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Diagnostic and treatment protocol for human infections

？with avian influenza A (H7N9) 

(2nd edition, 2013) 

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Human
infections with avian influenza A (H7N9) are known to cause acute and severe
respiratory illness and death. The first known human case became ill on
February 19, 2013 and through April 11, 2013 38 cases with nine deaths have
occurred, all in Anhui, Jiangsu, Shanghai, and Zhejiang. The cases are
distributed in a sporadic manner.？ 

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It is recommended to detect early, report early, diagnosis early and
treat early severely ill patients with efficacious medicines, emphasizing the
comprehensive effects from both traditional Chinese medicine and Western
medicine. These measures play a vital role in effective prevention and control,
improving the cure rate, and reducing mortality related to avian influenzas A
(H7N9). 





Ⅰ. Etiology？ 

Avian influenza viruses belong to the family Orthomyxoviridae of the
influenza A virus genus. Avian influenza A virus particles are pleomorphic, its
spherical diameter is between 80 to 120 nm with the presence of an envelope.
The genome consists of eight segments of negative-sense single-stranded RNA
molecules. Based on the antigenic properties of the hemagglutinin (HA) and
neuraminidase (NA) glycoproteins, influenza A viruses are classified into 16HA （H1～H16）and 9 NA (N1～N9）subtypes. In addition to infecting birds, avian influenza
A viruses also are known to have infected humans, swine, horses, mink, and
various marine mammals.？ While many different subtypes of avian influenza
A viruses have infected humans, the subtypes known to more commonly cause human
disease include H5N1, H9N2、H7N7、H7N2、and H7N3. This reported subtype is H7N9; this is a novel
genetic reassortment from an internal gene of an avian influenza A (H9N2)
virus. 

Avian
influenza viruses are sensitive to heat and strongly resistant to low
temperature.？ They can be inactivated either by heating for 30 minutes at
65℃ or boiling for two
minutes.？ The virus can survive in feces for 1 week at low temperatures,
and also can survive in 4℃ water for 1 month. It has some resistance to alkaline
environments, and can survive at pH4.0. The virus can survive more than 1 year
if it is preserved with glycerol. 

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Ⅱ Epidemiology

1. Origin
of transmission. Avian influenza A (H7N9) has been isolated from the bodily
fluids and excreta of poultry. These viruses are highly congenetic with human
infections with avian influenza A (H7N9) virus. The source of transmission may
be avian influenza A (H7N9) infected poultry. Through April 11, 2013, there has
been no definitive case of human-to-human transmission. 

2. Route
of transmission. Influenza A viruses can be transmitted through the
respiratory tract, and can also be contracted through close contact？with
the bodily fluids and excreta of poultry, or direct contact with the virus. 

3. High
risk population. Persons with？ ILI and a history of contact？ with
poultry within 1 week？ of the onset of illness, especially a history of
having worked on poultry feeding, transportation, selling, slaughter, or
processing are more likely to be infected with avian influenza A (h7N9).

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Ⅲ Clinical Manifestations

Based data
from investigations of avian influenza A (H7N9) cases through April 11, 2013,
the incubation period is generally within seven days.

1.？？？ Symptoms, physical
signs and clinical characteristics

Patients
typically present with influenza-like illness (ILI) with symptoms such as
fever, cough with little to no sputum production, and accompanied by headache,
muscular soreness, and general malaise. Patients can develop severe disease
rapidly. In those who develop it, severe pneumonia occurs in 5-7 days. Most of
these cases with severe pneumonia have a persistent temperature over 39℃, difficulty breathing,
？and may be accompanied by hemoptysis. Some rapidly progress to acute
respiratory distress syndrome (ARDS), sepsis, shock, and multi-organ
dysfunction syndrome. Complications to date have included pneumomediastinum and
pleural effusion.

2. Laboratory examination

2.1
Blood tests The total
number of white blood cells is generally neither extremely high or low, but
most patients with severe disease have exhibited leukopenia, lymphopenia and
thrombocytopenia. 

2.2 Blood chemistries Most patients have had an increase of creatine
kinase, lactate dehydrogenase, aspartate aminotransferase, alanine
aminotransferase, and C react protein. Myoglobin may rise also.

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2.3 Etiology and
related testing？ Respiratory tract samples (such as nasopharyngeal secretions,
concentrated oral rinse culture, tracheal aspirates and respiratory epithelial
cells) must be collected before antiviral treatment is started., Medical
Institutions who have a laboratory that can test for avian influenza A (H7N9)
infection should do so as soon as possible. If on site testing is not
available, then should send the clinical samples to the institution designated
to test their samples.（1）Influenza A virus antigen
screening:
Can use a rapid test kit in the clinic to test for the presence of influenza A
viruses. Only a screening test.（2）Nucleic acid testing PCR testing is done in
specialized, designated laboratories and can detect avian influenza A (H7N9)
virus.（3）Viral isolation Viral isolation is
performed on respiratory tract specimens in specialized, designated
laboratories. This is the gold standard for diagnosing infection with avian
influenza A (H7N9) virus.（4）Serology Two paired sera collected
at least four weeks apart that demonstrate a four-fold or greater increase in
the titer of the antibody against avian influenza A (h7N9) indicates acute
infection with this virus. Again, this is done in specialized, designated
laboratories. 

3. Chest
radiographs Pneumonia
caused by influenza A (H7N9) infection results in abnormal chest radiographs.
Abnormalities seen include a ground glass appreanceof the lung, severe patients
Lesions progress quickly, A double lung multiple ground glass shadow and the
image of consolidation of the lung, accompanied by a small amount of pleural
effusion, Lesions are widely distributed when in ARDS.

4. Prognosis. People
infected with avian influenza A (H7N9) virus who become critically ill have an
extremely poor prognosis. Prognostic factors may include the patient's age,
underlying diseases and complications.



Ⅳ. Diagnosis and
differential diagnosis

1.Diagnosis: Infection
with avian influenza A (H7N9) virus is suspected on the basis of clinical
presentation and a history of exposure to persons with an acute respiratory
infection. As of this writing other high risk factors for infection are not
well understood. The clinical presentation is that of any of a number of acute
febrile respiratory diseases including influenza caused by other influenza
viruses; i.e., fever, cough, coryza, difficulty breathing. Infection with avian
influenza A (H7N9) virus is confirmed with a positive laboratory test. A
naso-pharyngeal swab should be collected and it can be tested for avian
influenza A (H7N9) virus using PCR or viral isolation. Dynamic paired sera can
be collected at least four-weeks apart and tested for avian influenza A (H7N9) virus
specific antibody levels. A four-fold or greater increase in these antibody
levels is diagnostic. 

1.1？ ？Epidemiologic
history. Record exposure history to persons ill with an acute
respiratory infection and exposure history to poultry their blood and bodily
fluids.

1.2？ ？Diagnostic criteria

a)？？？？？ Suspected
case: clinical symptoms consistent with acute influenza (fever,
cough, coryza, difficulty breathing) and a laboratory test positive for
infection with an untyped influenza A virus or with a history of contact with a
confirmed or suspected case.

b)？？？？？ Confirmed
case: clinical symptoms consistent with acute influenza (fever,
cough, coryza, difficulty breathing) or with a history of contact with a
confirmed or suspected case and a laboratory test positive for avian influenza
A (H7N9) virus; PCR, viral isolation or a four-fold or greater increase in
serum antibodies specific for this virus isolated in paired sera.

Severe case: a confirmed case with pneumonia complicated by respiratory
failure or other organ failure.

2. Differential
diagnosis: The differential diagnosis is the same as for other
influenza viruses; all causes of acute respiratory infection should be
considered. but the more likely ones are other influenza viruses including highly
pathogenic H5N1 avian influenza and seasonal influenza (including pH1N1 2009),
other viral cause such as coronoviruses and adenoviruses and bacterial causes
including mycoplama and chlamydia. The patient’s age, underlying medical state
and exposure history determine the likelihood of each diagnosis. The diagnosis
depends ultimately on the results of tests for specific pathogens.

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Ⅴ. Treatment

1.？？？？？
Suspect and confirmed cases should both be placed in an
isolation room with respiratory and enteric precautions.

2.？？？？？
Symptomatic treatment. Oxygen, antipyretics and expectorants as
indicated. 

3.？？？？？
Anti-viral treatment. ？An appropriate antiviral drug
regimen for influenza should be administered as soon as the diagnosis of avian influenza
A (H7N9) is entertained. Do not wait for the results of definitive tests for
infection with this virus to initiate therapy. (see attached file).

3.1？ Principles
of anti-viral treatment

(1) Before the use of antiviral drugs, respiratory specimens should be
collected.

(2)？？ Antiviral drugs for
influenza should be initiated within 48 hours of symptom ？？onset. Focus
on the following populations:

①Patients
infected with avian influenza A (H7N9) virus;

②ILI cases
with a rapid test for influenza A positive; 

③ILI cases
with a negative rapid test for influenza A or without a test, but 

having
one or more of the following:

A. Close
contacts including health care workers; one of a cluster of ILI cases of
unknown etiology or exposure to poultry within the last week.

B.？？？？？ An underlying
medical condition associated with a higher risk of severe disease from
infleunza, including but not limited to cardiopulmonary disease, old age or
pregnancy;

C.？？？？？ Rapid
progression of the illness. and 

D.？？？？ Pneumonia of
unknown etiology consistent with influenza.

(3)？？ If more than 48 hours
have passed since symptom onset, anti-viral drugs may still provide some
benefit and should be considered in cases with severe disease or deterioration.


3.2？ Neuraminidase
inhibitors (please see the links below for more complete information on the
drugs below)

(1) Oseltamivir: adult dose
is 75mg twice daily, in severe cases the dose may be doubled, for 5-7 days. For
children one year and older dose by body weight as follows: less than 15 KG
30mg twice daily; 15-23kg 45mg twice daily; 23-40kg 60mg twice daily; 40kg and
more 75mg twice daily. For children with difficulty swallowing
capsules, may use oseltamivir suspension.

奥司他韦（Oseltamivir）

Chinese

http://www.roche.com.cn/fmfiles/re7185004/Tamiflu_approved.pdf

English

http://www.tamiflu.com/tamiflu-for-adults;jsessionid=C71B61A4C5676C22330B4BA0F299D8E0.gxeTam-m1

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(2) Zanamivir: For
persons seven years and above, the dose is10 mg twice daily (every 12 hours)
inhaled.

扎那米韦（Zanamivir）

Chinese

http://www.gsk.tw/PDF/medicines/RELENZA-2.pdf

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English

http://www.gsk.ca/english/docs-pdf/product-monographs/Relenza.pdf

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(3) Peramivir: In severe or
refractory cases or when oral
administration is not possible, may use peramivir sodium chloride injection. The daily
adult dose is 300-600mg via intravenous infusion, and it is administered
for 1-5 days of treatment.
There is limited clinical experience with peramivir so extra vigilance
monitoring for adverse reactions is indicated.

帕拉米韦（Peramivir）

Chinese

http://wenku.baidu.com/view/b4ae4f3cee06eff9aef80776.html

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English

http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm187811.pdf

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Mild
cases should be prescribed oseltamivir
or zanamivir. Whether
to extend the course of treatment should be
based on the individual patient’s response to therapy, his condition and
laboratory results suggesting drug resistance.

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3.3？ ？Ion
channel M2 blockers: is not recommended to use amantadine or
rimantadine monotherapy because of widespread resistance. 

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4？？？？？？？
Chinese traditional medicine treatment

4.1？ For patients with fever,
cough, scanty sputum, dyspnea and leukopenia, as well as suspect and confirmed
cases of avian influenza A (H7N9):

These symptoms indicate a pulmonary infection and result in compromised pulmonary
function. 

Syndromes: fever, cough,
scanty sputum, headache, muscle and joint pain.

？？
Signs: red tongue with thin tongue coating, slippery
and rapid pulse. 

Treatment: clear heat and
poison from the body, diffuse the lungs to relieve ？？？cough. 

Reference
prescription and dosage: Yin Qiao San and white tiger elixir.

Honeysuckle 30g, forsythia 15g, fried almonds 15g, raw gypsum 30g

Anemarrhena 10g, 15g mulberry leaves, reed rhizome 30g, 15g 

Artemisia
annua Scutellaria 15g, raw licorice 6g

Dissolve and boil in water, 1-2 does daily, take orally every 4-6 hours.

Modified prescription for cases with severe cough: add loquat leaf,
Fritillaria.

Synthetic traditional medicine: Shufeng detoxification capsules, Lianhuaqingwen
capsules, Jinlianqingre effervescent tablets can provide
treatment of clear heat and poison in the body, diffuse the lung to
suppress cough. 

Chinese medicine injection:？
Xiyanpin injection, Reduning injection, Shen Mai injection.

4.2？ For patients
with high fever, Acute Respiratory Distress Syndrome (ARDS), or septic shock:

These symptoms indicate toxins have
accumulated in the lungs and result in compromised pulmonary function. 

Syndromes: High fever, cough,
scanty sputum with difficulty coughing, stuffiness and shortness of breath,
hemoptysis, or cough with pink frothy sputum, with cold hands and feet, convulsions,
and even delirium and coma. 

Signs: Dark red
tongue, weak or undetectable pulse.

Treatment: detoxification to relieve the burden of lung, maintain and
support body functions 

Reference prescription and dosage: Xuanbai Cheng Qi Tang decoction and Senate dogwood decoction. 

Raw rhubarb 10g, Trichosanthes 30g, fried almonds 10g to fry Tinglizi 30g

Raw gypsum 30g, Raw gardenia 10g, Polygonum cuspidatum 15g, radish seed 15g,

Cornus 15g, American ginseng15g

Dissolve and boil in water, 1-2 doses daily, take orally or nasal feeding every
4-6 hours.

Modified prescription:

For patients with high fever, altered consciousness, and even delirium or coma,
add An Gong Niu Huang Pill ;

For patients with cold extremities or profuse sweating, add gun aconite,
calcined keel, calcined oyster;

For patients with hemoptysis, add red peony root, Agrimony, credit leaves;

For patients with cyanotic lips, add motherwort, astragalus, angelica.

Synthetic traditional medicine: Shen Mai injection, Shenfu Injection,
Xiyanping injection, Reduning injection.

4.3？ The above
mentioned Chinese traditional medical decoctions, synthetic medicines and
injections should not be used to prevent disease. 

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5？？？？？？？
Strengthen supportive treatment and prevent complications. 

Rest, drink plenty
of water, and eat nutritious food. ？Observe and monitor patients
vigilantly to prevent complications. Antimicrobial drugs should be used when
there is sufficient evidence of secondary bacterial infection only. 

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6？？？？？？？
Treatment of severe cases: for patients with respiratory
dysfunction, inspired oxygen and other respiratory support should be provided. Proper
treatment for other complications must also be provided.

6.1？ ？Respiratory
support:

6.1.1？？？？？？？
Mechanical ventilation: Severe cases can progress rapidly and
sometimes develop acute respiratory distress syndrome (ARDS). Mechanical
ventilator support is usually indicated once ARDS develops. 

6.1.1.1？ Noninvasive positive
pressure ventilation: For patients at an early stage of respiratory distress
and / or hypoxemia, noninvasive ventilation can be considered, but for severe
cases that do not improve with noninvasive ventilation, invasive mechanical
ventilation should be considered.

6.1.1.2？ Invasive positive
pressure ventilation: Given that some patients are more prone to barotrauma, the
ARDS protective ventilation approach should be adopted.

6.1.2？？？？？？？
？Extracorporeal membrane oxygenation (ECMO): ECMO is recommended
when oxygenation and / or ventilation cannot be maintained by conventional
mechanical ventilation.

6.1.3？？？？？？？
Other methods: Prone position ventilation or high-frequency
oscillatory ventilation (HFOV) should be considered when oxygenation cannot be
maintained by conventional mechanical ventilation.

6.2？ ？？Circulatory
support: Continuous monitoring of the patient’s cardiovascular state is
required to detect shock (severe hypotension with ineffective circulation) in a
timely manner. Early volume resuscitation and proper usage of vasoactive drugs
should be considered. Hemodynamic monitoring should be continuous, because
treatment should be guided by the patient’s hemodynamic status. 

6.3？ ？Other
treatment: The functional status of all other organs should be checked during
respiratory and circulatory support. This increases the prevention of
complications and allows for timely treatment when they do occur. Special
attention must be paid to prevent hospital acquired infections.

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Ⅵ.Others 

Hospitals
should adopt measures to reduce the incidence and severity of hospital acquired
infections in patients infected with avian influenza A (H7N9) in accordance
with "Technical Guidelines on the Prevention and Control of Hospital Infections
in Patients Infected with Avian Influenza A (H7N9) (2013)" ？？

《人感染H7N9禽流感医院感染预防与控制技术指南（2013年版）》

http://www.moh.gov.cn/mohyzs/s3586/201304/25a6ba8ff2214f6e89d9683cce25b2fc.shtml

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Ⅶ. Transfer or discharge standards

1. For
patients with chronic underlying disease or severe comorbidities, if two
consecutive PCR tests are negative, the patients can be transferred out from an
isolation room to the appropriate unit for further treatment as indicated.

2. For
patients who defervesce, whose clinical symptoms disappear, and have two
consecutive negative PCR tests, they can be discharged from hospital.

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Annex: Flow
chart for early detection and treatment of avian influenza A (H7N9) cases in an
epidemic area. (As of 11 April 2013, Anhui, Jiangsu, Shanghai and Zhejiang).

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Annex: Flow
chart for early detection and treatment of avian influenza A (H7N9) cases in an
epidemic area. (As of 13 April 2013, Anhui, Jiangsu, Shanghai and Zhejiang).

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A. ILI case
who is a close contact (including health care workers) one of a cluster
clustered of ILI cases or exposed to poultry within the last week;

B. ILI case
who has an underlying disease such as chronic pulmonary disease, heart disease,
old age, pregnant women;

C. ILI case
that progress rapidly or one prescribed antiviral drugs; or 

D. ILI case
with pneumonia of unknown etiology. 
Download: Diagnostic and treatment protocol for human infections with avian influenza A(H7N9) (2nd edition, 2013)



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