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Special Article
Histopathologic Features of
Human Infection with Avian H5N1
Influenza Virus
Yavarace (Vongsivavilas) Young*
Tawetong Koanantakool**
*Pathology Department, Chest Disease Institute, Department of Medical Services
Ministry of Public Health
**Cardiovascular and Thoracic Division, Chest Disease Institute, Department of Medical Services
Avian influenza (AI) or fowl plague (FP) is
defined as a disease of viral etiology that ranges
from a mild or asymptomatic infection to an acute,
fatal disease of chickens, turkeys, guinea fowls, and
other avian species, especially migratory water-
(1- 3)
fowl. The term FP was first used in 1878 to
describe a serious disease of chickens in Italy(1-3).
In 1955, it was discovered that FP was actually
(1-3)
caused by one of the influenza viruses (IV)
There are 3 types of IV, designated as A, B, or C
according to the antigenic character of the M pro-
tein of the virus envelope and the nucleoprotein
within the virus particle. IV is classified into sub-
type according to the serologic identity of the two
surface antigens, hemagglutinins (HA) and
neuraminidases (NA). There are now 16 HA and
9 NA antigens described among influenza type A
viruses and only 3 subtypes circulating among
humans (H1N1, H2N2, and H3N2). Therefore,
they are also known as human influenza viruses.
Journal of Health Science
Vol. 14 No. 5 September - October 2005
∫∑§«“¡æ‘‡»…
AI, subtype H5N1 viruses were first discov-
ered in domestic geese in Guangdong, China in
1996(4). In May of 1997, human infection with
this virus was detected for the first time during
the simultaneous outbreaks of H5N1 in poultry
in Hong Kong(5,6). The boy died 5 days after ad-
mission. Approximately 6 months later, 17 addi-
tional confirmed cases with 5 deaths were reported
. from Hong Kong(5, 6). These cases acquired the
infection directly from chickens, without the in-
volvement of an intermediate host. The outbreak
resulted in a territory-wide slaughter of more than
1.5 million chickens at the end of 1997. H5N1
infection in humans is a classic example of emerg-
ing infectious disease resulting from transmission
of a known causative organism to a new host.
In January of 2003, human disease caused by
influenza H5N1 re-emerged for the first time since
the 1997 outbreak(7). Two cases of H5N1 infec-
tion occurred among members of a Hong Kong
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 Histopathologic Features of Human Infection with Avian H5N1 Influenza Virus
family who had visited Fujian in Mainland China.
The diagnosis was confirmed by cell culture and
by reverse transcription-polymerase chain reaction
(RT-PCR) from their nasopharyngeal aspirates.
One of them was a 33-year-old Chinese man who
presented with a 4-day history of influenza-like
symptoms and a right lower lobe consolidation.
Despite a heroic treatment, he deteriorated and
(7)
expired 6 days after admission . A complete
autopsy was done. Prior to his illness, his 7-year-
old daughter had high fever and respiratory symp-
toms and died of a pneumonia-like illness 7 days
after the onset of symptoms. The exact cause of
her death could not be ascertained since no clini-
cal specimen was available for tests and no autopsy
was performed. The second confirmed case was
his 8-year-old son who was admitted with a 3-day
history of influenza-like symptoms and a left
lingular lobe consolidation. The boy was the only
one who recovered from his illness. Since mid
2003, lethal outbreaks of H5N1 viruses among
poultry have been reported to occur in several
countries in Asia and Eastern Europe. In spring
of 2005, more than 6000 migratory birds were
found dead due to H5N1 infection at the Qinghai
Lake in Qinghai, China. The death of wild birds
is frightening because it suggests adaptation of
H5N1 virus. Later on, H5N1 expanded in a north-
west direction and both Russia and Kazakhstan
have reported outbreaks in poultry as well as in
wild birds. H5N1 infection was not limited to poul-
try and wild birds but expanded to tigers, leop-
(8-10)
ards, cats, mice, ferrets, pigs and dogs . More
than 100 million birds either died of the disease
or were culled. The outbreaks were followed
by cross-species transmission of H5N1 from
chickens to humans with a case of probable hu-
(11)
man to human transmission . As of October of
2005, more than 100 confirmed human cases of
742
H5N1 disease were reported with 62 deaths. In
Thailand, there were 17 confirmed cases with 12
deaths during the 2004 outbreak. Indeed, it is the
largest and most lethal H5N1 virus outbreak in
humans to date.
It has been thought that AI viruses have wild
waterfowl as their natural reservoir and they
usually do not infect humans. However, the 1997
outbreak has changed our view regarding the po-
tential for cross-species transmission and virulence
of AI viruses for humans. Genetic analysis showed
all genes of the H5N1 human isolates were of avian
origin. In addition, the 1997 H5N1 virus, the an-
cestor of all H5N1 human isolates was the reas-
sortant of multiple co-circulating AI viruses in-
cluding genes from 1996 Guangdong goose
H5N1, a quail H9N2 virus, and a teal H6N1 vi-
rus(6, 12-17). This indicates that it is possible for avian
H5N1 viruses to jump species from chickens to
humans without using an intermediate host or a
mixing vessel for reassortment and they may not
have to combine with another variety of mammal
influenza in order to spread among humans.
The outbreaks of H5N1 not only cause eco-
nomic losses for poultry producers but also ignite
global fears that the devastating ‘bird flu’ pan-
demic is imminent. It was once predicted that in-
fluenza pandemic was likely to originate from
Southeast Asia. However, the recent outbreaks of
H5N1 and other subtypes of AI in various parts of
the world indicate that the next pandemic may
start anywhere on earth and at anytime.
Of all these years, great interest has been fo-
cused on molecular biology technique and a
wealth of information has been acquired from
numerous researches in this area. However,
merely genetic sequencing would not have been
adequate because the virus’s genes could react in
the live virus in ways no one predicted, resulting
Journal of Health Science 2005 Vol. 14 No. 5
≈—°…≥–®ÿ≈欓∏‘ ¿“æ¢Õß°“√µ‘¥‡™◊ÈÕ‰«√— ‰¢âÀ«—¥„À≠àπ° H5N1 „π§π
in protein changes that help the virus enter cells.
Histopathology would be another area to study to
see how the virus behave inside the cells and cause
damages to the host in real life. So far the publi-
cations on pathological findings are very limited.
Systematic reviews of research data with emphasis
on pathology of AI (H5N1) infection in human
were carried out.
This study includes 2 cases of complete
autopsies, 1 case of paramortem biopsies and 1
case of postmortem necropsies from the 1997
(6, 18-19)
Hong Kong outbreak ; 1 case of complete
(7)
autopsy from the year 2003 ; and 2 cases of com-
plete autopsies from the 2004 Thailand out-
break(11, 20-22). Clinical data and histopathologic
findings of the 7 proven cases of H5N1 virus in-
fection are shown in Table 1 and 2. Photomicro-
graphs of hematoxylin and eosin (H & E) section
of the lung of case 7 are shown in Figures 1 to 3.
All patients were of Asian descent, 4 being Chi-
nese, 1 Filipinos, and 2 Thais.
The clinical spectrum of human H5N1 infec-
tion ranged from asymptomatic infection to fatal
(6)
pneumonitis and multiple organ failure . The
postmortem examination of the 1997 outbreak
showed reactive hemophagocytic syndrome as the
most prominent feature. Other findings included
diffuse alveolar damage (DAD) with interstitial
fibrosis in the lungs, extensive hepatic centrilo-
bular necrosis, and vacuolation of renal proximal
tubules in case 1 to extensive acute tubular necro-
sis in cases 2, 3 and 4. No viral antigen was found
in any organs except case 3 in which H5 antigen
was detected from the lung only. Elevation of solu-
ble interleukin-2 receptor, interleukin-6 and in-
(6, 18)
terferon-γ was demonstrated in cases 2 and 4
Secondary bacterial pneumonia was not observed
in any case. Therefore, it was postulated that in
fatal human infections with H5N1, initial viral
«“√ “√«‘™“°“√ “∏“√≥ ÿ¢ ÚıÙ¯ ªï∑’Ë ÒÙ ©∫—∫∑’Ë ı
replication in the respiratory tract might trigger
hypercytokinemia resulting in reactive hemo-
phagocytic syndrome(6, 18).
The findings of autopsy in case 5 also sug-
gested cytokine dysfunction contribute to the
pathogenesis of H5N1 disease(7). H5N1 antigen
was also detected in the lungs of case 5, 6 and 7.
In contrast to the other cases, hemophagocytosis
is not seen in any organs of case 6. It is not clear
whether this is due to prior treatment with corti-
costeroid or the young age of the patient. In case
6, tumor necrotic factor-alpha (TNF-α) was de-
tected in the lungs only. This finding concurs with
previous observations that human H5N1 isolates
initiate the production of cytokines, most promi-
nently TNF-α, in cultured human macrophages
in vitro(23). Both viral mRNA and TNF-α are found
in the lungs of case 6. The simultaneous pre-
sence of viral antigen and cytokine TNF-α in the
same organ suggests a direct induction of cytokine
in the viral infected cells. However, the possibility
of Aspergillus induced cytokine in case 6 cannot
be ruled out.
The most consistent histopathology findings
in these cases are in the lung. Although, DAD
and interstitial pneumonitis are non-specific le-
sion, they are typical lesions of pneumonia of vi-
ral etiology. The diagnostic tests such as cultures,
electron microscopy, molecular diagnostics, and
immunohistochemistry are required in detecting
the causative agent. So far, human autopsy cases
have not shown viral spread beyond the lung ex-
cept case 6 in which H5 specific RNA was detected
in the lungs, spleen, and intestine and evidence
of viral replication was found in lungs and intes-
. tine(6, 7, 11, 21). Viral spread beyond the lungs in
case 6 could be related to corticosteroid admi-
nistration or virulent strain of the virus. The
damages seen in the lungs along with the finding
˜ÙÛ
 744
Table 1 Clinical data of 7 proven cases of H5N1 virus infection with available postmortem examination

Patient Outbreak Age/Sex Underlying Onset Treatment Outcome

Numer Nationality disease

1 1997 3/M No May 11, 97 Acyclovir started at late stage Died 5 days after admission
Hong Kong Chinese of disease (10 days after the onset of illness)
Paramortem biopsies were done.
2 1997 13/F No Nov 20, 97 Amantadine plus intravenous Died 25 days after admission
Hong Kong Chinese Ribavirin on day 7 after A complete autopsy was one.
admission
3 1997 54/M Old Nov 24, 97 Amantadine on admission Died 7 days after admission
Hong Kong Chinese myocardial (6 days after the onset of illness) (11 days after the onset of illness)
infarction
4 1997 25/F No Dec 17, 97 Amantadine on day 3 after Died 24 days after admission
Hong Kong Filipino admission A complete autopsy was done.
5 2003 33/M No Feb 7, 03 Intravenous cefotaxime and oral Died 6 days after admission
Hong Kong Chinese clarithromycin on admission A complete autopsy was done.
add oseltamivir on day 3
6 2004 6/M No Jan, 04 Multiple broad-spectrum antibiotics Died 6 days after admission
Thailand Thai Granulocyte colony-stimulating (17 days after the onset of illness)
factor then oseltamivir and methyl- A complete autopsy was one.
prednisone on day 15 until death
7 2004 26/F No Sept 11, 04 Antibiotic Died 4 days after admission
Thailand Thai A complete autopsy was done.

Journal of Health Science 2005 Vol. 14 No. 5

Histopathologic Features of Human Infection with Avian H5N1 Influenza Virus
 Table 2 Clinical and histopathologic findings of 7 proven cases of H5N1 virus infection
Patient Clinical conditions
number
1 Bilateral pneumonia
Reye’s syndrome
Renal failure, coagulopathy
MOF, H5N1 was detected from
tracheal aspirate
2 hemoptysis, ARDS
Gastrointestinal bleeding
Renal failure, MOF
3 Acute renal failure
MOF
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4 Left lower lobe pneumonia
Bilateral massive hemorrhagic
pleural effusion, ARDS
MOF
5 Right lower lobe pneumonia
ARDS, MOF
H5N1 was detected by cell
culture & RT-PCR from
nasopharyngeal aspirate
6 Right lower lobe pneumonia
ARDS, pneumothorax
Pneumomediastinum
MOF
7 Pneumonia
Respiratory failure
Patient numbers in this table correspond to those of table 1
Abbreviations: ARDS = Acute respiratory distress syndrome, DAD = Diffuse alveolar damage, MOF = Multiple organ failure, RT-PCR = Reverse transcription polymerase chain
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reaction, TNFa = Tumor necrosis factor alpha
Histopathologic findings
Bone marrow Bx: hypercellular marrow with left shift, active erythropoiesis, reactive histiocytes with
focal hemophagocytosis Liver Bx: microvesicualr fatty changes and Councilman bodies with scanty in
flammatory cells Kidney Bx: vacuolation and vesicular changes of proximal tubules No viral antigen was
detected in any ogans.
Lungs: organizing DAD, interestitial fibrosis, focal cystic changes, pneumocyte hyperplasia but no viral
inclusion, extensive hemorrhage, and focal hemorphagocytosis. No superimposed infection Bone marrow:
hypoplasia with reversed myeloid to erythroid ratio and focal hemophagocytosis Liver: centrilobular necrosis, fatty
changes, activated Kupffer’s cells with focal hemophagocytosis Kidneys: acute tubular necrosis and congestion
lymph nodes and spleen: prominent hemophagocytosis Brain: mild edema, hemophagocytosis in meninges and
demyelinated areas, and reactive histiocytes in the white matter of the cerebellum. No viral antigen was detected in
any organs.
Lung necropsy: intra-alveolar fibrinous exudates, hemorrhage, pneumocyte hyperplasia and minimal
interstitial inflammation. Lung was the only organ that showed positive H5 antigen. Renal necropsy: extensive
acute tubular necrosis.
Lungs: similar to that of patient number 2
Bone marrow: hypercellular marrow with left shift of myeloid series and hemophagocytosis
Liver: similar to that of patient number 2 plus extra-medullary hematopoiesis
Kidneys: similar to that of patient number 2
Lymph nodes and spleen: prominent hemophagocytosis and extra-medullary hematopoiesis
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Brain: mild edema otherwise unremarkable. No viral antigen was detected in any organs.
Lungs: edema, hemorrhage, intra-alveolar fibrinous exudates, pneumocyte type 2 hyperplasia with in-
creased expression of TNFa in these cells. No viral antigen was detected in these cells prominent CD68+
macrophages in alveoli, CD3+T-lymphocytes in interstitium Bone marrow, bronchial and hilar lymph
nodes: reactive hyperplasia with hemophagocytosis Other organs: unremarkable. Lung was the only
organ that showed positive influenza A antigen by culture and RT-PCR techniques.
Lungs: proliferative phase of DAD, interstitital pneumonia, focal hemorrhage, bronchiolitis, type2 pneumocyte
hyperplasia and superimposed aspergillosis Bone marrow, lymph nodes and spleen: slight histiocytic hyperplasia
but no hemophagocytosis Liver: mild fatty changes, activated Kuffer cells, and slight lymphoid infiltrates in the
portla areas Brain: edema, small foci of necrosis. Other organs: unremarkable H5 specific RNA was detected in the
lungs, spleen and intestines by RT-PCR. Immunohistochemical stain revealed influenza A viral antigen in pneumocyte
type 2. Electron microscopy: viral particles in pneumocytes and macrophages
A complete autopsy was done after the body had been preserved with formalin infusion. Lungs: exuda
tive phase of DAD, interstitital pneumonitis, hemorhage, reactive pneumocyte hyperplasia, bronchiolitis and pleuri-
tis. Immunohistochemical stain: influenza specific antigen in the desquamated epithelial cells. Lung tissue was
positive for H5N1 by RT-PCR. Liver: cholestasis, congestion, and hemophagocytosis
Spleen: congestion and lymphoid depletion
 Histopathologic Features of Human Infection with Avian H5N1 Influenza Virus
Figure 1 Section of the lung shows diffuse alveolar
damage, interstitial pneumonitis, and intra-
alveolar fibrinous exudate and hemorrhage,
(H & E section × 100)
Figure 3 A higher power view of the lung shows dif-
fuse alveolar damage, hyaline membrane, in-
tra-alveolar fibrinous exudate and diffuse
hemorrhage, (H & E section × 200)
of viral particles in cells suggest the direct cyto-
pathic effect of the virus. It is logical to assume
that the virus is not just sitting there and does
not do a darn thing. Once the virus continues
adapting to human and increasing efficiency for
cellular invasion, it can cause disseminated disease
as we have seen in poultry, wild birds, tigers, leo-
746
Figure 2 Section of the lung shows non-specific pleuri-
tis, subpleural blebs, diffuse alveolar damage,
intra-alveolar fibrinous exudate and diffuse
hemorrhage, (H & E section × 100)
pards, cats, and other experimental mammalian
models.
Autopsy has a special role in the under-
standing of pathology and pathogenesis of the
disease. It is the medical practice in the traditional
sense that studies of the deaths to benefit the
livings. However, doing an autopsy on an infec-
tious death case does not necessarily guarantee
that a causative organism will be found. Autopsy
pathologists often require ancillary tests beyond
gross and histologic evaluation. The diagnostic
tests such as cultures, electron microscopy, mo-
lecular diagnostics, and immunohistochemistry
are necessary in establishing an organism-specific
diagnosis. Autopsy is also a procedure to obtain
materials for various diagnostic tests as well as for
‘banking’ of appropriate laboratory specimens
for later research. The usefulness of autopsy in
detecting infectious disease is impaired by not per-
forming the appropriate ancillary tests. Unfortu-
nately, the facilities for autopsy and ancillary tests
are very limited, especially in Thailand due to a
Journal of Health Science 2005 Vol. 14 No. 5
≈—°…≥–®ÿ≈欓∏‘ ¿“æ¢Õß°“√µ‘¥‡™◊ÈÕ‰«√— ‰¢âÀ«—¥„À≠àπ° H5N1 „π§π
lack of qualified personnel, high cost, and a re-
quirement of high level of bio-safety.
Autopsy is very useful but it also carries with
it the risk of infectious disease transmission for
pathologists as well as for observers and the
publics. Infections have been transmitted at au-
topsy by both skin inoculation and aerosolization.
Funding is essential to bring an autopsy facilities
into compliance with the accepted public health
standards and should be able to function at
biosafety level 3 standard(24).
AI viruses are common, but H5N1 virus is un-
precedented in its geographic reach and its per-
sistence, despite efforts to eradicate it. The glo-
bal concern is the more it multiplies, the greater
the chance it will mutate into a form that easily
infects humans and spreads among humans. The
pandemic preparedness plan has begun. The
strategy should include improving surveillance,
applied research, prevention and control, and
infrastructure(25). The working group should be
organized and comprises multiple medical disci-
plines, i.e., infectious diseases, pulmonary medi-
cine, anatomic and clinical pathology, clinical
microbiology, molecular diagnostics, epidemio-
logy, and public health. The collaborative nature
of this working group not only broadens the con-
text of medical review and discussion but also fa-
10. Kuiken T, Rimmelzwaan G, van Riel D, van
cilitates the commitment of organizational and
institutional resources for more extensive case
investigations. Finally, global cooperation is ur-
11. Ungchusak K, Auewarakul P, Dowell SF, Kitphati R,
gently needed in controlling the devastating ‘bird
flu’ outbreak.
12. Subbarao K, Klimov A, Katz J, Regnery H, Lim W,
Acknowledgement
The authors would like to thank Dr. Mongkol
13. Guan Y, Shortridge KF, Krauss S, Webster RG. Mo-
Uiprasertkul for giving us one H & E slide of the
lung for photography.
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Journal of Health Science 2005 Vol. 14 No. 5