N1 viruses has been reported -It is very rare, but has been documented. This has occurred during close, prolonged, unprotected contact with a critically ill human H5N1 case. Most cases of human-to-human transmission have been from one family member to another, but hospital based transmission from a patient to an unrelated health care worker has also been reported. The best known example of human-to-human transmission occurred in a hospital in Thailand in which a critically ill patient is believed to have infected her mother and aunt through unprotected, close bedside contact. Note that sustained human-to-human transmission of H5N1 viruses has NOT occurred to date. *Currently, no evidence of sustained human-to-human H5N1 virus transmission

Human Influenza A(H5N1) Case Clusters Now we will talk about some of the H5N1 clusters that have occurred.

Occurrence of H5N1 Clusters >25% of all cases have occurred in clusters Clusters are 2 or more H5N1 cases that are epidemiologically-linked Occurred in several countries Hong Kong (2003) Thailand (2004) Indonesia (2006) More than 25% of all H5N1 cases have occurred in clusters. Clusters are defined as 2 or more H5N1 cases that are epidemiologically-linked. Clusters have occurred in several countries, including: Hong Kong (2003) Thailand (2004), and Indonesia (2006) These are just three examples, and there have been other clusters.

Human Case Cluster, Hong Kong 2003 Family of five Hong Kong residents visited Fujian Province, southern China in late January 2003 7-year old girl developed pneumonia and died, was buried, but not tested Four survivors returned to Hong Kong Father and son were hospitalized with pneumonia; both confirmed with H5N1, father died No direct link between cases and avian flu infection in poultry was found Let’s discuss the first cluster, which occurred in Hong Kong in 2003: A family of five from Hong Kong visited Fujian Province, southern China in late January 2003. A 7-year old girl in the family develop pneumonia and died. She was buried, but was not tested for H5N1 virus infection. Four survivors from the family returned to Hong Kong. The father and son in the family were then hospitalized with pneumonia and were both confirmed with H5N1 virus infection. The father died. No direct link between cases and avian flu infection in poultry was found. 18

Human Case Cluster, Thailand 2004 11-year old girl who lived in a rural village with her aunt where poultry deaths occurred Mother lived near Bangkok (no poultry exposure) The girl developed fever and lower respiratory tract disease, hospitalized with pneumonia Mother and aunt traveled to hospital to provide care The girl died 24 hours later Mother and aunt became sick, were confirmed with H5N1 virus infection; mother died Probable human-to-human transmission of H5N1 virus from girl to her mother and aunt This second case cluster we will talk about occurred in Thailand in 2004. This is a cluster in which probable, limited human-to-human transmission of H5N1 virus is believed to have occurred. An 11-year old girl who lived in a rural village with her aunt where poultry deaths occurred. The girl’s mother lived near Bangkok and had no known poultry exposure. The 11-year old girl developed fever and respiratory illness, and was hospitalized with pneumonia. The mother and aunt traveled to the hospital to provide close unprotected care to the girl. The girl died 24 hours later; and both the mother and aunt then became sick and were confirmed with H5N1 virus infection. The mother subsequently died. It is believed that the girl transmitted H5N1 virus to her mother and aunt through close, unprotected contact in the hospital prior to her death. 19

Human Case Cluster, Indonesia 2006 A large H5N1 family cluster occurred in North Sumatra 1 probable + 7 confirmed H5N1 cases 7 deaths H5N1 virus was isolated from 7 cases Index case was likely infected by contact with sick/dead chickens Limited human-to-human-to-human transmission The last cluster we will discuss occurred in May 2006, a large cluster of H5N1 cases in Indonesia. In this large cluster in North Sumatra, Indonesia, 8 cases including 7 deaths occurred. There was 1 probable case and 7 confirmed by H5N1 virus isolation. The WHO Investigation team concluded that: the index case had likely acquired H5N1 virus infection from contact with sick and dead chickens, and then limited, non-sustained, human-to-human-to-human transmission had occurred through the sharing of a common sleeping quarters, but that there was no evidence of sustained H5N1 virus transmission. 20

Interpretation of Case Clusters Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Interpretation of Case Clusters Cases with similar illness onset dates Same exposure source, similar incubation period? Cases with illness onset separated in time Similar exposure source, different incubation periods? Different exposure sources? Limited human-to-human transmission? Now that we’ve seen several examples of clusters, how do we interpret human H5N1 case cluster information? First, IF human H5N1 cases occur in a cluster with similar illness onset dates, this may indicate that the cases had the same exposure source and similar incubation period. IF, however, human H5N1 cases occur in a cluster with illness onset dates separated in time, this could suggest several possibilities: The cases may have had a similar exposure source with different incubation periods Cases may have had different exposure sources Cases could represent evidence of limited non-sustained human-to-human transmission 21

Significance of Case Clusters Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Significance of Case Clusters Increase in number and size of clusters, or increase in number of mild cases can indicate: That H5N1 viruses are spreading to more people Possible increased adaptability of H5N1 viruses to humans Signal for: An increased pandemic threat and a change in WHO Pandemic Alert Period Phases The beginning of a pandemic Early containment measures What is the significance of human H5N1 case clusters? An increase in numbers of clusters, the size of clusters, or an increase in the number of cases with mild illness could indicate that H5N1 viruses are spreading to more people, perhaps reflecting an increased adaptability of H5N1 viruses to humans. This could signal a number of key events including: An increased pandemic threat and a need for a change in the WHO Pandemic Alert Period Phases Or it may suggest the beginning of a pandemic and that early containment measures are needed. 22

Assessing for Possible Human-to- Human H5N1 Virus Transmission 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, No other sources of H5N1 exposures Such as: birds, other animals, feathers, droppings, fertilizers made of fresh bird droppings, live poultry markets, contaminated environments, or laboratory specimens Possible human-to-human H5N1 transmission should be considered for: Well 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 There is no other alternative source of H5N1 exposure such as exposures to birds, other animals, feathers, droppings, fertilizers made of fresh bird droppings, visits to live poultry markets or exposure to contaminated environments, or to laboratory specimens.

H5N1 Cluster Summary ~25% of confirmed H5N1 cases have occurred in clusters worldwide Mostly among blood related family members Most cluster cases had contact with sick birds Evidence of limited, non-sustained, human-to-human contact has occurred Clinically mild pediatric H5N1 cases identified during investigations of severely ill index cases Changes in size, number or epidemiology of clusters could signal important viral changes/adaptability, or pandemic Epidemiologic evidence that H5N1 virus can be transmitted from patients to healthcare workers Approximately 25% of confirmed H5N1 cases have occurred in clusters worldwide. Most clusters have been among blood related family members, and most cluster cases had contact with sick birds. Evidence of limited, non-sustained, human-to-human contact has occurred. Clinically mild pediatric H5N1 cases have been identified during investigations of severely ill index cases. Changes in size, number or epidemiology of clusters could signal important viral changes/adaptability, or pandemic. And finally, there is epidemiologic evidence that H5N1 virus can be transmitted from patients to healthcare workers.

Review Question 3 If you recognize a cluster of human H5N1 cases, what would cause you to suspect that human-to-human transmission of H5N1 virus has occurred? Documented exposure to a confirmed, probable, or suspected human H5N1 case The time interval between contact with a suspected, probable, or confirmed H5N1 case and illness onset is 7 days or less No other apparent source of H5N1 exposure 3 or more cases are reported H5N1 is isolated from common environment of cases Answer: a,b, and c NOTE: link to h2h slides in case investigation for 22,23 and 25. If you recognize a cluster of human H5N1 cases, what would cause you to suspect that human-to-human transmission of H5N1 virus has occurred? Documented exposure to a confirmed, probable, or suspected human H5N1 case The time interval between contact with a suspected, probable, or confirmed H5N1 case and illness onset is 7 days or less No other apparent source of H5N1 exposure 3 or more cases are reported H5N1 is isolated from common environment of cases Answer: Choices a, b, and c are correct. 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)

Clinical Features of Human Infection with H5N1 Virus Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Features of Human Infection with H5N1 Virus Now, let’s turn to the clinical features of human infection with H5N1 virus

H5N1 Viral Infection in Humans Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Viral Infection in Humans Incubation period Generally from 2 to 7 days Viral shedding period for H5N1 virus Still largely unknown May be 2 weeks or longer Longer for children and immune compromised The incubation period of H5N1 virus infection in humans appears to be 2 to 5 days. But the onset of fever may occur up to 7 days from the time of avian exposure or close contact with a human H5N1 case. The viral shedding period for human infection with H5N1 virus is not completely known, but appears to be up to 2 weeks or slightly longer (especially in immune-compromised or pediatric patients). Therefore, H5N1 patients should be considered contagious for at least 2 weeks after illness onset.

H5N1 Clinical Manifestations Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Clinical Manifestations Common signs and symptoms: Fever ≥38C, cough, shortness of breath, difficulty breathing Other findings (less common): Sore throat, headache, muscle aches, diarrhea Clinical findings are non-specific, and are similar to other common acute respiratory diseases Critical to ask about H5N1 exposures The clinical features of human illness due to infection with H5N1 virus include the following: Common signs and symptoms at hospital admission are: Fever ≥38C, cough, shortness of breath, and difficulty breathing. Other findings, though less common, may include: Sore throat, headache, muscle aches, runny nose, and diarrhea. However, it is important to note that the signs and symptoms of human infection with H5N1 virus are non-specific, and are similar to signs and symptoms of other more common respiratory diseases, including human influenza. Since clinical symptoms of H5N1 are non-specific, it is very important to ask about the patients exposure history prior to illness. We will talk about the types of exposures you should ask about coming up in the second half of this module.

Possible Complications of H5N1 Infection Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Possible Complications of H5N1 Infection Most common: pneumonia May progresses to respiratory failure May requires mechanical ventilation Acute respiratory distress syndrome (ARDS) Gastrointestinal disease Multi-organ failure Heart and kidney dysfunction Neurologic symptoms Encephalitis, seizures, altered mental status, progression to coma There are many possible complications of human infection with H5N1 virus. Pneumonia is the most common respiratory complication. Pneumonia may progress to respiratory failure and may require mechanical ventilation. Acute Respiratory Distress Syndrome (ARDS) may develop and is associated with high fatality rates. Gastrointestinal disease such as diarrhea has occurred in some children and adults. Severe complications such as multi-organ failure, including heart and kidney dysfunction, can occur. Finally, as with many viruses, neurologic disease is possible. Encephalitis, seizures, altered mental status and progression to coma have all been reported.

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Pathogenesis High H5N1 viral levels are associated with an abnormal inflammatory response Other blood changes Decreased white blood cell count Low lymphocyte count Mild to moderately decreased platelet count Infection and inflammation contribute to respiratory failure and multi-organ failure Cytokine dysregulation (cytokine “storm”) While the pathogenesis of human H5N1 virus infection is not completely understood, high H5N1 viral levels have also been associated with an abnormal inflammatory response in H5N1 patients. Other blood and immune system changes can include decreased white blood cell count, low lymphocyte count, and mild to moderately decreased platelet count. It is also thought that viral infection and inflammation contribute to respiratory disease and multi-organ failure in fatal cases. Cytokine disregulation, also called “cytokine storm,” is associated with high H5N1 viral loads and fatal outcomes. 30 30

Review Question 4 What clinical signs and symptoms are pathognomonic (distinguishing) for Influenza A (H5N1) infection? Fever Cough Shortness of breath Sore throat Pneumonia Gastrointestinal symptoms None of the above Answer: g. These symptoms may typically occur, but they are non-specific and similar to other acute respiratory diseases. What clinical signs and symptoms are pathognomonic for Influenza A (H5N1) infection? Answer: None. Some signs and symptoms may more commonly occur with Influenza A(H5N1) infection than with complications of severe seasonal influenza A virus infections. However the symptoms are non-specific, and similar to other common acute respiratory diseases. This points to the critical importance of understanding all epidemiologic linkages to possible sources of exposure in order to raise the index of suspicion of possible H5N1 infection.

Part 1 Summary: Epidemiology Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 1 Summary: Epidemiology Most human H5N1 cases have been healthy children and young adults Epidemiology and exposure sources critical to suspecting a case Most H5N1 cases had direct contact with sick or dead poultry or birds in the week prior to illness onset Limited, non-sustained human-to-human transmission of H5N1 virus is rare, but has occurred In summary: Most human H5N1 cases have been among previously healthy children and young adults Understanding the epidemiology and potential exposure sources are critical to determining whether a patient should be suspected as a case of H5N1 viral infection 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 is rare, but has occurred

Part 1 Summary: Clinical Manifestation Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 1 Summary: Clinical Manifestation Signs and symptoms of H5N1 infection are non-specific and are observed in other respiratory diseases: Fever, cough, shortness of breath, difficulty breathing Pneumonia Peripheral blood changes may occur but are non-specific The signs and symptoms of H5N1 infection are non-specific and are observed in other respiratory diseases. The most common of these symptoms are fever, cough, shortness of breath, and difficulty breathing. Pneumonia is evident on chest X-ray in most H5N1 patients at hospital admission Peripheral blood changes and laboratory findings in H5N1 patients may occur but are non-specific; these commonly include a decreased white blood cell count, low lymphocyte count, and mild to moderately decreased platelet count

Part 2: Diagnosis, Management, and Treatment Management of Suspect Cases of Human Infection with Avian Influenza A (H5N1) Virus Now we know how to recognize warning signs for H5N1 infection lets move on to Diagnosis, Management and Treatment of Human cases of H5N1 Part 2: Diagnosis, Management, and Treatment

Part 2: Overview Clinically assessing suspected patients: Collecting clinical and epidemiologic information Diagnostic and laboratory tests Current recommendations for clinical treatment First we will talk about assessing a suspected patient and what sources of data are important to collect for clinical and epidemiologic findings. We will also walk through the steps in diagnosing a case. Lastly, we will discuss the current recommendations for clinical case management and current antiviral treatment.

Part 2: Learning Objectives Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 2: Learning Objectives Identify important sources of clinical and epidemiologic information Recognize laboratory tests used for identification of new cases Clinical specimen collection, diagnostic and laboratory tests Know the treatments and interventions for suspected case-patients and their contacts At the end of this session should be able to identify important sources of clinical and epidemiological information about H5N1 patients, including the appropriate sources information. You will learn to recognize the laboratory tests that are used identify a new case which includes what kind of specimens to collect and which diagnostic tests are recommended. You should also know about the treatments and interventions for the different types of suspected H5N1 cases and their contacts.

Part 2: Learning Objectives, cont Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 2: Learning Objectives, cont Know what pharmaceutical treatments are available for seasonal and pandemic influenza Understand the difference in the recommendations between seasonal vs. pandemic flu treatment Know what pharmaceutical treatments are available for seasonal and pandemic influenza Understand the difference in the recommendations between seasonal vs. pandemic flu treatment

Assessing Suspected H5N1 Patients Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Assessing Suspected H5N1 Patients Let’s start with how to assess suspected human H5N1 case patients.

Assessing Suspected H5N1 Patients Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Assessing Suspected H5N1 Patients Does the patient have findings consistent with H5N1 virus infection? Collect clinical history and data on clinical findings Evaluate epidemiological data Consider clinical, laboratory, and epidemiologic information together Remember the signs and symptoms in H5N1 patients are not specific; many of the clinical signs of disease will appear like other respiratory disorders. So the logical question to assessing a patient is: “Does the patient have clinical signs of respiratory disease consistent with H5N1 infection?” (Fever ≥38C, cough, shortness of breath, and difficulty breathing) You will need to collect information about the clinical history, as well as data on clinical findings, including laboratory test results. Next, evaluate the epidemiological data to determine whether the patient may have been exposed to H5N1 virus (for example, risk factors such as exposure to sick or dead poultry or to a human H5N1 case). Finally, consider the clinical, laboratory, and epidemiological information all together to assess whether H5N1 virus infection is a likely possibility for the patient.

Clinical Data to Collect Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Data to Collect Date of illness onset Signs and symptoms Routine laboratory results Complications Type and date of onset Clinical specimens collected for H5N1 testing Precautions used, breaks in precautions Let’s review the clinical information that you should collect:  Date of illness onset  Signs and symptoms before hospital admission, at admission, and during hospitalization  Routine laboratory testing results if available  Complications (if present) and their dates of onset  Whether or not clinical specimens were collected for H5N1 testing, and the results if available It is also important to note what infection control precautions were used in the clinical management of the patient and if potential breaks in precautions could have occurred during patient care. This is important to identify healthcare workers or other persons who may have been exposed to the patient.

Clinical Data Common signs and symptoms: Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Data Common signs and symptoms: Fever Cough Shortness of breath Difficulty breathing Other signs and symptoms that may occur: Sore throat Sputum production (may be bloody) Diarrhea / abdominal pain Muscle aches Headache Runny nose Now let’s review the signs and symptoms that are observed in most H5N1 cases. Lower respiratory tract signs appear early in the course of illness, usually within several days. As mentioned earlier some common signs and symptoms include fever, cough, shortness of breath, and difficulty breathing. Almost all patients have clinically apparent pneumonia at the time they present with shortness of breath. It should be noted that some patients have had fever and diarrhea initially, and then progressed to signs of pneumonia (shortness of breath, difficulty breathing). Other signs and symptoms that may occur include: Sore throat, headache, fatigue, muscle aches Sputum production, which could be bloody Gastrointestinal symptoms such as diarrhea or abdominal pain are less common, but have also been observed

Clinical Complications Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Complications Respiratory failure Complication from pneumonia within a few days to 2 weeks after illness onset Acute Respiratory Distress Syndrome Multiple organ failure Renal dysfunction Cardiac dysfunction Abnormal lab values Low lymphocytes: <1500 / mm3 Low platelets: < 150,000 / mm3 Acute respiratory distress syndrome and respiratory failure are complications of pneumonia in H5N1 patients. Respiratory distress occurs about 6 days after illness onset, with a range of a few days to about 2 weeks. Multi-organ failure has been observed in H5N1 patients, including signs of renal, cardiac, and circulatory dysfunction, including arrhythmia and low blood pressure Low white blood cell counts may be observed in some patients, especially low blood lymphocytes Low blood lymphocyte counts is associated with higher mortality. Other laboratory findings include mild to moderately blood low platelet count. Normal lymphocyte and platelet values are shown in the lower right hand of the slide Normal lymphocyte count 1500 - 4000 / mm3 Normal platelet count 150,000 - 400,000 / mm3

Medical Charts Include: Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Medical Charts Include: Demographic information Medical history Illness signs and symptoms Physical examination findings Treatment Laboratory testing results In addition to information obtained by interviewing the patient or patient’s family members, the patient’s medical chart can sometimes be a primary source of information when you investigate a suspected human H5N1 patient. The medical chart is the record of a patient’s encounter with a doctor or nurse. The chart will include information such as: Demographic information Medical history (any previous medical problems that the patient has had) Information about the illness before hospitalization, signs and symptoms present at admission Physical examination findings, and diagnoses Clinical complications Treatment received (such as oseltamivir antiviral treatment) Laboratory test results

Epidemiologic Context Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Epidemiologic Context Potential exposure to H5N1 Occupational exposure Animal culler, veterinarian, health care workers Residence or travel in area affected by H5N1 outbreaks in birds or animals (e.g., poultry market) Direct contact with dead or diseased birds or other animals in affected area Close contact with a person with H5N1 virus infection, unexplained moderate or severe acute respiratory illness In addition to clinical findings, it is essential to determine if the patient has a history consistent with exposure to H5N1 virus. So that requires us to consider the epidemiologic context of the case: In countries where H5N1 viruses have been identified as a cause of illness in animals or people, the diagnosis of H5N1 virus infection should be included as a possibility in the differential diagnosis of all persons who have severe, unexplained, acute febrile respiratory illness. Situations with potential for H5N1 virus exposure include: Occupational exposure to poultry, including to sick or dead poultry, through work as an animal culler, veterinarian, or exposure to specimens in a laboratory, or exposure to an H5N1 patient by a health care worker Living in an area or travel to an area affected by H5N1 outbreaks in birds or other animals (for example visiting a live poultry market) Direct contact with dead or diseased birds or other animals in an affected area Close contact with an ill H5N1 patient or a person with unexplained severe acute respiratory illness. Even if there are NO reports of ill poultry in a location, there could be disease in that area, depending upon the quality of animal and human surveillance and reporting. H5N1 viruses can spread rapidly among poultry. The virus may also be new to an area that has previously had no reports of H5N1 virus activity. If poultry H5 vaccine is used, poultry may not get sick and die, but could still be infected with H5N1 viruses. 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 or reporting is poor

Sample Patient Chart: Exposure History Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Sample Patient Chart: Exposure History Contact with ill people? (If yes, date and name, relationship to patient) ___________________________________________ Contact with diseased poultry (Live or dead)? (If yes, date and location) Recent travel? (If yes, date and location) Other close patient contacts (Household members, close coworkers) Are any of these contacts ill? In the context of H5N1 or other potential disease outbreaks, it is critical to know patient exposure history for the 7 days prior to symptom onset! -The history may be noted in the medical chart when the doctor interviews the patient. If this information is not present, you may need to speak to the doctor or patient to get some answers. You might also need to interview family members to obtain all the information needed. You will need to know information such as the sample information listed in this sample chart, including but not limited to: Has the patient had close contact within 3 feet or 1 meter of other ill people? If yes, on what date, what are the names of the contacts, and what is their relationship to the patient? We are interested in exposures that occurred up to 7 days prior to symptom onset. Has the patient touched live or dead poultry? If yes, when and where? Did the patient travel to any other area with known outbreaks of H5N1 in poultry within the last 10 days? If yes, to where did they travel, how long were they there, and did they touch or handle sick animals or birds? Does the patient have other close contacts, such as household members or fellow workers, that might have been exposed to the patient’s illness? If yes, who are they? Close contact is contact with other persons from 1 day before to 14 days after symptom onset. Are they aware of other sick family members/close contacts?

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Review Question 5 What are the critical pieces of epidemiologic information that must be collected from a patient with illness that is clinically compatible with Influenza A (H5N1) infection? Answer: Occupational exposure - Animal culler, veterinarian, health care workers Residence or travel in area affected by H5N1 outbreaks in birds or animals (e.g., poultry market) Direct contact with dead or diseased birds or other animals in affected area Close contact with a person with H5N1 virus infection, unexplained moderate or severe acute respiratory illness What are the critical pieces of epidemiologic information that must be collected from a patient with illness that is clinically compatible with Influenza A (H5N1) infection? Answer: Occupational exposure Animal culler, veterinarian, health care workers Residence or travel in area affected by H5N1 outbreaks in birds or animals (e.g., poultry market) Direct contact with dead or diseased birds or other animals in affected area Close contact with a person with H5N1 virus infection, unexplained moderate or severe acute respiratory illness

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Use All Information Clinical signs compatible with H5N1 virus infection History suggests exposure to H5N1 virus 7 days prior to symptom onset Are there multiple cases or respiratory deaths in the same family or in contacts? Send samples for laboratory confirmation When assessing patients with potential H5N1 virus infection, you want to find out whether the clinical data are compatible with H5N1 virus infection, and more importantly, determine whether there is a history or epidemiologic link to suggest exposure to H5N1 virus up to 7 days prior to symptom onset. You will also want to determine whether there are multiple cases or respiratory deaths in the same family or in contacts. If 2 or more of these cases occur within 7 to 10 days of each other, this should be investigated urgently! Lastly, you will want to send samples for laboratory confirmation. Remember that suspect human cases of H5N1 virus infection can only be confirmed as H5N1 by testing clinical samples!

Specimen Collection and Diagnostics

Diagnostic and Laboratory Testing Suspected Human H5N1 Case Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnostic and Laboratory Testing Suspected Human H5N1 Case Clinical specimen collection Diagnostic tests Laboratory testing Imaging Chest X-ray Now lets turn to the Diagnostic and Laboratory testing of suspected cases of Human Infection with H5N1 Virus There are three areas to discuss are: First, Clinical specimen collection Second, ordering the correct diagnostic tests and laboratory testing Third, Imaging - Chest X-ray 49 49

Clinical Specimens: Lower Respiratory Tract Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Specimens: Lower Respiratory Tract H5N1 viruses primarily infect 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) It is very important to collect the most appropriate specimens for diagnostic testing to identify human infection with H5N1 virus. H5N1 viruses primarily infect lower respiratory tract tissue, especially deep lung tissues. Therefore, the lower respiratory tract provides the best specimens for detecting H5N1 viruses, including: Endotracheal aspirates from intubated, mechanically ventilated patients; or Bronchioalveolar lavage (BAL) or pleural fluid specimens if BAL, thorocentesis, or chest tube placement have been performed. 50 50

Other Clinical Specimens for H5N1 Testing Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Other Clinical Specimens for H5N1 Testing Upper respiratory tract has worse virus yield than lower respiratory tract Throat swabs better for detecting H5N1 virus than other upper respiratory tract locations Use for ambulatory patients H5N1 virus has also been detected* in: Rectal swab and stool Blood serum and plasma Cerebrospinal fluid (CSF) specimens We’ve already mentioned that the best specimens for testing are obtained from the lower respiratory tract. However, H5N1 virus has been found in other human clinical specimens. Upper respiratory tract specimens tend to have a worse viral yield than lower respiratory tract specimens. Of upper respiratory specimens, throat swabs have a higher yield for detecting H5N1 virus than other upper respiratory tract specimens, such as nasal or nasopharyngeal specimens. Upper respiratory tract specimens should be obtained from ambulatory patients, since lower respiratory tract specimens may not be obtainable. H5N1 virus has also been detected in other samples and tissues including: Rectal swab and stool samples Blood serum and plasma, And cerebrospinal fluid (CSF) specimens from fatal cases These specimens should not be collected to diagnose H5N1 virus infection, but are for research purposes. * These clinical specimens should not be the primary sources used for H5N1 diagnosis 51 51

Collecting Specimens for H5N1 Testing Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Collecting Specimens for H5N1 Testing All respiratory secretions and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus! Collect specimens from different respiratory sites from the same patient on multiple days Collect oropharyngeal and nasal/nasopharyngeal swabs from both ventilated and non- ventilated patients When collecting specimens for H5N1 testing, all respiratory secretions, blood, and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus, and appropriate infection control measures should be taken, including correct use of personal protective equipment and adherence to appropriate infection control precautions. To increase the chances of detecting H5N1 virus in a suspect human H5N1 case, specimens should be collected from different respiratory sites from the same patient on multiple days: Collect throat and nasal swabs from non-ventilated patients Collect throat, nasal, AND endotracheal aspirate specimens from mechanically ventilated patients 52 52

Collecting Specimens, cont. Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Collecting Specimens, cont. Respiratory Collect endotracheal specimens from mechanically ventilated patients Collect throat and nasal swabs from all patients Collect specimens as soon as possible Blood May be useful for detection of H5N1 antibodies three weeks after infection Not useful for rapid detection of H5N1 virus infection for rapid detection of outbreaks Need to collect paired sample: acute and convalescent Rectal swab or diarrheal stool Not primary specimen for confirming H5N1 virus infection Lets talk a little more specifically about collecting specimens. Respiratory samples are a priority for testing - especially lower respiratory, when available. Collect endotracheal and other lower respiratory specimens from mechanically ventilated patients Although throat and oropharyngeal swabs are preferable to nasal or nasopharyngeal swabs for detection of H5N1 virus -Both throat and nasal swabs should be collected Collect specimens as soon as possible to increase likelihood of detection of virus infection Blood or serum specimens can be collected and although they are not useful for primary diagnosis of infection they may be useful for detection of H5N1 antibodies 3 weeks after H5N1 virus infections have occurred. However, these specimens optimally require acute and convalescent sera and are therefore not useful for rapid diagnosis of H5N1 virus infection, for rapid detection of outbreaks. Rectal swabs or diarrheal stool should not be used as a primary specimen for confirming H5N1 virus infection but collecting these specimens can add to clinical information on disease and pathogenesis. 53 53

Review Question 6 What are the optimal specimens to collect from a non-ambulatory suspected case of Influenza A(H5N1) infection? Answer: Lower respiratory tract; endotracheal aspirates from intubated, mechanically ventilated patients What are the optimal specimens to collect from a non-ambulatory suspected case of Influenza A(H5N1) infection? Answer: Lower respiratory tract; endotracheal aspirates from intubated, mechanically ventilated patients

Review Question 7 What are the optimal specimens to collect from an ambulatory suspected case of Influenza A(H5N1) infection? Answer: Throat swabs What are the optimal specimens to collect from an ambulatory suspected case of Influenza A(H5N1) infection? Answer: Throat swabs

Diagnosis Tests on respiratory samples (most common): Tests on serum: PCR-based techniques Virus isolation Immunofluorescence Rapid antigen detection (Flu A or B) Tests on serum: Measurement of specific antibodies Other tools: Chest X-Ray LINK TO LAB MODULE ON THIS SECTION There are several ways to diagnose a human case of avian influenza. Which diagnostic test one uses will depend on the specimen type, laboratory safety and assay capabilities. Respiratory specimens are the most common sample available for testing. PCR-based techniques are the most commonly used diagnostic assay for human avian influenza and can be performed directly on respiratory specimens. Laboratories that have Biosafety level three capacity can perform viral isolation techniques. Immunoflourescence assays can be used, if appropriate monoclonal antibodies are available. And, commercially available rapid antigen detection tests can be used to screen for influenza type A viruses. These assays will not differentiate subtype, so a second test, like PCR, may have to be performed. However these assays have low sensitivity and will not differentiate subtype, so a second test, like PCR, may have to be performed. Serum can be tested for anti-H5 antibodies. Also, sera might also be useful for PCR-based techniques. Lastly Chest X-rays can provide important evidence of infection and disease progression. We will mention some of these methods here, but they are covered in more detail in the Laboratory module.

Tests on Respiratory Samples Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Tests on Respiratory Samples Reverse-transcription polymerase chain reaction (RT-PCR) Primary method of confirming H5N1 virus infection Highly sensitive and specific Virus Isolation “Gold standard” Requires BSL-3 laboratory Allows for characterization of the virus The primary method of detection of H5N1 virus infection is by a method called reverse-transcription polymerase chain reaction or RT-PCR. RT-PCR detects the presence of H5N1 viral RNA – or the genetic material – of the virus. These tests are highly sensitive and specific for the presence of H5N1. Viral isolation and growing the virus in culture has historically been considered the gold standard for detection of influenza viruses. The culture process allows for antigenic and genetic characterization of virus, and for testing for drug susceptibilities. However, viral isolation of highly pathogenic avian influenza requires a Biosafety level 3 (BSL-3) laboratory, which has requirements that many diagnostic labs do not have. 57 57

Other Tests Serological methods Immunoflorescence Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Other Tests Serological methods Require acute and convalescent sera (serum obtained >21 days from onset) Immunoflorescence Requires H5 monoclonal antibody Can be difficult to interpret Serologic testing is another method of detecting presence of human infection with H5N1 virus. However, there are several caveats to serological methods. One is that this method requires both acute and convalescent sera (or serum obtained >21 days from illness onset), therefore it is not useful for prompt diagnosis to guide clinical management of suspected H5N1 patients, or an early outbreak response. Immunofluorescence is another method that can be used to test a human specimen for influenza. Immunofluorescence assays can be difficult to interpret and should be done by a well qualified laboratory. 58 58

Rapid Influenza Test Commercially available Results in 15 - 30 minutes Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Rapid Influenza Test Commercially available Results in 15 - 30 minutes Detect human influenza A and B viruses Very low accuracy to detect H5N1 virus and seasonal influenza Not sensitive or specific for detecting H5N1 virus May result in false negatives and false positives NOT RECOMMENDED for DETECTION of H5N1 virus Rapid influenza diagnostic tests are common method of testing for human influenza viruses They are many kinds of commercially available rapid tests and produce results within 15-30 minutes. They are designed for detection of human influenza A and B viruses (seasonal influenza) HOWEVER, this method of testing is known to have very low accuracy to detect H5N1 virus in human clinical specimens It has low sensitivity and is not specific for detecting H5N1 virus and seasonal influenza AND, it may result in false negatives and false positives THEREFORE IT IMPORTANT TO EMPHASIZE THAT RAPID INFLUENZA DIAGNOSTIC TESTS ARE NOT RECOMMENDED TO DETECT H5N1 virus . 59 59

Other Diagnostic Tools Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Other Diagnostic Tools Peripheral blood Decrease in the white blood cell count (WBC) Decrease in lymphocyte count (one type of white blood cell) Mild to moderate decrease in the blood platelet count As discussed earlier, peripheral blood tests can also be used to aid in the diagnosis of H5N1 infection, although these tests do not isolate the virus and is non-specific. Very low white blood cell count (WBC) (called leukopenia) Very low lymphocyte count (a kind of white blood cells) (called lymphopenia) Mild to moderate decrease in platelet count (called thrombocytopenia) 60 60

Imaging Radiologic Imaging (X-ray) Non-specific evidence of pneumonia on admission Often progresses to bilateral, multi-lobar pneumonia Diffuse or patchy infiltrates Fluid in the space surrounding the lungs Cavities may form in the lung tissue Lastly, combined with previously mentioned tests, Chest X-rays can help identify suspected case of H5N1. A chest X-ray is a form of radiologic imaging which is recommended since X-ray abnormalities are common in the lungs of human H5N1 case patients and can indicate the presence of pneumonia. This includes Non-specific evidence of pneumonia on admission X-ray findings may rapidly progress over the hospitalization to non-specific bilateral, multi-lobar patchy infiltrates, consolidation, and or pleural effusions They often show Diffuse or patchy infiltrates, Fluid in the space surrounding the lungs and Cavities which may have formed in the lung tissue Pneumonia in patients with H5N1 tends to progress rapidly to respiratory failure, and patients may die in spite of mechanical ventilation.

Severe H5N1 Pneumonia - Vietnam 2004 Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Severe H5N1 Pneumonia - Vietnam 2004 DAY 5 DAY 7 DAY 10 Fever Progressive pulmonary disease Death Pneumonia may progress to respiratory failure and the acute respiratory distress syndrome (ARDS), but can also occur with other respiratory virus infections. 62 Hien TT et al., New England J Med 2004;350:1179-1188 62

Review Question 8 What is the most sensitive and specific laboratory test for confirmation of influenza A (H5N1) infection in humans? Real-time PCR Rapid influenza test Chest X-ray Serology Answer: a. Real-Time RT-PCR What is the most sensitive and specific laboratory test for diagnosis of influenza A (H5N1) infection? Real-time PCR Rapid influenza test Chest X-ray Serology Answer: a. Real-Time RT-PCR

A Clinician Should Suspect H5N1 Virus Infection: Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 A Clinician Should Suspect H5N1 Virus Infection: Severe acute respiratory illness AND Exposure 7 days before symptom onsets to: Sick poultry or wild birds Suspect , probable, confirmed H5N1 case OR Residence in an area with known H5N1 virus infections of poultry or other animals Occupational risk factors, or reported cases of severe respiratory illness among close contacts and household members Let summarize what we have discussed thus far, you should have a suspicion of H5N1 virus infection if: A patient has severe acute respiratory illness AND Was exposed in the 7 days before symptom onset to sick or dead poultry or wild birds or to a person that is a suspected, probable, or confirmed H5N1 case, or was exposed to a person with severe acute respiratory disease. (This does not include persons with chronic respiratory infection such as tuberculosis.) OR Comes from an area with H5N1 virus infections of poultry or other animals H5N1 (or another pandemic pathogen) may also be suspected if a case of severe acute respiratory illness has known occupational risk factors (e.g. poultry worker, health care worker who works with pneumonia cases, lab worker etc..) or has reported similar illness among close contacts or other household members. 64 64

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnostic Tests If Patient is suspected human H5N1 case or meets other trigger criteria (link to trigger criteria) Then Patient’s specimen should be sent to a WHO H5 Reference Laboratory* for further influenza testing and confirmation If a patient is suspected human H5N1 case or meets other trigger criteria (link to trigger criteria), Then the patient’s specimen should be sent to a WHO H5 Reference Laboratory for further influenza testing and confirmation. * Every country should have access to at least one laboratory capable of H5N1 virus detection by RT-PCR

Clinical Treatment for Seasonal and Pandemic Influenza The next step in management of human cases of H5N1 is treatment. We will now turn to treatment for seasonal and pandemic influenza.

Treatment for Influenza Viruses Neuraminidase Inhibitors Oseltamivir Zanamivir Other Treatments Chemoprophylaxis Clinical Management The current treatment regimes for influenza viruses include: Neuraminidase Inhibitors, two of the most important being Oseltamivir & Zanamivir, and Other Treatments Chemophro Clinical Management We will talk about each of these in turn, and we will also address the issue of chemoprophylaxis for persons who may have been exposed to influenza A(H5N1). Top image located at: http://www.biota.com.au/?page=1021001&subpage=1021019. Bottom image located at: http://www.free-rx-drugstore.com/gb/.

Antivirals

Antivirals Used for the treatment and prevention of seasonal influenza A and B virus infections Effectiveness against H5N1 virus infection is unknown WHO recommended first line therapy for treatment and prevention of H5N1 virus infection Treatment should be given as soon as possible May be given as chemoprophylaxis to prevent H5N1 disease in exposed persons Antiviral drugs are used for treatment and prevention of seasonal human influenza A and B virus infections. Although their effectiveness for H5N1 treatment is unknown, they are the WHO’s recommended first line of therapy for the treatment and prevention of human H5N1 virus infections. It is very important that you should not wait for a laboratory diagnosis before initiating treatment with antivirals if you are concerned about H5N1 virus infection; all suspected H5N1 patients should begin treatment as soon as possible if available. Antivirals can also be given as chemoprophylaxis to prevent the development of H5N1 disease in persons who have been exposed to H5N1 virus.

Neuraminidase Inhibitors Two drugs available: Oseltamivir (Tamiflu ®); Zanamivir (Relenza ®) Inhibit the Neuraminidase enzyme which provides the bond between infected cell and new virus particles Prevents the release of new virus particles from the infected cell Virus particles cannot go on to infect other cells Currently the most useful class of antiviral drugs for the treatment of seasonal influenza virus infections are the neuraminidase inhibitors. Neuraminidase inhibitors do just that – they inhibit the neuraminidase enzyme which provides the bond between infected cell and new virus particles, this prevents new influenza virus particles from being released from the infected cell. The newly formed virus particles cannot be released to go on and infect other cells.

Oseltamivir for Seasonal Influenza Capsule or suspension administered by mouth Approved in the U.S. for treatment of seasonal influenza in children aged ≥1 year Pediatric dosage depends on age and weight Administered twice a day for 5 days Side effects: nausea, vomiting Effectiveness Reduces influenza symptoms by 1 day when administered within 2 days of illness onset Reduces lower respiratory tract complications, pneumonia, and hospitalization Of the neuraminidase inhibitors, oseltamivir is the most widely available drug. It is available as a capsule or suspension administered by mouth, and it is approved in the U.S. for treatment of seasonal influenza in children aged one year and older. For pediatric patients, the dosage depends on age and weight. For treatment of human influenza A (H1), A (H3), or B virus infection, oseltamivir is administered twice a day, for 5 days. Side effects are generally mild, and may include nausea, vomiting Oseltamivir effectiveness is effective for seasonal influenza A (H1) or (H3). It reduces influenza symptoms by 1 day when administered within 2 days of illness onset, and may reduce lower respiratory tract complications and hospitalization due to seasonal influenza.

H1N1 Oseltamivir Resistance Seasonal H1N1 resistance observed EU in 2008 Prevalence varies: 0-60+% H1N1 resistance elsewhere 8% in the U.S. None reported elsewhere Implications for avian influenza H5N1 Need to know more about why H1N1 resistance occurred Theoretically viruses could swap genes, but evidence does not support this possibility Oseltamivir resistant H1N1 viruses was been identified among seasonal H1N1 viruses in several countries in the European Union beginning in early 2008. Prevalence reported by influenza surveillance networks varies from 0 to more than 60% of isolates being resistant. In other parts of the world, H1N1 resistance to oseltamivir has been much lower, with 8% being reported from isolates at the Centers for Disease Control in the US, and no resistance reported in other parts of the world, although this situation can rapidly change. What implications does oseltamivir resistance in seasonal H1N1 viruses have for avian influenza H5N1? Until we learn why the unexpected increase in oseltamivir resistance has occurred in H1N1 viruses, it is too early to know what, if any, potential there might be for a similar increase in resistance to occur in H5N1 viruses. A resistant human H1N1 virus could theoretically give its neuraminidase gene to an oseltamivir susceptible avian H5N1 virus if both viruses were to infect the same host. This is one way in which a resistant H5N1 could develop. However, none of the H5N1 viruses recovered from people have shown any evidence of such gene swapping to date. H5N1 viruses made from combinations of human and avian virus genes do not transmit or transmit very poorly in laboratory studies. Furthermore, H5N1 viruses have not shown the ability to spread efficiently from person-to-person. European Center for Disease Prevention and Control

Oseltamivir: Considerations 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 to oseltamivir is low Precautions should be taken when oseltamivir is administered to the following groups of patients: For people with kidney disease, the dose should be reduced Oseltamivir is normally not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown, however, if there is strong suspicion for H5N1 virus infection, the benefits may outweigh the risks There have been some reports from Japan of self-injury and delirium with the use of oseltamivir in patients with seasonal influenza. The relationship of these reported events to oseltamivir is not known. Antiviral resistance can develop with treatment, but the frequency of resistance to oseltamivir appears to be low

Oseltamivir for H5N1 Infection Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Oseltamivir for H5N1 Infection Effectiveness for H5N1 treatment is unknown However is first line therapy for H5N1 infections Like all antivirals, the effectiveness of treatment for H5N1 virus infection is unknown, nonetheless, oseltamivir is currently recommended as first line therapy for H5N1 virus infections

Recommended Treatment for Human H5N1 Infection WHO recommends Oseltamivir treatment Optimal dosage, duration for H5N1 unknown WHO recommends similar dosage to seasonal influenza (capsule and oral suspension) 75 mg twice per day, 7-10 days Pediatric dosing based upon age and weight Consider longer treatment, and higher doses (150 mg) on case by case basis, especially in patient with progressive disease First, we will briefly review the most current WHO guidance regarding recommended antiviral treatment for human infection with H5N1: WHO recommends oseltamivir as the first line antiviral treatment for suspected, probable, and confirmed H5N1 patients. The optimal dosage and duration for treatment of H5N1 virus infection with oseltamivir is unknown, although WHO recommends the same dosage as seasonal influenza (capsule and oral suspension) be used. Pediatric dosing is determined based upon age and weight. WHO recommends that one should consider a longer treatment period (7 to 10 days), and higher doses (150 mg per dose) on a case-by-case basis, especially in patients with progressive disease.

OseltamivirTreatment for Human H5N1 Infection Should be started as early as possible in suspected H5N1 patients Warranted even with late presentation Resistance has been reported during treatment of a small number of H5N1 patients Zanamivir can treat oseltamivir resistant viruses As we talked about previously, Oseltamivir treatment should be started as early as possible in suspected H5N1 patients. Limited data suggest its usefulness in reducing H5N1-associated mortality. In addition, oseltamivir should be administered to suspected H5N1 patients even when they present to medical care with severe disease late in their illness because H5N1 patients can have prolonged H5N1 virus replication. Finally keep in mind that oseltamivir resistance has been reported during treatment of a small number of H5N1 patients. Zanamivir, if available, can treat oseltamivir-resistant H5N1 virus infection.

Treatment of Children Different oseltamivir dosage Based on child’s weight Not approved in children <1 year old No aspirin for children <18 years of age Risk of Reye’s syndrome with aspirin Use paracetemol or ibuprofen Children potentially infectious for longer periods than adults after illness onset Children need careful consideration regarding treatment because of the high burden of disease and other risks. First, children should receive a dosage of oseltamivir based on their age and weight. Additionally, oseltamivir has not been approved in children under one year of age. Do not administer aspirin or products containing aspirin to children under 18 years of age, due to the risk of Reye’s syndrome, a serious complication that can lead to death. acetaminophen, paracetamol, or ibuprofen can be used instead to reduce fever. Children are potentially infectious for longer periods than adults after influenza illness onset.

Zanamivir Orally inhaled powder – administered by mouth via special device Approved in the U.S. for treatment of seasonal influenza in patients aged 7 years and older and for chemoprophylaxis in persons older than 5 years of age Treatment dosage for seasonal influenza is one puff in the morning and one at night for 5 days Side effects Wheezing, and breathing problems Zanamivir is a neuraminidase inhibitor that is not widely available for the treatment of influenza. It is an orally inhaled powder which is administered by mouth via a special inhaler device (shown here) . Zanamivir is approved in the U.S. for treatment of seasonal influenza in patients aged 7 years and older, and for the prevention (chemoprophylaxis) of seasonal influenza in patients aged 5 years and older. Treatment dosage for seasonal influenza is one puff in the morning and one at night for 5 days. Side effects may include wheezing and breathing problems.

Zanamivir: Effectiveness Effectiveness in seasonal influenza Can reduce influenza symptoms by 1 day if administered within 48 hours Reduces lower respiratory tract complications Oseltamivir-resistant influenza A(H1N1) viruses remain sensitive to zanamivir Zanamivir is also approved for use in patients with seasonal human influenza virus infection. It reduces influenza symptoms by 1 day when administered within 2 days of illness onset, and may reduce lower respiratory tract complications and hospitalization due to seasonal influenza. In addition, Oseltamivir-resistant influenza A(H1N1) viruses remain sensitive to zanamivir.

Zanamirvir: Considerations Not recommended for People with chronic respiratory disease Pregnant or nursing females Resistance Very low for human influenza A (H1 and H3) viruses Certain precautions should be taken with Zanamivir. Zanamivir is not recommended for people who have chronic lung disease such as asthma or chronic obstructive pulmonary disease. It may cause bronchospasm in these patients. It is also normally not recommended for use during pregnancy or nursing, as the effects on the unborn child or nursing infant are unknown. However, if there is strong suspicion for H5N1 virus infection and the there is evidence of oseltamivir resistant H5N1 virus infection, the benefits may outweigh the risks. Antiviral resistance to zanamivir is very low for human influenza A(H1) and (H3) viruses.

Zanamirvir for H5N1 Infection Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Zanamirvir for H5N1 Infection Effectiveness for H5N1 treatment is unknown Used as second line therapy for H5N1 infections when virus is resistant to oseltamivir The effectiveness of zanamivir for treatment of H5N1 virus infection is also unknown. It can be used as second line therapy for H5N1 virus infections when H5N1 viruses are resistant to oseltamivir.

Adamantanes Amantadine and Rimantadine Chemically related, orally administered drugs Reduce viral replication of Influenza A viruses No activity against Influenza B viruses High frequency of resistance among circulating human influenza A (H3) viruses Resistance develops rapidly influenza A viruses Adverse effects include gastrointestinal and neurological symptoms NOT recommend for H5N1 treatment There are a couple other treatments that exist for the treatment of human influenza A/H1 and A/H3. Amantadine and Rimantadine are two drugs that belong to the adamantane family of antivirals. They are chemically related, orally administered drugs. Both can reduce viral replication of influenza A viruses; however, adamantanes have no activity against influenza B viruses Unfortunately, most circulating human influenza A(H3) viruses are now resistant to the adamantanes THEREFORE, neither drug is recommended for the treatment of human influenza A (H1) or (H3) viruses in the United States Also, neither drug is currently recommended for use as primary treatment of H5N1 virus infection in humans, as many isolates demonstrate resistance. Resistance to these drugs develops rapidly with human influenza A viruses. Adverse effects with these drugs include gastrointestinal and neurological symptoms. Neither of these drugs is recommended to treat suspected H5N1 patients.

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Review Question 9 According to WHO, what drug is the first-line for treatment of Influenza A (H5N1) infection? Oseltamivir, 75 mg twice per day, 7-10 days Zanamirvir, 75 mg twice per day, 7-10 days Amandatine, 75 mg twice per day, 7-10 days Rimantadine, 75 mg twice per day, 7-10 days Answer: a. Consider longer treatment, and higher doses (150 mg) on case by case basis Pediatric dosing is based on age and weight According to WHO, what drug is the first-line for prevention and treatment of Influenza A (H5N1) infection? Oseltamivir, 75 mg twice per day, 7-10 days Zanamirvir, 75 mg twice per day, 7-10 days Amandatine, 75 mg twice per day, 7-10 days Rimantadine, 75 mg twice per day, 7-10 days Answer: For treatment, WHO recommends Oseltamivir 75 milligrams twice per day for 7-10 days. Pediatric dosing based upon age and weight However, consider longer treatment, and higher doses (150 mg) on case by case basis, especially in patient with progressive disease For prophylaxis, WHO recommends 75 milligrams once per day for 7-10 days.

Other Treatments

Corticosteroids No proven effectiveness on clinical H5N1 infection Risk of side effects, including opportunistic infections May be considered on case by case basis for persistent septic shock with adrenal insufficiency Lastly, corticosteroids have also been used when treating human influenza patients. However, according to expert consensus from the WHO, corticosteroid usage in the treatment of H5N1 has failed, so far, to show effectiveness. In fact, using these steroids, can result in serious adverse events in H5N1 case patients, including opportunistic infections. Therefore, corticosteroids should not be routinely used, except on a case by case basis for persistent septic shock with suspected adrenal insufficiency.

Recommended Treatment with Antibiotics Antibiotic prophylaxis should be avoided When pneumonia is present: Antibiotic treatment is appropriate Treat according to published evidence-based guidelines What is the role of broad spectrum antibiotics in the treatment of H5N1 virus infections? According to expert consensus from the WHO, prophylactic antibiotics should be avoided. When pneumonia is present, if bacterial infection is suspected, 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 in patients with H5N1 virus infection.

Treatment for the Acute Respiratory Distress Syndrome (ARDS) Therapy for H5N1 virus infection associated ARDS should be based upon published guidelines for ARDS Lung protective mechanical ventilation with low tidal volume What about the treatment for the acute respiratory distress syndrome (ARDS), which may be associated with H5N1 virus infection? Clinical management of patients with ARDS should ideally be by a critical care intensivist or a pulmonary specialist. According to WHO, therapy for H5N1 virus infection associated ARDS should be based upon published evidence-based guidelines for ARDS, including lung protective mechanical ventilation with low tidal volume.

WHO Recommnedations: Antiviral Chemoprophylaxis for Human Infections with H5N1 Virus Pre-exposure prophylaxis may be considered for Those involved in culling or disposing of infected poultry Post-exposure prophylaxis should be considered for Household and close contacts of suspected or confirmed H5N1 cases Healthcare worker with exposure without appropriate PPE to suspected or confirmed H5N1 patients Treatment depends on level of risk WHO recommends oseltamivir Antiviral chemoprophylaxis for human infection with H5N1 virus may be appropriate depending on the circumstances of the exposure. Pre-exposure chemoprophylaxis may be considered for persons who will be involved in killing or disposing of suspected or confirmed H5N1 virus infected poultry. Post-exposure chemoprophylaxis may be considered for household and close contacts of suspected, probable or confirmed H5N1 cases or for healthcare workers with exposure without appropriate PPE to suspect, probable, or confirmed H5N1 patients. Treatment regimes depend on level of risk based on the level of exposure and of protection the person may of been using at the time of exposure. The World Health Organization defines these levels of risk in detail. We will talk about the different treatment regimes in the next few slides. WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006

Antiviral Chemoprophylaxis: High Risk WHO recommends Oseltamivir for chemoprophylaxis of high-risk groups: 75 mg / day for 7-10 days after the last known exposure High-risk: Household or family members and close contacts, including pregnant women, of a strongly suspected or confirmed H5N1 patient Lets briefly expand on what criteria antiviral chemoprophylaxis is recommended when a person has exposure to H5N1 virus. WHO recommends oseltamivir for chemoprophylaxis but there are three levels of risk: high, moderate, and low. The chemoprophylaxis dosage is 75 mg once per day for 7-10 days. For high-risk groups, WHO recommends oseltamivir for chemoprophylaxis for 7-10 days after the last known exposure. Persons with high-risk exposure are defined as household or family members and close contacts, including pregnant women, of a strongly suspected or confirmed H5N1 patient. WHO. Rapid advice guidelines for pharmacological management of H5N1. 2006

Chemoprophylaxis: Moderate Risk Antiviral chemoprophylaxis may be considered in persons defined by WHO as having moderate risk Moderate Risk: Persons handling sick animals, decontaminating environments, without the appropriate use of PPE or without using PPE 100% of the time Unprotected and very close direct exposure to sick or dead animals infected with H5N1 virus or birds implicated in human cases Healthcare workers in close contact with strongly suspected or confirmed H5N1 patients (performing intubation, tracheal suctioning, delivering nebulized drugs, handling body fluids) without the appropriate use of PPE Antiviral chemoprophylaxis may be considered in persons defined by WHO as having moderate risk: Persons with moderate risk exposure are defined as: Persons handling sick animals and decontaminating environments without the proper use of PPE or without using PPE 100% of the time Persons unprotected and with very close direct exposure, including touching and handling of sick or dead animals infected with H5N1 virus or birds implicated in human cases Healthcare workers in close contact (less than 3 feet or 1 meter) with strongly suspected or confirmed H5N1 patients (including those may of performed procedures such as intubation, tracheal suctioning, delivering nebulized drugs, and handling body fluids) without appropriate use of PPE. Again, antiviral chemoprophylaxis may be considered in persons defined as having moderate risk

Chemoprophylaxis: Low Risk Antiviral chemoprophylaxis is generally not recommended for low risk persons Low Risk: Healthcare workers not in close contact with a strongly suspected or confirmed H5N1 patient and having no direct contact with infectious material Healthcare workers in contact with H5N1 cases wearing appropriate PPE Culling of non-infected or likely non-infected animals Handlers of sick animals or decontaminating environments while using appropriate PPE In contrast to high and moderate risk individuals Antiviral chemoprophylaxis is generally not recommended for those defined by WHO as low risk persons Persons with low risk exposure are defined as: Healthcare workers not in close contact with a strongly suspected or confirmed H5N1 patient and having no direct contact with infectious material Or, healthcare workers in close contact with strongly suspected or confirmed H5N1 patients while wearing appropriate PPE Or, persons involved in culling of non-infected or likely non-infected animals Or handling of sick animals or decontaminating environments while using appropriate PPE Antiviral chemoprophylaxis is generally not recommended for low risk persons

Clinical Management Infection control: Supportive care: Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Management Infection control: Isolate patient Implement infection control precautions All bodily fluids, secretions, clinical specimens should be considered potentially infectious Proper personal protective equipment (PPE) for caregivers Supportive care: Supplemental Oxygen Mechanical ventilation for respiratory failure in the intensive care unit For the health care provider, PPE and not prophylaxis is the first line of defense! Never forget, routine clinical management also includes the following: Good infection control practices: Start with isolation of the patient, Implementation of infection control precautions (discussed further in infection control module) All bodily fluids, secretions, and clinical specimens from a suspected H5N1 patient should be considered potentially infectious Use of the proper personal protective equipment (PPE) should be routine for caregivers, including health care workers and family members The World Health Organization recommends PPE for health care workers administering direct care to suspected, probable, or confirmed H5N1 patients should include eye protection (goggles), disposable gloves, disposable gown, and surgical mask. For aerosol-generating or close procedures such as suctioning and intubating a patient, a fit-tested N95 respirator or equivalent should be worn instead of a surgical mask. Supportive care measures for the patient include: Supplemental oxygen And mechanical ventilation for respiratory failure in the intensive care unit For the health care provider, PPE and not prophylaxis is the first line of defense!

Summary Treatment with antibiotics should be avoided Oseltamivir is first line therapy for treatment and prevention of H5N1 virus infection Chemoprophylaxis is recommended depending on level of risk (low, moderate, high) Treatment with antibiotics should be avoided To summarize the pharmaceutical interventions we have discussed: Oseltamivir is first line therapy for treatment and prevention of H5N1 virus infection according to WHO Chemoprophylaxis recommended depending on level of risk associated with exposure to H5N1 virus (low, moderate, high). Treatment with antibiotics should be avoided unless medically necessary due to secondary infection.

Part 2 Summary: Epidemiology and Diagnosis Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 2 Summary: Epidemiology and Diagnosis Collect clinical and epidemiologic data from multiple sources Identify and collect appropriate specimens for diagnostic testing Lower respiratory tract Multiple respiratory samples should be collected for H5N1 testing Diagnostic Tests: Real-time reverse-transcription polymerase chain reaction (RT-RT-PCR) is the most sensitive and timely method for confirming H5N1. Rapid influenza tests are not sensitive for detecting H5N1 Let’s summarize what we have learned in Part 2: The first step when presented with s suspected case of H5N1 it is to collect any relevant and important clinical and epidemiologic data from multiple sources including medical charts and patient history (exposures). This data can help to assess whether the patient has findings consistent with exposure to and clinical characteristics of H5N1 virus infection. Recall from part 1 that he most common symptoms of H5N1 virus infection are fever, cough, and shortness of breath. These symptoms are non-specific and common to many respiratory illnesses. Thus a comprehensive epidemiologic investigation is critical. Laboratory and clinical information in the patient’s medical chart can also be used to look for characteristics of H5N1 virus infection. Second, it is important to collect the appropriate clinical specimens for diagnostic testing and disease verification. Remember the lower respiratory tract provides the best specimens for detecting H5N1 viruses. But don’t forget that all respiratory secretions and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus! Multiple respiratory specimens should be collected on different days from a patient suspected of having H5N1 virus infection for H5N1 testing. Lastly, for diagnostic purposes real-time reverse-transcription polymerase chain reaction (RT-RT-PCR) is the most sensitive and timely method for confirming H5N1. Rapid influenza tests are not sensitive for detecting H5N1.

Part 2 Summary: Clinical Management and Treatment Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Part 2 Summary: Clinical Management and Treatment Consider all evidence together (epidemiologic, clinical and diagnostic) Treatments and interventions for suspected H5N1 patients include Antiviral treatment with oseltamivir Oxygen and mechanical ventilation Supportive care To manage and treat a suspected case of H5N1, all the epidemiologic, clinical and diagnostic evidence needs to be considered to assess the possibility of H5N1 virus infection in a patient. Treatments for suspected H5N1 patients include antiviral treatment with oseltamivir, oxygen, mechanical ventilation, and supportive care.

Glossary Case fatality proportion: The proportion (percentage) of all the cases of disease who died within a specific time period. Also know as the case fatality rate Incubation period The period of time between the exposure to a virus or disease causing pathogen and when the actual infection or disease onset begins. Viral shedding process that occurs when a virus is present in bodily secretions and can thereby be transmitted to another persons. Encephalitis Inflammation in the brain usually caused by a virus (viral encephalitis). Pathogenesis The origination and development of a disease or the mechanism through which the disease causes illness

Glossary Cytokine dysregulation (“cytokine storm”) A complicated and uncontrolled immune response caused by severe infections. This exaggerated and damaging immune response can lead to organ damage, multi-organ failure, and death. Symptoms include: hypotension, tachycardia, dyspnea, fever, ischemia, or insufficient tissue perfusion (especially involving the major organs), uncontrollable hemorrhage, and multisystem organ failure (caused primarily by hypoxia, tissue acidosis, and severe metabolism dysregulation Lower respiratory tract: Portion of the respiratory system that refers to the Trachea, Primary bonchi and lungs Upper respiratory tract Portion of the respiratory system that refers to the nasal cavity, pharynx and larynx

Glossary Sensitive Used to describe a test that is “accurate” or “sensitive” to cases of true disease The proportion of specimens that are infected with the Influenza A(H5N1) virus that test positive based on diagnostic criteria. Specificity Proportion of true negatives among specimens that are not infected with Influenza A(H5N1) virus. False negatives A case that tests negative for disease although they are actually infected   False positive A person who tests positive for disease but are not actually infected Biosafety Level 3 (BSL3) The level of biocontainment and safety practices for facilities that work on potentially dangerous agents (biological or environmental). Level three is applicable for agents which cause serious or potentially lethal disease (e.g., anthrax, SARS, Typhus, etc).

References and Resources Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 References and Resources WHO. Update: WHO-confirmed human cases of avian influenza A(H5N1) infection, 25 November 2003 – 24 November 2006. Weekly Epidemiological Record 2007;82:41-48. Recommendations and laboratory procedures for detection of avian influenza A(H5N1) virus in specimens from suspected human cases, August 2007. http://www.who.int/csr/disease/avian_influenza/guidelines/RecAIlabtestsAug07.pdf WHO. WHO Rapid Advice Guidelines for pharmacological management of human infection with avian influenza A (H5N1) virus. 2006 http://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf WHO. Avian influenza, including influenza A (H5N1), in humans: WHO interim infection control guideline for health care facilities. 24 April 2006. http://www.wpro.who.int/NR/rdonlyres/EA6D9DF3-688D-43161DF5553E7B1DBCD/0/InfectionControlAIinhumansWHOInterimGuidelinesfor2b_0628.pdf Clinical management of human infection with avian influenza A (H5N1) virus. 15 August 2007. http://www.who.int/csr/disease/avian_influenza/guidelines/ClinicalManagement07.pdf Risk of Influenza A (H5N1) Infection among Health Care Workers Exposed to Patients with Influenza A (H5N1), Hong Kong Carolyn Buxton Bridges, Katz JM, Seto WH, Chan PKS, Tsang D, Ho W, Mak KH, Lim W, Tam JS, Clarke M, Williams SG, Mounts AW, Bresee JS, Conn LA, Rowe T, Hu‐Primmer J, Abernathy RA, Lu X, Cox NJ, and Fukuda K. The Journal of Infectious Diseases 2000 181:1, 344-348