Lec 26 Influenza Flashcards
What is uncomplicated influenza?
- acute, self limited
- febrile
- due to URI by influenza A or B
What are most common symptoms of uncomplicated influenza
- fever
- cough
- malaise
What symptoms separate influenza from common cold?
systemic symptoms
- fever +/- chills
- headache, myalgias
- malaise, anorexia
both can have:cough, sore throat, rhinorrhea
sneezing more frequent with common cold than flu
What is onset of flu systemic symptoms? how long do they last? Compared to respiratory?
systemic: abrupt onset, last for first 3 days of illness
respiratory: 7-8 days, persist or worsen after resolution of systemic symptoms
What are the respiratory symptoms of flu?
- dry cough, sore throat, rhinorrhea
- usually sneeze more frequent with common cold than flu
What are the 2 pulmonary complicationf of influenza?
- primary viral pneumonia
- secondary bacterial pneumonia
- acute exacerbation of asthma or COPD
What is primary viral pneumonia / signs of disease?
- extension of URI into URI
- monophasic illness:
- — starts like typical influenza but instead of getting better develop symptoms of pneumonia [dyspnea, hypoxemia, cyanosis +/- hemoptysis]
- CXR shows diffuse, bilateral/multilobar opacities
Who is at most risk for primary viral pneumonia?
- CV diseases [esp rheumatic disease with mitral stenosis]
- elderly esp w/ chronic CV or pulmonary comorbidities
- pregnant
- immunosuppressed
What is the most rare but most severe complication of influenza?
primary viral pneumonia
What is secondary bacterial pneumonia?
- bacterial pneumonia following seemingly uncomplicated influenza
- biphasic illness
- — initial improvement after typical influenza, then 4-14 days later have bacterial pneumonia symptoms [fever/chills, cough with sputum, dyspnea, pleuritic chest pain]
- crx: lobar/focal consolidation
What are the bacterial pathogens associated with secondary bacterial pneumonia?
- strep pneumo
- staph aureus
- less commonly: haemophilus influenza
Who is at risk for complicated influenza?
- older adults
- chronic pulmonary, cardiac, metabolic, or renal disease
What is effect of acute exarcebation of asthma or COPD related to viral influenza?
- very common
- may result in permanent decrease in pulm function
What are the non-pulmonary complications of influenza?
- myositis and myoglobinuria [in childrens]
- myocarditis and pericarditis, MI [mostly with pre-existing cardiac disease]
- toxic shock syndrome
- guillan-barre, tranverse myelitis, encephalitis
- reye’s syndrome
Whos is at most risk for reye’s syndrome?
kids taking aspirin
What are complications of influenza in pregnancy?
- fetal loss + pre-term labor
- neural tube defects
What is structure of influenza?
- family orthomyoviridae, genera A, B, C
- negative sense
- segmented
- enveloped
- RNA
What is nucleoprotein NP in influenza?
- binds genomic viral RNA
- NP + vRNA = ribonucleoprotein complex [RNP]
- genetically stable protein across strains
- target of most diagnostic tests
What is algorithm for diagnosing influenza clinically? who does it not work as well for?
flu season + fever + cough = influenza = 60-80% sensitive, 55-80% specific not as good of a marker in: - elderly/immunosuppressed/comorbid - young children
how is influenza diagnosed besides clinical symptoms?
- rapid influenza diagnostic testing [RIDT] = usually enzyme immunoassay for NP
- direct fluorescent antigen [DFA] test = best test
- nucleic acid amplification test [NAAT]
What does a positive RIDT tell you? A negative?
positive tells you its the flu = very speicifc test
negative does not ruel out the flu = only 62% sensitive so may miss some cases, higher sensitivity in children
What is DFA?
- epithelial cells from nasopharyngeal specimen fixed to glass slide, stained with fluorescent labeled NP specific antibodies, viewed under fluorescence microscope
- best test for flu
What is NAAT?
- detection of influenza viral RNA [usually NP or M genes] by qRT-PCR
- becoming gold standard test
What is neuraminidase [NA]?
- glycoprotein on influenza viral surface
- increases ability of progeny virus to bud and be released from infected cell
- enzymes that cleaves bond between sialic acid and galactose to allow progency of virus to leave
- propeller-shaped tetramer
- sialic acid is enzymatic subtstrate
What is NA the target of?
- neuraminidase inhibitor antivirals –> oseltamivir, zanamivir
What is matrix 2 [M2]?
- ion channel in influenza viral envelope
- helps in fusion/uncoating
What is M2 the target of?
- adamantane [M2 inhibitor] antivirals:
- – amantadine
- – rimantadine
What is hemagglutinin [HA]?
- receptor binding glyocoprotein on viral surface
- helps in fusion
- binds celllular glycoconjugates to initiated infection of host cell
What is life cycle of influenza?
- attachment [HA]
- entry into cell
- fusion and uncoating [M2]
- goes into nucleus
- RNA synthesized
- leaves nucleus
- translation and post-translation processing in cyto
- assembly of virus
- budding and released [NA]
What is oseltamivir [tamiflu]? mech? type of administration? side effects?
- NA inhibitor
- given orally
- ester prodrug, cleaved by hepatic esterases
- side effects: nausea/vomitting
What is zanamivir [relenza]? mech? type of administration? contraindications?
- NA inhibitor
- inhaled
- poor oral bioavailability –> inhaled gives direct delivery
- contraindications:
- —- reactive airway disease due to bronchospasm [asthma/COPD]
- —- kids < 7 yrs
What is mech of NA inhibitors?
- act as sialic acid analogs, bind enzyme’s catalytic site and prevent it binding natural substrate
What is mech of M2 inhibitors? what are they active against? type of administration? side effects?
- oral administration
- target M2 ion channel
- – inhibit pH depedent virus-endosome membrane fusion and genome uncoating
- – active only against influenza A
- side effects: CNS [sleep disruption, weakness, dizziness], nausea/vomiting, anorexia
Why are adamantanes [M2 inhibitors] not clinically useful?
- all influenza A viruses currently circulating in humans are amantadine resistant
What are the two M2 inhibitors?
amantadine
rimantadine
Are oseltamivir/zanamivir safe for pregnancy?
pregnancy class C = inadequate data to assess safety, need to weigh fetal risk vs maternal benefit
oseltamivir preferred in pregnancy
both compatible with breastfeeding
What is the target of the majority of neutralizing antibody response?
HA
What is antigenic drift in HA?
- over time accumulate AA mut in HA that allow it to escape from anitbody recognition and thus get reinfection
- novel HA genes from animal reservoir can make new virus and introduce to human population causing pandemic influenza
What is the polymerase complex?
PA, PB1, and PB2
- RNA dependent RNA polymerase
- transcribes neg sense genomic vRNA into + sense mRNA and complementary RNA
- sense mRNA then used for translation of viral proteins by cellular machinery
- complement RNA is intermediated in synthesis of vRNA
- very error-prone = has no proofreading capability
What do mutations in HA cause?
antigenic drift
What do mutations in M2 or NA cause?
drug resistance
What is antigenic drift?
accumulation of random point mutation in major antigenic parts of HA and NA surface proteins allowing drifted virus to escape pre-existing antibody recognition
Whare are requirements for pandemic influenza?
- segmented genome: get antigenic shift mix/match of genome segments from different animals creating new virus expressing HA that humans have no baseline immunity to
- antigenically novel surface proteins HA and NA
- animal reservoir [source of novel HA/NA]
What is the immunogen in inactivated influenza vaccine?
inactivated HA
What is the newest influenza vaccine?
QIV = quadrivalent inactivated influenza vaccine
What is a split virus vaccine?
- egg grown virus disrupted with detergent to solubilize viral membrane
- releases surface HA/NA
what is subunit vaccine?
- after detergent treatment, HA/NA separated out from rest of virus components
What are contraindications of influenza vaccine?
- severe allergic rxn to influenza vaccine
- anaphylactice hypersensitivity to eggs
- history of guillain-barre within 6 wks of prior flu vaccine [ascending paralysis]
- current fever
What is fluzone high-dose? for who?
- 4x the HA antigen per dose of normal inactivated influenza vaccine
- showed improved antibody response in elderly
What is the live-attenuated flu vaccine?
- backbone is influenza virus that is cold-adapted
- get it to express vaccine strain HA/NA antigens
- give intranasally
What are contraindications for live-attenuated flu vaccine?
- < 2 or > 49 yrs
- chronic pulm, cardio, renal, hepatic, neuro, hematologic, or metabolic disease
- immunosuppression
- close contact with immunosuppressed
- < 18 yrs old on long term aspirin
- pregnant
- egg allergy
What is the recombinant HA influenza vaccine [RIV]? who should get it?
- antigens are recombinant cell culture-grown HA proteins
- give IM
- shorter shelf life, rapid production
- similar efficacy/contraindications as conventional
- give to adults with egg allergies
