UOA01-09: On the Front Line: Defining the Clinical Features of H5N1 in Vietnam
Submitting InstitutionUniversity of Oxford
Unit of AssessmentClinical Medicine
Summary Impact TypePolitical
Research Subject Area(s)
Medical and Health Sciences: Medical Microbiology, Other Medical and Health Sciences
Summary of the impact
The human influenza A (H5N1) infection emerged in China in 2003 and
quickly spread throughout Asia, killing more than half of those infected.
Researchers at the Oxford University Clinical Research Unit in Vietnam
(OUCRU) provided rapid information to the World Health Organization (WHO)
on the pathological and clinical features of H5N1 infection in humans, as
it emerged in Vietnam. The WHO used this front line information to inform
recommendations for the investigation, diagnosis, management, and
treatment of H5N1 globally, ultimately reducing mortality by up to 19%.
H5N1, also known as "bird flu", is a type of influenza virus that causes
a highly infectious and deadly respiratory disease in birds. Initially
identified in a farmed goose in China in 1996, the first human case of
avian influenza was reported 12 months later, in Hong Kong. After a
five-year hiatus, H5N1 infection was again reported in birds and humans in
Hong Kong in February 2003, and quickly spread from China throughout Asia.
The first human case of H5N1 was reported in Vietnam in January 2004.
OUCRU researchers swiftly undertook studies on the initial 10 patients
admitted to hospitals in Ho Chi Minh City and Hanoi, to gain a better
understanding of this largely unknown and deadly virus. This research was
significant in classifying the clinical and pathological features of H5N1
infection in and in identifying the preliminary epidemiologic findings1.
The 2004 study showed that H5N1 infection resulted in fever, respiratory
symptoms, and lymphopenia, and confirmed the high risk of death. It also
confirmed that the virus was transmitted from infected poultry in all 10
In a further study conducted in 2005 OUCRU researchers investigated the
use of antiviral treatment in the disease. They identified high-level
resistance to antiviral influenza treatment with Oseltamivir in two of
eight Vietnamese patients. While Oseltamivir treatment led to a rapid
decline in viral loads among six patients (all of whom survived), the two
resistant patients died of H5N1 infection, in spite of early treatment2.
This study identified the effectiveness of existing antiviral treatments
in some cases, whilst also highlighting the significant danger of
resistance in the event of viral spread.
As avian and human cases of H5N1 began to spread from Asia to Siberia in
2005 the WHO assembled a review panel of 13 clinicians and experts from
around the world to identify key features of H5N1 infection in humans. The
Writing Committee of the World Health Organization Consultation on Human
Influenza3, including four researchers from OUCRU,
provided a comprehensive review of essential information on H5N1
transmission, clinical severity, diagnosis, pathogenesis, and responses to
treatment. This review also exposed the urgent need for additional
clinical and epidemiological research3.
Accordingly, at the height of the outbreak in 2006, researchers from
OUCRU performed further immunological and viral studies to better
understand the virulence of H5N1 infection in humans. This study showed
that an adverse outcome during human H5N1 infection was determined by high
viral loads and inflammatory responses; it also emphasised the importance
of early diagnosis and treatment4. This study provided The
Writing Committee of the Second World Health Organization Consultation
on H5N1 Virus, with key information on the virulence of the
infection in humans5.
To better understand treatment options for human H5N1 infection, OUCRU
researchers conducted a retrospective study of H5N1 management in Vietnam
between 2004 and 2006. This study showed that while Oseltamivir treatment
is indeed beneficial to patients, treatment with corticosteroids is
associated with an increased risk in mortality6.
References to the research
1. Tran, T. H. et al. Avian influenza A (H5N1) in 10 patients in
Vietnam. N. Engl. J. Med. 350, 1179-1188 (2004).
Early study reporting clinical features and preliminary
epidemiologic findings in 10 patients with confirmed cases of human
H5N1. Referred to as (Hien et al. 2004) in WHO guidelines.
2. de Jong, M. D. et al. Oseltamivir resistance during treatment
of influenza A (H5N1) infection. N. Engl. J. Med. 353,
Study showing that while Oseltamivir treatment is successful,
resistance may occur in a small percentage of patients, highlighting
the need for alternative or combination antiviral therapy.
3. Beigel, J. H. et al. Avian influenza A (H5N1) infection in
humans. N. Engl. J. Med. 353, 1374-1385 (2005).
Review from `The Writing Committee of the World Health Organization
Consultation on Human Influenza', providing essential information on
4. de Jong, M. D. et al. Fatal outcome of human influenza A
(H5N1) is associated with high viral load and hypercytokinemia. Nat.
Med. 12, 1203-1207 (2006).
A study showing that high viral load and inflammatory responses are
key outcomes of H5N1 infection in humans, emphasising the importance
of early diagnosis and treatment.
5. Writing Committee of the Second World Health Organization Consultation
on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus
Abdel-Ghafar, A.N. et al. Update on avian influenza A (H5N1) virus
infection in humans. N. Engl. J. Med. 358, 261-273 (2008).
WHO Writing Committee Report citing (de Jong, M.D. et al. 2006) in
regards to the virulence of H5N1 infection in humans. de Jong was also
listed as an author on this report.
6. Liem, N. T. et al. Clinical features of human influenza A
(H5N1) infection in Vietnam: 2004-2006. Clin. Infect. Dis. 48,
1639-1646 (2009). doi:10.1086/599031
Study showing that treatment with corticosteroids is associated
with an increased risk in mortality.
This research was funded by the Wellcome Trust.
Details of the impact
The rapid spread of avian and human H5N1 infection throughout Asia in
2004 occurred less than 12 months after the global SARS outbreak, which
almost reached pandemic proportions (8,273 cases worldwide, 9.6% fatality)
in 2003. Not surprisingly the unknown and significantly more deadly human
H5N1 virus, with a fatality rate of 60%, became a high priority concern to
the WHO. Fortunately, unlike SARS, first responders soon realised that
human cases of H5N1 were mostly contracted through direct contact with
birds, reducing the frightening possibility of human-to-human infection.
As a result, containment of H5N1 in humans has been relatively successful.
The WHO recently reported a total of 608 confirmed human cases of H5N1 and
359 deaths between 2003 and 2012.
As Vietnam faced the third largest number of all cases worldwide (after
Egypt and Indonesia) the University of Oxford's OUCRU researchers in
Vietnam were at the frontline of the global investigation into H5N1. As a
result, Oxford's research into the epidemiological and pathological
features of human H5N1 infection provided the WHO with key evidence for
rapid clinical guidelines for the management and investigation of H5N1
infection globally during the period from 2006-2013.
WHO rapid advice guidelines on pharmacological management of humans
infected with avian influenza A (H5N1) virus7
In early 2006, as mortality rates rose and infection spread throughout
the world, the WHO assembled an international panel of experts and
clinicians, including Professor Jeremy Farrar (Director of OUCRU Vietnam),
to assist in developing rapid advice for the pharmacological management of
patients with human H5N1 infection.
The early research from OUCRU1 provided the panel with key
data on the clinical features of H5N1 infection in humans, as well as
preliminary epidemiologic findings. Research from OUCRU Vietnam directly
led to the WHO's strong recommendations for the use of Oseltamivir
antiviral drugs in patients with, "confirmed or strongly suspected H5N1
The 2006 guidelines also included a clinical algorithm adapted from an
algorithm used at the Hospital for Tropical Diseases, in Ho Chi Minh City,
by OUCRU's Dr Tran Tinh Hien7. The WHO guidelines for the
management of H5N1 have remained in place since 2006 and have been the
major instrument for the treatment of cases in the period 2006-2013.
WHO guidelines for investigation of human cases of avian influenza
The WHO's 2007 guidelines provide a framework for public health
authorities and researchers to investigate H5N1 infection in humans. Based
on research from OUCRU the guidelines recommend that clinicians
investigating patients with possible H5N1 infection should obtain
background information on the patients family and household, including all
people who have come into contact with the patient within two weeks of the
onset of symptoms. This information directly cites research from OUCRU,
which shows that H5N1 virus is mostly detected in respiratory specimens
within two weeks of symptomatic illness2-4. Studies from OUCRU
also underpin recommendations for the collection of specimens (for
laboratory testing) in patients with fever or respiratory symptoms,
followed by appropriate medical management, including antiviral therapy
(Oseltamivir)8. The WHO guidelines for the investigation of
H5N1 have been used continuously for the investigation of sporadic cases
since 2007 without modification.
WHO guidelines for pharmacological management of pandemic influenza
A(H1N1) 2009 and other influenza viruses. Part II - review of evidence9
OUCR's research on H5N1 has additionally had important impact on the
management of other forms of influenza since 2008. H1N1 influenza or
"Swine Flu" was first identified in April 2009, claiming the lives of over
294,500 people globally in just 12 months. After declaring H1N1 a pandemic
in June 2009, the WHO published recommendations for the Pharmacological
Management of Pandemic Influenza A (H1N1) in August 2009. In the
absence of any systematic reviews for the treatment of H1N1, the WHO used
OUCRU Vietnam's 2009 study of H5N1 to provide key evidence regarding
safety concerns for corticosteroid treatment in influenza A viruses6.
As a result of this research routine use of corticosteroids is no longer
recommended in patients suffering from influenza A viruses9.
Reduction in mortality
Cases of H5N1 infection have slowly been decreasing since the height of
the outbreak in 2006, when a reported 115 cases resulted in 79 deaths
worldwide10. In 2012 these numbers had reduced significantly,
down to just 30 cases and 19 related deaths worldwide. Although the
reduction in mortality is in line with the reduction of cases, a small
decrease can be seen in mortality rates from 68.6% in 2006 to 63.3% in
2012. In Vietnam these rates have fallen even further from 69% mortality
in 2006 to 50% in 201210. While there are many factors involved
in the reduction in human cases of H5N1, improved clinical management
(particularly in Vietnam) has been a key determinant of increased
Sources to corroborate the impact
World Health Organization WHO Rapid Advice Guidelines on
pharmacological management of humans infected with avian influenza A
(H5N1) virus [online]. Geneva: WHO Press. (2006). Available at:
WHO rapid advice guidelines for pharmacological management of
H5N1 citing several papers from OUCRU Vietnam.
World Health Organization WHO guidelines for investigation of
human cases of avian influenza A(H5N1) [online]. (2007).Available at:
WHO guidelines for investigation of H5N1 citing several papers
from OUCRU Vietnam.
World Health Organization WHO Guidelines for Pharmacological
Management of Pandemic Influenza A(H1N1) 2009 and other Influenza
Viruses [online]. (2010).Available at:
WHO guidelines for pharmacological management of H1N1, and other
influenza viruses, citing OUCRU Vietnam paper on H5N1 treatment.
World Health Organization Cumulative number of confirmed human
cases for avian influenza A(H5N1) reported to WHO, 2003-2012 [online].
WHO report on number of cases and deaths related to H5N1
between 2003 and 2012.