The new england journal of medicine

review article

current concepts

Avian Influenza A (H5N1) Infection in Humans
The Writing Committee of the World Health Organization (WHO) Consultationon Human Influenza A/H5
The writing committee consisted of thefollowing: John H. Beigel, M.D., National
Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Md.; Jeremy Farrar, D.Phil., Hospital for
Tropical Diseases, Ho Chi Minh City, Vietnam; Aye Maung Han, M.B., B.S., Department of Child Health, Institute of Medicine, Yangon, Myanmar; Frederick G.
Hayden, M.D. (rapporteur), University ofVirginia, Charlottesville; Randy Hyer, M.D.,
World Health Organization, Geneva; Menno D. de Jong, M.D., Ph.D., Hospital for
Tropical Diseases, Ho Chi Minh City, Vietnam; Sorasak Lochindarat, M.D., Queen
Sirikit National Institute of Child Health,Bangkok, Thailand; Nguyen Thi Kim Tien,
M.D., Ph.D., Pasteur Institute, Ho Chi
Minh City, Vietnam; Nguyen Tran Hien,
M.D., Ph.D., National Institute of Hygieneand Epidemiology, Hanoi; Tran Tinh Hien,
M.D., Ph.D., Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; Angus
Nicoll, M.Sc., Health Protection Agency,
London; Sok Touch, M.D., Ministry of
Health, Phnom Penh, Cambodia; andKwok-Yung Yuen, M.D., University ofHong Kong, Hong Kong SAR, China. Address reprint requests to Dr. Hayden at
the Department of Internal Medicine,
P.O. Box 800473, University of Virginia
Health Sciences Center, Charlottesville, VA
22908, or at fgh@virginia.edu.
N Engl J Med 2005;353:1374-85.
Copyright © 2005 Massachusetts Medical Society.

an unprecedented epizootic avian influenza a (h5n1) virusthat is highly pathogenic has crossed the species barrier in Asia to cause many
human fatalities and poses an increasing pandemic threat. This summary describes the features of human infection with influenza A (H5N1) and reviews recommendations for prevention and clinical management presented in part at the recent
World Health Organization (WHO) Meeting on Case Management and Research on
Human Influenza A/H5, which was held in Hanoi, May 10 through 12, 2005.1 Because
many critical questions remain, modifications of these recommendations are likely.

incidence
The occurrence of human influenza A (H5N1) in Southeast Asia (Table 1) has paralleledlarge outbreaks of avian influenza A (H5N1), although the avian epidemics in 2004 and2005 have only rarely led to disease in humans. The largest number of cases has occurredin Vietnam, particularly during the third, ongoing wave, and the first human death wasrecently reported in Indonesia. The frequencies of human infection have not been determined, and seroprevalence studies are urgently needed. The expanding geographic
distribution of avian influenza A (H5N1) infections, with recent outbreaks in Kazakstan, Mongolia, and Russia, indicates that more human populations are at risk.2,3transmission
Human influenza is transmitted by inhalation of infectious droplets and droplet nuclei, by direct contact, and perhaps, by indirect (fomite) contact, with self-inoculation
onto the upper respiratory tract or conjunctival mucosa.4,5 The relative efficiency of thedifferent routes of transmission has not been defined. For human influenza A (H5N1)
infections, evidence is consistent with bird-to-human, possibly environment-to-human,
and limited, nonsustained human-to-human transmission to date.
animal to human

In 1997, exposure to live poultry within a week before the onset of illness was associated with disease in humans, whereas there was no significant risk related to eating or
preparing poultry products or exposure to persons with influenza A (H5N1) disease.6
Exposure to ill poultry and butchering of birds were associated with seropositivity for
influenza A (H5N1)7 (Table 2). Recently, most patients have had a history of direct contact with poultry (Table 3), although not those who were involved in mass culling ofpoultry. Plucking and preparing of diseased birds; handling fighting cocks; playing
with poultry, particularly asymptomatic infected ducks; and consumption of duck’s
blood or possibly undercooked poultry have all been implicated. Transmission to felids
has been observed by feeding raw infected chickens to tigers and leopards in zoos in1374

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current concepts

Table 1. Cumulative Number of Virologically Confirmed Cases of Avian Influenza A (H5N1) in Humans Reported to the WHO since 2003.*
Date of Onset

VietnamThailandCambodia

Indonesia

Total

No. ofCases

No. ofDeathsNo. ofCases

No. ofDeathsNo. ofCases

No. ofDeathsNo. ofCases

No. ofDeathsNo. ofCases

No. ofDeaths

December 26, 2003, to March 10, 2004
July 19, 2004, to October 8, 2004

23
4

16
4

12
5

8
4

0
0

0
0

0
0

0
0

35
9

24
8

December 16, 2004, to August 5, 2005†
Total

63
90

20
40

0
17

0
12

4
4

4
4

1
1

1
1

68
112

25
57

* Additional details are available at www.who.int/csr/disease/avian_influenza/country/cases_table_2005_08_05/en/print.
† Cases continue to occur. The total number of cases includes fatal ones. This list does not include the 18 patients, 6 of whom died, identifiedin Hong Kong in 1997 or the 2 patients, 1 of whom died, identified in Fujian Province, China, in 2003.

Table 2. Serologic and Clinical Characteristics of Avian Influenza A (H5N1) Infection among Contacts of Patients or Infected Animals.*No.
Year Assay Method† Tested

No. (%)
PositiveGroup

Location

Household contacts
Tour group contacts
Workplace contacts

Hong Kong 1997 MN, ELISA, WB

51
26
47

6 (12)1 (4)0Poultry cullers

Hong Kong 1997 MN, WB

293

9 (3)

Poultry-market workers

Hong Kong 1997 MN, WB

1525

Health care workers
with contact
Household contacts§

Hong Kong 1997 MN, WB

217

VietnamVietnamVietnam2004 MN
2004 MN
2004 MN

51
25
83

Vietnam2004 MN, RT-PCR

60

Thailand2004 Clinical only

54

0

No recognized illness

Thailand2004 Clinical only

35

0Indonesia

2005 MN79

1 (1)No fever or influenza-like
illness
AsymptomaticContacts of sick poultry§
Health care workers
with contact
Health care workers
with contact
Health care workers
with contact§
Health care workers
with contact
Poultry cullers§Comment

Reference

Concurrent exposure to poul- Katz et al.8
try in 5 of 6 positive household contacts; 0 of 9 nonhousehold contacts positive
Seroconversion in 1 with mild Bridges et al.7
acute respiratory illness
Most asymptomatic
Bridges et al.7—
(estimated 10%)
8 (4)‡
Seroconversion in 2; most
asymptomatic
00 of 83 controls positive0—
0
2 with suspected illness (notconfirmed)
0
No recognized illness

Buxton Bridges
et al.9

Liem et al.10
Schultsz et al.11

Apisarnthanarak
et al.12* Some serologic surveys of apparent human-to-human transmission may have been confounded by concurrent exposure to ill poultry.
† MN denotes identification of serum antibody against influenza A (H5N1) by microneutralization, ELISA enzyme-linked immunosorbent assay, WB detection of influenza A (H5)–specific bands by Western blotting, and RT-PCR reverse-transcriptase–polymerase-chain-reaction assay
for viral RNA.
‡ P=0.01 for the comparison with 2 of 309 health care workers without contact (0.6 percent).
§ Data are from the WHO Meeting on Case Management and Research on Human Influenza A (H5) held in Hanoi, May 10 through 12, 2005.

clusters16 and in one case of apparent child-to-mother transmission (Table 3).20 Intimate contact without the use of precautions was implicated, and so
far no case of human-to-human transmission bysmall-particle aerosols has been identified. In 1997,
human-to-human transmission did not apparently
human to humanoccur through social contact,8 and serologic studHuman-to-human transmission of influenza A ies of exposed health care workers indicated that
(H5N1) has been suggested in several household transmission was inefficient9 (Table 2). Serologic
Thailand17,18 and to domestic cats under experimental conditions.19 Transmission between felids
has been found under such conditions. Some infections may be initiated by pharyngeal or gastrointestinal inoculation of virus.

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Table 3. Presentation and Outcomes among Patients with Confirmed Avian Influenza A (H5N1).*
Hong Kong,
1997(N=18)

Outcome or Measure

Thailand,2004(N=17)

Vietnam,
2004(N=10)

Ho Chi Minh City, Cambodia,
2005
2005
(N=10)(N=4)

Age — yrMedian

9.5

14

13.7†

19.4†

22

Range

1–60

2–58

5–24

6–35

8–28

8 (44)

9 (53)

6 (60)

3 (30)

1 (25)

4

3

NS

NS

2–8

2–4

Male sex — no. (%)
Time from last presumed exposure to
onset of illness — days
MedianNS

Range
No. of family clusters

1

Patients with exposure to ill poultry— no./total no. (%)

11/16 (70)
14/17 (82)
visited poultrymarkets

2

1

1

8/9 (89)

6/6 (100)
Status of
4 unknown

3/4 (75)

6

6

8‡

3–8

4–7

5–8

Time from onset of illness to presentationor hospitalization — days
Median

3

Range

1–7

NS

Clinical presentation — no./total no. (%)
Fever (temperature >38°C)

17/18 (94)

Headache

4/18 (22)NS

10/10 (100)

4/4 (100)NS

1/10 (10)

4/4 (100)

Myalgia

2/18 (11)Diarrhea

3/18 (17)

9/17 (53)02/10 (20)NS

7/17 (41)

7/10 (70)NS

2/4 (50)

Abdominal pain
Vomiting

3/18 (17)

4/17 (24)NSNS

2/4 (50)

6/18 (33)

4/17 (24)NS

1/10 (10)0Cough§
Sputum12/18 (67)

16/17 (94)

10/10 (100)10/10 (100)

4/4 (100)NS

13/17 (76)5/10 (50)

3/10 (30)NS

Sore throat

4/12 (33)

12/17 (71)00

1/4 (25)

Rhinorrhea

7/12 (58)

9/17 (53)

0

0

NS

Shortness of breath§

1/18 (6)

13/17 (76)10/10 (100)10/10 (100)NS

Pulmonary infiltrates

11/18 (61)17/17 (100) 10/10 (100)10/10 (100)

4/4 (100)

Lymphopenia¶

11/18 (61)7/12 (58)NS

8/10 (80)

1/2 (50)NS

4/12 (33)NS

8/10 (80)

1/2 (50)

11/18 (61)8/12 (67)

5/6 (83)

7/10 (70)NS

Thrombocytopenia
Increased aminotransferase levels

surveys in Vietnam and Thailand have not foundevidence of asymptomatic infections among contacts (Table 2). Recently, intensified surveillance ofcontacts of patients by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay has led tothe detection of mild cases, more infections in older adults, and an increased number and duration ofclusters in families in northern Vietnam,21 findings suggesting that the local virus strains may be
adapting to humans. However, epidemiologic andvirologic studies are needed to confirm these findings. To date, the risk of nosocomial transmission

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17/17 (100) 10/10 (100)to health care workers has been low, even when appropriate isolation measures were not used10,11 (Table 2). However, one case of severe illness was reported in a nurse exposed to an infected patient in
Vietnam.
environment to human

Given the survival of influenza A (H5N1) in the environment, several other modes of transmission aretheoretically possible. Oral ingestion of contaminated water during swimming and direct intranasal or conjunctival inoculation during exposure to

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Table 3. (Continued.)Hong Kong,
1997(N=18)

Thailand,2004(N=17)

Respiratory failure

8 (44)

13 (76)9 (90)

7 (70)

4 (100)

Cardiac failureNS

7 (41)NS

0

NS

Renal dysfunction

4 (22)

5 (29)

1 (10)

2 (20)NS

Amantadine

10 (56)

0

0

0

NS

Ribavirin

1 (6)

0

2 (20)

0

Outcome or Measure

Vietnam,
2004(N=10)

Ho Chi Minh City, Cambodia,
2005
2005
(N=10)(N=4)

Hospital course — no. (%)

Antiviral therapy¿0

10 (59)5 (50)

10 (100)

Corticosteroids**

Oseltamivir

5 (28)

8 (47)

7 (70)

5 (50)

Inotropic agentsNS

8 (47)

2 (20)NS

NS

Time from onset of illness to death— daysMedian

23

12

9

12.8†

8

Range

8–29

9–30

4–17

4–21

6–10

6 (33)

12 (71)8 (80)

8 (80)

4 (100)Deaths — no. (%)* Data from Hong Kong are from Yuen et al.13 and Chan,14 data on Thailand are from Chotpitayasunondh et al.,15 data on
Vietnam are from Hien et al.,16 or data were presented at the WHO Consultation. NS denotes not stated.
† The median was unavailable, and the mean is given.
‡ Some patients had multiple outpatient illness visits before hospitalization.
§ In Hong Kong, shortness of breath later developed in 11 of 18 patients (61 percent) during hospitalization. In Thailand,
all patients had cough and shortness of breath at hospitalization.
¶ In Vietnam, the median lymphocyte count was 700 per cubic millimeter (range, 250 to 1100), and the median leukocyte
count was 2100 per cubic millimeter (range, 1200 to 3400).16 In Thailand, the mean leukocyte count was 4900 per cubic
millimeter (range, 1200 to 13,600),15 and the lymphocyte count was 1453 per cubic millimeter (range, 454 to 3400).
¿ In Thailand, 7 of 10 patients given oseltamivir died a mean of 11 days after the onset of symptoms (range, 5 to 22 days),
as compared with 5 of 7 untreated patients. Oseltamivir was used in conventional doses (75 mg orally, twice daily for
5 to 10 days with a weight-based dose reduction in children) in the majority of recipients. In Vietnam, one of five recipients of oseltamivir recovered, as compared with one of five untreated patients.16 The use of relatively low doses of oralribavirin in two patients was not associated with obvious effectiveness.
** Initial patients in Vietnam received methylprednisolone (5 mg per kilogram of body weight per day or 1 to 2 mg per
kilogram) for one to four days16; subsequent patients in Ho Chi Minh City received dexamethasone at 0.4 mg per kilogram per day for five days in a randomized trial. In Thailand, methylprednisolone (2 mg per kilogram per day) was
administered for two to five days.

water are other potential modes, as is contamination of hands from infected fomites and subsequent
self-inoculation. The widespread use of untreatedpoultry feces as fertilizer is another possible risk
factor.

clinical features
The clinical spectrum of influenza A (H5N1) in humans is based on descriptions of hospitalized patients. The frequencies of milder illnesses, subclinical infections, and atypical presentations (e.g.,
encephalopathy and gastroenteritis) have not been
determined, but case reports12,21,22 indicate thatn engl j med 353;13

each occurs. Most patients have been previously
healthy young children or adults (Table 3).
incubation

The incubation period of avian influenza A (H5N1)
may be longer than for other known human influenzas. In 1997, most cases occurred within two tofour days after exposure13; recent reports15,16 indicate similar intervals but with ranges of up to eightdays (Table 3). The case-to-case intervals in household clusters have generally been 2 to 5 days, but theupper limit has been 8 to 17 days, possibly owing tounrecognized exposure to infected animals or environmental sources.

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initial symptoms

Most patients have initial symptoms of high fever(typically a temperature of more than 38°C) and an
influenza-like illness with lower respiratory tract
symptoms1 (Table 3). Upper respiratory tract symptoms are present only sometimes. Unlike patientswith infections caused by avian influenza A (H7) viruses,23 patients with avian influenza A (H5N1) rarely have conjunctivitis. Diarrhea, vomiting, abdominal pain, pleuritic pain, and bleeding from the noseand gums have also been reported early in the courseof illness in some patients.14-16,24 Watery diarrhea
without blood or inflammatory changes appears
to be more common than in influenza due to human viruses25 and may precede respiratory manifestations by up to one week.12 One report described
two patients who presented with an encephalopathic illness and diarrhea without apparent respiratory
symptoms.22

ventilator-associated pneumonia, pulmonary hemorrhage, pneumothorax, pancytopenia, Reye’s syndrome, and sepsis syndrome without documented
bacteremia.
mortality

The fatality rate among hospitalized patients has
been high (Table 3), although the overall rate isprobably much lower.21 In contrast to 1997, whenmost deaths occurred among patients older than
13 years of age, recent avian influenza A (H5N1) infections have caused high rates of death among infants and young children. The case fatality rate was
89 percent among those younger than 15 years ofage in Thailand. Death has occurred an average of
9 or 10 days after the onset of illness (range, 6 to30),15,16 and most patients have died of progressive respiratory failure.
laboratory findings

clinical course

Lower respiratory tract manifestations develop
early in the course of illness and are usually foundat presentation (Table 3). In one series, dyspnea developed a median of 5 days after the onset of illness (range, 1 to 16).15 Respiratory distress, tachypnea, and inspiratory crackles are common. Sputum
production is variable and sometimes bloody. Almost all patients have clinically apparent pneumonia; radiographic changes include diffuse, multifocal, or patchy infiltrates; interstitial infiltrates;and segmental or lobular consolidation with air
bronchograms. Radiographic abnormalities were
present a median of 7 days after the onset of feverin one study (range, 3 to 17).15 In Ho Chi Minh
City, Vietnam, multifocal consolidation involving atleast two zones was the most common abnormality among patients at the time of admission. Pleural
effusions are uncommon. Limited microbiologic
data indicate that this process is a primary viralpneumonia, usually without bacterial suprainfection at the time of hospitalization.
Progression to respiratory failure has been associated with diffuse, bilateral, ground-glass infiltrates and manifestations of the acute respiratory distress syndrome (ARDS). In Thailand,15 themedian time from the onset of illness to ARDS was
6 days (range, 4 to 13). Multiorgan failure withsigns of renal dysfunction and sometimes cardiac
compromise, including cardiac dilatation and supraventricular tachyarrhythmias, has been common.14-16,24 Other complications have included

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Common laboratory findings have been leukopenia, particularly lymphopenia; mild-to-moderate
thrombocytopenia; and slightly or moderately elevated aminotransferase levels (Table 3). Marked hyperglycemia, perhaps related to corticosteroid use,and elevated creatinine levels also occur.16 In Thailand,15 an increased risk of death was associatedwith decreased leukocyte, platelet, and particularly,
lymphocyte counts at the time of admission.
virologic diagnosis

Antemortem diagnosis of influenza A (H5N1) has
been confirmed by viral isolation, the detection ofH5-specific RNA, or both methods. Unlike human
influenza A infection,26 avian influenza A (H5N1)
infection may be associated with a higher frequencyof virus detection and higher viral RNA levels in pharyngeal than in nasal samples. In Vietnam, the interval from the onset of illness to the detection ofviral RNA in throat-swab samples ranged from 2 to
15 days (median, 5.5), and the viral loads in pharyngeal swabs 4 to 8 days after the onset of illness wereat least 10 times as high among patients with influenza A (H5N1) as among those with influenza A(H3N2) or (H1N1). Earlier studies in Hong Kong
also found low viral loads in nasopharyngeal samples.27 Commercial rapid antigen tests are less sensitive in detecting influenza A (H5N1) infections
than are RT-PCR assays.15 In Thailand, the resultsof rapid antigen testing were positive in only 4 of 11
patients with culture-positive influenza A (H5N1)(36 percent) 4 to 18 days after the onset of illness.

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management

Most hospitalized patients with avian influenza A(H5N1) have required ventilatory support within
48 hours after admission,15,16 as well as intensive
care for multiorgan failure and sometimes hypotension. In addition to empirical treatment withbroad-spectrum antibiotics, antiviral agents, alone
or with corticosteroids, have been used in most patients (Table 3), although their effects have not been
rigorously assessed. The institution of these interventions late in the course of the disease has notbeen associated with an apparent decrease in theoverall mortality rate, although early initiation ofantiviral agents appears to be beneficial.1,15,16 Cultivable virus generally disappears within two or threedays after the initiation of oseltamivir among survivors, but clinical progression despite early therapy with oseltamivir and a lack of reductions in pharyngeal viral load have been described in patients
who have died.

pathogenesis
characterization of virus

Studies of isolates of avian influenza A (H5N1)
from patients in 1997 revealed that virulence factors included the highly cleavable hemagglutininthat can be activated by multiple cellular proteases,
a specific substitution in the polymerase basic protein 2 (Glu627Lys) that enhances replication,28,29
and a substitution in nonstructural protein 1(Asp92Glu) that confers increased resistance to inhibition by interferons and tumor necrosis factora (TNF-a) in vitro and prolonged replication inswine,30 as well as greater elaboration of cytokines,
particularly TNF-a, in human macrophages exposed to the virus.31 Since 1997, studies of influenza A (H5N1)32-34 indicate that these viruses continue to evolve, with changes in antigenicity35,36
and internal gene constellations; an expanded hostrange in avian species37,38 and the ability to infectfelids17,18; enhanced pathogenicity in experimentally infected mice and ferrets, in which they cause
systemic infections39,40; and increased environmental stability.
Phylogenetic analyses indicate that the Z genotype has become dominant33 and that the virus has
evolved into two distinct clades, one encompassing isolates from Cambodia, Laos, Malaysia, Thailand, and Vietnam and the other isolates from China, Indonesia, Japan, and South Korea.21 Recently,
a separate cluster of isolates has appeared in north-n engl j med 353;13

ern Vietnam and Thailand, which includes variable changes near the receptor-binding site and one
fewer arginine residue in the polybasic cleavage
site of the hemagglutinin. However, the importanceof these genetic and biologic changes with respect
to human epidemiology or virulence is uncertain.
patterns of viral replication

The virologic course of human influenza A (H5N1)
is incompletely characterized, but studies of hospitalized patients indicate that viral replication
is prolonged. In 1997, virus could be detected innasopharyngeal isolates for a median of 6.5 days
(range, 1 to 16), and in Thailand, the interval fromthe onset of illness to the first positive culture ranged
from 3 to 16 days. Nasopharyngeal replication isless than in human influenza,27 and studies of lower respiratory tract replication are needed. The majority of fecal samples tested have been positive forviral RNA (seven of nine), whereas urine samples
were negative. The high frequency of diarrhea
among affected patients and the detection of viral
RNA in fecal samples, including infectious virus in
one case,22 suggest that the virus replicates in thegastrointestinal tract. The findings in one autopsy
confirmed this observation.41
Highly pathogenic influenza A (H5N1) viruses possess the polybasic amino acid sequence at
the hemagglutinin-cleavage site that is associated with visceral dissemination in avian species.
Invasive infection has been documented in mammals,28,29,39,40 and in humans, six of six serum
specimens were positive for viral RNA four to ninedays after the onset of illness. Infectious virus andRNA were detected in blood, cerebrospinal fluid,
and feces in one patient.22 Whether feces or blood
serves to transmit infection under some circumstances is unknown.
host immune responses

The relatively low frequencies of influenza A (H5N1)
illness in humans despite widespread exposure to
infected poultry indicate that the species barrier toacquisition of this avian virus is substantial. Clusters of cases in family members may be caused bycommon exposures, although the genetic factorsthat may affect a host’s susceptibility to disease
warrant study.
The innate immune responses to influenza A(H5N1) may contribute to disease pathogenesis. In
the 1997 outbreaks, elevated blood levels of interleukin-6, TNF-a, interferon-g, and soluble inter-

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nition of cases is confounded by the nonspecificityof the initial clinical manifestations and high background rates of acute respiratory illnesses from other causes. In addition, the possibility of influenza A(H5N1) warrants consideration in patients presenting with serious unexplained illness (e.g., encephalopathy or diarrhea) in areas with known influenza A (H5N1) activity in humans or animals.
The diagnostic yield of different types of samples
and virologic assays is not well defined. In contrast
to infections with human influenza virus, throat
samples may have better yields than nasal samples.
Rapid antigen assays may help provide support fora diagnosis of influenza A infection, but they havepoor negative predictive value and lack specificity
for influenza A (H5N1). The detection of viral RNA
in respiratory samples appears to offer the greatest sensitivity for early identification, but the sensitivity depends heavily on the primers and assay
method used. Laboratory confirmation of influenza A (H5N1) requires one or more of the following: a positive viral culture, a positive PCR assay for
influenza A (H5N1) RNA, a positive immunofluopathological findings
rescence test for antigen with the use of monocloLimited postmortem analyses have documented se- nal antibody against H5, and at least a fourfold
vere pulmonary injury with histopathological chang- rise in H5-specific antibody titer in paired serum
es of diffuse alveolar damage,27,41,42 consistent samples.44
with findings in other reports of pneumonia due tohuman influenza virus.43 Changes include filling hospitalizationof the alveolar spaces with fibrinous exudates and Whenever feasible while the numbers of affected
red cells, hyaline-membrane formation, vascular persons are small, patients with suspected or provcongestion, infiltration of lymphocytes into the in- en influenza A (H5N1) should be hospitalized in
terstitial areas, and the proliferation of reactive fibro- isolation for clinical monitoring, appropriate diagblasts. Infection of type II pneumocytes occurs.41,42 nostic testing, and antiviral therapy. If patients are
Antemortem biopsy of bone marrow specimens has discharged early, both the patients and their famishown reactive histiocytosis with hemophagocyto- lies require education on personal hygiene and insis in several patients, and lymphoid depletion and fection-control measures (Table 5). Supportive careatypical lymphocytes have been noted in spleen and with provision of supplemental oxygen and ventilymphoid tissues at autopsy.13,15,27,42 Centrilobu- latory support is the foundation of management.1
lar hepatic necrosis and acute tubular necrosis have Nebulizers and high–air flow oxygen masks havebeen noted in several instances.
been implicated in the nosocomial spread of severe
acute respiratory syndrome (SARS) and should be
used only with strict airborne precautions.

leukin-2 receptor were observed in individual patients,42 and in the patients in 2003, elevated levelsof the chemokines interferon-inducible protein 10,
monocyte chemoattractant protein 1, and monokine induced by interferon-g were found three toeight days after the onset of illness.27 Recently, plasma levels of inflammatory mediators (interleukin-6,
interleukin-8, interleukin-1b, and monocyte chemoattractant protein 1) were found to be higher
among patients who died than among those who
survived (Simmons C: personal communication),and the average levels of plasma interferon-a wereabout three times as high among patients with avian influenza A who died as among healthy controls.
Such responses may be responsible in part for thesepsis syndrome, ARDS, and multiorgan failure observed in many patients.
Among survivors, specific humoral immune responses to influenza A (H5N1) are detectable by microneutralization assay 10 to 14 days after the onsetof illness. Corticosteroid use may delay or bluntthese responses.

case detection
and management

antiviral agents

The possibility of influenza A (H5N1) should beconsidered in all patients with severe acute respiratory illness in countries or territories with animal
influenza A (H5N1), particularly in patients who
have been exposed to poultry (Table 4). However,some outbreaks in poultry were recognized only after sentinel cases occurred in humans. Early recog-

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Patients with suspected influenza A (H5N1) should
promptly receive a neuraminidase inhibitor pending the results of diagnostic laboratory testing.
The optimal dose and duration of treatment withneuraminidase inhibitors are uncertain, and currently approved regimens likely represent the minimum required. These viruses are susceptible in

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Table 4. Exposures That May Put a Person at Risk for Infection with Influenza A (H5N1).*
Countries and territories where influenza A (H5) viruses have been identified as a cause of illness in human or animal
populations since October 1, 2003
During the 7 to 14 days before the onset of symptoms, one or more of the following:
Contact (within 1 m) with live or dead domestic fowl or wild birds or domestic ducks
Exposure to settings in which domestic fowl were confined or had been confined in the previous 6 weeks
Unprotected contact (within touching or speaking distance) with a person for whom the diagnosis of influenza A(H5N1) is confirmed or being considered
Unprotected contact (within touching or speaking distance, 1 m) with a person with an unexplained acute respiratory
illness that later resulted in severe pneumonia or death
Occupational exposure†
Countries and territories where influenza A (H5) viruses have not been identified as a cause of illness in human or animal
populations since October 1, 2003
During the 7 to 14 days before the onset of symptoms, close contact with an ill traveler from one of the areas withknown influenza A (H5) activity, history of travel to a country or territory with reported avian influenza activity due
to influenza A (H5N1) in the animal populations, or living in an area in which there are rumors of the death of domestic fowl, and one or more of the following:
Contact (within 1 m) with live or dead domestic fowl or wild birds in any setting or with domestic ducks
Exposure to settings in which domestic fowl were confined or had been confined in the previous 6 weeks
Contact (within touching or speaking distance) with a patient with a confirmed case of influenza A (H5)Contact (within touching or speaking distance) with a person with an unexplained acute respiratory illness that later
resulted in severe pneumonia or death
Occupational exposure†* These summaries do not present formal WHO guidelines, although they contain content from WHO documents. 1† At-risk occupations include domestic-fowl worker, worker in a domestic-fowl processing plant, domestic-fowl culler(catching, bagging, or transporting birds or disposing of dead birds), worker in a live-animal market, chef working withlive or recently killed domestic fowl, dealer or trader in pet birds, health care worker, and a worker in a laboratory processing samples possibly containing influenza A (H5N1) virus.

vitro to oseltamivir and zanamivir.46,47 Oral oseltamivir46 and topical zanamivir are active in animalmodels of influenza A (H5N1).48,49 Recent murine
studies indicate that as compared with an influenza A (H5N1) strain from 1997, the strain isolated
in 2004 requires higher oseltamivir doses and more
prolonged administration (eight days) to induce
similar antiviral effects and survival rates.50 Inhaledzanamivir has not been studied in cases of influenza A (H5N1) in humans.
Early treatment will provide the greatest clinicalbenefit,15 although the use of therapy is reasonable
when there is a likelihood of ongoing viral replication. Placebo-controlled clinical studies of oral
oseltamivir51,52 and inhaled zanamivir 53 comparing currently approved doses with doses that are
twice as high found that the two doses had similar
tolerability but no consistent difference in clinicalor antiviral benefits in adults with uncomplicatedhuman influenza. Although approved doses of oseltamivir (75 mg twice daily for five days in adults
and weight-adjusted twice-daily doses for five daysn engl j med 353;13

in children older than one year of age — twice-daily
doses of 30 mg for those weighing 15 kg or less,
45 mg for those weighing more than 15 to 23 kg,
60 mg for those weighing more than 23 to 40 kg,
and 75 mg for those weighing more than 40 kg) arereasonable for treating early, mild cases of influenza A (H5N1), higher doses (150 mg twice daily
in adults) and treatment for 7 to 10 days are considerations in treating severe infections, but prospective studies are needed.
High-level antiviral resistance to oseltamivir results from the substitution of a single amino acidin N1 neuraminidase (His274Tyr). Such variants
have been detected in up to 16 percent of children
with human influenza A (H1N1) who have received
oseltamivir.54 Not surprisingly, this resistant variant has been detected recently in several patientswith influenza A (H5N1) who were treated with
oseltamivir.21 Although less infectious in cell culture
and in animals than susceptible parental virus,55
oseltamivir-resistant H1N1 variants are transmissible in ferrets.56 Such variants retain full suscepti-

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Table 5. Strategies to Prevent Avian Influenza A (H5N1) in Humans in a Nonpandemic Setting.*
Isolation precautions in health care facilities
Patients should be treated with a combination of standard, contact, droplet, and airborne isolation precautions.†
Patients should be housed alone in a negative-pressure room, if available, or in a single room with the door closed.
If a single room is not available, patients should be housed in designated multibed rooms or wards. The beds should be
at least 1 m apart and preferably separated by a physical barrier.
High-efficiency masks (NIOSH-certified N-95 or equivalent), long-sleeved cuffed gowns, face shield or eye goggles,
and gloves are recommended for health care workers.
When feasible, limit the number of health care workers with direct contact with patient and limit access to the environment of patients. If possible, these health care workers should not look after other patients.
Restrict visitors to a minimum and give them proper personal protective equipment and instructions in its use.
Health care worker exposures
Those caring for infected patients should monitor temperature twice daily and report any febrile event. If unwell for any
reason, health care workers should not be involved in direct patient care. Health care workers with fever (temperature >38°C) and patient contact should undergo appropriate diagnostic testing. If an alternative cause is not identified, they should be treated immediately with oseltamivir on the assumption of influenza infection.
Those who have had a possible exposure to infectious aerosols, secretions, or other body fluids or excretions because ofa lapse in aseptic technique should be considered for postexposure chemoprophylaxis with oseltamivir at a suggested dose of 75 mg once daily for 7 to 10 days.
Health care workers involved in high-risk procedures (e.g., aerosol-generating procedures) should consider the need forpreexposure prophylaxis.
Precautions for household and close contacts
Household contacts should use appropriate hand hygiene, should not share utensils, should avoid face-to-face contact
with patients with suspected or proven cases, and should consider donning high-efficiency masks and eye protection.†Contacts who have shared a defined setting (household, extended family, hospital or other residential institution, or military service) with a patient with proven or suspected avian influenza A (H5N1) infection should monitor their own
temperature twice daily and check for symptoms for 7 days after their last exposure.
In such persons, postexposure prophylaxis with oseltamivir at a suggested dose for adults of 75 mg once daily for 7 to
10 days is advisable.
Household or close contacts should receive empirical antiviral treatment and undergo diagnostic testing if fever(temperature >38°C) and cough, shortness of breath, diarrhea, or other systemic symptoms develop.
Precautions for travelers45
Travelers to areas with avian influenza activity should be immunized with the available trivalent human vaccine, preferably at least 2 weeks before traveling.
Travelers should avoid all direct contact with poultry, including chickens, ducks, or geese that appear to be well, andfarms or live-animal markets with poultry, and should avoid touching surfaces contaminated with poultry feces or secretions.
Travelers should reduce possible exposure by practicing good hand hygiene with frequent hand washing or use of alcohol gels and by not ingesting undercooked eggs or foods from poultry.
Hand washing is important when handling raw poultry for cooking (e.g., during cooking classes).
Travelers should be advised to consult a health care provider if they become ill with fever and respiratory symptoms within 10 days of returning from an affected area.
* These summaries do not present formal WHO guidelines, although they contain content from WHO documents. 1 The
guidelines are adapted in part from the Centers for Disease Control and Prevention.45 NIOSH denotes National Institutefor Occupational Safety and Health, and N-95 a non-oilproof respirator with at least 95 percent efficiency in filtering particles with a mean diameter of more than 3 µm.
† The duration of viral shedding in children younger than 12 years of age who have human influenza can last up to 21 days
and also may be protracted in children and adults with avian influenza A (H5N1), so that infection-control precautions
should be maintained for at least 7 days after the resolution of fever or possibly up to 21 days.

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current concepts

and other patients in a nonpandemic situation andon the interventions used to contain SARS (Table
5).1 The efficiency of surgical masks, even multiple
ones,69 is much less than that of N-95 masks, butthey could be used if the latter are not available.
Chemoprophylaxis with 75 mg of oseltamivir once
daily for 7 to 10 days is warranted for persons who
have had a possible unprotected exposure.70,71 The
use of preexposure prophylaxis warrants consideration if evidence indicates that the influenza A(H5N1) strain is being transmitted from person toperson with increased efficiency or if there is a likeimmunomodulators
lihood of a high-risk exposure (e.g., an aerosol-genCorticosteroids have been used frequently in treat- erating procedure).
ing patients with influenza A (H5N1), with uncertain effects. Among five patients given corticoste- household and close contacts
roids in 1997, two treated later in their course for Household contacts of persons with confirmed
the fibroproliferative phase of ARDS survived. In a cases of influenza A (H5N1) should receive postrandomized trial in Vietnam, all four patients given exposure prophylaxis as described above. Contacts
dexamethasone died. Interferon alfa possesses both of a patient with proven or suspected virus should
antiviral and immunomodulatory activities, but ap- monitor their temperature and symptoms (Table 5).
propriately controlled trials of immunomodulatory Although the risk of secondary transmission has
interventions are needed before routine use is rec- appeared low to date, self-quarantine for a periodommended.
of one week after the last exposure to an infected
person is appropriate. If evidence indicates that
person-to-person transmission may be occurring,
prevention
quarantine of exposed contacts should be enimmunization
forced. For others who have had an unprotected exNo influenza A (H5) vaccines are currently com- posure to an infected person or to an environmenmercially available for humans. Earlier H5 vaccines tal source (e.g., exposure to poultry) implicated inwere poorly immunogenic and required two doses the transmission of influenza A (H5N1), postexof high hemagglutinin antigen content62 or the ad- posure chemoprophylaxis as described above may
dition of MF59 adjuvant63 to generate neutralizing be warranted.
antibody responses. A third injection of adjuvanted
1997 H5 vaccine variably induced cross-reacting
conclusions
antibodies to human isolates from 2004.64 Reverse
genetics has been used for the rapid generation of Infected birds have been the primary source of innonvirulent vaccine viruses from recent influenza fluenza A (H5N1) infections in humans in Asia.
A (H5) isolates,65,66 and several candidate vaccines Transmission between humans is very limited atare under study. One such inactivated vaccine with present, but continued monitoring is required tothe use of a human H5N1 isolate from 2004 has identify any increase in viral adaptation to humanbeen reported to be immunogenic at high hemag- hosts. Avian influenza A (H5N1) in humans differs
glutinin doses.67 Studies with approved adjuvants in multiple ways from influenza due to human vilike alum are urgently needed. Live attenuated, cold- ruses, including the routes of transmission, cliniadapted intranasal vaccines are also under develop- cal severity, pathogenesis, and perhaps, response
ment. These are protective against human influenza to treatment. Case detection is confounded by theafter a single dose in young children.68
nonspecificity of initial manifestations of illness,so that detailed contact and travel histories andhospital-infection control
knowledge of viral activity in poultry are essential.
Influenza is a well-recognized nosocomial patho- Commercial rapid antigen tests are insensitive, andgen.4,5 Current recommendations are based on ef- confirmatory diagnosis requires sophisticated labforts to reduce transmission to health care workers oratory support. Unlike human influenza, avian inbility to zanamivir and partial susceptibility to theinvestigational neuraminidase inhibitor peramivir
in vitro.57,58
In contrast to isolates from the 1997 outbreak,recent human influenza A (H5N1) isolates are highly resistant to the M2 inhibitors amantadine andrimantadine, and consequently, these drugs do nothave a therapeutic role. Agents of clinical investigational interest for treatment include zanamivir, peramivir, long-acting topical neuraminidase inhibitors, ribavirin,59,60 and possibly, interferon alfa.61

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fluenza A (H5N1) may have higher viral titers in the ologic research among institutions in countries withthroat than in the nose, and hence, analysis of throat cases of influenza A (H5N1) and internationally.
The views expressed in this article do not necessarily reflectswabs or lower respiratory samples may offer moreof the WHO or other meeting sponsors.
sensitive means of diagnosis. Recent human iso- those
We are indebted to the National Institute of Allergy and Infectious
lates are fully resistant to M2 inhibitors, and in- Diseases and the Wellcome Trust for their collaborative support ofcreased doses of oral oseltamivir may be warranted the WHO meeting; to Drs. Klaus Stohr and Alice Croisier of the GloInfluenza Program at the WHO, Geneva; and to Drs. Peter Horbyfor the treatment of severe illness. Despite recent bal
and Monica Guardo and the staff of the WHO Country Offices, Vietprogress, knowledge of the epidemiology, natural nam, for organizing the WHO consultation and for support in thehistory, and management of influenza A (H5N1) dis- preparation of the manuscript; and to Diane Ramm for help in theease in humans is incomplete. There is an urgent preparation of the manuscript.
need for more coordination in clinical and epidemireferences

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