Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza.

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 case management of suspect cases of human infection with avian influenza A H5N1 virus -Part 1 focuses on background information on the epidemiology, clinical features, and management of H5N1 in humans. Part 1: Background information on epidemiology, clinical features and management of human cases of avian influenza A (H5N1)

Learning Objectives Understand the epidemiology of human H5N1 cases
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Learning Objectives Understand the epidemiology of human H5N1 cases Recognize clinical features of H5N1 in humans Understand current treatment recommendations The purpose of this topic is to provide an overview of the epidemiology and clinical characteristics of highly pathogenic avian influenza A (H5N1) virus infections in humans. By the end of this presentation, you should: -Have a good understanding of the epidemiology of human H5N1 cases. This includes risk factors for the infection and the way in which the virus is transmitted. You should also understand how additional information about your patient in the weeks before illness can help you suspect H5N1 virus infection. Understand the epidemiology, geographic and age distribution of human H5N1 cases. -Secondly, you should be able to recognize the clinical features of avian influenza A H5N1 virus infection in humans. We will review signs and symptoms, laboratory findings, and complications. -Finally, you should have an understanding of the current treatment recommendations for suspect or confirmed human H5N1 cases. This topic will also focus on case management of suspected H5N1 patients and current antiviral treatment recommendations.

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

Global Epidemiology 318 cases reported to WHO from 12 countries that occurred since November 2003* Case fatality proportion: ~ 60% Human surveillance has focused upon severe respiratory disease We will begin by reviewing the epidemiology of human H5N1 cases. *As of July 10th, 2007, a total of 318 confirmed human H5N1 cases had been reported to the World Health Organization (WHO) from 12 countries since November 2003. *The case fatality proportion to date is approximately 60%. *Due to the epidemiology and clinical findings of H5N1 cases, human surveillance has been focused upon severe respiratory disease. *The frequency of asymptomatic or mild H5N1 virus infection in humans is unknown but thought to be rare based on limited sero surveys conducted among poultry workers and other exposed populations since 1997. *Reported as of July 17, 2007

This is a world map displaying the geographic distribution of all confirmed human H5N1 cases reported to WHO as of July 11, 2007:

2003 2003 Sequentially move through slides to show rapid expansion of cases in 2006. Available 3 October 2006 at:

Sequentially move through slides to show rapid expansion of cases in 2006. Available 3 October 2006 at:

This slide illustrates the epidemic curve of human H5N1 cases from November 2003 to the end of February 2007. -Each color represents a different country with confirmed human H5N1 cases reported to WHO -The first wave of cases occurred in late 2003 to early 2004; -The second wave of cases occurred in the middle of 2004. -Both waves of cases resulted in human H5N1 cases in Vietnam and Thailand. -The third wave of cases started in late 2005; during this wave, human H5N1 cases were reported in several new countries as H5N1 virus infection spread to domestic poultry and wild birds in many countries of Asia, Europe, the Middle East, and Africa. Seasonality seems present, but less so in indonesia.

Epidemiology of Human H5N1 Cases
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Epidemiology of Human H5N1 Cases WHO summary of 256 H5N1 cases* Median age: 18 years (range 3 months - 75 years) 89% of cases were aged <40 years Male to female ratio = 1:1 Median time to hospitalization: 4 days Case fatality proportion: ~60% Highest case fatality: years (76%) Lowest case fatality: ≥50 years (40%) Median time to death: 9 days (range 2 – 31 days) According to the most recent WHO summary of human H5N1 cases published in Feb. 2007: -The median age of human H5N1 cases was 18 years with a range of range 3 months to 75 years. -There was an equal ratio of male to female cases. -The median time from onset of symptoms to hospitalization was 4 days. -To date, the worldwide case fatality proportion has been approximately 60% -The greatest proportion of cases occurred in children aged years old (approximately 26%) and young adults aged (approximately 21%), with a case fatality proportion of approximately 76% -The lowest case fatality proportion has been among adults aged ≥50 years, with a case fatality proportion of approximately 40% -The median time from the reported onset of symptoms to death was approximately 9 days, with a range of 2 to 31 days *WHO Weekly Epidemiological Record 2007;82:41-8.

This figure shows the age distribution of confirmed human H5N1 cases reported to WHO. The different colors represent human H5N1 cases in different countries. -The median and mean age of cases is approximately years. -Notice that the vast majority of cases are aged less than 40 years old. -The greatest proportion of cases occurred in children aged years old (approximately 26%) and young adults aged (approximately 21%).

This figure shows the age distribution of confirmed human H5N1 cases reported to WHO by outcome. -The dark blue color represents human H5N1 cases who died. -The light blue color represents human H5N1 cases who survived. -You will again notice the majority of deaths occurred among those aged less than 40 years old. -The highest case fatality proportion has been among older children aged years old, with a case fatality proportion of 76%; followed by adults aged years old and young adults aged 20-29, with both age groups having a case fatality proportion of 66%

Risk Factors for Human Infection with H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Risk Factors for Human Infection with H5N1 Exposures in the week before illness Touching sick or dead poultry Slaughtering, preparing for cooking Touching dead wild birds Having sick or dead poultry in the household Visiting a live poultry market Risk factors for human infection with H5N1 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. -Having sick or dead poultry in the household -Visiting a live poultry market -Touching dead wild birds. -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)

Risk Factors for Human Infection with H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Risk Factors for Human Infection with H5N1 Be aware of culture-specific risk factors Duck blood pudding Defeathering of swans Consumption of undercooked chicken Playing with dead chickens Cock Fighting Its important to remember that there may be culture-specific risk factors for exposure that may not have been observed previously.

Transmission of H5N1 Virus Infection to Humans
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Transmission of H5N1 Virus Infection to Humans Avian-to-human transmission (zoonoses) Predominant mode of transmission Exposure to infected poultry Touching sick or dead poultry (handling, slaughtering, cleaning, defeathering, preparing for cooking) Indirect animal-to-human transmission Contact with surfaces contaminated with infected poultry feces containing H5N1 virus Ingestion of H5N1 virus-infected poultry (undercooked meat, uncooked duck blood) Contact with other infected animals that ate dead poultry is theoretically possible H5N1 virus infection is primarily a zoonotic disease. -Avian-to-human transmission of H5N1 viruses has been the predominate mode of transmission of H5N1 virus to humans. As previously stated, the primary risk factor for transmission of H5N1 viruses to humans is touching sick or dead infected poultry (including handling, slaughtering and cleaning, de-feathering or preparing poultry for cooking). -Indirect avian-to-human transmission of H5N1 viruses is also possible through the following : -Contact with surfaces that are contaminated with infected poultry feces containing H5N1 virus; -Ingestion of H5N1 virus-infected poultry or poultry products (e.g. undercooked meat infected with H5N1, uncooked duck blood infected with H5N1 virus) -Contact with other infected animals that ate dead poultry is theoretically possible -Inhalation of aerosolized H5N1 virus-infected debris (e.g. while visiting a live poultry market)

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 Limited, non-sustained human-to-human transmission* Close, prolonged unprotected contact with a sick human H5N1 case Very rare, but documented Mostly in family members Hospital transmission documented -Limited, non-sustained, human-to-human transmission of H5N1 viruses has been reported: -This occurred after close, prolonged unprotected contact with a critically ill human H5N1 case -However, it is very rare, but has been documented. The best known example 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. -Most cases of human-to-human transmission have been among family members of human H5N1 cases -Hospital based transmission from a patient to a health care worker has also been previously documented -Note that sustained human-to-human transmission of H5N1 viruses has NOT occurred to date. *Currently no evidence of sustained human-to-human transmission of H5N1 viruses

H5N1 Case Clusters Clusters of 2 or more confirmed H5N1 cases that are epidemiologically-linked have occurred in several countries >25% of all H5N1 cases have occurred in clusters Most H5N1 cluster cases have had directly touched sick/dead poultry or wild birds -Clusters of 2 or more confirmed H5N1 cases that are epidemiologically-linked have occurred in several countries >25% of all H5N1 cases have occurred in clusters -Most H5N1 cluster cases have directly touched sick/dead poultry or wild birds - A cluster of cases does not necessarily mean that human-to-human transmission has occurred. 18

H5N1 Case Clusters Interpretation:
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Case Clusters Interpretation: 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 non-sustained person-to-person transmission? -How do we interpret human H5N1 case cluster information? -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 human H5N1 cases occur in a cluster with illness onset dates separated in time: -This may indicate several different possibilities: -Either the cases had a similar exposure source with different incubation periods -Or cases had different exposure sources -OR cases represent evidence of limited non-sustained human-to-human transmission? 19

Significance of H5N1 Case Clusters
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Significance of H5N1 Case Clusters Increase in numbers of clusters, size of clusters, or mild illness could indicate that H5N1 viruses are spreading to more people, reflecting a possible increased adaptability of H5N1 viruses to humans. This may signal: beginning of a pandemic change in WHO Pandemic Alert Period Phases that early containment is needed -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 the H5N1 virus is spreading to more people, perhaps reflecting an increased adaptability of H5N1 viruses to humans. This could signal a number of key events including: -The beginning of a pandemic -A change in the WHO Pandemic Alert Period Phases -Or it may suggest that early containment is needed 20

H5N1 Case Clusters Limited, non-sustained human-to-human transmission of H5N1 virus, though rare, has been documented and cannot be excluded in some clusters Most clusters have occurred among blood-related family members Clinically mild H5N1 cases have been identified from investigation of index cases Shared source, genetic predisposition, or true human-to-human transmission? Finally, It is important to remember that: -Limited, non-sustained human-to-human transmission of H5N1 virus, though rare, has been documented and cannot be excluded in some clusters of disease. -In general, most clusters to date have occurred among blood-related family members -Clinically mild H5N1 cases have been identified from investigations of index cases -Most clusters have occurred among blood-related family members Clusters may suggest shared source, genetic predisposition, or true human-to-human transmission Additional information on clusters will be discussed in the module covering investigation of suspect cases of human infection with avian influenza A (H5N1) virus. 21

Diagnosis of Human Infection with H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnosis of Human Infection with H5N1 Now lets turn to the Diagnosis of Human Infection with H5N1

Specimens for H5N1 Testing
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Specimens for H5N1 Testing H5N1 viruses primarily infect the lower respiratory tract tissue Deep lung tissues Best specimens for detecting H5N1 viruses: Lower respiratory tract Endotracheal aspirates from intubated, mechanically ventilated patients Bronchioalveolar lavage (BAL) Naturally the first question is: what are the appropriate specimens for diagnostic testing of human infection with H5N1? -We know that H5N1 viruses primarily infect the lower respiratory tract tissue, especially the deep lung tissues -To increase the chances of detecting H5N1 virus in a suspected human H5N1 case, specimens should ideally be collected from different respiratory sites on multiple days. Best specimens for detecting H5N1 viruses: Lower respiratory tract Endotracheal aspirates from intubated, mechanically ventilated patients Bronchioalveolar lavage (BAL) or pleural fluid if these procedures are being implemented for other reasons (not just for influenza diagnostics)

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Specimens for H5N1 Testing Upper respiratory tract Lower yield than lower respiratory specimens Oropharyngeal or throat swabs have higher yield for detecting H5N1 virus than nasal or nasopharyngeal swabs H5N1 virus has also been detected in rectal swab, blood, and cerebrospinal fluid (CSF) specimens from fatal case Should not be the primary sources of specimens for the diagnosis of H5N1 Upper respiratory tract Lower yield than lower respiratory specimens Oropharyngeal (throat) swabs have higher yield for detecting H5N1 virus than nasal or nasopharyngeal swabs H5N1 virus has also been detected in rectal swab, serum, plasma, and cerebrospinal fluid (CSF) specimens from fatal cases Should not be the primary specimens for diagnosis of H5N1 virus infection

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Specimens for H5N1 Testing Collect specimens from different respiratory sites from the same patient on multiple days Collect oropharyngeal / throat and nasal swabs from non- ventilated patients Collect oropharngeal/throat, nasal, and endotracheal aspirate specimens from mechanically ventilated patients To increase the chances of detecting H5N1 virus in a suspect human H5N1 case, specimens should ideally be collected from different respiratory sites, from the same patient on multiple days: - one should collect throat and nasal swabs from non-ventilated patients - Whereas one should collect oropharyngeal/throat, nasal, AND endotracheal aspirate specimens from mechanically ventilated patients

H5N1 Virus Testing Primary method: detection of H5N1 viral RNA by reverse-transcription polymerase chain reaction (RT-PCR) Conventional RT-PCR Real-time RT-PCR (RT-RT-PCR) Sensitive and specific Isolation of H5N1 virus Requires special Biosafety level 3 (BSL3) conditions at WHO laboratories -Once the appropriate specimens have been collected, they must be tested for H5N1 virus. -There are several laboratory methods that can be used to detect the presence of H5N1 virus. -The primary method of detection of H5N1 viral RNA is by a method known as reverse-transcription polymerase chain reaction or RT-PCR -Two forms of RT-PCR exist: conventional RT-PCR and real-time RT-PCR, otherwise known as RT-RT-PCR -Real-time RT-PCR can produce results rapidly in several hours -Both forms of RT-PCR are both sensitive and specific at detecting evidence of the H5N1 virus -Real-time RT-PCR is becoming increasingly available throughout world and has become the preferred method of testing for H5N1 virus as developing countries develop diagnostic laboratory capacity -Another method of detecting H5N1 virus involves isolation of live H5N1 virus from the clinical specimen -Since the isolation of virus can pose a significant infectious risk, this method requires special Biosafety level 3 (or BSL3) conditions at WHO H5 Reference Laboratories

H5N1 Virus Testing Serological testing
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Virus Testing Serological testing Requires acute and convalescent sera (serum obtained >21 days from onset) Microneutralization assay is the “gold standard” (uses live H5N1 virus) Available only at specialized WHO H5 Reference Laboratories (requires BSL3 conditions) Serological testing is another method of detecting evidence of human infection with H5N1 virus. However, keep in mind that: -This method requires both acute and convalescent sera (or serum obtained >21 days from onset), therefore it may be less useful for the rapid diagnosis of human H5N1 virus infection -Two types of serologic assay are available for the detection of -Microneutralization assay, a form of serologic testing, is considered the “gold standard” since it is both sensitive and specific, -However, since the this method of testing uses live H5N1 virus--which may pose an infectious risk--it is only available at specialized WHO H5 Reference Laboratories with BSL3 conditions

H5N1 Virus Testing Rapid influenza diagnostic test
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Virus Testing Rapid influenza diagnostic test Commercially available Detects human influenza A and B viruses Very low accuracy to detect H5N1 virus Not sensitive or specific for detecting H5N1 virus May result in false negatives and false positives NOT RECOMMENDED for DETECTION of H5N1 virus Rapid influenza diagnostic tests are another method of testing for influenza virus - They are often commercially available - And can detects human influenza A and B viruses - HOWEVER, this method of testing is known to have very low accuracy to detect H5N1 virus in clinical specimens - It is neither sensitive nor specific for detecting H5N1 virus - AND, it may result in false negatives and false positives - THEREFORE IT IMPORTANT TO EMPHASIZE THAT RAPID INFLUENZA TESTS ARE NOT RECOMMENDED FOR THE DETECTION OF H5N1 virus ,

H5N1 Virus Found in Other Human Specimens
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Virus Found in Other Human Specimens H5N1 virus infection of cerebrospinal fluid documented in fatal cases with seizures and coma H5N1 virus has been found to be present in: rectal swab specimens and stool of fatal cases with diarrhea serum and plasma of fatal cases All respiratory secretions and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus As mentioned before, H5N1 virus can be found in other human clinical specimens: -H5N1 virus infection of cerebrospinal fluid has been documented in fatal cases with seizures and coma -H5N1 virus has also been found in: -rectal swab specimens and stool of fatal cases with diarrhea -as well as in serum and plasma of fatal cases -Therefore, all respiratory secretions and bodily fluids of H5N1 patients should be considered potentially infected with H5N1 virus, and appropriate infection control measures should be taken with the correct use of personal protective equipment and adherence to appropriate infection control precautions

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 learn about the clinical features of human infection with H5N1 virus

H5N1 Virus Infection of Humans
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Virus Infection of Humans Incubation period From 2 to 7 days from exposure to poultry or a human H5N1 case until fever onset Viral shedding period for H5N1 virus Still largely unknown -The incubation period of H5N1 virus infection in humans is from 2 to 7 days from the time of exposure to poultry or a human H5N1 case until onset of fever -The viral shedding period for human infection with H5N1 virus is still largely unknown, but may be up to 2 weeks or slightly longer.

Common signs and symptoms:
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Clinical Features Common signs and symptoms: Fever ≥38C, cough, shortness of breath, difficulty breathing Other findings (less common): Sore throat, headache, muscle aches, runny nose, diarrhea Clinical findings are non-specific, common, and may be similar to other respiratory disease Critical to ask about exposures What are the clinical features of human infection with H5N1 virus? -Common signs and symptoms include: -Fever ≥38C, cough, shortness of breath, and difficulty breathing -Other findings, though less common, may include: -Sore throat, headache, muscle aches, runny nose, diarrhea -However, it is important to note that the signs and symptoms associated with human infection with H5N1 virus are non-specific, common, and similar to signs and symptoms of other respiratory diseases. -Since these clinical findings are non-specific it important to ask about a history of the relevant exposures that may increase your index of suspicion for H5N1 virus infection. Later we will discuss the exposures you should ask about to suspect H5N1 virus infection

H5N1 Chest X-ray and Laboratory Findings
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Chest X-ray and Laboratory Findings Chest X-ray Non-specific evidence of pneumonia on admission Often progresses to multi-lobar pneumonia Peripheral blood: Decrease in the white blood cell count (WBC) Decrease in lymphocyte count (one type of white blood cell) Mild to moderate decrease in the blood platelet count Elevated aminotransferases (Liver enzymes) In addition to signs and symptoms, it is important to note what chest X-ray and laboratory findings one might expect with human H5N1 cases. Chest X-ray: -Non-specific evidence of pneumonia on admission -X-ray findings may rapidly progress over the hospitalization to non-specific multi-lobar patchy infiltrates, consolidation, and or pleural effusions Some laboratory findings that have been seen with human infections with H5N1 include: Peripheral blood: Very low white blood cell count (WBC) (called leukopenia) Very low lymphocyte count (one type of white blood cell) (called lymphopenia) Mild to moderate decrease in platelet count Elevated aminotransferases (Liver enzymes)

Complications of H5N1 Virus Infection
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Complications of H5N1 Virus Infection Most common complication: pneumonia Progresses to respiratory failure requiring mechanical ventilation Acute respiratory distress syndrome (ARDS) Multi-organ failure Heart and kidney dysfunction Encephalitis has been reported There are many possible severe complications of human infection with H5N1: Most common complications: Respiratory Pneumonia With progression to respiratory failure or the Acute Respiratory Distress Syndrome (ARDS) requiring mechanical ventilation Gastrointestinal Diarrhea has occurred in children and adults Neurologic Encephalitis has been reported in one case Occurred with seizures and progression to coma Multi-organ failure Heart and kidney dysfunction

H5N1 Influenza Severe Pneumonia - Vietnam 2004
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 H5N1 Influenza Severe Pneumonia - Vietnam 2004 DAY DAY DAY 10 Fever Progressive respiratory disease Death The progression of pneumonia to respiratory failure is severe, but not specific to influenza A (H5N1). Hien TT et al., New England J Med 2004;350:

H5N1 Pathogenesis High H5N1 viral levels are associated with abnormal inflammatory response Viral infection and inflammation contribute to respiratory failure and multi-organ failure Cytokine dysregulation: Cytokine “storm” Associated with high viral load and fatal outcomes While the pathogenesis of human H5N1 infection is not completely understood, it is known that: -High H5N1 viral levels are often associated with an abnormal innate inflammatory response by the patient. -It is also thought that viral infection and inflammation contribute to respiratory and multi-organ failure in fatal cases. A cytokine disregulation or “cytokine storm” is associated with high viral loads and fatal outcomes.

Part 1 Summary Most human H5N1 cases had direct contact with sick or dead poultry or birds in the week prior to illness onset Limited, non-sustained human-to-human transmission of H5N1 virus has occurred In summary: -Most human H5N1 cases had direct contact with sick or dead poultry or birds in the week prior to illness onset -Limited, non sustained human-to-human transmission of H5N1 virus has been documented

Part 1 Summary The most common signs and symptoms in H5N1 patients are: Fever, cough, shortness of breath, difficulty breathing However, these signs and symptoms are non-specific and may be seen in other respiratory diseases Chest X-ray and laboratory findings in human H5N1 patients may include: Pneumonia on chest X-ray Decreased white blood cell count, decreased lymphocyte count, and mild to moderately decreased platelet count -The most common signs and symptoms in H5N1 patients are fever, cough, shortness of breath, and difficulty breathing; pneumonia is often seen on the chest x-ray -Laboratory findings in H5N1 patients may include a decreased white blood cell count, low lymphocyte count, and mild to moderately decreased platelet count

Part 2: Case Management of Suspected Avian Influenza Cases
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Case Management of Suspected Human Infection with Avian Influenza A (H5N1) Virus This topic will focus on the case management of suspected H5N1 patients. Rapid responders will not be expected to manage suspected H5N1 cases, but knowing how cases are managed may be useful in working with doctors, hospitals and other public health agencies. In this section you will learn skills to help you coordinate with clinicians and public health officers. These skills include learning how to collect appropriate clinical and exposure information from suspected human H5N1 patients (e.g. clinical data, information from medical charts, epidemiologic context (exposures)). Part 2: Case Management of Suspected Avian Influenza Cases

Learning Objectives Collect appropriate clinical and exposure information Clinical data Information from medical charts Epidemiologic context (exposures) Recognize laboratory tests used for diagnosis of a suspected human H5N1 case patient Clinical specimens Types of laboratory tests Imaging (chest x-rays) Know the treatments and interventions for suspected case-patients and their contacts Antiviral drugs Supportive care In this session, you will learn skills to help you coordinate with clinicians and public health officers. These skill include: -How to collect appropriate clinical and exposure information from suspect human H5N1 patients. -This includes clinical data on the patient, some which may be gathered from information on the medical chart, as well as information about the epidemiologic context, in other words the exposures that may have put the patient at risk for H5N1 virus infection -Next, you will learn to recognize the laboratory testing needs for a suspected H5N1 case patient: -This includes the clinical specimens that are often collected from a patient, and the general types of laboratory tests and x-rays that are done. -Finally, you will learn what treatments and interventions are available for suspected H5N1 cases and their contacts, -This section covers provision of medical care to the case patient, including providing antiviral drugs and or supportive care.

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

Assess Suspected Human H5N1 Case Patients
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Assess Suspected Human H5N1 Case Patients Does the patient have H5N1? Confirm and / or collect clinical history and physical exam data Evaluate the epidemiologic context Consider clinical, laboratory, and epidemiologic information together -As mentioned earlier, the signs and symptoms of H5N1 are not specific, and may be similar to many other types of respiratory illnesses that commonly occur. -So how do you know whether to suspect a patient with influenza-like illness of having H5N1 virus infection? -We will discuss a few steps that will help you assess patients that are suspected of having H5N1 virus infection. -The steps are listed here, but we will talk about each one of them in more detail in the next several slides. First, you want to confirm the clinical history, including laboratory test results and physical exams. You may need to collect the appropriate clinical data if this has not already been done. Next, evaluate the epidemiologic context of the case. This means determining whether exposure to H5N1 virus was even possible for the patient. Finally, consider clinical, laboratory, and epidemiologic information to decide whether H5N1 virus infection is likely 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 Laboratory results Complications Types and dates of onset Clinical specimens collected for laboratory testing Precautions used, breaks in precautions Let’s first review the pieces of clinical information that you should collect:  Date of illness onset  Signs and symptoms before admission, at admission, and during hospitalization  Laboratory testing results if available  Complications (if present) and their dates of onset  Whether or not clinical specimens were collected for laboratory testing, and the results if available It is also important to note what precautions were used in the clinical management of the patient and if potential breaks in precautions occurred during the care of the patient. This is important to note in order to identify healthcare workers or other persons who may have been exposed.

Clinical Data Common symptoms: Other symptoms that may occur: Fever
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Data Common symptoms: Fever Cough Shortness of breath Difficulty breathing Other symptoms that may occur: Sore throat Sputum (may be bloody) Diarrhea / abdominal pain Muscle aches Headache Runny nose Now let’s review the symptoms that are most likely in an human H5N1 case patient. 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 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 May occur within a few days to 2 weeks after illness onset Acute Respiratory Distress Syndrome Multiple organ failure Renal dysfunction Cardiac dysfunction Abnormal lab values Low lymphocytes and platelets Normal lymphocytes / mm3 Normal platelet count 150, ,000 / mm3 -Acute respiratory distress syndrome and respiratory failure are two complications of H5N1 virus infection that may occur. -Onset of respiratory distress occurs about 6 days after the onset of illness, with a range of just a few days to about 2 weeks. -Multi-organ failure has been observed among human H5N1 patients, including: -Signs of renal, cardiac, and circulatory dysfunction, including arrhythmia and hypotension -Low white blood cell counts may be observed in some patients, especially low blood lymphocytes -Low blood lymphocytes have been associated with higher mortality. -Other laboratory findings that may be observed in some patients include a low blood platelet count. -Normal lymphocyte and platelet values are shown in the lower right hand of the slide

Medical Charts Include:
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Medical Charts Include: Demographic information Medical history Current medical complaint / symptom history Physical examination findings Recommended treatment Laboratory or other test results In addition to information obtained by interviewing the patient or patient’s family members, the patient’s medical chart can sometimes be the primary source of information when you investigate a suspected human H5N1 case. A patient’s medical chart is the record of a patient encounter with a doctor or nurse. The chart will include information such as: Demographic information Medical history (or the previous medical problems that the patient has had) Information about the current medical complaint and a history of the sign and symptoms Physical examination findings from the doctor or nurse Clinical complications Treatment received Laboratory test results

Sample Patient Chart: Clinical Information
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Sample Patient Chart: Clinical Information Demographic Information Date: _____ Name __________ Age ____ Gender ___ Occupation_______ Address______________________________________________________ History of Illness Chief Complaint_____________________ Date of Illness Onset _________________ Other Symptoms and symptom onset date: _______________________________________________________ Physical Exam Findings -Here is a sample medical chart showing the type of clinical information that would be collected. -In this example, demographic characteristics are first – the name, age, gender, and occupation of the individual, and the address where the individual lives. Note that if the patient is a young child, the occupation may be “student”, or there may be no occupation. -Next is a section on the history of the illness. -The chief complaint is the reason why the patient is presenting for medical care. This could be a high fever, for example, or trouble breathing. The patient (or the patient’s family member) should be asked when these symptom began occurring. -Next, the patient should be asked about other symptoms. Does the patient have a cough? If yes, when did the cough begin? Does the patient have a fever, runny nose, or gastrointestinal symptoms? All symptoms should be noted, and the date they began should be written down. -The last section shown is for physical exam findings. Here, the doctor or nurse may record the patient’s temperature, blood pressure, and weight, and may also note findings such as the respiratory rate, pulse, or how the patient’s lungs sound when listening with a stethoscope. Basic laboratory measurements such as a complete blood count may also be noted.

Sample Patient Chart: Clinical Information
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Sample Patient Chart: Clinical Information Demographic Information Date: _Nov 1, 2006 Name _Sok Phhoung_ Age __21_ Gender:_F_ Occupation______ Address___Patang village, Rattanakiri, Cambodia_____________ History of Illness Chief Complaint___Dyspnea_________ Date of Illness Onset ___Oct 27, 2006______ Other Symptoms and symptom onset date: Fever – onset Oct25____________ Cough – onset Oct 25___________ Physical Exam Findings _Current fever – 39.4°C, Pulse 123 beats/min___ -Here is an example of a chart that has been filled out for a patient. -The patient in this example is a 21-year old female from Rattanakiri province, Cambodia. - We see that she is seeking medical care because of dyspnea or trouble breathing, and is also complaining of cough and fever. The doctor has noted the patient’s current temperature and pulse. -When assessing a patient with dyspnea, shortness or breath, or difficulty breathing, a clinician needs to collect data to assess the possibility of a number of diagnosis including H5N1 virus infection -What other information would you need to collect or verify about this patient before you suspect her of having symptoms compatible with H5N1? -Knowledge of other symptoms may be helpful, for example information about: -a runny nose, gastrointestinal symptoms, or body aches. -Additionally, a more thorough physical exam may be needed. - You will want to know additional clinical information, for example: -What is the patient’s respiratory rate? -Can crackles or rales be heard in the patient’s lungs? -What is the patients blood pressure? -Was a white blood cell count taken? -You may note that information on occupation is missing. This information could be useful later when determining a possible epidemiologic link with avian influenza; for example, if she is a farmer she may have contact with chickens.

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 Travel or residence in area affected by H5N1 outbreaks in birds or animals Direct contact with dead or diseased birds or other animals in affected area Close contact with a person with H5N1 virus infection, unexplained moderate or severe acute respiratory illness -In countries where avian influenza A, H5N1 viruses have been identified as a cause of illness in animals or people, the diagnosis of H5N1 virus infection should be included in the differential diagnosis of all persons who have severe, unexplained acute febrile respiratory illness. Differential diagnosis is the determination of which one of two or more diseases with similar symptoms is the one from which the patient is suffering - In addition to symptoms, we want to consider the epidemiologic context of a patient that has acute respiratory disease. Given the current global situation with few documented instances of human to human transmission of H5N1 virus infection, people who have touched ill poultry or have touched poultry that died of illness are at the greatest potential risk of infection. -Earlier, we mentioned that a patient suspected of having H5N1 virus infection should have a history strongly suggesting potential exposure to the H5N1 virus. -Situations with potential for H5N1 virus exposure include: – A possible occupational exposure, including employment as an animal culler, veterinarian, laboratory worker, or health care worker – Travel to or residence in an area affected by H5N1 outbreaks in birds or other animals - Visit to a live poultry market – Directly touching dead or diseased birds or other animals in an affected area – Close contact with an H5N1 patient (living or deceased) or a person with unexplained moderate-to-severe acute respiratory illness; and finally, Warning! 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 surveillance. 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. 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

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) In the context of H5N1 or other potential disease outbreaks, patient exposure history is important to know. -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 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 3ft or 1m of other ill people? If yes, on what date, what are the names of the contacts, and what is their relationship to the patient? - Close contact is contact with other persons from 1 day before to 14 days after symptomonset. - 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?

Use All Information Clinical signs compatible with H5N1 virus infection History suggests exposure to H5N1 virus Are there multiple cases or respiratory deaths in the same family or in contacts? Send samples for laboratory confirmation When assessing patients with potential H5N1 virus infection, you want to confirm that : -The clinical data are compatible with H5N1 virus infection, -Determine whether there is a history or epidemiologic link to suggest exposure to H5N1 virus. You will also want to determine: Are there 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!

Diagnostic Testing for a Suspected Human H5N1 Case
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnostic Testing for a Suspected Human H5N1 Case Now we will focus on current antiviral treatment recommendations for human influenza A.

Diagnosis of Suspect Human H5N1 Cases
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnosis of Suspect Human H5N1 Cases Influenza diagnostics General laboratory testing Imaging Chest X-ray -You need to be able to understand and offer advice on laboratory testing needs for a suspected case of H5N1 virus infection. -This includes knowing: -What tests are used to diagnose H5N1 virus infection, -What other laboratory tests that should be performed -And about the use of imaging tests, particularly chest X-ray in diagnosis

Diagnostics Every country should have access to at least one laboratory capable of H5N1 virus detection by RT-PCR Commercial rapid diagnostic tests may be used to detect human influenza but not to detect H5N1 virus -Let’s begin with the basic requirements of diagnosing human influenza in general, and H5N1 influenza in particular -The World Health Organization (WHO) recommends that every country should have access to at least one laboratory capable of influenza typing and strain identification, especially one capable of H5N1 virus detection by RT-PCR -Recall that commercial rapid diagnostic kits may be used to detect human influenza, but these are not meant for detection of H5N1 virus.

Clinical Specimens Respiratory Blood Rectal swab or diarrheal stool
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Clinical Specimens Respiratory Collect endotracheal specimens from mechanically ventilated patients Collect throat and nasal swabs Collect specimens as soon as possible Collect multiple specimens on different days Blood Useful for detection of H5N1 antibodies three week after infection Not useful for detection of acute infection Rectal swab or diarrheal stool Not for confirming H5N1 virus infection To reiterate what we have said earlier about specimen collection: -Respiratory samples, especially lower respiratory, when available, are ideal for RT-PCR testing -Collect endotracheal specimens from mechanically ventilated patients -Collect both throat and nasal swabs, although throat and oropharyngeal swabs are preferable to nasal or nasopharyngeal swabs for detection of H5N1 virus -Always try to collect specimens as soon as possible to increase likelihood of detection of virus infection -Always try to collect multiple specimens on different days to increase the diagnostic yield of testing in any patient -Blood or serum specimens can be collected and -May be useful for detection of H5N1 antibodies 3 weeks after H5N1 infections have occurred, but generally require acute and convalescent sera and therefore not as useful for rapid diagnosis of H5N1 virus infection -Rectal swab or diarrheal stool -should not be used for confirming H5N1 virus infection

Lab Tests for Influenza
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Lab Tests for Influenza Rapid tests Several types Not specific for H5N1 Results in minutes NOT RECOMMENDED FOR DETECTION OF H5N1 VIRUS Virus culture Results in days Must be done in special conditions at WHO H5 Reference laboratories PCR Detects viral genes Results in a few hours Uses respiratory sample, serum or culture Can be sensitive and specific for H5N1 Recall that several different tests can be used to detect infection with influenza A viruses. Some of these tests can only detect influenza A viruses in general while others can specifically detect influenza A H5N1 virus. -One type of influenza test is the commercially available rapid influenza test. -There are actually many different kinds of commercially available rapid tests; they are sold as kits designed for easy testing of specimens and results in only 15 to 30 minutes. -There are some limitations to rapid tests, however; including as mentioned earlier, not being able to differentiate between H5N1 and human influenza A virus infections. They may give false negative as well as false positive results. -Another way to test for influenza is to grow the virus in culture. -This process takes longer—usually 2 to 10 days, and due to the infectious risk of handling live H5N1 virus, the process requires special Biosafety level 3 (or BSL3) conditions at a WHO laboratory -A third type of test is PCR, or polymerase chain reaction. -As discussed earlier, this test looks for the RNA – or the genetic material – of a virus. -This test requires more technology, but this method can be used to rapidly and specifically identify H5N1. -Some countries have the laboratory capacity to perform this test, while others do not.

Diagnosing H5N1 If: Patient is suspect human H5N1 case
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Diagnosing H5N1 If: Patient is suspect human H5N1 case AND, the patient’s specimen is positive for influenza A or for influenza A/H5 Then: Patient’s specimen should be sent to a WHO H5 Reference Laboratory for further testing and confirmation -If a you are investigating a suspect human H5N1 case, AND -The patient’s diagnostic specimens test positive for influenza A virus infection or if a more specific PCR test is available and the patients specimen test positive for influenza A H5, THEN: -The patient’s specimen should be sent to one of the four WHO H5 reference laboratories for further testing and for confirmation. The four global WHO reference laboratories are located in Melbourne, Australia, Tokyo, Japan; London, United Kingdom; and Atlanta, USA

Radiologic Imaging Chest x-ray changes are common in H5N1 patients
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Radiologic Imaging Chest x-ray changes are common in H5N1 patients Non-specific changes Diffuse or patchy infiltrates Fluid in the space surrounding the lungs Cavities may form in the lung tissue Often there is progression of pneumonia on serial chest X-ray -The final type of testing we want to review is radiologic imaging. -A chest X-ray is a form of radiologic imaging which is recommended since X-ray changes are common in the lungs of human H5N1 case patients and can indicate the presence of pneumonia. -Pneumonia in patients with H5N1 tends to rapidly progress to respiratory failure, and cases may die in spite of mechanical ventilation. -Typical x-ray findings are: -fairly non-specific -may including diffuse, multi-focal or patchy infiltrates, -pleural effusions or fluid may develop in the space surrounding the lungs -cavities may form in the lung tissue -and there is often progression of pneumonia on serial chest X-rays throughout the hospitalization

Current Antiviral Treatment for Influenza A Viruses
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Current Antiviral Treatment for Influenza A Viruses Now lets turn to current antiviral treatment recommendations for influenza

Neuraminidase Inhibitors
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Neuraminidase Inhibitors Neuraminidase enzyme breaks bond between infected cell and newly formed virus particles Inhibitor prevents enzyme from breaking bonds, preventing the release of the new virus from the infected cell Virus particles cannot go on to infect other cells Currently the most useful class of antivirals for the treatment of infection with influenza A viruses are the neuraminidase inhibitors. To understand how these medications work you have to understand the following regarding how the neuraminidase enzyme on the surface of influenza virus functions: Neuraminidase enzyme breaks the bond between an infected cell and newly formed virus particles, thereby allowing the new virus to release itself from the infected cell. The neuramindase inhibitor prevents this neuraminidase enzyme from breaking chemical bonds, preventing the release of the new virus from the infected cell. Thus, newly formed virus particles cannot go on to infect other uninfected human cells

Source: Moscona, A. (2005). Neuraminidase Inhibitors for Influenza. N Engl J Med 353:

Neuraminidase Inhibitors
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Neuraminidase Inhibitors Two drugs are available: Oseltamivir (Tamiflu®); Zanamivir (Relenza ®) Used for the treatment and prevention of human influenza A, H1 and H3 viruses Effectiveness against H5N1 virus infection is unknown WHO recommended first line antivirals for the treatment and prevention of H5N1 virus infection Treatment should be given as soon as possible May be given as prophylaxis to prevent H5N1 disease in exposed persons Two neuraminidase inhibitor antiviral drugs are available: Oseltamivir (Tamiflu®) and Zanamivir (Relenza ®): -These drugs are used for treatment and prevention of human influenza A, (H1) and (H3) viruses, -Their effectiveness for H5N1 treatment is unknown, however they are the WHO recommended first line antivirals for the treatment and prevention of human H5N1 infections. -It is very important to remember that you should not wait for laboratory diagnosis before initiating treatment with oseltamivir or zanamivir if you are concerned about H5N1 virus infection; all patients should begin treatment as soon as possible. -Antivirals can also be given as prophylaxis to prevent the development of H5N1 disease in those who have been exposed to H5N1 virus

Oseltamivir Available as a capsule or suspension administered by mouth
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Oseltamivir Available as a capsule or suspension administered by mouth Approved in the U.S. for treatment of influenza in children aged ≥1 year Pediatric dosage depends on age and weight For treatment of human influenza (H1 or H3), administered twice a day for 5 days Side effects: nausea, vomiting Oseltamivir, the first of the two neuraminidase inhibitors is: -Available as a capsule or suspension administered by mouth -Oseltamivir is approved in the U.S. for treatment of human influenza in children aged one year or greater -For pediatric patients, the dosage depends on age and weight, -For treatment of human influenza A, (H1) or (H3) virus infection, oseltamivir is administered twice a day, for 5 days -Side effects are generally mild, and may include nausea, vomiting

Oseltamivir Effectiveness in human influenza (H1 or H3)
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Oseltamivir Effectiveness in human influenza (H1 or H3) Reduces influenza symptoms by 1 day when administered within 2 days of illness onset Reduces lower respiratory tract complications, pneumonia, and hospitalization Effectiveness for H5N1 treatment is unknown However, currently used as first line therapy for H5N1 infections Precautions People with kidney disease (reduce dose) Pregnant or nursing females Reports of delirium in pediatric patients (mostly from Japan) Resistance Can develop with treatment, but frequency of resistance is low The effectiveness of oseltamivir for human influenza A (H1) or (H3) has been studied and the following has been found: Effectiveness in human influenza A (H1) or (H3) Reduces influenza symptoms by 1 day when administered within 2 days of illness onset Reduces lower respiratory tract complications, pneumonia and hospitalization due to seasonal influenza -Recall that the effectiveness of treatment for H5N1 virus infection is unknown, nonetheless, oseltamivir is currently recommended as first line therapy for H5N1 virus infections -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 influenza -The relationship of these reported events to oseltamivir is not known. -Remember that antiviral resistance can develop with treatment, but frequency of resistance is low

Zanamivir Orally inhaled powder – administered by mouth via special device Approved in the U.S. for treatment of human influenza A (H1 and H3) in patients aged 7 years and older Treatment dosage is one puff in the morning and one at night for 5 days Side effects Wheezing, and breathing problems Zanamivir is the second neuraminidase inhibitor to become available for the treatment of influenza A viurses: - It is available as an orally inhaled powder (shown here) – which is administered by mouth via a special inhaler device - It is approved in the U.S. for treatment of human influenza A, (H1) and (H3), in patients aged 7 years and older, and for the prevention of human influenza in patients aged 5 years and older - Treatment dosage is one puff in the morning and one at night for 5 days -Side effects may include wheezing and breathing problems

Recommended Treatment for Human Infection with H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Recommended Treatment for Human Infection with H5N1 WHO recommends Oseltamivir treatment for H5N1 case patients Optimal dosage, duration for H5N1 unknown WHO recommends same dosage as seasonal influenza (capsule and oral suspension) Pediatric dosing based upon age and weight However, consider longer treatment (7 to 10 days), or higher doses (150 mg) on case by case basis, especially in patient with progressive disease Now we will briefly review the most current WHO guidance regarding recommended antiviral treatment for human infection with H5N1: -Based on expert consensus from the second WHO consultation on clinical aspects of human infection with avian influenza A(H5N1) virus held in Turkey in March 2007: -WHO continues to recommend oseltamivir as the first line antiviral treatment for H5N1 case patients -The optimal dosage and duration for treatment of H5N1 virus infection with oseltamivir is unknown, -WHO recommends the same dosage as seasonal influenza (capsule and oral suspension) be used -Pediatric dosing is based upon age and weight -WHO recommends that one should consider a longer treatment period (7 to 10 days), or higher doses (150 mg per dose) on a case-by-case basis, especially in patients with progressive disease. -Start treatment as early as possible -Oseltamivir treatment is warranted even with late presentation -Oseltamivir resistance has been reported during treatment of H5N1 case patients -Zanamivir can treat oseltamivir-resistant virus infection -As mentioned before, Zanamivir can be used treat oseltamivir-resistant viruses

A Clinician Should Suspect H5N1 Virus Infection if a Patient Has:
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 A Clinician Should Suspect H5N1 Virus Infection if a Patient Has: Severe acute respiratory illness AND Exposure 7 days before symptoms to: Sick poultry or wild birds Suspect / confirmed H5N1 patient OR Residence in an area with known H5N1 virus activity in poultry or other animals 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 -A patient has been exposed in the 10 days before symptoms began to sick birds or an individual with a suspect or confirmed H5N1 virus infection, OR -A patient had direct contact with sick birds -If you know that a patient with a severe illness comes from an area with H5N1 virus activity in poultry or other animals

Clinical management of human infection with avian influenza A(H5N1) viruses
Oseltamivir is the primary recommended antiviral treatment. Reducing A(H5N1) virus infection-associated mortality if used in the early stages of the disease Treatment with oseltamivir is also warranted at a later stage of illness. A(H5N1) virus continues to replicate for a prolonged period In patients with pneumonia or progressive disease, modified regimen may be considered on a case by case basis: two-fold higher dosage, Longer duration, combination therapy with amantadine or rimantadine (in countries where A(H5N1) viruses are likely to be susceptible to adamantanes) Ideally this should be done in the context of prospective data collection. Corticosteroids should not be used routinely may be considered for septic shock with suspected adrenal insufficiency requiring vasopressors. Prolonged or high dose corticosteroids can result in serious adverse events including opportunistic infection.

Clinical management of human infection with avian influenza A(H5N1) viruses- contd.
Antibiotic chemoprophylaxis should not be used. when pneumonia is present, antibiotic treatment is appropriate initially for community-acquired pneumonia according to published evidence-based guidelines. When available, the results of microbiologic studies should be used to guide antibiotic usage for suspected bacterial co-infection. Monitoring of oxygen saturation should be performed whenever possible at presentation and routinely during subsequent care (e.g. pulse oximetry, arterial blood gases), and supplemental oxygen should be provided to correct hypoxemia. Therapy for A(H5N1) virus-associated ARDS should be based upon published evidencebased guidelines for sepsis-associated ARDS, specifically including lung protective mechanical ventilation strategies.

Summary of treatment modalities for clinical management of human A(H5N1) virus infection
NOT Recommended Strategies Adamantane monotherapy When neuraminidase inhibitors are available, monotherapy with amantadine or rimantadine is not recommended. Combination therapy is consideration in areas where A(H5N1) virus is likely susceptible (see text). Antibiotic chemoprophylaxis Not recommended NPPV (Non-invasive positive pressure ventilation) Generally not recommended (see text). Systemic corticosteroids Moderate to high doses of unproven benefit and potentially harmful: not recommended; Salicylates Avoid administration of salicylates (such as aspirin and aspirin containing products) in children and young adults (<18 years old) because of the risk of Reye Syndrome.

Antiviral Chemoprophylaxis for Human Infections with H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Antiviral Chemoprophylaxis for Human Infections with H5N1 Pre-exposure Persons involved in killing or disposing of infected poultry Post-exposure Household and close contacts of H5N1 cases Healthcare worker with exposure without appropriate PPE WHO recommends oseltamivir for chemoprophylaxis of high-risk groups -Antiviral chemoprophylaxis for human infection with H5N1 may be appropriate depending on the circumstances of the exposure. -In terms of pre-exposure prophylaxis, one may consider prophylaxis for: -Persons involved in killing or disposing of infected poultry -In terms of post-exposure prophylaxis, one should consider prophylaxis for: -Household and close contacts of suspected or confirmed H5N1 cases -Or for healthcare worker with exposure without appropriate PPE to suspect or confirmed H5N1 patients -WHO recommends oseltamivir for chemoprophylaxis of high-risk groups. I’ll say more on this on the next slide. WHO. Rapid advance guidelines for pharmacological management of H5N

Antiviral Chemoprophylaxis for H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Antiviral Chemoprophylaxis for H5N1 WHO recommends antiviral chemoprohylaxis depending on level of risk: High risk, medium risk, or low risk High-risk: Household or family members and close contacts of a strongly suspected or confirmed H5N1 patient, including pregnant women WHO recommends oseltamivir for chemoprophylaxis of high-risk groups for 7-10 days after the last exposure: -Lets briefly expand on what criteria antiviral chemoprohylaxis is recommended when a person has exposure to H5N1 virus -WHO recommends antiviral chemoprohylaxis based on the level of risk associated with certain types of exposures -There are three levels of risk, depending on the type of exposure a person has and the level of protection the person may of been using at the time of exposure. The three levels of risk are: high risk, medium risk, and low risk. -Persons with high-risk exposure are defined as: -Household or family members and close contacts of a strongly suspected or confirmed H5N1 patient, including pregnant women -WHO recommends oseltamivir for chemoprophylaxis of high-risk groups for 7-10 days after the last exposure Persons with moderate risk exposure are defined as: Persons handling sick animals, decontaminating environments, without the appropriate use of PPE Unprotected and very close direct exposure to sick or dead animals infected with H5N1 virus or birds implicated in human cases Healthcare workers in close contact with strongly suspected or confirmed H5N1 patients (performing intubation, tracheal suctioning, delivering nebulized drugs, handling body fluids) without the appropriate use of PPE Antiviral chemoprophylaxis may be considered in persons defined as having moderate risk WHO. Rapid advice guidelines for pharmacological management of H5N

Antiviral Chemoprophylaxis for H5N1
Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Antiviral Chemoprophylaxis for H5N1 Moderate risk: Persons handling sick animals, decontaminating environments, without the appropriate use of PPE Unprotected and very close direct exposure to sick or dead animals infected with H5N1 virus or birds implicated in human cases Healthcare workers in close contact with strongly suspected or confirmed H5N1 patients (performing intubation, tracheal suctioning, delivering nebulized drugs, handling body fluids) without the appropriate use of PPE Antiviral chemoprophylaxis may be considered in persons defined as having moderate risk -Persons with moderate risk exposure are defined as: -Persons handling sick animals and decontaminating environments without the proper use of PPE -Or, unprotected and very close direct exposure, including touching and handling of sick or dead animals infected with H5N1 virus or birds implicated in human cases -Or, healthcare workers in close contact (less than 3feet/1meter) 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. -Antiviral chemoprophylaxis may be considered in persons defined as having moderate risk

Summary of Part 2 Laboratory and clinical information in the patient’s medical chart can be used to look for characteristics of H5N1 virus infection Multiple clinical samples should be collected Laboratory and clinical information should be examined in context of whether the person could have been exposed to H5N1 Let’s summarize what we have learned in Part 2: -First, 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 epidemiologic investigation is important. - Laboratory and clinical information in the patient’s medical chart can also be used to look for characteristics of H5N1 virus infection. -Multiple clinical respiratory specimens should be collected at multiple times from a patient suspected of having H5N1 virus infection -Laboratory and clinical information should be examined in context of whether the person could have been exposed to H5N1 virus.

Summary of Part 2 Treatments and interventions for suspected case-patients include antiviral drugs supportive care Antiviral medication may be recommended as chemoprophylaxis depending on level of risk associated with exposure to H5N1 virus -All evidence, once analyzed together, should be used to assess the possibility of H5N1 virus infection in a patient. -Treatments and interventions for suspected case-patients include: -Antiviral drugs and supportive care -Antiviral medication may be used as chemoprophylaxis depending on the level of risk associated with a particular exposure to H5N1 virus

Thank you This concludes the session on management of suspect cases of human infection with avian influenza A, H5N1 Virus

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 Weekly Epidemiological Record 2007;82:41-48. Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005;353: WHO. WHO Rapid Advice Guidelines for pharmacological management of human infection with avian influenza A (H5N1) virus WHO. Avian influenza, including influenza A (H5N1), in humans: WHO interim infection control guideline for health care facilities. 24 April 2006. WHO. Avian influenza, including influenza A (H5N1), in humans: WHO interim infection control guideline for health care facilities. 24 April Summary of the second WHO consultation on clinical aspects of human infection with avian influenza A(H5N1) virus

Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza.

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Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza.

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Presentation on theme: "Module 4: Case Management of Suspect Human Avian Influenza Infection; Parts 1 & 2 Management of Suspect Cases of Human Infection with Avian Influenza."— Presentation transcript:

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