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Official reprint from UpToDate®

www.uptodate.com ©2017 UpToDate®

Avian influenza A H7N9: Epidemiology, clinical manifestations, and diagnosis

Author: Anna R Thorner, MD

Section Editor: Martin S Hirsch, MD
Deputy Editor: Allyson Bloom, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2017. | This topic last updated: Feb 15, 2017.

INTRODUCTION — In late March and April 2013, human cases of novel avian influenza A H7N9 infection
in China were reported to the World Health Organization [1-7]. The initial wave occurred from February to
May 2013, during which 133 cases were detected [8]. The number of new cases peaked in April 2013 and
then declined [9], likely related, at least in part, to implementation of control strategies including closure of
live bird markets and increased public awareness. A rise in the number of cases occurred in late 2013 and
early 2014, late 2014 and early 2015, and late 2016 and early 2017, coinciding with influenza season
[10,11]. Cases continue to be detected [12].

The epidemiology, clinical manifestations, and diagnosis of avian influenza A H7N9 infections will be
reviewed here. The treatment and prevention of avian influenza A H7N9 infections are discussed
separately. (See "Avian influenza A H7N9: Treatment and prevention".)

Other avian influenza viruses (eg, H5N1 influenza) and seasonal influenza viruses are also reviewed
separately. (See "Epidemiology, transmission, and pathogenesis of avian influenza" and "Clinical
manifestations and diagnosis of avian influenza" and "Treatment and prevention of avian influenza" and
"Avian influenza vaccines" and "Epidemiology of influenza" and "Clinical manifestations of seasonal
influenza in adults" and "Diagnosis of seasonal influenza in adults" and "Seasonal influenza in children:
Clinical features and diagnosis" and "Treatment of seasonal influenza in adults" and "Seasonal influenza
in children: Prevention and treatment with antiviral drugs" and "Seasonal influenza vaccination in adults"
and "Seasonal influenza in children: Prevention with vaccines".)

VIROLOGY

Sources of the reassortant virus — Avian influenza A H7N9 virus appears to have derived from multiple
reassortment events of several avian influenza viruses (figure 1) [4,13-18]. One study, which was based
on the first four human isolates, showed the following results [14]:

● The novel H7N9 avian influenza A virus appears to have derived from at least four different avian
influenza viruses. The H7 gene is genetically close to sequences isolated from ducks in Zhejiang
province. The NA gene is genetically close to genes from H7N9 viruses isolated from wild ducks in
South Korea. The six internal genes are clustered together with H9N2 viruses isolated from poultry
and ducks in China. Analyses suggest at least two different origins of H9N2 viruses, one for the NS
gene and one for the remaining internal genes.

● Detailed analyses show that ducks and chickens probably acted as intermediate hosts in which
viruses reassorted, leading to the emergence of this novel virus.

● The authors hypothesize that the HA genes were circulating in wild birds and ducks along the East
Asian flyway (which covers eastern China, South Korea, and Japan) and that the NA genes were
introduced from European lineages and transferred to ducks in China by wild birds through migration

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along the East Asian flyway. H9N2 avian influenza viruses circulating in chicken and duck populations
in eastern China possibly reassorted with the H7 and N9 avian influenza viruses in ducks, which led
to the emergence of the new H7N9 lineage. After these reassortment events took place, the new
H7N9 viruses began to circulate in chickens. The isolates causing the human cases and avian
outbreaks appear to form two separate subclades, with one of the human isolates differing from the
other three in the HA, NA, and internal genes.

The role of avian species in the spread of infection is discussed below. (See 'Role of avian species'
below.)

Genetic characteristics — Several genetic characteristics of the first four avian influenza A H7N9 viruses
isolated from humans, as well as isolates collected at a Shanghai market from a pigeon, a chicken, and
the environment, have allowed experts to evaluate and possibly predict the behavior of H7N9 influenza
viruses in humans and birds [13]:

● The HA cleavage sequence possesses a single basic amino acid, suggesting that these viruses are
of low pathogenicity in avian species [13]. This has important public health implications, since viruses
with low pathogenicity are able to spread in poultry undetected and potentially cause "silent"
epidemics and outbreaks resulting in sporadic infections in humans who come into direct contact with
infected birds. In contrast, highly pathogenic avian influenza viruses (such as H5N1) have a series of
basic amino acids at the HA cleavage site that confer virulence and kill birds rapidly.

● The amino acid sequence of the receptor-binding site of HA determines the preference for
human-type (alpha 2-6 galactose) or avian-type (alpha 2-3 galactose) receptors. Certain mutations at
the HA receptor-binding site (eg, the Q226L mutation) may increase the binding of avian influenza
viruses to human-type receptors [13,14]. In one study, recombinant viruses containing avian influenza
A H7N9 HA genes possessing the Q226L or Q226I mutation bound preferentially to human-type
receptors, whereas a recombinant virus lacking these mutations bound equally well to both
human-type and avian-type receptors [19]. (See 'Receptor and tissue tropism' below.)

● Several other nucleotide sequences are present in the avian influenza A H7N9 isolates that are
expected to increase virulence in mammals [13].

Avian influenza A H7N9 viruses isolated during the second wave in late 2013 and early 2014 differed
genetically in five of eight RNA segments from viruses isolated during the first wave in early 2013 [20].
The five novel RNA segments were similar to those of locally circulating H9N2 influenza viruses,
suggesting that continued reassortment with H9N2 influenza viruses occurred during the second wave.
Viruses isolated during the fifth wave in late 2016 were similar to viruses from 2013 [21].

PATHOGENESIS

Receptor and tissue tropism — Tropism of avian influenza A H7N9 viruses for human-type (alpha 2-6
galactose) or avian-type (alpha 2-3 galactose) receptors may affect their pathogenicity (see 'Genetic
characteristics' above). Human upper respiratory tract tissues and trachea contain mainly alpha 2-6
galactose receptors, whereas human lung tissues contain a mixture of alpha 2-3 galactose and alpha 2-6
galactose receptors [22]. Avian influenza A H7N9 viruses appear to bind to human-type receptors,
suggesting that they have tropism for cells in the human upper and lower respiratory tract and that they
may be transmissible among humans [19,22-25]. However, in one study, the H7 hemagglutinin showed a
strong preference for binding avian-type receptors over human-type receptors [26].

In a study in which sections of explanted human tracheal and lung tissues were infected with avian
influenza A H7N9, epithelial cells in the lower respiratory tract and type II pneumocytes in alveoli were
susceptible to infection as evidenced by the expression of viral nucleoprotein; the virus titer in lung tissues
was approximately 10-fold higher than in tracheal tissues and the viruses bound to both human-type and

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avian-type receptors [22].

Influenza virus infection begins with attachment of hemagglutinin to the cellular receptor and subsequent
fusion of viral envelope and cellular endosomal membrane [27]. Posttranslational cleavage of
hemagglutinin by host protease is a prerequisite for fusion and therefore for virus infectivity, tissue tropism,
and pathogenicity. Transmembrane protease S2 (TMPRSS2) is a host protease that cleaves and activates
the hemagglutinin of influenza viruses in the human respiratory tract. In a genome-wide association study,
a polymorphism that upregulates TMPRSS2 expression was associated with severe H7N9 influenza
infection.

Receptor binding and tissue tropism among avian influenza A H5N1 viruses are discussed separately.
(See "Epidemiology, transmission, and pathogenesis of avian influenza", section on 'Tissue tropism'.)

Transmission — Whether novel avian influenza viruses are (or will become) readily transmissible among
humans is an important question. To date, there is no evidence of sustained human-to-human
transmission, although several small clusters of infections have been reported. (See 'Epidemiology'
below.)

Ferrets are often used as a model for human influenza infections because transmission is similar in ferrets
and humans. In some studies in ferrets, avian influenza A H7N9 viruses isolated from humans were
transmitted via respiratory droplets [19,23,28,29]. However, in another study in ferrets, these viruses were
transmitted efficiently by direct contact, but were not readily transmissible via respiratory droplets [30].

Chemokines and cytokines — High levels of chemokines and cytokines might contribute to the severity
of infection. In a study that measured the concentrations of chemokines and cytokines in the serum of
patients with avian influenza A H7N9 infection, the levels of several chemokines and cytokines (eg,
interferon inducible protein-10 [IP-10], monocyte chemoattractant protein-1, interleukin [IL]-6, IL-8) were
elevated compared with levels in healthy individuals [22].

In another study, IP-10, IL-6, IL-17, and IL-2 concentrations were increased in the serum of patients
infected with avian influenza A H7N9 [31]. IL-6 and IP-10 were significantly higher in severely ill patients
compared with patients who were not severely ill.

EPIDEMIOLOGY — In late March and April 2013, human cases of novel avian influenza A H7N9 infection
were reported to the World Health Organization (WHO); the earliest cases occurred in eastern China
[1-7,32-35]. The first was identified on February 19, 2013 [36]. Additional cases have been detected in
other parts of mainland China as well as in Hong Kong, Taiwan, Malaysia, and Canada [37-39]. The case
in Malaysia occurred in a Chinese traveler to Malaysia who was symptomatic before leaving China; the
two in Canada occurred in travelers who had visited China [37].

Of 130 laboratory-confirmed cases, the median age of patients was 62 years (interquartile range 47 to 73
years) [9]. In contrast, the median age of avian influenza A H5N1 cases in China is 26 [9,40]. The majority
of patients (72 percent) lived in an urban area [9]. In urban areas, the male-to-female ratio was 2.9 to 1,
whereas in rural areas, the ratio was 1.6 to 1; this difference is likely due to varying patterns of exposure
to poultry, with men in urban areas having greater exposure to poultry in live markets.

Forty-seven of 111 cases (42 percent) occurred in patients ≥65 years of age [41]. Of the first 100 adult
cases, men and women were equally represented in the youngest age group (20 to 34 years), but men
were two- to threefold more frequently affected in older age groups [42]. Few cases have been detected in
children. Among 111 cases, 68 (61 percent) occurred in patients with at least one coexisting medical
condition [41]. In a case-control study, chronic medical conditions (excluding hypertension) were a risk
factor for infection [43]. In another study, obesity, chronic obstructive pulmonary disease, and
immunosuppressive medications were associated with avian influenza A H7N9 infection [44]. After
adjusting for age and sex, chronic heart disease was associated with an increased risk of hospitalization

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[45].

To date, there is no evidence of sustained human-to-human transmission [39,46], although several small
clusters of infections have been reported [6,37,47,48]. No clusters have involved healthcare workers [37].
Likely human-to-human transmission was reported from a man to his adult daughter [47]. The man
became ill five to six days after his last exposure to poultry, and his daughter, who had no known exposure
to poultry, provided bedside care to him while he was hospitalized and became ill six days after her last
contact with him. The viruses isolated from these patients were nearly identical. Forty-three close contacts
of both patients were identified. One had mild illness but had negative results for avian influenza A H7N9
virus by real-time reverse-transcriptase polymerase chain reaction. All 43 close contacts tested negative
for avian influenza A H7N9 hemagglutinin-inhibition antibodies.

Likely nosocomial transmission was reported in China, involving a 57-year-old man admitted for an
exacerbation of chronic obstructive pulmonary disease who developed influenza-like symptoms after
sharing a hospital ward for five days with a patient who was ill with influenza A H7N9 infection after visiting
a live poultry market [48]. Genome sequences of the viruses isolated from both patients were nearly
identical to one another and were also genetically similar to a fecal virus isolate from a chicken at the live
poultry market.

Among 2675 close contacts of 139 confirmed cases, respiratory symptoms developed in 28 (1 percent)
during the seven-day surveillance period [6]. All of the throat swabs collected from these 28 individuals
were negative for avian influenza A H7N9 by real-time reverse transcriptase polymerase chain reaction. In
another study, none of 330 close contacts of 14 patients who died from avian influenza A H7N9 infection
developed infection within seven days of monitoring [49].

One case of human coinfection with avian influenza A H7N9 and influenza A H3N2 was reported in a
previously healthy 15-year-old boy in Jiangsu province, China [50]. The patient was hospitalized and
treated with oseltamivir; he recovered without developing respiratory failure or other signs of severe
infection. None of the patient’s close contacts developed influenza-like symptoms. The finding of human
coinfection suggests that humans can act as mixing vessels for virus reassortment, which might facilitate
human-to-human transmission.

Updated information about the novel avian influenza A H7N9 can found on the WHO website.

Case counts — During the initial wave from February to May 2013, 133 cases were detected [8]. The
number of new cases peaked in April 2013 and then declined [9]; it is likely that the reduction in cases
was related, at least in part, to implementation of control strategies including closure of live poultry
markets and increased public awareness. (See "Avian influenza A H7N9: Treatment and prevention",
section on 'Prevention'.)

A rise in the number of cases also occurred in late 2013 and early 2014, late 2014 and early 2015, and
late 2016 and early 2017, coinciding with influenza season [11,37]. The fifth wave in late 2016 and early
2017 has been particularly large, involving more than 300 cases [51]. Over 90 percent of cases reported
exposure to poultry, mostly at live poultry markets. Three clusters of cases were detected, but there has
been no evidence of sustained human-to-human transmission [21].

Case definitions — The following case definitions have been adapted from those developed by the
United States Centers for Disease Control and Prevention (CDC) [52]:

● Confirmed case – Avian influenza A H7N9 virus infection in a patient that is confirmed by the CDC’s
Influenza Laboratory or a CDC-certified public health laboratory using methods agreed upon by the
CDC and the Council of State and Territorial Epidemiologists. Confirmation of avian influenza A H7N9
viruses may be made by public health laboratories following CDC-approved protocols for detection of
avian influenza A H7N9 virus or by laboratories using a US Food and Drug Administration

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(FDA)-authorized test specific for the detection of avian influenza A H7N9 virus.

● Probable case – Illness compatible with influenza in a patient meeting any of the exposure criteria
described below and for whom laboratory diagnostic testing is positive for influenza A, negative for
H1, negative for H1pdm09, and negative for H3 by real-time reverse transcription polymerase chain
reaction (RT-PCR) and therefore unsubtypeable.

● Case under investigation – Illness compatible with influenza in a patient meeting any of the
exposure criteria below and for whom laboratory confirmation is not known or pending or for whom
test results do not provide a sufficient level of detail to confirm novel influenza A virus infection:

• Patients with recent travel (within <10 days of illness onset) to areas where human cases of
avian influenza A H7N9 virus infection have been detected or to areas where avian influenza A
H7N9 viruses are known to be circulating in animals or

• Patients who have had recent close contact within 10 days of illness onset with confirmed cases
of human infection with avian influenza A H7N9 virus

● Close contact – Close contact involves coming within about 6 feet (2 meters) or within the room or
care area of a confirmed or probable case for a prolonged period of time or having direct contact with
infectious secretions (such as being directly in the path of a sneeze) while the patient was likely to be
infectious (beginning one day prior to illness onset and continuing until resolution of illness) [53].

Role of avian species — Avian influenza A H7N9 viruses have been isolated from poultry (including
ducks and chickens) and pigeons and their environment in some areas of China; most of the positive
samples have been detected from live poultry markets [13,54-56]. The genes of isolates from two infected
patients were nearly identical to those of an isolate from a chicken and a poultry cage specimen,
respectively, that were epidemiologically linked to the patients [57,58].

It is likely that avian influenza A H7N9 has been transmitted to humans from the secretions or excretions
of infected poultry [9,59,60]. Among 131 patients, 107 (82 percent) had a history of recent exposure to
animals: 82 percent to chickens, 22 percent to ducks, and 6 percent to swine [6]. These exposures
occurred while visiting or working at a live animal market. Other animals that these patients had been
exposed to included pigeons, geese, quail, wild birds, pet birds, cats, and dogs.

In a case-control study, risk factors for infection included direct contact with poultry or other birds during
the two weeks before illness onset and environment-related exposure (eg, visiting a live poultry market)
[43]. In another study, visiting a live poultry market was associated with avian influenza A H7N9 infection
but having backyard poultry was not [44].

Because wild and domestic songbirds (finches, sparrows, parakeets) interact with both humans and
poultry and avian influenza A H7N9 can replicate in and be shed by these birds, they have the potential to
serve as intermediate hosts [61].

Pandemic potential — Public health officials are monitoring cases of avian influenza A H7N9 infection
carefully. Some experts have suggested that the genetic characteristics of the virus raise concern that a
pandemic with this virus could occur. However, to date, there has been no evidence of sustained human-
to-human transmission. (See 'Genetic characteristics' above and 'Transmission' above.)

All influenza pandemics since 1918 have been caused by influenza viruses that have derived from wild
bird viruses and have serially acquired certain mutations associated with circulation in humans [62].
However, scientists have not found evidence of a direct mutational mechanism that has caused these
pandemics. Conversely, many avian influenza viruses have infected humans and have acquired such
mutations without causing a pandemic.

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Based on nearly a century of observations, among the 17 influenza hemagglutinin and 10 neuraminidase
genes known to exist in nature, only a few subtype combinations (H1N1, H2N2, and H3N2) have been
incorporated into any human-adapted or pandemic influenza virus strain [62]. Nevertheless, influenza
viruses are unpredictable and much remains unknown about the risk of avian influenza A H7N9 causing a
pandemic. Preparing for a possible pandemic remains an important priority [62,63].

CLINICAL MANIFESTATIONS

Incubation period — The usual incubation period has been estimated to be from 3 to 7 days but has
been reported to be as long as 10 days [6,9,53,57].

Clinical features — Patients have presented with respiratory tract infections, many of which have
progressed to severe pneumonia [64]. Presenting signs and symptoms may include fever, cough,
dyspnea, headache, myalgias, and malaise [9,41,57,59].

In an analysis that used China’s national integrated database to evaluate 123 cases of laboratory-
confirmed avian influenza A H7N9 hospitalized by late May 2013, the estimated fatality risk on hospital
admission was 36 percent [65]. Risks of mechanical ventilation or fatality (69 percent) and of intensive
care unit (ICU) admission, mechanical ventilation, or fatality (83 percent) were high.

Early in an outbreak, case detection is usually skewed towards severe cases, laboratory-based case
ascertainment can vary by location and over time, and there are delays between onset, death, and
reporting [66]. Severity estimates will be refined further as the outcomes of patients who are currently ill
become clear and as serologic surveillance studies are completed.

Severe disease — In case reports and case series, clinical features included fulminant pneumonia,
respiratory failure, acute respiratory distress syndrome (ARDS), septic shock, multiorgan failure,
rhabdomyolysis, disseminated intravascular coagulation, and encephalopathy [4,6,57,67,68]. Some
patients with severe pneumonia have required extracorporeal membrane oxygenation (ECMO) [41,68,69].
(See "Extracorporeal membrane oxygenation (ECMO) in adults".)

One patient initially had fever and general malaise without respiratory symptoms or myalgias and sought
medical attention on the fifth day of illness because of high fever (40°C) and mild sore throat [67,70]. A
right lower lobe interstitial pneumonia developed on the seventh day of illness and progressed to bilateral
lower lung consolidation and respiratory failure.

Various case series have described cases of avian influenza A H7N9 infection [6,9,33,41,45,49,71].
Selected findings include the following:

● Among 130 patients with confirmed infection, the median time from onset of illness to hospital
admission was 4.2 days (95% CI 3.7-4.9 days), from onset of illness to laboratory confirmation was
8.3 days (95% CI 7.3-9.5 days), and from hospital admission to death was 12.0 days [9].

● Among 137 patients with confirmed infection for whom data were available, the median time from
onset of illness to the first medical visit was one day [6]. Patients were hospitalized a median of four
days after the onset of illness.

● In a report that described the characteristics of 24 fatal cases, the median number of days from
symptom onset to first medical visit was 2 days (interquartile range [IQR] 0 to 4.0 days), to
hospitalization was 5 days (IQR 2.8 to 6.3 days), to confirmation of diagnosis was 9.5 days (IQR 6.3
to 14.5 days), and to death was 13 days (IQR 8.5 to 16.0 days) [49]. The median number of days
from first medical visit to death was 11 days (IQR 4.5 to 16.0 days), from hospitalization to death was
10 days (IQR 1.8 to 14.5 days), and from confirmation of diagnosis to death was 5 days (IQR 1.0 to
9.5 days).

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● Among 109 patients for whom treatment data were available, 79 (72 percent) received oseltamivir,
beginning a median of six days after onset of illness [6]. ARDS developed in 48 of 83 patients (58
percent) for whom data were available after a median of 7 days, and 47 of 139 patients (34 percent)
died a median of 21 days after the onset of illness.

In a study of 111 hospitalized patients with avian influenza A H7N9 infection, 85 (77 percent) were
admitted to an intensive care unit and 30 (27 percent) died [41]. The most common presenting symptoms
were fever (100 percent) and cough (90 percent). The majority of patients had sputum production (56
percent) and shortness of breath (56 percent). Some patients (14 percent) had diarrhea or vomiting. At the
time of admission, 108 patients (97 percent) had findings consistent with pneumonia. Bacteria were
isolated from cultures of respiratory specimens (and in a few cases also from blood cultures) in 29
patients (26 percent); bacterial pathogens were detected at least 48 hours following hospital admission in
all patients. No patients had conjunctivitis, in contrast to past cases and outbreaks of avian influenza H7
infection in the Netherlands and elsewhere. (See "Epidemiology, transmission, and pathogenesis of avian
influenza", section on 'Avian influenza H7'.)

The most common complications were moderate to severe ARDS (in 71 percent), shock (26 percent),
acute kidney injury (16 percent), and rhabdomyolysis (10 percent) [41]. The median time from onset of
illness to ARDS was 7 days (range 1 to 19 days) and from onset illness to shock was 8 days (range 3 to
55 days). Of the 79 patients with ARDS, 65 required mechanical ventilation, and, of these, 20 went on to
receive ECMO. On multivariate analysis, the presence of a coexisting medical condition was the only
independent risk factor for the development of moderate to severe ARDS (odds ratio [OR] 3.4, 95% CI
1.2-9.7). On multivariate analysis, shock was the only predictor of death (OR 6.5, 95% CI 1.1-38.9).

Mild or moderate disease — Although most of the patients described have been severely ill, there is
some evidence that mild and moderate disease also occurs. Using China’s national sentinel surveillance
system in outpatient clinics and emergency departments of 554 sentinel hospitals across 31 provinces in
mainland China, a subset of patients with influenza-like illness underwent testing for avian influenza A
H7N9 using real-time reverse-transcriptase polymerase chain reaction of nasopharyngeal swabs [72].
Among the 130 individuals with laboratory-confirmed avian influenza A H7N9 infection in China through
late May 2013, five (4 percent) were detected using the sentinel surveillance system. The mean age of
patients identified through the surveillance system was 13 years (range 2 to 26) and none had any
underlying medical conditions. All patients presented with fever and most had upper respiratory tract
symptoms; one patient had pneumonia. Only two of the five patients required hospitalization and all five
had mild or moderate disease and recovered uneventfully.

Asymptomatic infections and pre-existing immunity — One asymptomatic H7N9 infection has been
detected in a child [7,73].

Most studies have shown that people in Asia lack preexisting immunity to avian influenza A H7N9
[19,22,74-76], although two studies have shown evidence of immunity in a subset of poultry workers in
China [77,78]:

● In a retrospective serologic study, none of 1544 serum samples collected between January and
November 2012 from workers from live poultry markets, farms, poultry yards, slaughterhouses, and
wild bird habitats in China were positive for avian influenza A H7N9 using a microneutralization assay
[74].

● In a retrospective serologic study, between April 1 and May 1, 2013, none of 126 healthy healthcare
workers or 615 healthy non-healthcare workers in Zhejiang province, China, had a hemagglutinin-
inhibition (HI) titer ≥20 for H7-specific antibodies [75].

● Among 90 children and adults in China who had serum stored between 2012 and 2013, none had

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antibodies against avian influenza A H7N9 [22]. In addition, no cross-reactive antibodies against
avian influenza A H7N9 were detected following seasonal influenza vaccination.

● A surveillance study conducted in H7N9 outbreak areas of China found no seropositivity for
antibodies specific for avian-origin H7N9 virus among 1129 individuals of the general population,
whereas 6 percent among 396 poultry workers had an HI titer ≥80, suggesting that infected poultry is
the principal source of human infections and that subclinical infections are possible [77].

● In poultry workers in southern China, 36 of 501 (7 percent) in May 2013 and 56 of 375 (15 percent) in
December 2013 had HI titers ≥160 against H7N9 [78]. Of 96 workers who participated in both
surveys, 52 (54 percent) workers had a ≥4-fold rise in H7N9 titers from May to December 2013. In the
general population, 0 of 417 individuals in March 2013 and 0 of 408 individuals in September 2013
had titers ≥160 against H7N9.

● In a study that evaluated 500 serum samples from individuals in Japan, none had antibodies against
avian influenza A H7N9 [19].

Laboratory findings — In a study of 111 hospitalized patients with avian influenza A H7N9 infection, 88
percent had lymphopenia and 73 percent had thrombocytopenia [41]. The white blood cell count was
normal or slightly decreased in most patients. Elevated levels of aspartate aminotransferase, alanine
aminotransferase, lactate dehydrogenase, creatine kinase, and C-reactive protein have been reported
[41,45].

Avian influenza A H7N9 can be detected by real-time reverse transcriptase polymerase chain reaction
(rRT-PCR) from nasopharyngeal and/or lower respiratory tract samples. (See 'Diagnosis' below.)

In a study of 14 hospitalized patients with avian influenza A H7N9 pneumonia, viral RNA was also
detected from the serum in 12 patients (86 percent), including all 3 patients requiring ECMO, all 4 patients
requiring mechanical ventilation, and 5 of 7 patients with pneumonia who did not require mechanical
ventilation or ECMO [69]. Viral RNA was also detected in the urine and/or stool of some patients.

In a study of 12 ICU patients with avian influenza A H7N9 infection, viral RNA was detected in the stool of
6 of 12 patients (50 percent) but was not detected in the cerebrospinal fluid, urine, or blood of any patients
[71].

Imaging — On chest radiograph and computed tomography (CT) scanning, patients with pneumonia have
had multilobar patchy consolidations and diffuse ground-glass opacities (image 1 and image 2)
[41,57,79-81]. Other CT findings have included air bronchograms, interlobular septal thickening,
centrilobular nodules, reticular opacities, cystic changes, bronchial dilatation, and subpleural linear
opacities [79].

Histopathology — Postmortem histopathology from three patients with fatal avian influenza A H7N9
infection has been reported [71]. The lungs of one patient showed intraalveolar hemorrhage, diffuse
alveolar damage, and hyaline formation without fibroproliferative changes; these features are compatible
with the acute exudative inflammatory phase of infection. The lungs of two other patients, who died on day
11 after symptom onset, demonstrated pneumocyte hyperplasia and interstitial fibrosis in addition to the
diffuse alveolar damage, which is compatible with the fibroproliferative phase of infection. Reactive
hemophagocytosis in the bone marrow and lymphoid atrophy in splenic tissues were compatible with
laboratory findings of leukopenia, lymphopenia, and thrombocytopenia. Hypoxic and fatty changes of
kidney and liver tissues were compatible with impaired renal or liver function.

DIAGNOSIS — In patients suspected of having avian influenza A H7N9 infection, respiratory specimens
should be obtained as soon as possible after illness onset and tested using real-time reverse-
transcriptase polymerase chain reaction (rRT-PCR) for avian influenza A H7N9 [82]. The following

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recommendations have been adapted from those issued by the United States Centers for Disease Control
and Prevention (CDC) and the World Health Organization (WHO) [7,54,82,83].

The diagnosis of avian and seasonal influenza is discussed in greater detail separately. (See "Clinical
manifestations and diagnosis of avian influenza", section on 'Diagnosis' and "Diagnosis of seasonal
influenza in adults".)

Whom to test — Patients who meet both the clinical illness and exposure criteria described below should
be tested for avian influenza A H7N9 infection using rRT-PCR [84]. Decisions regarding diagnostic testing
for influenza using rRT-PCR should be made using available clinical and epidemiologic information, and
additional persons in whom clinicians suspect H7N9 infection should also be tested.

● Clinical illness criteria:

• Patients with new-onset severe acute respiratory infection requiring hospitalization and

• Patients for whom no alternative infectious etiology is identified

● Exposure criteria:

• Patients who inhabit or have had recent travel (within 10 days of illness onset) to areas where
human cases of avian influenza A H7N9 infection have been detected or to areas where avian
influenza A H7N9 viruses are known to be circulating in animals or

• Patients who have had recent close contact (within 10 days of illness onset) with confirmed
cases of human infection with avian influenza A H7N9. Close contact involves coming within
about 6 feet (2 meters) of a confirmed case while the case was ill (beginning one day prior to
illness onset and continuing until resolution of illness). Close contacts may include healthcare
workers providing care for a confirmed case, family members of a confirmed case, persons who
lived with or stayed overnight with a confirmed case, and others who have had similar close
physical contact.

Specimen types — rRT-PCR is the preferred diagnostic test for avian influenza A H7N9.

The preferred specimen types for patients presenting with signs of upper respiratory tract infection are
[82]:

● A nasopharyngeal swab or

● A nasal aspirate or wash or

● Two swabs combined into one viral transport media vial (eg, combined nasal swab with
oropharyngeal swab or combined nasopharyngeal swab with oropharyngeal swab)

If it is not possible to obtain one of these specimen types, then a single nasal swab or oropharyngeal
swab is acceptable. For patients with lower respiratory tract involvement, a lower respiratory tract
specimen (eg, an endotracheal aspirate or bronchoalveolar lavage fluid) should be tested [82]. The results
of such testing can be used to help guide decisions regarding whether to extend the duration of therapy
for longer than the usual five-day course; an oropharyngeal (throat) swab may be collected if lower
respiratory specimens are not available [85]. (See "Avian influenza A H7N9: Treatment and prevention",
section on 'Hospitalized patients'.)

Choice of diagnostic test — rRT-PCR is the preferred diagnostic test for avian influenza A H7N9 [54,82].
The WHO has released a protocol for rRT-PCR for avian influenza A H7N9 that can be found at the WHO
website [83]. All unsubtypeable influenza A virus specimens should be submitted to a WHO collaborating
center or the CDC in a timely fashion for additional diagnostic testing [82].

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Commercially available rapid influenza diagnostic tests (RIDTs) may not detect H7N9 viruses in
respiratory specimens. Therefore, a negative rapid influenza diagnostic test result does not exclude
infection with H7N9. In addition, a positive test result for influenza A cannot confirm avian influenza virus
infection because these tests cannot distinguish between influenza A virus subtypes (they do not
differentiate between human influenza A viruses and novel influenza viruses). Therefore, when RIDTs are
positive for influenza A and there is concern for novel influenza A virus infection, respiratory specimens
should be collected and sent for rRT-PCR testing at a state public health laboratory. Clinical treatment
decisions should not be made on the basis of a negative rapid influenza diagnostic test result since the
test has only moderate sensitivity.

The diagnosis of avian influenza A H7N9 infection can also be made retrospectively by hemagglutinin-
inhibition assays that detect an increase in specific antibodies in serum collected during the acute and
convalescent phases of infection [54]. The WHO has developed laboratory protocols for both
hemagglutinin-inhibition and microneutralization assays.

Viral culture is not recommended [84].

Additional information about testing can be found on the CDC website.

Timing of testing — The duration of shedding of avian influenza A H7N9 virus in humans is unknown
[82]. Until data are available, the estimated duration of viral shedding is based upon seasonal influenza
virus infection. Specimens should be obtained for avian influenza A H7N9 virus testing as soon as
possible, ideally within seven days of illness onset. However, because some persons who are infected
with seasonal influenza viruses are known to shed virus for longer periods (eg, children and
immunocompromised individuals), specimens should be tested for avian influenza A H7N9 virus even if
obtained more than seven days from illness onset.

Specimen handling — If infection with avian influenza A H7N9 virus is suspected based on current
clinical and epidemiologic screening criteria recommended by public health authorities, specimens should
be collected with appropriate infection control precautions for novel virulent influenza viruses and sent to
the appropriate state or local health department for testing.

Clinicians should place swabs or aspirates in viral transport medium and contact their state or local health
department to arrange transport and request a timely diagnosis at a state public health laboratory or the
CDC. Clinicians outside the United States should contact their local public health authorities for
information about where to send diagnostic specimens.

Swab specimens should be collected using swabs with a synthetic tip (eg, polyester or Dacron) and an
aluminum or plastic shaft [82]. Swabs with cotton tips and wooden shafts are not recommended.
Specimens collected with swabs made of calcium alginate should not be used.

The swab specimen collection vials should contain 1 to 3 mL of viral transport medium (eg, containing
protein stabilizer, antibiotics to discourage bacterial and fungal growth, and buffer solution). Respiratory
specimens should be kept at 4°C for no longer than three days. Alternatively, specimens be frozen at
≤-70°C. Avoid freezing and thawing specimens if possible.

Clinical specimens sent to state public health laboratories should be shipped in the appropriate packaging
and according to instructions by the laboratory. If clinical specimens will be examined within 72 hours after
collection, keep the specimen at 4°C (2 to 8°C) and ship on refrigerant gel-packs, otherwise, store frozen
at ≤-70°C and ship on dry ice.

Additional information can be at the CDC website and the WHO website.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The

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Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the
5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a
given condition. These articles are best for patients who want a general overview and who prefer short,
easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Bird flu (avian influenza) (The Basics)")

SUMMARY AND RECOMMENDATIONS

● In late March and April 2013, human cases of novel avian influenza A H7N9 infection in China were
reported to the World Health Organization (WHO). The earliest cases occurred in eastern China, but
additional cases have been detected in other parts of mainland China as well as in Hong Kong,
Taiwan, Malaysia, and Canada. The initial wave occurred from February to May 2013, during which
133 cases were detected. The number of new cases during the first wave peaked in April 2013 and
then declined, likely related, at least in part, to implementation of control strategies including closure
of live bird markets and increased public awareness. A rise in the number of cases occurred in late
2013 and early 2014, late 2014 and early 2015, and late 2016 and early 2017, coinciding with
influenza season. Cases continue to be detected. (See 'Introduction' above and 'Epidemiology'
above.)

● Some of the affected patients had exposures to poultry before becoming ill. To date, there is no
evidence of sustained human-to-human transmission. (See 'Epidemiology' above.)

● Avian influenza A H7N9 virus appears to have derived from reassortment of at least four avian
influenza viruses. (See 'Sources of the reassortant virus' above.)

● Several genetic characteristics of avian influenza A H7N9 viruses isolated from humans suggest that
it may have potential for high virulence. As an example, mutations at the receptor-binding site
suggest that it has adapted to be able to bind to human-type (alpha 2-6 galactose) receptors in the
respiratory tract. (See 'Genetic characteristics' above and 'Receptor and tissue tropism' above.)

● Patients have presented with respiratory tract infections, many of which have progressed to severe
pneumonia. Other clinical features have included acute respiratory distress syndrome, septic shock,
multiorgan failure, rhabdomyolysis, and encephalopathy. (See 'Clinical manifestations' above.)

● Real-time reverse-transcriptase polymerase chain reaction is the preferred diagnostic test for avian
influenza A H7N9, since rapid antigen tests may be insensitive for novel or avian influenza strains.
Nasopharyngeal swabs or aspirates should be obtained for testing. (See 'Diagnosis' above.)

● Updated information can be found at the WHO website and CDC website.

Use of UpToDate is subject to the Subscription and License Agreement.

Topic 89040 Version 44.0

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GRAPHICS

Genetic evolution of H7N9 virus in China, 2013

The eight genes of the H7N9 virus are closely related to avian influenza viruses found in domestic
ducks, wild birds, and domestic poultry in Asia. The virus likely emerged from "reassortment," a
process in which two or more influenza viruses co-infect a single host and exchange genes. This can
result in the creation of a new influenza virus. Experts think multiple reassortment events led to the
creation of the H7N9 virus. These events may have occurred in habitats shared by wild and domestic
birds and/or in live bird/poultry markets where different species of birds are bought and sold for food.
As the above diagram shows, the H7N9 virus likely obtained its HA (hemagglutinin) gene from
domestic ducks, its NA (neuraminidase) gene from wild birds, and its six remaining genes from
multiple related H9N2 influenza viruses in domestic poultry.

Reproduced from: Centers for Disease Control and Prevention. Images of Avian Influenza A H7N9. Available
at: http://www.cdc.gov/flu/avianflu/h7n9-images.htm (Accessed May 17, 2013).

Graphic 89436 Version 1.0

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Chest CT and x-ray images of a patient with avian influenza A H7N9 virus
infection

CT: computed tomography.

Images were taken 1, 5, 7, and 11 days after illness onset.
(Panels A and B) CT scan images on day 1, showing bilateral pleural effusion but no obvious lesions.
(Panel C) CT scan image on day 5, showing extensive ground-glass opacity and consolidation.
(Panels D and E) X-ray images on days 7 and 11, respectively, showing reduced light transmittance on
both sides of the lung.

Reproduced from: Lu S, Zheng Y, Li T, et al. Clinical findings for early human cases of influenza A(H7N9) virus
infection, Shanghai, China. Emerg Infect Dis 2013. DOI: 10.3201/eid1907.130612.

Graphic 89432 Version 2.0

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Chest CT images of a patient with avian influenza A H7N9 virus infection

(Panel A) Image taken 6 days after illness onset shows ground-glass opacity in the left lower and right
upper lobes.
(Panel B) Image taken 16 days after illness onset shows absorption of ground-glass opacity.

CT: computed tomography.

Reproduced from: Lu S, Zheng Y, Li T, et al. Clinical findings for early human cases of influenza A(H7N9) virus
infection, Shanghai, China. Emerg Infect Dis 2013. DOI: 10.3201/eid1907.130612.

Graphic 89433 Version 3.0

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