InfluenzaInfluenzaSHU Xin MDSHU Xin MD

The department of infectious diseases, The department of infectious diseases, 33rdrd affiliated hospital of SUN Yet-Sen univer affiliated hospital of SUN Yet-Sen univer

sity sity

Definition Definition EtiologyEtiology EpidemiologyEpidemiology Pathology and pathogenesisPathology and pathogenesis Clinical manifestationsClinical manifestations Complications Complications Laboratory findingsLaboratory findings Diagnosis and differential diagnosisDiagnosis and differential diagnosis Treatment Treatment Prophylaxis Prophylaxis

DefinitionDefinition

Acute respiratory illness caused by inflAcute respiratory illness caused by influenza viruses.uenza viruses.

Typical symptoms-fever, chills, myalgiTypical symptoms-fever, chills, myalgia, headache, sore throat, cough.a, headache, sore throat, cough.

Serious cases in young children and elSerious cases in young children and elderly.derly.

Etiologic agentEtiologic agent

Etiologic agentEtiologic agent

Etiologic agentEtiologic agent

Influenza A viruses are subdivided on the Influenza A viruses are subdivided on the basis of the HA and NA antigens.basis of the HA and NA antigens.

Designation:Designation:

SpeciesSpecies/ / A/Beijing/32/92(H3N2)A/Beijing/32/92(H3N2) virus typevirus type

Geographic origin

Strain number

Year of Isolation

Virus subtype

EpidemiologyEpidemiology

Source of infection: patients and covert Source of infection: patients and covert infection carrier.infection carrier.

EpidemiologyEpidemiology

Transmission: primarily via respiratory Transmission: primarily via respiratory droplets.droplets.

person to person( hand-to-hand, hand-to-mouth)person to person( hand-to-hand, hand-to-mouth) direct contactdirect contact aerosols—sneezing, coughing.aerosols—sneezing, coughing. susceptible :the immunity in the population at susceptible :the immunity in the population at

risk is the major determinant of the extent and risk is the major determinant of the extent and severity of an outbreak.severity of an outbreak.

EpidemiologyEpidemiology

DateDate DeathsDeaths SubtySubtypepe

Spanish Spanish fluflu

1918-1918-2020

40-100 40-100 millionmillion

H1N1H1N1

Asian Asian fluflu

1957-1957-5858

1-1.5 1-1.5 millionmillion

H2N2H2N2

Hong Hong Kong Kong fluflu

1968-1968-6969

0.75-1 0.75-1 millionmillion

H3N2H3N2

Russian Russian fluflu

19771977 H1N1H1N1

Street car conductor in Seattle not allowing passengers aboard without a mask in 1918

From April 2007 to April 2008 , From April 2007 to April 2008 , there are 13553 cases and 191 there are 13553 cases and 191 outbreaks of influenza reported to outbreaks of influenza reported to CDC in China. CDC in China.

The outbreaks are mainly in primary The outbreaks are mainly in primary school and school and secondary school.secondary school.

The epidemic of influenza in China

PathogenesisPathogenesis

PathogenesisPathogenesis

Histopathologic study reveals degenerative Histopathologic study reveals degenerative changes, including granulation, vacuolizatchanges, including granulation, vacuolization, swelling, and pyknotic nuclei.ion, swelling, and pyknotic nuclei.

The severity of illness is correlated with thThe severity of illness is correlated with the quantity of virus shed in secretions;e quantity of virus shed in secretions;

Only rarely been detected in extra pulmonOnly rarely been detected in extra pulmonary sites. ary sites.

Primary influenza viral pneumonia( particPrimary influenza viral pneumonia( particularly the elderly, children, and immuno-sularly the elderly, children, and immuno-suppressed patients) uppressed patients) interstitial infiltration.

ManifestationsManifestations

Incubation period:1-3 daysIncubation period:1-3 days Typical influenzaTypical influenza An illness characterized by the abrupt oAn illness characterized by the abrupt o

nset of systemic symptoms.nset of systemic symptoms. Headache, fever, chills, myalgia, or malHeadache, fever, chills, myalgia, or mal

aise.aise. respiratory tract signs, particularly cougrespiratory tract signs, particularly coug

h and sore throat. h and sore throat. Ocular signs and symptoms include pain Ocular signs and symptoms include pain

on motion of the eyes, photophobia, anon motion of the eyes, photophobia, and burning of the eye. d burning of the eye.

ManifestationsManifestations

Physical findings:Physical findings: examination of the pharynx: severe sorexamination of the pharynx: severe sor

e throat.e throat. injection of the mucous membranes aninjection of the mucous membranes an

d postnasal discharge.d postnasal discharge. mild cervical lymphadenopathy.mild cervical lymphadenopathy. Chest examination: largely negative.Chest examination: largely negative. rhonchi, wheezes, and scattered rales.rhonchi, wheezes, and scattered rales. last for 4-7days.last for 4-7days.

ManifestationsManifestations

Primary influenza virus pneumonia:Primary influenza virus pneumonia: presents as acute influenza that does not rpresents as acute influenza that does not r

esolve but instead progresses relentlessly.esolve but instead progresses relentlessly. persistent fever, dyspnea, and eventual cypersistent fever, dyspnea, and eventual cy

anosis.anosis. sputum production is generally scanty. sputum production is generally scanty. cardiac failure, liver failure and renal failurcardiac failure, liver failure and renal failur

e.e. Physical findings: no consolidation signs.Physical findings: no consolidation signs.

Mild form influenza:Mild form influenza: Other forms: Other forms: stomach flu stomach flu encephalitis, transverse myelitis, encephalitis, transverse myelitis, myocarditis and pericarditis, myocarditis and pericarditis, myositismyositis

ComplicationsComplications

Secondary bacterial infection: Secondary bacterial infection: pneumonia: cough, purulent sputum, ppneumonia: cough, purulent sputum, p

hysical and x-ray signs of consolidation.hysical and x-ray signs of consolidation. Most common bacterial pathogens are sMost common bacterial pathogens are s

treptococcus pneumoniae, staphylococctreptococcus pneumoniae, staphylococcus aureus, and haemophilus influenzae.us aureus, and haemophilus influenzae.

ComplicationsComplications

Reye's syndrome:Reye's syndrome:

The disease causes fatty liver with The disease causes fatty liver with minimal inflammation, and severe minimal inflammation, and severe encephalopathy (with swelling of the encephalopathy (with swelling of the brain). The liver may become slightly brain). The liver may become slightly enlarged and firm, and jaundice is enlarged and firm, and jaundice is not usually present.not usually present.

Early diagnosis is vital, otherwise Early diagnosis is vital, otherwise death or severe brain damage may death or severe brain damage may follow. follow.

Laboratory findingsLaboratory findings

Blood routine testBlood routine test WBC counts are variable, frequently bWBC counts are variable, frequently b

eing low early in illness and normal or eing low early in illness and normal or slightly elevated later.slightly elevated later.

while leukocytosis with more than 15,0while leukocytosis with more than 15,000 cells/ml raises the suspicion to seco00 cells/ml raises the suspicion to secondary bacterial infection.ndary bacterial infection.

Laboratory findingsLaboratory findings

Virus isolationVirus isolation

Isolation the virus from throat Isolation the virus from throat swabs, nasopharyngeal wash, or swabs, nasopharyngeal wash, or sputum.sputum.

virus usually is detected in tissue virus usually is detected in tissue culture or the amniotic cavity of culture or the amniotic cavity of chick embryos within 48-72 h after chick embryos within 48-72 h after inoculation.inoculation.

Laboratory findingsLaboratory findings Serum testsSerum tests Fourfold or greater titer rises as detecFourfold or greater titer rises as detec

ted by HAI or CF or significant rises ted by HAI or CF or significant rises as measured by ELISA are diagnostic as measured by ELISA are diagnostic of acute infection. of acute infection.

viral antigens:viral antigens: indirect immunofluorescence, enzyme immunoassays.

Diagnosis Diagnosis

Influenza season– winter and spring Influenza season– winter and spring Clinic manifestations:Clinic manifestations: Laboratory findings:Laboratory findings:

Differential diagnosisDifferential diagnosis

On clinical grounds alone, an individuOn clinical grounds alone, an individual case of influenza may be difficult to al case of influenza may be difficult to differentiate from an acute respiratory differentiate from an acute respiratory illness caused by any of a variety of resillness caused by any of a variety of respiratory viruses or by piratory viruses or by mycoplasma pnemycoplasma pneumoniae.----umoniae.----virus isolation and serum test or virus isolation and serum test or antigens detect are very important.antigens detect are very important.

Leptospirosis;Leptospirosis;

calf muscle tenderness, calf muscle tenderness,

lymphadenopathylymphadenopathy

TreatmentTreatment

1 1 General treatmentGeneral treatment Rest, maintain hydration.Rest, maintain hydration. symptomatic treatment:symptomatic treatment: acetaminophen or salicylates acetaminophen or salicylates The use of salicylates should be avoided in The use of salicylates should be avoided in

children below 18 years of age (reye’s sychildren below 18 years of age (reye’s syndrome).ndrome).

codeine-containing compounds :codeine-containing compounds :Antibiotics for the secondary bacterial infecAntibiotics for the secondary bacterial infec

tiontion. .

2 antiviral therapy:2 antiviral therapy: M2 inhibitors: amantadine and rimanM2 inhibitors: amantadine and riman

tadinetadine Side effects:Side effects: rimantadine only for adults. rimantadine only for adults. Dose: 200mg/d for 3-4 days.Dose: 200mg/d for 3-4 days.

Neuraminidase inhibitors Neuraminidase inhibitors oseltamivir: designed to halt the spreaoseltamivir: designed to halt the sprea

d of the virus in the body. These drugs d of the virus in the body. These drugs are often effective against both influenare often effective against both influenza A and B. they reduce symptoms and za A and B. they reduce symptoms and complications. Different strains of inflcomplications. Different strains of influenza viruses have differing degrees ouenza viruses have differing degrees of resistance against these antivirals. f resistance against these antivirals.

ProphylaxisProphylaxis

VaccinationVaccination

Human avian influenzaHuman avian influenza

Definition Definition

Influenza caused by influenza virus A Influenza caused by influenza virus A adapted to birds.adapted to birds.

Etiology Etiology

Avian influenza virus AAvian influenza virus A Highly pathogenic avian Highly pathogenic avian

influenza( HPAI )influenza( HPAI )

H5N1H5N1

H7N7H7N7

H9N2H9N2

Distinguish the avian flu and the human fluDistinguish the avian flu and the human flu HA:HA: avian flu α2-3 sialic acid receptorsavian flu α2-3 sialic acid receptors human flu α2-6 sialic acid receptorshuman flu α2-6 sialic acid receptors The presence of both -2,3 and -2,6 linkages in

the pig tracheal epithelium In the human respiratory epithelium, it has b

een shown that -2,3 and -2,6 linkages are found on ciliated and nonciliated cells

EpidemiologyEpidemiology Source of infection:Source of infection: birds with the avian influenza virus.birds with the avian influenza virus. others: pig, catothers: pig, cat human?human? Transmission:Transmission: direct contact with infectious secretions

and excreta from infected birds or contaminated poultry products.

direct animal to human transmission Human to human?

EpidemiologyEpidemiology

Susceptible:Susceptible: people are all susceptible, especially in people are all susceptible, especially in

children < 12 years.children < 12 years. People who People who direct contact with

infectious secretions and excreta from infected birds or contaminated poultry products are at high risk.

wild waterfowl likely plays a role in the avian influenza cycle and could be the initial source for AI viruses.

virus may be passed on virus may be passed on through contact with through contact with resident waterfowl or resident waterfowl or domestic poultrydomestic poultry

20032003 20042004 20052005 20062006 20072007 20082008 totaltotal

AzerbaijaAzerbaijan n

00 00 00 8/58/5 00 00 8/58/5

BangladeBangladesh sh

1/01/0 1/01/0

CambodiCambodia a

4/44/4 2/22/2 1/11/1 7/77/7

China China 1/11/1 8/58/5 13/813/8 5/35/3 3/33/3 30/2030/20

Djibouti Djibouti 1/01/0 1/01/0

Egypt Egypt 18/1018/10 25/925/9 7/37/3 50/2250/22

IndonesiIndonesia  a 

20/1320/13 55/4555/45 42/3742/37 20/1720/17 137/112137/112

Iraq Iraq 3/23/2

Lao Lao 2/22/2

Viet Nam Viet Nam 3/33/3 29/2029/20 61/1961/19 8/58/5 5/55/5 106/52106/52

Thailand Thailand 17/1217/12 5/25/2 3/33/3 25/1725/17

Turkey Turkey 12/412/4 12/412/4

NigeriaNigeria 1/11/1

PakistanPakistan 3/13/1

totaltotal 4/44/4 46/3246/32 98/4398/43 115/79115/79 88/5988/59 36/2836/28 387/245387/245

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO( Cases/Deaths)

1997 in Hong Kong, resulting in 18 documented cases and six fatalities.

The outbreak was controlled after depopulating 1.5 million chickens in Hong Kong farms and markets.

Human infections due to A/H5N1 resurfaced in Hong Kong in 2003.

Pathogenesis and Pathogenesis and pathologypathology

The pathogenesis and pathology is The pathogenesis and pathology is similar to that in influenza.similar to that in influenza.

Alveolar hemorrhage and hyaline membranes were seen in some patients.

H5N1 vs. previous pandemics of human influenza

The human incubation period of avian The human incubation period of avian influenza A (H5N1) is 1to 3 days (usuallinfluenza A (H5N1) is 1to 3 days (usually less than 7 days)y less than 7 days)

The main clinical manifestations of avian influenza infections depend on the viral subtype causing the disease.

A/H7N7 infections mainly result in conjunctivitis and/or an influenza-like illness.

A/H5N1 outbreak, an influenza-like illness typically appeared early in the course of the disease, and conjunctivitis was seen in some patients.

Pneumonia. Some patients had prominent GI

symptoms with abdominal pain, diarrhea, and vomiting.

Severe cases progressed to respiratory distress in a week, physical examination would find the consolidation signs.

Laboratory findingsLaboratory findings

Blood routine testBlood routine test WBC counts are variable, frequently beinWBC counts are variable, frequently bein

g low early in illness. g low early in illness. The The leukopenia, Lymphopenia and thro

mbocytopenia are risk factors associated with

severe disease and prognostic indicators for ARDS and death.

Laboratory findingsLaboratory findings

Viral antibody: fourfold rise in serum neutralizing anti

body titer toward the presently circulating genotype of avian viruses.

The convalescent serum should be taken at least 14 days after the onset of illness.

Laboratory findingsLaboratory findings

Rapid antigen detection. Results can be obtained in 15–30 minutes.

Immunofluorescence assay. Enzyme immunoassay for NP Virus culture: : Provides results in 2–10

days Polymerase chain reaction and Real-

time PCR assays.

Laboratory findingsLaboratory findings

Chest X rays interstitial infiltration, lobar infiltration,

collapse/ consolidation, and air bronchograms, pl

eural effusions CT extensive pneumonic infiltration showin

g segmental distribution, and air bronchograms

Laboratory findingsLaboratory findings

The 1st day after the admission

The 2nd day after the admission

The 4th day after the admission

Interstitial infiltrates were seen in the right lower lung fields on admission (A) .after the treatment, there was prominent improvement observed in involved lung fields (B).

Extensive pneumonic infiltrations showing segmental and multifocal distribution in CT.

CT in a 6 years Chinese CT in a 6 years Chinese boyboy

The CT at the 2nd week of the illness. Infiltrations in the left lung.

ComplicationsComplications

ARDSARDS Lung hemorrhageLung hemorrhage pleural effusions Renal failure Shock sepsis Reye syndrome

Diagnosis Diagnosis

Person under investigation

A person whom public health A person whom public health authorities have decided to investigate authorities have decided to investigate for possible H5N1 for possible H5N1

1 1 exposure to the infectious to the infectious sourcessources

2 influenza-like symptoms2 influenza-like symptoms

Suspected H5N1 caseSuspected H5N1 caseA person presenting with unexplained acute lower respiratory illness with fever (>38 ºC ) and cough, shortness of breath or difficulty breathing

one or more of the following exposures in the 7 days prior to symptom onset:

a. Close contact (within 1 metre) with a person wh who is a suspected, probable, or confirmed H5N1 co is a suspected, probable, or confirmed H5N1 case ase

b. Exposure to poultry or wild birds or their remab. Exposure to poultry or wild birds or their remains or to environments contaminated by their fains or to environments contaminated by their faeces in an area where H5N1 infections in animaleces in an area where H5N1 infections in animals or humans have been suspected or confirmed is or humans have been suspected or confirmed in the last month;n the last month;

c. Consumption of raw or undercooked c. Consumption of raw or undercooked poultry products in an area where H5N1 poultry products in an area where H5N1 infections in animals or humans have been infections in animals or humans have been suspected or confirmed in the last month suspected or confirmed in the last month

d. Close contact with a confirmed H5N1 d. Close contact with a confirmed H5N1 infected animal other than poultry or wild infected animal other than poultry or wild birds birds

e. Handling samples suspected of containing e. Handling samples suspected of containing H5N1 virus in a laboratory or other setting. H5N1 virus in a laboratory or other setting.

Probable H5N1 case A person meeting the criteria for a suspected

case a. infiltrates or evidence of an acute pneumoni

a on chest radiograph plus evidence of respiratory failure (hypoxemia, severe tachypnea ) )

b. positive laboratory confirmation of an influenza A infection but insufficient laboratory evidence for H5N1 infection.

Probable definition 2Probable definition 2::A person dying of an unexplained acute respA person dying of an unexplained acute respiratory illness who is considered to be epideiratory illness who is considered to be epidemiologically linked by time, place, and exposmiologically linked by time, place, and exposure to a probable or confirmed H5N1 case. ure to a probable or confirmed H5N1 case.

Confirmed H5N1 caseConfirmed H5N1 case A person meeting the criteria for a suspeA person meeting the criteria for a suspe

cted or probable case cted or probable case a. Isolation of an H5N1 virus; a. Isolation of an H5N1 virus;

b. Positive H5 PCR results from tests usib. Positive H5 PCR results from tests using two different PCR targets, ng two different PCR targets, c. A fourfold or greater rise in neutralizac. A fourfold or greater rise in neutralization antibody titer for H5N1 tion antibody titer for H5N1

. d. A microneutralization antibody titer f. d. A microneutralization antibody titer for H5N1 of 1:80 or greater at day 14 and or H5N1 of 1:80 or greater at day 14 and a positive result using a different seroloa positive result using a different serological assay gical assay

Differential diagnosisDifferential diagnosis

Influenza Influenza ColdCold Bacterial pneumoniaBacterial pneumonia SARSSARS Infectious mononucleosisInfectious mononucleosis chlamydia pneumoniachlamydia pneumonia mycoplasma pneumoniamycoplasma pneumonia

Treatment Treatment IsolationIsolation Symptomatic treatment:Symptomatic treatment: Antiviral treatmentAntiviral treatment neuraminidase inhibitors (oseltamivi

r and zanamivir) Patients who had survived after oseltamivir tr

eatment appeared to have received the agent earlier than those who subsequently died (4.5 days vs 9 days after disease onset).

adamantanes (amantadine and rimantadine)

Summary of clinical management advice

Oseltamivir remains the primary recommended antiviral treatment.

Modified regimens of oseltamivir treatment Corticosteroids should not be used routinely Antibiotic chemoprophylaxis should not be

used. Monitoring of oxygen saturation should be p

erformed Therapy for A(H5N1) virus-associated ARDS

prophylaxisprophylaxis

Control the infection sourcesControl the infection sources Cut off the transmission Cut off the transmission Protect the susceptible peopleProtect the susceptible people