USA FDA IND# 74,213 RCHSPB/OCR/OD/NIAID/NIH

 
 
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                High-Dose versus Standard-Dose Oseltamivir for the Treatment of
                             Severe Influenza and Avian Influenza:
                      A Phase II Double-Blind, Randomized Clinical Trial



                   Short Title: High vs. Standard Dose Oseltamivir in Influenza



                                Randomized Clinical Trials in Influenza
  A Partnership between hospitals in Viet Nam, Thailand, Indonesia, and other sites in Asia with support
       from Oxford University, the Wellcome Trust UK a nd the National Institutes of Health USA



Principal Investigator: Tawee Chotpitayasunondh, MD and Tran Tinh Hien, MD
Country Principal Investigator Indonesia: Dr Sardikin Giriputro
Country Principal Investigator Thailand: Tawee Chotpitayasunondh, MD
Country Principal Investigator Viet Nam: Nguyen Van Kinh, M.D., Ph.D
Study Clinical Coordinator NCC: Bob Taylor FRCP
Study Laboratory Coordinator NCC: Heiman Wertheim MD PhD

Network Coordination Centre: Jeremy Farrar FRCP DPhil
Oxford University Clinical Research Unit Ho Chi Minh City Viet Nam
Network Coordination Centre email: jfarrar@oucru.org


IND Sponsor:                                                             USA FDA IND# 74,213
RCHSPB/OCR/OD/NIAID/NIH
National Institutes of Health
6700-B Rockledge Drive, MSC -7609
Bethesda, MD 20892

Version: 7.0
Date: 16 September, 2009




Protocol tracking numbers:                               Clinical Trial Registrations:
US FDA IND # 74,213                                      Current Clinical Trials: ISRCTN43083885
Roche: MV200 50                                          ClinicalTrials.gov: NCT00298233
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 Study Sites:
 The following sites may participate in this study:
 National Institute of Infectious and Tropical Diseases, Hanoi, Viet Nam
 PI: Nguyen Van Kinh, M.D., Ph.D
 FWA: 00009740

 Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
 PI: Dr Tran Tinh Hien
 FWA: 00009829

 Children’s Hospital #1, Ho Chi Minh City, Viet Nam
 PI: BS. Tröông Höõu Khanh
 FWA: 00009748

 Pediatric Hospital #2, Ho Chi Minh City, Viet Nam
 PI: Dr. Ha Manh Tuan
 FWA: 00009743

 National Hospital of Pediatrics, Hanoi, Viet Nam
 PI: Professor Nguyen Thanh Liem
 FWA: 00009744

 Persahabatan Hospital, Jakarta, Indonesia
 PI: dr. Prijanti Soepandi
 FWA: 00009543

 Sulianto Saroso Hospital, Jakarta, Indonesia
 PI: Dr Sardikin Giriputro
 FWA: 00009905

 Rumah Sakit Hasan Sadikan, Bandung, Indonesia
 PI: Dr Hadi Jusuf
 FWA: 00013129

 Queen Sirikit National Institute of Child Health, Bangkok, Thailand
 PI: Professor Tawee Chotpitayasunondh
 FWA: 00002250

 Chest Disease Institute, Nonthaburi, Thailand
 PI: Dr Charoen Chuchottaworn
 FWA: 00010083
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 Bamrasnaradura Infectious Disease Institute, Nonthaburi, Thailand
 PI: Dr.Chariya Sangsajja
 FWA: 00008374

Siriraj Hospital Mahidol University Thailand
PI: Dr.Kulkanya Chokephaibulkit
FWA: 00002882

Tan Tock Seng Hospital, Singapore
PI: Dr. Leo Yee Sin
FWA: 00005822

National University Hospital, National University of Singapore, Singapore
PI: Paul Anantharajah Tambyah
FWA: 00000205

Singapore General Hospital, Singapore
PI: Dr. Tan Ban Hock
FWA: 00001436

Changi General Hospital, Singapore
PI: Dr. Helen Oh
FWA: 00013868
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Collaborating Laboratories:

National Institute of Health Research and Development
(Litbangkes), Jakarta, Indonesia
FWA: 00004441

Eijkman Institute (Alert Asia), Jakarta, Indonesia
FWA: 00010678

Mahidol University Department of Tropical Medicine Bangkok Thailand
FWA: 00002882

Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
FWA: 00009745

Dept of Virology, Siriraj Hospital Mahidol University Thailand
FWA: 00002882




Collaborating Institutions & Organizations:

The Wellcome Trust UK

Global Influenza Program World Health Organization

Oxford University UK


              Statistician: Kasia Stepniewska, Bangkok, Thailand. kasia@tropmedres.ac
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                                                                Table of Contents

Table of Contents ............................................................................................................................................... v
Précis ................................................................................................................................................................. ix
Protocol Synopsis............................................................................................................................................... x
1. Background ................................................................................................................................................ 1
    1.1. Avian Influenza Infections in Humans................................................................................................ 1
            1.1.1          Current Avian Influenza Outbreak.......................................................................................2
            1.1.2          Incubation ............................................................................................................................2
            1.1.3          Clinical Features ..................................................................................................................2
            1.1.4          Laboratory findings ..............................................................................................................3
            1.1.5          Clinical course and Epidemiology .......................................................................................3
            1.1.6          Viral replication patterns......................................................................................................3
            1.1.7          Host immune responses .......................................................................................................4
            1.1.8          Pathology .............................................................................................................................4
            1.1.9          Management .........................................................................................................................4
            1.1.10 Mortality ..............................................................................................................................5
            1.1.11 Predictors of mortality .........................................................................................................5
            1.1.12 Diagnosis..............................................................................................................................5
    1.2. Severe Human Influenza ..................................................................................................................... 6
    1.3. Transmission ....................................................................................................................................... 6
            1.3.1          Route of Exposure................................................................................................................6
            1.3.2          Animal-to-Human Transmission of Avian Influenza ..........................................................7
            1.3.3          Human-to-Human Transmission of Avian Influenza ..........................................................7
            1.3.4          Environment to human transmission of Avian Influenza ....................................................8
            1.3.5          Recommended Isolation Precautions ...................................................................................8
    1.4. Treatment ............................................................................................................................................ 8
            1.4.1          Oseltamivir ...........................................................................................................................8
            1.4.2          Standard Oseltamivir Dosing ...............................................................................................9
            1.4.3          Oseltamivir Therapy for Human Influenza ..........................................................................9
            1.4.4          Oseltamivir in Avian Influenza in Humans .......................................................................10
            1.4.5          Oseltamivir in Avian Influenza in Animal Models............................................................10
            1.4.6          Previous Experience with Higher Doses of Oseltamivir ...................................................11
2. Study Objectives....................................................................................................................................... 12
    2.1 Primary Objective ............................................................................................................................. 12
    2.2 Secondary Objectives ........................................................................................................................ 12
3. Study Plan................................................................................................................................................. 13
    3.1 Study Design and Overview .............................................................................................................. 13
    3.2 Definitions: ........................................................................................................................................ 15
    3.3 General .............................................................................................................................................. 16
    3.4 Pharmaceutical Involvement ............................................................................................................. 16
    3.5 Statistical Methods ............................................................................................................................ 17
            3.5.1.         Sample Size Justification ...................................................................................................17
            3.5.2. Statistical Analysis .............................................................................................................18
    3.6 Study Endpoints ................................................................................................................................ 19
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     3.7 Study Population ............................................................................................................................... 21
          3.7.1. Inclusion Criteria ...............................................................................................................21
          3.7.2. Exclusion Criteria (any of the following): .........................................................................21
     3.8 Randomization and Blinding............................................................................................................. 22
     3.9 Recruitment ....................................................................................................................................... 22
     3.10 Subject and Study Discontinuation ................................................................................................... 22
          3.10.1. Subject Withdrawal of Consent .........................................................................................22
          3.10.2. Discontinuation of Oseltamivir by the Investigator ...........................................................23
          3.10.3. Subject Withdrawal from the Study by the Investigator ....................................................23
          3.10.4. Study Discontinuation ........................................................................................................23
4.   Study Treatment ....................................................................................................................................... 23
     4.1 Overview ........................................................................................................................................... 23
     4.2 Products ............................................................................................................................................. 24
          4.2.1      Study Treatment: Oseltamivir Capsules ............................................................................24
          4.2.2. Study Treatment: Oseltamivir Suspension.........................................................................24
          4.2.3. Study Treatment: Placebo Capsules...................................................................................24
          4.2.4. Study Treatment: Placebo Suspension ...............................................................................24
     4.3 Storage and Handling ........................................................................................................................ 24
     4.4 Product Accountability...................................................................................................................... 24
     4.5 Study Drug Dosing ........................................................................................................................... 25
          4.5.1. Change in Renal Function on Therapy ..............................................................................26
     4.6 Product Administration ..................................................................................................................... 26
     4.7 Post-Dose Emesis .............................................................................................................................. 26
     4.8 Prohibited Medications ..................................................................................................................... 26
          4.8.1. Antivirals............................................................................................................................26
     4.9 Concomitant Medications ................................................................................................................. 27
          4.9.1. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including Salicylates .......................27
          4.9.2. Steroids (Corticosteroids) ..................................................................................................27
          4.9.3. Anti-pyretic ........................................................................................................................27
          4.9.4. Anti-emetic ........................................................................................................................27
     4.10 Emergency Unblinding ..................................................................................................................... 27
5    Screening .................................................................................................................................................. 28
6.   Study Procedure ....................................................................................................................................... 29
     6.1 Enrollment ......................................................................................................................................... 29
     6.2 Prior Data Collection ......................................................................................................................... 30
     6.3 Prior Clinical Specimen Collection ................................................................................................... 30
     6.4 Hospitalization .................................................................................................................................. 30
     6.5 Initial Evaluation ............................................................................................................................... 30
          6.5.1. History and Physical Examination on Day 0 .....................................................................30
          6.5.2. Clinical Laboratory Tests on Day 0 ...................................................................................31
          6.5.3. Research Procedures on Day 0 ..........................................................................................31
          6.5.4. Research Laboratory Tests on Day 0 .................................................................................31
          6.5.5. Admission Chest X-ray on Day 0 ......................................................................................32
     6.6 Interval Assessments (while hospitalized) ........................................................................................ 32
          6.6.1. Interval History and Physical Exam ..................................................................................32
          6.6.2. Interval Clinical Laboratory...............................................................................................33
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          6.6.3. Interval Research Procedures .............................................................................................33
          6.6.4         Interval Research Laboratory Tests ...................................................................................33
          6.6.5         Follow-up Chest X-ray ......................................................................................................33
     6.7 Other Samples ................................................................................................................................... 34
          6.7.1         Bronchial Alveolar Lavage ................................................................................................34
          6.7.2         Endotracheal aspirates .......................................................................................................34
          6.7.3         Cerebral Spinal Fluid (CSF) ..............................................................................................34
          6.7.4         Pleural Fluid .......................................................................................................................34
          6.7.5         Autopsy/Biopsy..................................................................................................................34
     6.8. Outpatient Visits (Day 10, 14, 28, for all subjects, plus Day 56 and 180 for AI cases) ................... 34
          6.8.1. Interval History and Physical Exam ..................................................................................34
          6.8.2. Interval Clinical Laboratory (Day 14 and Day 28 for all subjects, and Day 10 for...........34
          6.8.3. Interval Research Procedures (Day 14 and 28)..................................................................34
     6.9. Clinical Diagnosis and Diagnosis Specific Assessments .................................................................. 35
7.   Clinical Failure ......................................................................................................................................... 35
8.   Special Follow-up..................................................................................... Error! Bookmark not defined.
     8.1 Pregnancy .......................................................................................... Error! Bookmark not defined.
9    Public Health Reporting Plan ................................................................................................................... 36
10   Risks ......................................................................................................................................................... 37
     10.1 Risks of Oseltamivir ........................................................................................................................ 37
     10.2 Risk of Phlebotomy ......................................................................................................................... 38
     10.3 Risk of Nasal Swab ......................................................................................................................... 38
     10.4 Risk of Oropharyngeal Swab .......................................................................................................... 38
     10.5 Risk of Nasal Wash ......................................................................................................................... 38
     10.6 Risk of Diagnosis ............................................................................................................................ 38
11   Benefit(s) .................................................................................................................................................. 38
     11.1 Benefits of Treatment ...................................................................................................................... 38
     11.2 Benefits of Diagnosis ...................................................................................................................... 39
12   Alternatives .............................................................................................................................................. 39
13   Data Management..................................................................................................................................... 39
14   Monitoring ................................................................................................................................................ 39
     14.1 Study Monitoring ............................................................................................................................ 39
     14.2 Data and Safety Monitoring Plan .................................................................................................... 40
15   Adverse Event Reporting ......................................................................................................................... 40
     15.1 Definitions ....................................................................................................................................... 40
     15.2 Serious Adverse Event .................................................................................................................... 41
     15.3 Assessing an Adverse Event............................................................................................................ 41
     15.4 Relatedness of Adverse Event to the Intervention .......................................................................... 41
     15.5 Expectedness of an Adverse Drug (Intervention) Reaction ............................................................ 42
     15.6 Adverse Event Reporting ................................................................................................................ 43
     15.7 Expedited Reporting of Serious Adverse Events (SAE) ................................................................. 43
     15.8 Sponsor Reporting Requirements .................................................................................................... 43
     15.9 Unexpected SAE reporting to DSMB ............................................................................................. 44
     15.10 Continuing Review Reporting ........................................................................................................ 44
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16 Record Retention ...................................................................................................................................... 44
17. Research Use of Stored Human Samples, Specimens and Data .............................................................. 44
    17.1. Intended Use of the Samples/Specimens/Data ................................................................................ 44
    17.2. S torage of Samples/Specimens/Data .............................................................................................. 44
    17.3. Storage of Genetic Sample .............................................................................................................. 44
    17.4. Tracking Samples/Specimens/Data ................................................................................................. 45
    17.5. Use of Samples/Specimens/Data at the Completion of the Protocol .............................................. 45
    17.6. Reporting Loss or Destruction of Samples/Specimens/Data .......................................................... 45
    17.7. Stopping Storage of Samples .......................................................................................................... 45
18. Human Subject Protections ...................................................................................................................... 45
    18.1. IRB/IEC Approval ........................................................................................................................... 45
    18.2. Compliance with Good Clinical Practices (GCP) ........................................................................... 46
    18.3. Informed Consent ............................................................................................................................ 46
    18.4. Rationale for Research Subject Selection ....................................................................................... 46
        18.4.1. Inclusion of Children .........................................................................................................46
        18.4.2. Justification of Exclusions .................................................................................................46
    18.5 Anonymity and Confidentiality........................................................................................................ 46
    18.6 Compensation ................................................................................................................................... 46
19 References ................................................................................................................................................ 47
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Précis
Human influenza is a serious disease causing an estimated 500,000-1,000,000 deaths worldwide
each year. In addition, there have been increasing numbers of cases of avian influenza in the
last several years, which may pose a threat of a future pandemic with a novel influenza virus.

Oseltamivir is one therapeutic agent available for human influenza, and would be considered
standard therapy for treatment of avian influenza. Both severe human influenza and avian
influenza have a higher mortality than uncomplicated human influenza, have higher viral
replication, shed larger amounts of virus, and shed virus longer. Oseltamivir has been shown to
decrease viral replication and shedding in uncomplicated influenza, but similar studies have not
been performed in severe human and avian influenza.

The primary purpose of this protocol is to evaluate high-dose oseltamivir (twice the standard
dose) as compared to standard-dose oseltamivir in the treatment of severe human or avian
influenza with the hypothesis that high-dose will decrease viral replication and shedding, and
therefore may confer a clinical or survival advantage. This protocol will also attempt to define
differences in the clinical manifestation, the relationship between antiviral plasma
concentrations and viral dynamics, and pathogenesis of human and avian influenza, which may
help to improve the treatment of these diseases.
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Protocol Synopsis
Title: High-Dose versus Standard-Dose Oseltamivir for the Treatment of Severe
Influenza and Avian Influenza: A Phase II Double-Blind, Randomized Clinical Trial

Primary Objective
The primary objective is to compare the antiviral efficacy of standard and high-dose oseltamivir in
the treatment of severe influenza infections as assessed by negative reverse transcriptase (RT)-PCR
detection of viral RNA in nose and throat swabs at Day 5.

Secondary Objectives

1.     Compare the antiviral efficacy of standard and high-dose oseltamivir in the treatment of
       severe influenza infections as assessed by negative RT-PCR for viral RNA in nose and throat
       swabs at Day 5 and Day 7 (sustained clearance).
2.     Compare the antiviral efficacy of standard-dose versus high-dose oseltamivir in the treatment
       of severe human influenza infections as assessed by negative RT-PCR for viral RNA in nose
       and throat swabs at Day 5.
3.     Compare the antiviral efficacy of standard-dose versus high-dose oseltamivir in the treatment
       of avian influenza infections as assessed by negative RT-PCR for viral RNA in nose and
       throat swab at Day 5.
4.     Compare the antiviral efficacy of standard-dose versus high-dose oseltamivir in the treatment
       of avian influenza infections as assessed by time to sustained negativity of RT-PCR and viral
       culture in any sample.
5.     Compare the clinical outcome between high-dose versus standard-dose oseltamivir in the
       treatment of severe influenza and avian influenza.
6.     Compare the tolerability of high-dose versus standard-dose oseltamivir as assessed by
       incidence of clinical findings and adverse events.
7.     Compare the frequency of clinical failure (as defined in the protocol) at days 5 and 10 of
       high-dose versus standard-dose oseltamivir in the treatment of severe influenza and avian
       influenza.
8.     Develop a population pharmacokinetic model of oseltamivir phosphate and oseltamivir
       carboxylate absorption and disposition, and characterize the sources of variance in
       pharmacokinetic parameters.
9.     Assess the relationship between pharmacokinetic variables and measures of viral clearance.
10.    Assess viral replication dynamics (frequency, duration, and level of viral replication) in the
       upper and lower respiratory tract, gastrointestinal tract (feces), and blood (viremia) in the
       high-dose versus standard-dose oseltamivir cohorts, and stratified by avian and human
       influenza.
11.    Assess the frequency, genetic basis, and duration of antiviral resistance during and after
       therapy.
12.    Characterize the innate and adaptive immune responses with respect to avian and human
       influenza, severe and mild disease, and standard-dose versus high-dose oseltamivir cohorts.
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13.    Assess the absorption and achievable blood levels of oseltamivir carboxylate in seriously ill
       hospitalized patients with lower respiratory tract disease.
14.    Determine possible host genetic factors predisposing to severe influenza.
15.    Describe the clinical course (symptoms, vital signs, clinical features and laboratory findings)
       of severe influenza and avian influenza.


Study Phase: II

Study Design:
This study is a double-blind, randomized, multi-center, international clinical trial, designed to
assess the safety and efficacy of standard- and high-dose oseltamivir in patients hospitalized with
severe influenza or avian influenza.

This protocol is designed to capture both avian influenza (non-severe and severe) and severe
human influenza cases. This will allow comparisons of relevant pathogenesis and clinical
parameters (viral replication dynamics, cytokine responses, outcomes, etc.) between avian and
human influenza infections.

At study sites, influenza diagnostic tests (both rapid antigen and PCR) are available as part of
routine clinical care. Therefore patients that are found to have influenza and an illness consistent
with avian or severe influenza will be evaluated for possible enrollment into this study. Those that
meet the enrollment criteria will be approached for consent to enroll into this study.

As the study requires a serum creatinine and a pregnancy test (for females of child bearing age), if
any of these tests have not been performed prior to evaluation for enrollment these can be
performed after the subject signs the consent but before the study drug administration. This will be
considered the screening population.

Study size: Enrollment of up to 840 subjects
            • 540 subjects meeting criteria for severe influenza
               - The maximum number of subjects to be recruited into each of the following age
               groups will be 270 :
                 o 1-
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Inclusion Criteria
    1. Age ≥ 1 year
    AND
    2. At least one respiratory symptom:
         • Cough
         • Dyspnea (shortness of breath)
         • Sore throat
    AND
    3. Have evidence of severe influenza or avian influenza as defined below (A or B)

           A. Evidence of severe influenza infection

             1. Need for hospitalization (as determined by investigator or clinician)
             AND
             2. One of the following: (all criteria as judged by the investigator)
                • New infiltrate on chest X-ray (or any infiltrate if no prior chest X-ray or not
                   known)
                • Severe tachypnea (respiratory rate 30 for ages 12 years, rate 40 for ages 6 to
                   12 years, rate   45 for ages 3 to 6 years, rate 50 for ages 1 –to 3 years)
                • Severe dyspnea (unable to speak full sentences, or use of accessory respiratory
                   muscles)
                • Arterial oxygen saturation ≤ 92% on room air by trans-cutaneous method
              AND
             3. Positive diagnostic testing for influenza defined as (one of the following)
                • Rapid influenza antigen (Ag) positive (A or B)
                • Qualitative RT-PCR positive for influenza (any)
              AND
             4. Illness (onset of fever, respiratory symptoms, or constitutional symptoms) began
                within the 10 days prior to enrollment

           B. Evidence of avian influenza infection

               1. Nasal wash, nasopharyngeal aspirate, endotracheal aspirate, nasal swab, or throat
                  swab that is RT-PCR positive influenza for H5 influenza
               AND
               2. Illness (onset of fever, respiratory symptoms, or constitutional symptoms) began
                  within the 14 days prior to enrollment

Exclusion Criteria: (any of the following):
1.   Pregnancy or urine ß-hCG positive
2.   Females who are actively breast feeding
3.   Receipt of more than 72 hours of oseltamivir (six doses) within the 14 days.
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4.     Receipt of oseltamivir at higher than standard doses (75 mg bid, or equivalent dose adjusted
       for age, weight and creatinine clearance) within the last 14 days or during this acute illness,
       whichever is longer.
5.     History of allergy or severe intolerance of oseltamivir as determined by the investigator.
6.     Alternate explanation for the clinical findings as determined by the investigator with the
       information immediately available
7.     Creatinine Clearance (estimated by serum Cr) < 10 mL/min


Study Treatment:
Eligible patients will be randomized to receive oseltamivir at standard-dose (75mg bid or
equivalent dose adjusted for age, weight and renal function) or high-dose (150mg bid or equivalent
adjusted dose). Treatment will be continued for 5 days. Pediatric dosing will be weight-adjusted
with standard or two-fold higher doses. Drugs will be administered orally in standard formulations
(capsules for adults and children = 15 years; suspension for children < 15 years). At 5 days,
subjects will be assessed for clinical failure by predefined criteria. Those meeting clinical failure
will continue at the randomized dose for an additional 5 days (total of 10 days).

Evaluation:
Detailed serial evaluations including symptoms, functional status, clinical parameters, clinical
laboratory and samples for research studies (viral shedding, antibody response, cytokine profile,
genomics, etc.) will be obtained. See protocol for details.
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1.       Background

1.1.      Avian Influenza Infections in Humans
Emerging infectious diseases can be defined as “infections that have newly appeared in a
population or have existed previously but are rapidly increasing in incidence or geographic range”.
[1] Over the last decade there has been an increase in recognized emerging or re-emerging
infectious diseases. This includes, but in no means limited to Nipah virus, Lassa virus, Hantavirus,
Hendra virus, West Nile virus, and Severe Acute Respiratory Syndrome (SARS). However, one of
the most concerning is the recognition of avian influenza infections in humans.

Over the last decade multiple limited outbreaks of avian influenza infections in humans have
occurred. This includes:

         1995 in the UK: H7N7 (A/Eng/268/95) infecting one person (conjunctivitis),and causing
         no death.
         1997 in Hong Kong: H5N1 (A/HK/156/97 & A/HK/148/97) infecting 18 people
         (pneumonia in 61%, intensive care 55%), and causing 6 deaths (mortality 33%).
         1999 in Hong Kong: H9N2 (A/HK/1073/99 and A/HK/1074/99) infecting 2 children
         (febrile pharyngitis), and causing no deaths.
         2003 in Hong Kong: H5N1 (A/HK/213/03) infecting 2 people (father and son, both with
         pneumonia), and causing 1 death
         2003 in the Netherlands: H7N7 (A/Neth/33/03 & A/Neth/219/03) infecting 83 people
         (primarily conjunctivitis, 5 also had influenza like illness [ILI], 2 had isolated respiratory
         disease), and causing 1 death
         2003 in Hong Kong: H9N2 (A/HK/2018/03) infecting one child (pneumonia) and
         causing no death
         2004 in Canada: H7N3 infecting 2 poultry workers (conjunctivitis in 2, cough but no
         pneumonia in 1), and causing no deaths
         2004 in Egypt: H10N7 infecting 2 infants (fever and cough, no pneumonia), and causing
         no deaths

The largest and most concerning outbreak, however, is the current avian influenza outbreak in
Asia. This outbreak began in late 2003, and is caused by an avian H5N1 influenza A virus.
Previous influenza pandemic viruses have been shown to derive genes from influenza viruses
circulating in birds prior to the pandemic (conclusive shown in 1957 and 1968, while the source of
the 1918 pandemic has not been conclusively defined). In addition to this, the last pandemic
occurred more than 30 years ago. Therefore, these recent outbreaks of avian influenza in
Southeast Asia raises concern that this avian influenza virus may soon engender the next influenza
pandemic.
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1.1.1    Current Avian Influenza Outbreak
Three waves of infections have occurred in Southeast Asia since the virus re-emerged in late 2003.
During the first wave, December 2003 through March 2005, there were 35 cases and 24 deaths.
During the second smaller wave, July through September 2004, there were 9 cases and 8 deaths.
During the third wave January 2005 through present there have been 64 cases with 22 deaths
through June. As of June 28, 2005, there have been a total of 108 laboratory-documented cases.
The largest number of cases has occurred in Viet Nam, particularly during the third wave. The
occurrence of human H5N1 has paralleled large outbreaks of avian H5N1 in birds, both domestic
poultry and waterfowl. Countries with confirmed infections in birds within the last 2 years
include: Cambodia, China, Indonesia, Hong Kong, Laos, Japan, South Korea, Thailand, and
VietNam.


1.1.2     Incubation
The incubation period of influenza A (H5N1) may be slightly longer than typical for human
influenza (1-3 days). In Hong Kong in 1997, most cases occurred within 2-4 days of apparent
exposure, while reports from Thailand and Viet Nam indicate similar intervals but ranging up to 8
days. [2, 3] The intervals between illness onsets in household clusters have been longer ranging up
to 8-17 days. [4] It is uncertain whether these prolonged inter-case periods could be due to
unrecognized animal or environmental exposures.


1.1.3     Clinical Features
The clinical spectrum of avian influenza A (H5N1) illness in humans is based largely on
descriptions of hospitalized patients with severe illness. Many of the cases identified to date have
been previously healthy young children and adults, though all age groups have been affected.

Most documented cases presented with fever, shortness of breath, and a cough. [4] Sputum
production, pleuritic pain, and diarrhea were often but not invariably reported. Upper respiratory
symptoms are much less frequent. Conjunctivitis, a hallmark of human infection by avian A (H7)
viruses, has not been a feature. In addition to the typical influenza presentations, there have been
recent case reports of encephalopathy, gastroenteritis, and asymptomatic infections suggesting the
spectrum of disease is not fully defined. [5, 6] The frequency of milder influenza-like illnesses,
sub-clinical infections, and atypical presentations has not been determined.

For patients presenting with pulmonary manifestations, the median time to onset of dyspnea was 5
days after onset of illness (range 1-16 days). [7] Respiratory distress, tachypnea, and inspiratory
crackles are common findings while wheezing is less common. [4] Radiographic pneumonia has
occurred in almost all patients though the radiographic changes are non-specific and include
diffuse, multi-focal or patchy infiltrates, interstitial infiltrates, and segmental or lobular
consolidation with air bronchograms. Pleural effusions are uncommon.
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1.1.4   Laboratory findings
Common laboratory findings have been leukopenia, particularly lymphopenia, mild-moderate
thrombocytopenia, and slightly or moderately raised aminotransferase levels. [4] Marked
hyperglycemia, perhaps related to corticosteroid use, and mildly elevated creatinine also occur.[8]

1.1.5      Clinical course and Epidemiology
Progression to respiratory failure has usually been associated with diffuse bilateral ground-glass
infiltrates and manifestations of acute respiratory distress syndrome (ARDS). [4] In Thailand, the
median time from onset to ARDS was 6 days (range, 4-13 days). [7] ARDS developed in most of
patients and all but one died. Multi-organ failure with signs of renal dysfunction and cardiac
compromise, including cardiac dilation and supraventricular tachyarrhythmias, has also been
reported.

Other complications have included ventilator-associated pneumonia, pulmonary hemorrhage,
pneumothorax, pancytopenia, Reye’s syndrome (possibly related to concurrent salicylates), and
sepsis syndrome without documented bacteremia.


1.1.6     Viral replication patterns
The virologic course of human infections with influenza H5N1 is incompletely characterized with
respect to the initial sites of infection and the replication dynamics at different body sites (i.e.,
upper and lower respiratory tract, feces, blood, urine).

In 1997 the median duration of virus detection in the nasopharynx was 6.5 days (range, 1 – 16 days).
In Viet Nam the viral loads in pharyngeal swabs collected after median 6 days of illness (range, 4-8
days) were apparently at least 10-fold higher in avian H5N1 infected patients than in patients with
human influenza A (H3N2 or H1N1) infection. (M. de Jong, personal communication).

Fecal samples have been positive for viral RNA in 5/7 (Viet Nam) and 2/2 (Cambodia) patients,
whereas urine was negative in 5 patients. [4] The high frequency of diarrhea in affected persons
and detection of viral RNA in the majority of fecal samples tested suggest that the H5N1 virus may
replicate in the human gastrointestinal tract.

The frequency of viremia and extra-pulmonary dissemination in humans are uncertain but invasive
infection has been documented in other mammals. [9-12] Dissemination of virus from mucosal
sites has been documented by virus culture and RNA detection in blood, cerebrospinal fluid, and
feces in one published case report. [5] Another recent report found that serum was positive in 6/6
samples at days 4-9 after onset of illness.
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1.1.7     Host immune responses
The innate immune responses developing in humans infected with avian influenza H5N1 are only
partially characterized but available findings suggest that pro-inflammatory mediators are
contributing to disease pathogenesis. In 1997 elevated blood levels of IL-6, TNF-a, IFN- , and sIL-
2R were observed in individual patients [13], and in 2003 elevated levels of the chemokines IP-10,
MCP-1, and MIG were found at 3-8 days post illness onset. [14] Increased TNF-a expression was
noted in type 2 pneumocytes in one patient. [14] Recent studies found elevated plasma
concentrations of cytokines and chemokines in H5N1-infected patients; some of these (IL-6, IL-8,
IL-1ß, MCP-1) tended to be higher in fatal than non-fatal cases. Plasma IFN-a levels averaged
about 3 times higher than in healthy controls. Such responses may be responsible in part for the
ARDS, sepsis syndrome, and multi-organ failure observed in many patients, although hypoxemia
and in some patients hypotension are also implicated in some instances of multi-organ failure.

Among survivors specific humoral immune responses are detectable by neutralization assay at 10-
14 days after illness onset and titers increase over several weeks. [4]


1.1.8     Pathology
Post-mortem analyses have documented severe pulmonary injury with histopathologic changes of
diffuse alveolar damage[13], consistent with other reports of human influenza viral pneumonia.
Changes include fibrinous exudates and hemorrhage filling the alveolar spaces, hyaline membrane
formation, vascular congestion, infiltrating lymphocytes in the interstitial areas, and proliferating
reactive fibroblasts in some areas. Antemortem bone marrow biopsies have shown reactive
histiocytosis with hemophagocytosis in several patients, and lymphoid depletion and atypical
lymphocytes have been noted in spleen and lymphoid tissues on autopsy. [13, 14] Centrolobular
hepatic necrosis and acute tubular necrosis have been noted in several instances.


1.1.9     Management
Most hospitalized patients have required mechanical ventilatory support within 48 hours of
admission, necessitating admission to the intensive care unit (ICU). [8] Occasionally this is
associated with hypotension, requiring fluids and/or vasopressors. In addition to empiric, broad-
spectrum antimicrobials for treating community-acquired pneumonia and sometimes sepsis,
antiviral agents and/or corticosteroids have been used in most patients, although their effects have
not been rigorously assessed. Patients often experience dramatic deterioration of gas-exchange
despite support.

The institution of these interventions late in disease course has not been associated with apparent
improvement in overall mortality, although early initiation of antivirals appears beneficial. [7, 8]
However, in Viet Nam 2 young adults progressed from mild disease to respiratory failure and
death despite receiving early treatment with conventional doses of oseltamivir (Peter Horby,
personal communication), although details of these patients are currently unavailable. Cultivable
virus generally disappears within 2-3 days in oseltamivir-treated survivors, but recent viral RNA
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measurements in throat swab samples have found inconsistent reductions in viral load in
oseltamivir-treated non-survivors. [4]


1.1.10 Mortality
In contrast to 1997, when most deaths occurred in patients older than 13 years of age, recent H5N1
infections have caused high mortality in infants and young children. In Thailand the case-fatality
rate was 50% in those aged >15 years but 89% in those
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1.2.      Severe Human Influenza
Although human influenza is associated with an acute self-limited febrile illness in most patients,
several more severe manifestations can occur, including lower respiratory manifestations such as
viral pneumonia and tracheo-bronchitis. The risk factors for these more severe manifestations are
not well defined, but generally more severe disease is seen among persons aged >65 years, young
children, and persons of any age with underlying health conditions. [15]

Patients with lower respiratory manifestations also shed virus longer than uncomplicated influenza,
with a median duration of viral shedding of 4 days with rimantadine therapy [16], compared to one
day shedding with therapy for uncomplicated influenza. [17] However, comparison has never been
performed using a standardized treatment regimen. Furthermore there is very little information on
the sites of replication (upper vs. lower respiratory tract) in such patients.

The optimal antiviral therapy for lower respiratory tract manifestations is not clear. Only a few
studies have described this manifestation of influenza. In one study enrolling 41 hospitalized
patients with influenza treated with rimantadine +/- nebulized zanamivir, the mortality was 8%.
[16] The criteria for enrollment in this study included hospitalization and a new infiltrate on chest
X-ray, new respiratory distress, or hypoxia.

In another study retrospectively evaluating patients admitted to a tertiary care hospital with
influenza pneumonia, the mortality was 29% despite treatment in most patients with both
oseltamivir and rimantadine (mean age 63 years). [18] In an older study treating 11 hospitalized
influenza A pneumonia patients with high dose oral amantadine, the mortality was 45%. [19]
Lastly, in the outbreak of influenza in several nursing facilities in Canada, and despite 89% being
previously vaccinated and 35% receiving prophylaxis, death occurred in 84% of hospitalized
patients (16/19) (mean age 85 years). [20]

Since March 2009, a new type of H1N1 influenza A virus, “ swine flu”, has emerged in Mexico
and has spread to a number of countries around the world. There a few clinical data regarding this
new virus but it has caused a small number of deaths.

1.3.      Transmission
1.3.1     Route of Exposure
Human influenza infection occurs by inhalation of infectious droplets and droplet nuclei
(airborne), by direct contact, and perhaps by indirect (fomite) contact with self-inoculation onto the
upper respiratory tract or conjunctival mucosa. [21, 22] The relative efficiency of the different
possible routes of transmission of avian influenza (H5N1) has not been defined. The site of initial
viral infection in such instances in human is uncertain, but it remains possible that some infections
may be initiated by pharyngeal or gastrointestinal inoculation of virus. Whether the route of
exposure and infectious dose influence the incubation period or clinical manifestations is presently
unknown.
Available evidence is consistent with bird-to-human, possibly environment to human, and limited,
non-sustained human-to-human transmission of influenza A (H5N1) to date.
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1.3.2     Animal-to-Human Transmission of Avian Influenza
One case-control study of the 1997 Hong Kong outbreak found that exposure to live poultry within
a week before illness onset was associated with human disease, whereas there was no significant
risk related to traveling, eating or preparing poultry products or exposure to persons with H5N1
disease. [23] Another study found that exposure to ill poultry and butchering of birds was
associated with seropositivity to H5. [24]

In recent influenza A (H5N1) patients, a history of direct contact with poultry was found in most
patients. Different activities including plucking and preparing of diseased birds, handling fighting
cocks, or playing with poultry, particularly asymptomatically infected ducks have been implicated.
Infection following ingestion of undercooked poultry products (including ingestion of duck blood)
has also been implicated in some cases.

About 30% of cases in Viet Nam do not have recognized poultry exposure, although non-reporting
because of concerns regarding implications of reporting sick poultry might have occurred.

1.3.3     Human-to-Human Transmission of Avian Influenza
Human-to-human transmission of avian influenza (H5N1) has been implicated in several
household clusters and in one well-documented child to mother transmission in Thailand. [25]
Intimate face-to-face contact without precautions was implicated in these circumstances, and so far
there is no evidence to indicate human-to-human transmission by small particle aerosols. Cohort
studies in 1997 found that human-to-human transmission might have occurred through close
physical contact but not from social contact. [26]

Small-scale sero-surveys in southern Viet Nam and Thailand have not found evidence for
unapparent infections in family contacts or health care workers (HCW). Recently, intensified
sampling in contacts has detected milder cases, more infections in older adults, and an increased
number and duration of family clusters. However, molecular epidemiologic studies have not been
completed to prove human-to-human transmission that would indicate that the virus strains in
this region may be adapting to humans and possibly transmitting more efficiently from person-to-
person.

To date the risk of nosocomial transmission to healthcare workers has been low, even when
appropriate isolation measures were not used. However, serologic studies in 1997 detected
evidence of infection in several healthcare workers (HCW). [27] No illness or seroconversion
occurred among exposed HCW in Hanoi who employed masks and variably other protection
measures. [28]

Another report of 60 unprotected HCW from Viet Nam also found no illness or seroconversion.
[29] However, one case of severe illness was reported in a nurse exposed to an infected patient in
Viet Nam.
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1.3.4      Environment to human transmission of Avian Influenza
Given the survival of avian influenza (H5N1) in the environment, several other modes of
transmission are theoretically possible. Oral ingestion of contaminated water during swimming in
canals or lakes or perhaps direct intranasal or conjunctival inoculation during water exposure are
other potential modes of transmission, as is hand contamination from contaminated fomites and
subsequent self-inoculation. Untreated poultry feces are used extensively in Southeast (SE) Asia as
a fertilizer for some fruit and coffee trees; whether this might be a source for some infections
following aerosolization or ingestion (pica) in young children remains to be determined.

1.3.5    Recommended Isolation Precautions
The World Health Organization recommends a combination of contact, droplet, and airborne
precautions (when feasible) for patients suspected of having avian influenza. [30] These should be
implemented at the time of admission, and continued at least 7 days after the resolution of fever for
adults and children = 12 years old, or until 21 days after the onset of illness for children
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