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Influenza SHU Xin MD The department of infectious diseases, 3rd affiliated hospital of SUN Yet-Sen university Definition Etiology Epidemiology Pathology and pathogenesis Clinical manifestations Complications Laboratory findings Diagnosis and differential diagnosis Treatment Prophylaxis Definition Acute respiratory illness caused by influenza viruses. Typical symptoms-fever, chills, myalgia, headache, sore throat, cough. Serious cases in young children and elderly. Etiologic agent Etiologic agent Etiologic agent Influenza A viruses are subdivided on the basis of the HA and NA antigens. Designation: Species/ A/Beijing/32/92(H3N2) virus type Geographic Strain Year of origin number Isolation Virus subtype Epidemiology Source of infection: patients and covert infection carrier. Epidemiology Transmission: primarily via respiratory droplets. person to person( hand-to-hand, hand-to-mouth) direct contact aerosols—sneezing, coughing. susceptible :the immunity in the population at risk is the major determinant of the extent and severity of an outbreak. Epidemiology Date Deaths 1918-20 40-100 million Subtype H1N1 1957-58 1-1.5 million H2N2 Hong Kong flu 1968-69 0.75-1 million H3N2 Russian flu 1977 H1N1 Spanish flu Asian flu Street car conductor in Seattle not allowing passengers aboard without a mask in 1918 From April 2007 to April 2008 , there are 13553 cases and 191 outbreaks of influenza reported to CDC in China. The outbreaks are mainly in primary school and secondary school. The epidemic of influenza in China Pathogenesis Pathogenesis Histopathologic study reveals degenerative changes, including granulation, vacuolization, swelling, and pyknotic nuclei. The severity of illness is correlated with the quantity of virus shed in secretions; Only rarely been detected in extra pulmonary sites. Primary influenza viral pneumonia( particularly the elderly, children, and immuno-suppressed patients) interstitial infiltration. Manifestations Incubation period:1-3 days Typical influenza An illness characterized by the abrupt onset of systemic symptoms. Headache, fever, chills, myalgia, or malaise. respiratory tract signs, particularly cough and sore throat. Ocular signs and symptoms include pain on motion of the eyes, photophobia, and burning of the eye. Manifestations Physical findings: examination of the pharynx: severe sore throat. injection of the mucous membranes and postnasal discharge. mild cervical lymphadenopathy. Chest examination: largely negative. rhonchi, wheezes, and scattered rales. last for 4-7days. Manifestations Primary influenza virus pneumonia: presents as acute influenza that does not resolve but instead progresses relentlessly. persistent fever, dyspnea, and eventual cyanosis. sputum production is generally scanty. cardiac failure, liver failure and renal failure. Physical findings: no consolidation signs. Mild form influenza: Other forms: stomach flu encephalitis, transverse myelitis, myocarditis and pericarditis, myositis Complications Secondary bacterial infection: pneumonia: cough, purulent sputum, physical and x-ray signs of consolidation. Most common bacterial pathogens are streptococcus pneumoniae, staphylococcus aureus, and haemophilus influenzae. Complications Reye's syndrome: The disease causes fatty liver with minimal inflammation, and severe encephalopathy (with swelling of the brain). The liver may become slightly enlarged and firm, and jaundice is not usually present. Early diagnosis is vital, otherwise death or severe brain damage may follow. Laboratory findings Blood routine test WBC counts are variable, frequently being low early in illness and normal or slightly elevated later. while leukocytosis with more than 15,000 cells/ml raises the suspicion to secondary bacterial infection. Laboratory findings Virus isolation Isolation the virus from throat swabs, nasopharyngeal wash, or sputum. virus usually is detected in tissue culture or the amniotic cavity of chick embryos within 48-72 h after inoculation. Laboratory findings Serum tests Fourfold or greater titer rises as detected by HAI or CF or significant rises as measured by ELISA are diagnostic of acute infection. viral antigens: indirect immunofluorescence, enzyme immunoassays. Diagnosis Influenza season– winter and spring Clinic manifestations: Laboratory findings: Differential diagnosis On clinical grounds alone, an individual case of influenza may be difficult to differentiate from an acute respiratory illness caused by any of a variety of respiratory viruses or by mycoplasma pneumoniae.----virus isolation and serum test or antigens detect are very important. Leptospirosis; calf muscle tenderness, lymphadenopathy Treatment 1 General treatment Rest, maintain hydration. symptomatic treatment: acetaminophen or salicylates The use of salicylates should be avoided in children below 18 years of age (reye’s syndrome). codeine-containing compounds : Antibiotics for the secondary bacterial infection. 2 antiviral therapy: M2 inhibitors: amantadine and rimantadine Side effects: rimantadine only for adults. Dose: 200mg/d for 3-4 days. Neuraminidase inhibitors oseltamivir: designed to halt the spread of the virus in the body. These drugs are often effective against both influenza A and B. they reduce symptoms and complications. Different strains of influenza viruses have differing degrees of resistance against these antivirals. Prophylaxis Vaccination Human avian influenza Definition Influenza caused by influenza virus A adapted to birds. Etiology Avian influenza virus A Highly pathogenic avian influenza( HPAI ) H5N1 H7N7 H9N2 Distinguish the avian flu and the human flu HA: avian flu α2-3 sialic acid receptors human 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 been shown that -2,3 and -2,6 linkages are found on ciliated and nonciliated cells Epidemiology Source of infection: birds with the avian influenza virus. others: pig, cat human? Transmission: direct contact with infectious secretions and excreta from infected birds or contaminated poultry products. direct animal to human transmission Human to human? Epidemiology Susceptible: people are all susceptible, especially in children < 12 years. 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 through contact with resident waterfowl or domestic poultry Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO( Cases/Deaths) Azerbaijan 2003 2004 2005 2006 2007 2008 total 0 0 0 8/5 0 0 8/5 1/0 1/0 Bangladesh Cambodia China 1/1 4/4 2/2 1/1 8/5 13/8 5/3 7/7 3/3 30/20 Djibouti 1/0 Egypt 18/10 25/9 7/3 50/22 55/45 42/37 20/17 137/112 5/5 106/52 Indonesia 20/13 Iraq 3/2 Lao Viet Nam 1/0 2/2 3/3 Thailand 29/20 61/19 17/12 5/2 Turkey 8/5 3/3 25/17 12/4 12/4 Nigeria 1/1 Pakistan 3/1 total 4/4 46/32 98/43 115/79 88/59 36/28 387/245 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 pathology The pathogenesis and pathology is 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 influenza A (H5N1) is 1to 3 days (usually 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 findings Blood routine test WBC counts are variable, frequently being low early in illness. The leukopenia, Lymphopenia and thrombocytopenia are risk factors associated with severe disease and prognostic indicators for ARDS and death. Laboratory findings Viral antibody: fourfold rise in serum neutralizing antibody 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 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 findings Chest X rays interstitial infiltration, lobar infiltration, collapse/ consolidation, and air bronchograms, pleural effusions CT extensive pneumonic infiltration showing segmental distribution, and air bronchograms Laboratory 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 boy The CT at the 2nd week of the illness. Infiltrations in the left lung. Complications ARDS Lung hemorrhage pleural effusions Renal failure Shock sepsis Reye syndrome Diagnosis Person under investigation A person whom public health authorities have decided to investigate for possible H5N1 1 exposure to the infectious sources 2 influenza-like symptoms Suspected H5N1 case A 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 who is a suspected, probable, or confirmed H5N1 case b. Exposure to poultry or wild birds or their remains or to environments contaminated by their faeces in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month; c. Consumption of raw or undercooked poultry products in an area where H5N1 infections in animals or humans have been suspected or confirmed in the last month d. Close contact with a confirmed H5N1 infected animal other than poultry or wild birds e. Handling samples suspected of containing 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 pneumonia 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 2: A person dying of an unexplained acute respiratory illness who is considered to be epidemiologically linked by time, place, and exposure to a probable or confirmed H5N1 case. Confirmed H5N1 case A person meeting the criteria for a suspected or probable case a. Isolation of an H5N1 virus; b. Positive H5 PCR results from tests using two different PCR targets, c. A fourfold or greater rise in neutralization antibody titer for H5N1 . d. A microneutralization antibody titer for H5N1 of 1:80 or greater at day 14 and a positive result using a different serological assay Differential diagnosis Influenza Cold Bacterial pneumonia SARS Infectious mononucleosis chlamydia pneumonia mycoplasma pneumonia Treatment Isolation Symptomatic treatment: Antiviral treatment neuraminidase inhibitors (oseltamivir and zanamivir) Patients who had survived after oseltamivir treatment 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 performed Therapy for A(H5N1) virus-associated ARDS prophylaxis Control the infection sources Cut off the transmission Protect the susceptible people