Morbidity and Mortality Weekly Report

Early Release / Vol. 62 May 1, 2013

Emergence of Avian Influenza A(H7N9) Virus Causing Severe Human Illness

— China, February–April 2013

On March 29, 2013, the Chinese Center for Disease Control which exposure information is available, 63 (77%) involved
and Prevention completed laboratory confirmation of three reported exposure to live animals, primarily chickens (76%) and
human infections with an avian influenza A(H7N9) virus not ducks (20%) (3). However, at least three family clusters of two or
previously reported in humans (1). These infections were reported three confirmed cases have been reported where limited human-
to the World Health Organization (WHO) on March 31, 2013, to-human transmission might have occurred (3).
in accordance with International Health Regulations. The cases The median age of patients with confirmed infection is 61 years
involved two adults in Shanghai and one in Anhui Province. All (interquartile range: 48–74); 17 (21%) of the cases are among
three patients had severe pneumonia, developed acute respiratory persons aged ≥75 years and 58 (71%) of the cases are among
distress syndrome (ARDS), and died from their illness (2). males. Only four cases have been confirmed among children; in
The cases were not epidemiologically linked. The detection of addition, a specimen from one asymptomatic child was positive
these cases initiated a cascade of activities in China, including for H7N9 by real-time reverse transcription–polymerase chain
diagnostic test development, enhanced surveillance for new reaction (rRT-PCR). Among the 71 cases for which complete
cases, and investigations to identify the source(s) of infection. data are available, 54 (76%) patients had at least one underlying
No evidence of sustained human-to-human transmission has health condition (3). Most of the confirmed cases involved severe
been found, and no human cases of H7N9 virus infection have respiratory illness. Of 82 confirmed cases for which data were
been detected outside China, including the United States. This available as of April 17, 81 (99%) required hospitalization (3).
report summarizes recent findings and recommendations for Among those patients hospitalized, 17 (21%) died of ARDS or
preparing and responding to potential H7N9 cases in the United multiorgan failure, 60 (74%) remained hospitalized, and only four
States. Clinicians should consider the diagnosis of avian influenza (5%) had been discharged (3).
A(H7N9) virus infection in persons with acute respiratory Chinese public health officials have investigated human
illness and relevant exposure history and should contact their contacts of patients with confirmed H7N9. In a detailed report
state health departments regarding specimen collection and of a follow-up investigation of 1,689 contacts of 82 infected
facilitation of confirmatory testing. persons, including health-care workers who cared for those
patients, no transmission to close contacts of confirmed cases was
Epidemiologic Investigation reported, although investigations including serologic studies are
As of April 29, 2013, China had reported 126 confirmed ongoing (3). In addition, influenza surveillance systems in China
H7N9 infections in humans, among whom 24 (19%) died (1). have identified no sign of increased community transmission of
Cases have been confirmed in eight contiguous provinces in this virus. Seasonal influenza A(pH1N1) and influenza B viruses
eastern China (Anhui, Fujian, Henan, Hunan, Jiangsu, Jiangxi, continue to circulate among persons in areas where H7N9 cases
Shandong, and Zhejiang), two municipalities (Beijing and have been detected, and the Chinese Centers for Disease Control
Shanghai), and Taiwan (Figure 1). Illness onset of confirmed cases and Prevention has reported that rates of influenza-like illness
occurred during February 19–April 29 (Figure 2). The source of are consistent with expected seasonal levels.
the human infections remains under investigation. Almost all CDC, along with state and local health departments, is
confirmed cases have been sporadic, with no epidemiologic link continuing epidemiologic and laboratory surveillance for
to other human cases, and are presumed to have resulted from influenza in the United States. On April 5, 2013, CDC
exposure to infected birds (3,4). Among 82 confirmed cases for requested state and local health departments to initiate enhanced

U.S. Department of Health and Human Services

Centers for Disease Control and Prevention
 Early Release

FIGURE 1. Location of confirmed cases of human infection (n = 126) with avian influenza A(H7N9) virus and deaths (n = 24) — China,
February 19–April 29, 2013

A
No. of cases
1 Beijing North
Proportion of deaths
! Korea
4

N
! City with H7N9 case reported
2 South

I
" City with a poultry market, farm,
Shandong Korea
or household with an animal

H
positive for H7N9 27
! "
!
( !
Province with confirmed cases !
C
Henan Jiangsu
"
!
!
( !
4
!
! "
Anhui ! ! !

A " "
!
( " Shanghai
! ! !!"
!
!
!"
!
!
(

N
"
!
( ! 33

I
4
"
!
(
!!

C H 1
Hunan
!
!
Jiangxi
"
!
East China Sea

! Fujian 46
5 Zhejiang
2
!
! !
1
Taiwan

Vietnam

surveillance for H7N9 among symptomatic patients who had Laboratory Investigation
returned from China in the previous 10 days (5). As of April As of April 30, 2013, Chinese investigators had posted 19
29, 37 such travelers had been reported to CDC by 18 states. partial or complete genome sequences from avian influenza
Among those 37 travelers, none were found to have infection A(H7N9) viruses to a publicly available database at the Global
with H7N9; seven had an infection with a seasonal influenza Initiative on Sharing All Influenza Data (http://www.gisaid.
virus, one had rhinovirus, one had respiratory syncytial virus, org). Sequences are from viruses infecting 12 humans and five
and 28 were negative for influenza A and B. Among 31 cases birds, and two are from viruses collected from the environment.
with known patient age, seven travelers were aged <18 years, 13 These sequences indicate that all eight genes of the H7N9
were aged 18–64 years, and 11 were aged ≥65 years. Additionally, virus are of avian origin, with the closest phylogenetic relatives
influenza activity in the United States is low and continues to from three Eurasian influenza virus lineages (H7N3 from
decrease, with morbidity and mortality surveillance systems domestic ducks, H7N9 from wild birds, and H9N2 from
reporting activity below seasonal baseline levels. Although low birds widely distributed throughout East Asia). In addition,
numbers of influenza viruses are being detected, the majority genetic changes in the sequences are present that have been
in recent weeks have been influenza B.* associated with adaptations leading to enhanced virus binding
to and replication in mammalian respiratory cells and increased
* Additional information available at http://www.cdc.gov/flu/weekly. severity of infection (2,4,6).

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FIGURE 2. Number of confirmed cases of human infection with avian influenza A(H7N9) virus (N = 126), by date of onset of illness and province,
municipality, or area — China, February 19–April 29, 2013
10

Hunan (1)
9
Fujian (2)
8 Jiangxi (5)
Taiwan (1)
7
Shandong (2)
6 Henan (4)
No. of cases

Beijing (1)
5
Zhejiang (46)
4 Jiangsu (27)
Anhui (4)
3
Shanghai (33)
2

0
18 20 22 24 26 28 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 2 4 6 8 10 12 14 16 18 20 22 24 26 28 2 4
Feb Mar Apr May
Date of illness onset

CDC’s Influenza Division Laboratory has received two H7N9 Immediately after notification by Chinese health authorities
influenza viruses (A/Anhui/1/2013 and A/Shanghai/1/2013) of the H7N9 cases, CDC began development of a new H7
from the WHO Collaborating Centre for Reference and diagnostic test for use with the existing CDC influenza rRT-
Research on Influenza at the Chinese Center for Disease PCR kit. This test has been designed to diagnose infection with
Control and Prevention (Figure 3). Full characterization of Eurasian H7 viruses, including the recently recognized China
these viruses is ongoing; however, studies to date have shown H7N9 and other representative H7 viruses from Southeast
robust viral replication in eggs, cell culture, and the respiratory Asia and Bangladesh. On April 22, this new H7 test was
tract of animal models (ferrets and mice). At higher inoculum cleared by the Food and Drug Administration for use as an in
doses (106–104 plaque forming units), the virus shows some vitro diagnostic test under an Emergency Use Authorization,
lethality for BALB/c mice. thus allowing distribution and use of the test in the United
Laboratory testing of the A/Anhui/1/2013 virus isolate at the States. The CDC H7 rRT-PCR test is now available to all
Chinese Center for Disease Control and Prevention, CDC, and qualified U.S. public health and U.S. Department of Defense
other laboratories indicates that this virus is susceptible to oseltamivir laboratories and WHO-recognized National Influenza Centers
and zanamivir, the two neuraminidase-inhibiting (NAI) antiviral globally and can be ordered from the Influenza Reagent
drugs licensed in the United States for treatment of seasonal Resource (http://www.influenzareagentresource.org). Access
influenza. The genetic sequence of one of the publicly posted H7N9 to the CDC H7 rRT-PCR test protocol is available at http:/
viruses (A/Shanghai/1/2013) contains a known marker of NAI www.cdc.gov/flu/clsis. Guidance on appropriate biosafety
resistance (2). The clinical relevance of this genetic change is under levels for working with the virus and suspect clinical specimens
investigation but it serves as a reminder that resistance to antiviral is being developed.
drugs can occur spontaneously through genetic mutations or emerge
during antiviral treatment. The genetic sequences of all viruses tested Animal Investigation and U.S. Animal Health
showed a known marker of resistance to the adamantanes, indicating Preparedness Activities
that, although these drugs (amantadine and rimantadine) are As of April 26, reports from the China Ministry of Agriculture
licensed for use in the United States, they should not be prescribed indicate that 68,060 bird and environmental specimens have
for patients with H7N9 virus infection. been tested, 46 (0.07%) were confirmed H7N9-positive by

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culture (7). The H7N9 virus has been confirmed in chickens, FIGURE 3. Electron micrograph image of influenza A/Anhui/1/2013
ducks, pigeons (feral and captive), and environmental samples (H7N9), showing spherical virus particles characteristic of influenza
virions — April 15, 2013
in four of the eight provinces and in Shanghai municipality
(Figure 1). As of April 17, approximately 4,150 swine and
environmental samples from farms and slaughterhouses were
reported to have been tested; all swine samples were negative.†
The China Ministry of Agriculture is jointly engaged with
the National Health and Family Planning Commission in
conducting animal sampling to assist in ascertaining the extent
of the animal reservoir of the H7N9 virus. Sampling of animals
is concentrated in the provinces and cities where human cases
have been reported. Poultry markets in Shanghai and other
affected areas have been closed temporarily, and some markets
might remain closed.
The U.S. Department of Agriculture (USDA) has set up a
Situational Awareness Coordination Unit with a core team of
subject matter experts and other USDA representatives, including
the Animal and Plant Health Inspection Service (APHIS), the
Agricultural Research Service (ARS), the Food Safety and
Inspection Service, and the Foreign Agricultural Service.
USDA and CDC are working collaboratively to understand the
epidemiology of H7N9 infections among humans and animals
in China. To date, no evidence of this strain of avian influenza
Photo/CDC
A(H7N9) virus has been identified in animals in the United
States. The U.S. government does not allow importation of live
birds, poultry, and hatching eggs from countries affected with mapping study to help identify virus isolates that could be
highly pathogenic avian influenza. The current U.S. surveillance used to develop a vaccine for poultry if needed.
program for avian influenza in commercial poultry actively tests
Reported by
for any form of avian influenza virus and would be expected to
detect avian influenza A(H7N9) if it were introduced to the China–US Collaborative Program on Emerging and Re-emerging
United States. A screening test for avian influenza is available Diseases, Chinese Center for Disease Control and Prevention and
from the National Animal Health Laboratory Network and the CDC, Beijing, China. US Dept of Agriculture. Div of Global
National Veterinary Services Laboratories (NVSL), which can Migration and Quarantine, National Center for Emerging and
be used together with confirmatory tests at NVSL to detect Zoonotic Infectious Diseases; Div of State and Local Readiness,
this strain of avian influenza A(H7N9) in poultry and wild Office of Public Health Preparedness and Response; Influenza
bird samples. Coordination Unit, Office of Infectious Diseases; Influenza Div,
APHIS is working with the U.S. Department of the Interior Immunization Svcs Div and Office of the Director, National
to prepare a pathway assessment, using current literature, Center for Immunization and Respiratory Diseases; CDC.
to assess evidence for potential movement of Eurasian Corresponding contributor: Daniel Jernigan, MD, djernigan@
avian influenza viruses into North America via wild birds. cdc.gov, 404-639-2621.
USDA is conducting animal studies to characterize the virus
Editorial Note
pathogenicity and transmission properties of this virus in avian
and swine species. Preliminary results from studies performed After recognition of the first human infections with avian
on poultry by ARS in high-containment laboratories indicate influenza A(H7N9), Chinese public health officials and
that chickens and quail are showing no signs of illness but scientists rapidly reported information about identified cases
are shedding avian influenza A(H7N9) virus in these studies and posted whole virus genome sequences for public access.
(Southeast Poultry Research Laboratory, unpublished data; During April, laboratory and surveillance efforts quickly
2013). ARS also has completed a preliminary antigenic characterized the virus, developed diagnostic tests, generated
candidate vaccine viruses, identified cases and contacts,
† Additional information available at http://www.chinacdc.cn. described clinical illness, evaluated animal sources of infection,

4 MMWR / May 1, 2013 / Vol. 62

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relatively few H7N9 virus–infected birds have been detected.

What is already known on this topic?
During the month after recognition of H7N9, increasing
Human infections with a new avian influenza A(H7N9) virus numbers of infected humans have been identified in additional
were first reported to the World Health Organization on March
31, 2013. Available information suggests that poultry is the
areas of eastern China, suggesting possible widespread occurrence
source of infection in most cases. Although no evidence of of H7N9 virus in poultry. Enhanced surveillance in poultry and
sustained (ongoing) human-to-human spread of this virus has other birds in China is needed to better clarify the magnitude
been identified; small family clusters have occurred where of H7N9 virus infection in birds and to better target control
human-to-human spread cannot be conclusively ruled out. measures for preventing further transmission.
What is added by this report? The emergence of this previously unknown avian influenza
By April 29, a total of 126 H7N9 human infections (including 24 A(H7N9) virus as a cause of severe respiratory disease and death
deaths) had been confirmed. Although a number of travelers in humans raises numerous public health concerns. First, the
returning to the United States from affected areas of China have virus has several genetic differences compared with other avian
developed influenza-like symptoms and been tested for H7N9
infection, no cases have been detected in the United
influenza A viruses. These genetic changes have been evaluated
States. Laboratory and epidemiologic evidence suggest that previously in ferret and mouse studies with other influenza
this H7N9 virus is more easily transmitted from birds to humans A viruses, including highly pathogenic avian influenza
than other avian influenza viruses. Candidate vaccine viruses A(H5N1) virus, and were associated with respiratory droplet
are being evaluated and human clinical vaccine trials are transmission, increased binding of the virus to receptors on cells
forthcoming, but no decision has been made regarding a U.S.
in the respiratory tract of mammals, increased virulence, and
H7N9 vaccination program.
increased replication of virus (5). Epidemiologic investigations
What are the implications for public health practice?
have not yielded conclusive evidence of sustained human-to-
State and local health authorities are encouraged to review human H7N9 virus transmission; however, further adaptation
pandemic influenza preparedness plans to ensure response
readiness. Clinicians in the United States should consider H7N9
of the virus in mammals might lead to more efficient and
virus infection in recent travelers from China who exhibit signs sustained transmission among humans. Second, human illness
and symptoms consistent with influenza. Patients with H7N9 with H7N9 virus infection, characterized by lower respiratory
virus infection (laboratory-confirmed, probable, or under inves- tract disease with progression to ARDS and multiorgan
tigation) should receive antiviral treatment with oral oseltamivir failure, is significantly more severe than in previously reported
or inhaled zanamivir as early as possible.
infection with other H7 viruses. Over a 2-month period, 24
deaths (19% of cases) have occurred, compared with only
and implemented control measures. Preliminary investigations one human death attributed to other subtypes of H7 virus
of patients and close contacts have not revealed evidence reported previously. Third, H7N9-infected poultry are the
of sustained human-to-human transmission, but limited likely source of infection in humans, but might not display
nonsustained human-to-human H7N9 virus transmission illness symptoms. Consequently, efforts to detect infection
could not be excluded in a few family clusters (3). Despite in poultry and prevent virus transmission will be challenging
these efforts, many questions remain. for countries lacking a surveillance program for actively
The epidemiology of H7N9 infections in humans so far identifying low-pathogenicity avian influenza in poultry. In the
reveals that most symptomatic patients are older (median age: United States, an active surveillance program is in place that
61 years), most are male (71%), and most had underlying routinely identifies low–pathogenicity viruses. If this newly
medical conditions. In comparison, among the 45 avian recognized H7N9 is detected, public health and animal health
influenza A(H5N1) cases reported from China during 2003– officials should identify means for monitoring the spread of
2013, the median patient age is 26 years (8). This difference asymptomatic H7N9 virus infections in poultry and maintain
in median age might represent actual differences in exposure vigilance for virus adaptation and early indications of potential
or susceptibility to H7N9 virus infection and clinical illness, human-to-human transmission.
or preliminary H7N9 case identification approaches might Beginning in early April 2013, CDC and U.S. state and
be more likely to capture cases in older persons. Ongoing local health departments initiated enhanced surveillance for
surveillance and case-control studies are needed to better H7N9 virus infections in patients with a travel history to
understand the epidemiology of H7N9 virus infections, and affected areas. A new CDC influenza rRT-PCR diagnostic test
to determine whether younger persons might be more mildly has been cleared by the Food and Drug Administration under
affected, and therefore less likely to be detected via surveillance. an Emergency Use Authorization and is being distributed to
Available animal testing data and human case histories indicate public health laboratories to assist in evaluating these suspect
that most human patients have poultry exposure; however,

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 Early Release

cases. Clinicians should consider the possibility of H7N9 virus United States, CDC recommends that local authorities and
infection in patients with illness compatible with influenza who preparedness programs take time to review and update their
1) have traveled within ≤10 days of illness onset to countries pandemic influenza vaccine preparedness plans because it
where avian influenza A(H7N9) virus infection recently has been could take several months to ready a vaccination program, if
detected in humans or animals, or 2) have had recent contact one becomes necessary. CDC also recommends that public
(within ≤10 days of illness onset) with a person confirmed to health agencies review their overall pandemic influenza plans to
have infection with avian influenza A(H7N9) virus. Because of identify operational gaps and to ensure administrative readiness
the potential severity of illness associated with avian influenza for an influenza pandemic. Continued collaboration between
A(H7N9) virus infection, CDC recommends that all H7N9 the human and animal health sectors is essential to better
patients (confirmed, probable, or under investigation for understand the epidemiology and ecology of H7N9 infections
H7N9 infection) receive antiviral treatment with oseltamivir or among humans and animals and target control measures for
zanamivir as early as possible. Treatment should be initiated even preventing further transmission.
>48 hours after onset of illness. Guidance on testing, treatment,
References
and infection control measures for H7N9 cases has been posted
to the CDC H7N9 website (9). 1. World Health Organization. Global Alert and Response (GAR): human
infection with influenza A(H7N9) virus in China. Geneva, Switzerland:
On April 5, CDC posted a Travel Notice on the Traveler’s World Health Organization; 2013. Available at http://www.who.int/csr/
Health website informing travelers and U.S. citizens living in don/2013_04_01/en/index.html.
China of the current H7N9 cases in China and reminding 2. Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza
A (H7N9) virus. N Engl J Med 2013; April 11 [Epub ahead of print].
them to practice good hand hygiene, follow food safety 3. Li Q, Zhou L, Zhou M, et al. Preliminary report: epidemiology of the
practices, and avoid contact with animals (10). CDC and avian influenza A (H7N9) outbreak in China. N Engl J Med 2013;
WHO do not recommend restricting travel to China at this April 24 [Epub ahead of print].
4. CDC. CDC health advisory: human infections with novel influenza A
time. If travelers to China become ill with influenza signs or (H7N9) viruses. Atlanta, GA: US Department of Health and Human
symptoms (e.g., fever, cough, or shortness of breath) during Services, CDC, Health Alert Network; 2013. Available at http://
or after returning from their visit, they should seek medical emergency.cdc.gov/han/han00344.asp.
treatment and inform their doctor about their recent travel. 5. Uyeki TM, Cox NJ. Global concerns regarding novel influenza A (H7N9)
virus infections. N Engl J Med 2013; April 11 [Epub ahead of print].
Travelers should continue to visit www.cdc.gov/travel or follow 6. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian
@CDCtravel on Twitter for up-to-date information about influenza A H7N9 virus from wet market poultry: clinical analysis and
CDC’s travel recommendations. characterisation of viral genome. Lancet 2013; April 25 [Epub ahead of print].
7. Ministry of Agriculture of the People’s Republic of China. No H7N9
Given the number and severity of human H7N9 illnesses virus found in poultry farm samples. Beijing, China: Ministry of
in China, CDC and its partners are taking steps to develop a Agriculture; 2013. Available at http://english.agri.gov.cn/news/
H7N9 candidate vaccine virus. Past serologic studies evaluating dqnf/201304/t20130427_19537.htm.
8. World Health Organization. Update on human cases of influenza at the
immune response to H7 subtypes of influenza viruses have human – animal interface, 2012. Wkly Epidemiol Rec 2013;88:137–44).
shown no existing cross-reactive antibodies in human sera. In 9. CDC. Avian influenza A (H7N9) virus. Atlanta, GA: US Department
addition, CDC has activated its Emergency Operations Center of Health and Human Services, CDC; 2013. Available at http://www.
to coordinate efforts. In the United States, planning for H7N9 cdc.gov/flu/avianflu/h7n9-virus.htm.
10. CDC. Travelers’ health. Watch: level 1, practice usual precautions—avian
vaccine clinical trials is under way. Although no decision has flu (H7N9). Atlanta, GA: US Department of Health and Human
been made to initiate an H7N9 vaccination program in the Services, CDC; 2013. Available at http://wwwnc.cdc.gov/travel/notices/
watch/avian-flu-h7n9.htm.

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