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The new england journal of medicine c u r r e n t c o n c e p t s
Avian Influenza A (H5N1) Infection in Humans The Writing Committee of the World Health Organization (WHO) Consultation n unprecedented epizootic avian influenza a (h5n1) virus following: John H. Beigel, M.D., National that is highly pathogenic has crossed the species barrier in Asia to cause many Institute of Allergy and Infectious Diseas- human fatalities and poses an increasing pandemic threat. This summary de- es, National Institutes of Health, Bethesda,Md.; Jeremy Farrar, D.Phil., Hospital for scribes the features of human infection with influenza A (H5N1) and reviews recom- Tropical Diseases, Ho Chi Minh City, Viet- mendations for prevention and clinical management presented in part at the recent World Health Organization (WHO) Meeting on Case Management and Research on ment of Child Health, Institute of Medi-cine, Yangon, Myanmar; Frederick G.
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.
Virginia, Charlottesville; Randy Hyer, M.D.,World Health Organization, Geneva; Men-no D. de Jong, M.D., Ph.D., Hospital for Tropical Diseases, Ho Chi Minh City, Viet-nam; Sorasak Lochindarat, M.D., QueenSirikit National Institute of Child Health, The occurrence of human influenza A (H5N1) in Southeast Asia (Table 1) has paralleled large outbreaks of avian influenza A (H5N1), although the avian epidemics in 2004 and 2005 have only rarely led to disease in humans. The largest number of cases has occurred Minh City, Vietnam; Nguyen Tran Hien,M.D., Ph.D., National Institute of Hygiene in Vietnam, particularly during the third, ongoing wave, and the first human death was recently reported in Indonesia. The frequencies of human infection have not been de- M.D., Ph.D., Hospital for Tropical Diseas- termined, and seroprevalence studies are urgently needed. The expanding geographic es, Ho Chi Minh City, Vietnam; AngusNicoll, M.Sc., Health Protection Agency, distribution of avian influenza A (H5N1) infections, with recent outbreaks in Kazak- stan, Mongolia, and Russia, indicates that more human populations are at risk.2,3 Health, Phnom Penh, Cambodia; andKwok-Yung Yuen, M.D., University ofHong Kong, Hong Kong SAR, China. Ad- dress reprint requests to Dr. Hayden atthe Department of Internal Medicine, Human influenza is transmitted by inhalation of infectious droplets and droplet nu- clei, by direct contact, and perhaps, by indirect (fomite) contact, with self-inoculation Health Sciences Center, Charlottesville, VA22908, or at [email protected].
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, Copyright 2005 Massachusetts Medical Society. and limited, nonsustained human-to-human transmission to date.
a n i m a l t o h u m a n
In 1997, exposure to live poultry within a week before the onset of illness was associ-ated with disease in humans, whereas there was no significant risk related to eating orpreparing poultry products or exposure to persons with influenza A (H5N1) disease.6Exposure to ill poultry and butchering of birds were associated with seropositivity forinfluenza A (H5N1)7 (Table 2). Recently, most patients have had a history of direct con-tact with poultry (Table 3), although not those who were involved in mass culling ofpoultry. Plucking and preparing of diseased birds; handling fighting cocks; playingwith poultry, particularly asymptomatic infected ducks; and consumption of duck’sblood or possibly undercooked poultry have all been implicated. Transmission to felidshas been observed by feeding raw infected chickens to tigers and leopards in zoos in Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. Table 1. Cumulative Number of Virologically Confirmed Cases of Avian Influenza A (H5N1) in Humans Reported to the WHO since 2003.*
Date of Onset
Thailand
Cambodia
Indonesia
* 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, identified in 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.*
Location
Year Assay Method†
Positive
Reference
hold contacts; 0 of 9 non-household contacts positive Seroconversion in 1 with mild Bridges et al.7 * 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 as- say, 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.
Thailand17,18 and to domestic cats under experi- clusters16 and in one case of apparent child-to-moth-mental conditions.19 Transmission between felids er transmission (Table 3).20 Intimate contact with-has been found under such conditions. Some infec- out the use of precautions was implicated, and sotions may be initiated by pharyngeal or gastrointes- far no case of human-to-human transmission bytinal inoculation of virus.
small-particle aerosols has been identified. In 1997,human-to-human transmission did not apparently h u m a n t o h u m a n
occur through social contact, and serologic stud- Human-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 Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 3. Presentation and Outcomes among Patients with Confirmed Avian Influenza A (H5N1).*
Hong Kong,
Thailand,
Vietnam,
Ho Chi Minh City, Cambodia,
Outcome or Measure
Time from onset of illness to presentation Clinical presentation — no./total no. (%) surveys in Vietnam and Thailand have not found to health care workers has been low, even when ap-
evidence of asymptomatic infections among con- propriate isolation measures were not used10,11 (Ta-
tacts (Table 2). Recently, intensified surveillance of ble 2). However, one case of severe illness was re-
contacts of patients by reverse-transcriptase–poly- ported in a nurse exposed to an infected patient in
merase-chain-reaction (RT-PCR) assay has led to Vietnam.
the detection of mild cases, more infections in old-
er adults, and an increased number and duration of environment to human
clusters in families in northern Vietnam,21 find- Given the survival of influenza A (H5N1) in the envi-
ings suggesting that the local virus strains may be ronment, several other modes of transmission are
adapting to humans. However, epidemiologic and theoretically possible. Oral ingestion of contami-
virologic studies are needed to confirm these find- nated water during swimming and direct intrana-
ings. To date, the risk of nosocomial transmission sal or conjunctival inoculation during exposure to
Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. Table 3. (Continued.)
Hong Kong,
Thailand,
Vietnam,
Ho Chi Minh City, Cambodia,
Outcome or Measure
* 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 recip-ients of oseltamivir recovered, as compared with one of five untreated patients.16 The use of relatively low doses of oral ribavirin 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 kilo-gram 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 contamina- each occurs. Most patients have been previously
tion of hands from infected fomites and subsequent healthy young children or adults (Table 3).
self-inoculation. The widespread use of untreated
poultry feces as fertilizer is another possible risk incubation
factor.
The incubation period of avian influenza A (H5N1)may be longer than for other known human influ-enzas. In 1997, most cases occurred within two to four days after exposure13; recent reports15,16 indi- The clinical spectrum of influenza A (H5N1) in hu- cate similar intervals but with ranges of up to eightmans is based on descriptions of hospitalized pa- days (Table 3). The case-to-case intervals in house-tients. The frequencies of milder illnesses, sub- hold clusters have generally been 2 to 5 days, but theclinical infections, and atypical presentations (e.g., upper limit has been 8 to 17 days, possibly owing toencephalopathy and gastroenteritis) have not been unrecognized exposure to infected animals or envi-determined, but case reports12,21,22 indicate that ronmental sources.
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ventilator-associated pneumonia, pulmonary hem- Most patients have initial symptoms of high fever orrhage, pneumothorax, pancytopenia, Reye’s syn-
(typically a temperature of more than 38°C) and an drome, and sepsis syndrome without documented
influenza-like illness with lower respiratory tract bacteremia.
symptoms1 (Table 3). Upper respiratory tract symp-
toms are present only sometimes. Unlike patients mortality
with infections caused by avian influenza A (H7) vi- The fatality rate among hospitalized patients has
ruses,23 patients with avian influenza A (H5N1) rare- been high (Table 3), although the overall rate is
ly have conjunctivitis. Diarrhea, vomiting, abdomi- probably much lower.21 In contrast to 1997, when
nal pain, pleuritic pain, and bleeding from the nose most deaths occurred among patients older than
and gums have also been reported early in the course 13 years of age, recent avian influenza A (H5N1) in-
of illness in some patients.14-16,24 Watery diarrhea fections have caused high rates of death among in-
without blood or inflammatory changes appears fants and young children. The case fatality rate was
to be more common than in influenza due to hu- 89 percent among those younger than 15 years of
man viruses25 and may precede respiratory mani- age in Thailand. Death has occurred an average of
festations by up to one week.12 One report described 9 or 10 days after the onset of illness (range, 6 to
two patients who presented with an encephalopath- 30),15,16 and most patients have died of progres-
ic illness and diarrhea without apparent respiratory sive respiratory failure.
symptoms.22
l a b o r a t o r y f i n d i n g s
c l i n i c a l c o u r s e
Common laboratory findings have been leukope- Lower respiratory tract manifestations develop nia, particularly lymphopenia; mild-to-moderate
early in the course of illness and are usually found thrombocytopenia; and slightly or moderately ele-
at presentation (Table 3). In one series, dyspnea de- vated aminotransferase levels (Table 3). Marked hy-
veloped a median of 5 days after the onset of ill- perglycemia, perhaps related to corticosteroid use,
ness (range, 1 to 16).15 Respiratory distress, tachyp- and elevated creatinine levels also occur.16 In Thai-
nea, and inspiratory crackles are common. Sputum land,15 an increased risk of death was associated
production is variable and sometimes bloody. Al- with decreased leukocyte, platelet, and particularly,
most all patients have clinically apparent pneumo- lymphocyte counts at the time of admission.
nia; radiographic changes include diffuse, multi-
focal, or patchy infiltrates; interstitial infiltrates; virologic diagnosis
and segmental or lobular consolidation with air Antemortem diagnosis of influenza A (H5N1) has
bronchograms. Radiographic abnormalities were been confirmed by viral isolation, the detection of
present a median of 7 days after the onset of fever H5-specific RNA, or both methods. Unlike human
in one study (range, 3 to 17).15 In Ho Chi Minh influenza A infection,26 avian influenza A (H5N1)
City, Vietnam, multifocal consolidation involving at infection may be associated with a higher frequency
least two zones was the most common abnormali- of virus detection and higher viral RNA levels in pha-
ty among patients at the time of admission. Pleural ryngeal than in nasal samples. In Vietnam, the in-
effusions are uncommon. Limited microbiologic terval from the onset of illness to the detection of
data indicate that this process is a primary viral viral RNA in throat-swab samples ranged from 2 to
pneumonia, usually without bacterial suprainfec- 15 days (median, 5.5), and the viral loads in pharyn-
tion at the time of hospitalization.
geal swabs 4 to 8 days after the onset of illness were Progression to respiratory failure has been as- at least 10 times as high among patients with influ- sociated with diffuse, bilateral, ground-glass infil- enza A (H5N1) as among those with influenza Atrates and manifestations of the acute respirato- (H3N2) or (H1N1). Earlier studies in Hong Kongry distress syndrome (ARDS). In Thailand,15 the also found low viral loads in nasopharyngeal sam-median time from the onset of illness to ARDS was ples.27 Commercial rapid antigen tests are less sen-6 days (range, 4 to 13). Multiorgan failure with sitive in detecting influenza A (H5N1) infectionssigns of renal dysfunction and sometimes cardiac than are RT-PCR assays.15 In Thailand, the resultscompromise, including cardiac dilatation and su- of rapid antigen testing were positive in only 4 of 11praventricular tachyarrhythmias, has been com- patients with culture-positive influenza A (H5N1)mon.14-16,24 Other complications have included (36 percent) 4 to 18 days after the onset of illness.
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ern Vietnam and Thailand, which includes varia- Most hospitalized patients with avian influenza A ble changes near the receptor-binding site and one
(H5N1) have required ventilatory support within fewer arginine residue in the polybasic cleavage
48 hours after admission,15,16 as well as intensive site of the hemagglutinin. However, the importance
care for multiorgan failure and sometimes hypo- of these genetic and biologic changes with respect
tension. In addition to empirical treatment with to human epidemiology or virulence is uncertain.
broad-spectrum antibiotics, antiviral agents, alone
or with corticosteroids, have been used in most pa- patterns of viral replication
tients (Table 3), although their effects have not been The virologic course of human influenza A (H5N1)
rigorously assessed. The institution of these inter- is incompletely characterized, but studies of hos-
ventions late in the course of the disease has not pitalized patients indicate that viral replication
been associated with an apparent decrease in the is prolonged. In 1997, virus could be detected in
overall mortality rate, although early initiation of nasopharyngeal isolates for a median of 6.5 days
antiviral agents appears to be beneficial.1,15,16 Cul- (range, 1 to 16), and in Thailand, the interval from
tivable virus generally disappears within two or three the onset of illness to the first positive culture ranged
days after the initiation of oseltamivir among sur- from 3 to 16 days. Nasopharyngeal replication is
vivors, but clinical progression despite early thera- less than in human influenza,27 and studies of low-
py with oseltamivir and a lack of reductions in pha- er respiratory tract replication are needed. The ma-
ryngeal viral load have been described in patients jority of fecal samples tested have been positive for
who have died.
viral RNA (seven of nine), whereas urine sampleswere negative. The high frequency of diarrheaamong affected patients and the detection of viral RNA in fecal samples, including infectious virus in c h a r a c t e r i z a t i o n o f v i r u s
one case, suggest that the virus replicates in the Studies of isolates of avian influenza A (H5N1) gastrointestinal tract. The findings in one autopsyfrom patients in 1997 revealed that virulence fac- confirmed this observation.41tors included the highly cleavable hemagglutinin Highly pathogenic influenza A (H5N1) virus- that can be activated by multiple cellular proteases, es possess the polybasic amino acid sequence at
a specific substitution in the polymerase basic pro- the hemagglutinin-cleavage site that is associat-
tein 2 (Glu627Lys) that enhances replication,28,29 ed with visceral dissemination in avian species.
and a substitution in nonstructural protein 1 Invasive infection has been documented in mam-
(Asp92Glu) that confers increased resistance to in- mals,28,29,39,40 and in humans, six of six serum
hibition by interferons and tumor necrosis factor specimens were positive for viral RNA four to nine
a (TNF-a) in vitro and prolonged replication in days after the onset of illness. Infectious virus and
swine,30 as well as greater elaboration of cytokines, RNA were detected in blood, cerebrospinal fluid,
particularly TNF-a, in human macrophages ex- and feces in one patient.22 Whether feces or blood
posed to the virus.31 Since 1997, studies of influen- serves to transmit infection under some circum-
za A (H5N1)32-34 indicate that these viruses con- stances is unknown.
tinue to evolve, with changes in antigenicity35,36
and internal gene constellations; an expanded host host immune responses
range in avian species37,38 and the ability to infect The relatively low frequencies of influenza A (H5N1)
felids17,18; enhanced pathogenicity in experimen- illness in humans despite widespread exposure to
tally infected mice and ferrets, in which they cause infected poultry indicate that the species barrier to
systemic infections39,40; and increased environ- acquisition of this avian virus is substantial. Clus-
mental stability.
ters of cases in family members may be caused by Phylogenetic analyses indicate that the Z geno- common exposures, although the genetic factors type has become dominant33 and that the virus has that may affect a host’s susceptibility to diseaseevolved into two distinct clades, one encompass- warrant study.
ing isolates from Cambodia, Laos, Malaysia, Thai- The innate immune responses to influenza A land, and Vietnam and the other isolates from Chi- (H5N1) may contribute to disease pathogenesis. Inna, Indonesia, Japan, and South Korea.21 Recently, the 1997 outbreaks, elevated blood levels of inter-a separate cluster of isolates has appeared in north- leukin-6, TNF-a, interferon-g, and soluble inter- Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine leukin-2 receptor were observed in individual pa- nition of cases is confounded by the nonspecificitytients,42 and in the patients in 2003, elevated levels of the initial clinical manifestations and high back-of the chemokines interferon-inducible protein 10, ground rates of acute respiratory illnesses from oth-monocyte chemoattractant protein 1, and mono- er causes. In addition, the possibility of influenza Akine induced by interferon-g were found three to (H5N1) warrants consideration in patients present-eight days after the onset of illness.27 Recently, plas- ing with serious unexplained illness (e.g., enceph-ma levels of inflammatory mediators (interleukin-6, alopathy or diarrhea) in areas with known influen-interleukin-8, interleukin-1b, and monocyte che- za A (H5N1) activity in humans or animals.
moattractant protein 1) were found to be higher The diagnostic yield of different types of samples among patients who died than among those who and virologic assays is not well defined. In contrastsurvived (Simmons C: personal communication), to infections with human influenza virus, throatand the average levels of plasma interferon-a were samples may have better yields than nasal samples.
about three times as high among patients with avi- Rapid antigen assays may help provide support foran influenza A who died as among healthy controls. a diagnosis of influenza A infection, but they haveSuch responses may be responsible in part for the poor negative predictive value and lack specificitysepsis syndrome, ARDS, and multiorgan failure ob- for influenza A (H5N1). The detection of viral RNAserved in many patients.
in respiratory samples appears to offer the great- Among survivors, specific humoral immune re- est sensitivity for early identification, but the sen- sponses to influenza A (H5N1) are detectable by mi- sitivity depends heavily on the primers and assaycroneutralization assay 10 to 14 days after the onset method used. Laboratory confirmation of influen-of illness. Corticosteroid use may delay or blunt za A (H5N1) requires one or more of the follow-these responses.
ing: a positive viral culture, a positive PCR assay forinfluenza A (H5N1) RNA, a positive immunofluo- p a t h o l o g i c a l f i n d i n g s
rescence test for antigen with the use of monoclo- Limited 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 to
human influenza virus.43 Changes include filling hospitalization
of 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 prov-
congestion, 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 diag-
blasts. 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 fami-
shown reactive histiocytosis with hemophagocyto- lies require education on personal hygiene and in-
sis in several patients, and lymphoid depletion and fection-control measures (Table 5). Supportive care
atypical lymphocytes have been noted in spleen and with provision of supplemental oxygen and venti-
lymphoid 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 have
been noted in several instances.
been implicated in the nosocomial spread of severeacute respiratory syndrome (SARS) and should beused only with strict airborne precautions.
a n t i v i r a l a g e n t s
The possibility of influenza A (H5N1) should be Patients with suspected influenza A (H5N1) shouldconsidered in all patients with severe acute respira- promptly receive a neuraminidase inhibitor pend-tory illness in countries or territories with animal ing the results of diagnostic laboratory testing.
influenza A (H5N1), particularly in patients who The optimal dose and duration of treatment withhave been exposed to poultry (Table 4). However, neuraminidase inhibitors are uncertain, and cur-some outbreaks in poultry were recognized only af- rently approved regimens likely represent the min-ter sentinel cases occurred in humans. Early recog- imum required. These viruses are susceptible in Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. 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 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 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 with known 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 do-mestic 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 * 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 with live or recently killed domestic fowl, dealer or trader in pet birds, health care worker, and a worker in a laboratory process-ing samples possibly containing influenza A (H5N1) virus.
vitro to oseltamivir and zanamivir.46,47 Oral osel- in children older than one year of age — twice-dailytamivir46 and topical zanamivir are active in animal doses of 30 mg for those weighing 15 kg or less,models of influenza A (H5N1).48,49 Recent murine 45 mg for those weighing more than 15 to 23 kg,studies indicate that as compared with an influen- 60 mg for those weighing more than 23 to 40 kg,za A (H5N1) strain from 1997, the strain isolated and 75 mg for those weighing more than 40 kg) arein 2004 requires higher oseltamivir doses and more reasonable for treating early, mild cases of influ-prolonged administration (eight days) to induce enza A (H5N1), higher doses (150 mg twice dailysimilar antiviral effects and survival rates.50 Inhaled in adults) and treatment for 7 to 10 days are consid-zanamivir has not been studied in cases of influen- erations in treating severe infections, but prospec-za A (H5N1) in humans.
Early treatment will provide the greatest clinical High-level antiviral resistance to oseltamivir re- benefit,15 although the use of therapy is reasonable sults from the substitution of a single amino acidwhen there is a likelihood of ongoing viral repli- in N1 neuraminidase (His274Tyr). Such variantscation. Placebo-controlled clinical studies of oral have been detected in up to 16 percent of childrenoseltamivir51,52 and inhaled zanamivir53 compar- with human influenza A (H1N1) who have receiveding currently approved doses with doses that are oseltamivir.54 Not surprisingly, this resistant vari-twice as high found that the two doses had similar ant has been detected recently in several patientstolerability but no consistent difference in clinical with influenza A (H5N1) who were treated withor antiviral benefits in adults with uncomplicated oseltamivir.21 Although less infectious in cell culturehuman influenza. Although approved doses of osel- and in animals than susceptible parental virus,55tamivir (75 mg twice daily for five days in adults oseltamivir-resistant H1N1 variants are transmis-and weight-adjusted twice-daily doses for five days sible in ferrets.56 Such variants retain full suscepti- Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 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 environ- ment 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 (tempera-ture >38°C) and patient contact should undergo appropriate diagnostic testing. If an alternative cause is not identi-fied, 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 of a lapse in aseptic technique should be considered for postexposure chemoprophylaxis with oseltamivir at a suggest-ed 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 for 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 protec-tion.† Contacts who have shared a defined setting (household, extended family, hospital or other residential institution, or mil- itary 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 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, prefera- bly at least 2 weeks before traveling.
Travelers should avoid all direct contact with poultry, including chickens, ducks, or geese that appear to be well, and farms or live-animal markets with poultry, and should avoid touching surfaces contaminated with poultry feces or se-cretions.
Travelers should reduce possible exposure by practicing good hand hygiene with frequent hand washing or use of alco- hol 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 with- in 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 Institute for Occupational Safety and Health, and N-95 a non-oilproof respirator with at least 95 percent efficiency in filtering par-ticles 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.
Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. bility to zanamivir and partial susceptibility to the and other patients in a nonpandemic situation andinvestigational neuraminidase inhibitor peramivir on the interventions used to contain SARS (Tablein vitro.57,58 5).1 The efficiency of surgical masks, even multiple In contrast to isolates from the 1997 outbreak, ones,69 is much less than that of N-95 masks, but recent human influenza A (H5N1) isolates are high- they could be used if the latter are not available.
ly resistant to the M2 inhibitors amantadine and Chemoprophylaxis with 75 mg of oseltamivir oncerimantadine, and consequently, these drugs do not daily for 7 to 10 days is warranted for persons whohave a therapeutic role. Agents of clinical investiga- have had a possible unprotected exposure.70,71 Thetional interest for treatment include zanamivir, per- use of preexposure prophylaxis warrants consid-amivir, long-acting topical neuraminidase inhibi- eration if evidence indicates that the influenza Ators, ribavirin,59,60 and possibly, interferon alfa.61 (H5N1) strain is being transmitted from person toperson with increased efficiency or if there is a like- i m m u n o m o d u l a t o r s
lihood of a high-risk exposure (e.g., an aerosol-gen- Corticosteroids have been used frequently in treat- erating procedure).
ing patients with influenza A (H5N1), with uncer-
tain 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 post-
randomized 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 period
ommended.
of one week after the last exposure to an infectedperson is appropriate. If evidence indicates thatperson-to-person transmission may be occurring, quarantine of exposed contacts should be en- i m m u n i z a t i o n
forced. For others who have had an unprotected ex- No influenza A (H5) vaccines are currently com- posure to an infected person or to an environmen-mercially 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), postex-of high hemagglutinin antigen content62 or the ad- posure chemoprophylaxis as described above maydition of MF59 adjuvant63 to generate neutralizing be warranted.
antibody responses. A third injection of adjuvanted1997 H5 vaccine variably induced cross-reacting antibodies to human isolates from 2004.64 Reversegenetics has been used for the rapid generation of Infected birds have been the primary source of in-nonvirulent 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 differsglutinin doses.67 Studies with approved adjuvants in multiple ways from influenza due to human vi-like alum are urgently needed. Live attenuated, cold- ruses, including the routes of transmission, clini-adapted intranasal vaccines are also under develop- cal severity, pathogenesis, and perhaps, responsement. 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 and h o s p i t a l - i n f e c t i o n c o n t r o l
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 lab-forts to reduce transmission to health care workers oratory support. Unlike human influenza, avian in- Downloaded from www.nejm.org on November 3, 2005 . This article is being provided free of charge for use in Argentina. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 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.
swabs or lower respiratory samples may offer more The views expressed in this article do not necessarily reflect sensitive means of diagnosis. Recent human iso- those of the WHO or other meeting sponsors.
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 Glo-for the treatment of severe illness. Despite recent bal Influenza Program at the WHO, Geneva; and to Drs. Peter Horby and Monica Guardo and the staff of the WHO Country Offices, Viet- progress, 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 epidemi- r e f e r e n c e s
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