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Slide3David J. Miller, M.D., Ph.D.
Respiratory Viruses
Infectious Diseases/Microbiology Sequence CourseSpring 2010
Slide4Objectives
Know the major respiratory viruses and their clinical presentation
influenza, rhinovirus, respiratory syncytial virus (RSV), coronavirus, adenovirusAppreciate key features of structure and replication strategies related to pathogenesis, treatment, and preventionReading assignment: Schaechter’s, 4th edition, chapters 32, 34, 36, and 39
Slide530 year old generally healthy female returning from
a trip to San Francisco in January sat in front of passengeron the plane who was coughing repeatedly throughout
the flight. Two days later she developed fever to 39°Cwith shaking chills, non-productive cough, headache,and severe myalgias. Because of her severe symptomsshe was bedridden for three days, but eventually fullyrecovered without specific treatment after a week andreturned to work.
Slide6Source Undetermined
Slide730 year old generally healthy female returning from
a trip to San Francisco in January sat in front of passenger
on the plane who was coughing repeatedly throughoutthe flight. Two days later she developed fever to 39°Cwith shaking chills, non-productive cough, headache,and severe myalgias. Because of her severe symptomsshe was bedridden for three days, but eventually fullyrecovered without specific treatment after a week andreturned to work.Diagnosis?
Slide8Can this happen again?
Iconicphotos
Slide9Life expectancy in the United States, 1900-2001
35
4555657585Age (years)
1900
19201940196019802000YearWorldWar IWorldWar IIKoreanWarVietnamWarAntibiotics
Vaccines
Source Undetermined
Slide10Influenza virus
Yearly impact for endemic/epidemic disease (CDC estimates)
>200,000 hospitalizationsEstimated 36,000 deaths (mortality rate <0.1%)Greater than $1 billion (U.S.) economic lossEstimated impact for new pandemic disease500,000 to 700,000 hospitalizations100,000 to 200,000 deathsGreater than $100 billion (U.S.) economic loss2009 H1N1 pandemic (CDC estimates as of Feb. 2010)U.S. - ~57 million cases, ~250,000 hospitalizations, ~11,000 deathsInternational - 213 countries with confirmed casesEconomic losses ???Vaccine costs about $10 per person
Slide11Influenza virus
Family:
OrthomyxoviridaeEnvelopedNegative (-) strand RNA genome, 8 (7) segmentsThree influenza types: A, B, CSource Undetermined
Slide12Comparison of Influenza A, B, and C Viruses
A
B
C
Severity of illness+++++++SubtypesYesNo
No
Animal reservoir
Yes
No
No
Spread in humans
Pandemic
Epidemic
Sporadic
Antigenic changes
Shift, drift
Drift
Drift
D. Miller
Slide13Influenza A Virus Structure
Hemagglutinin (HA)
Receptor binding (sialic acid)Membrane fusionNeutralizing antibody targetNeuraminidase (NA)Remove sialic acid residuesVirion releaseIon channel (M2)H+-dependent uncoatingInfluenza A onlyInfluenza A subtypes based on HA (16) and NA (9)H1N1, H3N2A/Hong Kong/8/68
CSB
Slide14Influenza virus life cycle
YK
Times, wikimedia commons
Slide15Influenza Pathogenesis
Direct cell lysis
Primary mechanism for influenza virusUpper and lower respiratory tractsRole of immune responsePrimarily protective rather than pathogenicInduces virus- and type-specific immunityVirus-mediated suppression (NS1 protein)Why was the 1918 virus so deadly?
Slide16Influenza Epidemiology
Winter
EndemicEpidemic
Pandemic
Rapid globalspreadSource Undetermined
Slide17Influenza Antigenic Variation
Antigenic drift
Antigenic shift
Slide18Influenza Antigenic Variation
Antigenic drift
Occurs with influenza A, B, and CSmall number of slowly occurring changes (mutations)Error-prone viral RNA polymeraseHA changes most prominent, but can occur in any viral genePartially responsible for yearly vaccine changesMAY result in breach of species barrier and pandemic
Slide19CDC
Slide20Influenza Antigenic Variation
Antigenic shift
Influenza A onlyLarge dramatic changes that occur rapidlyPrimarily responsible for pandemicsDue to gene shuffling and reassortment RequirementsSegmented genomeMultiple HA and NA subtypesAnimal reservoir (wild aquatic birds)Susceptible species for both avian and human influenza (swine)
Slide21Influenza Pandemics
Image of past influenza pandemics
Removed Please see: http://www.lincoln.ac.uk/dbs/images/birdflu1.jpg 1918 “Spanish influenza”H1N1 influenza virusBird-to-human transmission of H1N1 virus All 8 genetic segments thought to have originated from avian influenza virus1957 “Asian influenza”H2N2 influenza virusH2N2 avian virus – H1N1 human virus
Reassortment 3 new genetic segments from avian influenza virus introduced
(HA, NA, PB1):Contained 5 RNA segments from 19181968 “Hong Kong influenza”H3N2 influenza virusH3 avian virus – H2N2 human virusReassortment 2 new genetic segments from avian influenza introduced(HA, PB1):Contained 5 RNA segments from 1918Next pandemic influenzaAvian virusOrAvian virus – H3N2 human virus All 8 genes new or further derivative of 1918 virus
Slide22Pathways for generation of virulent pandemic influenza viruses
Human influenza virus
Avian influenza virus?
Intraspecies
transmissionIntraspeciestransmissionInterspeciestransmissionReassortmentHerr Kriss, wikimedia commonstitanium 22, flickrNevit Dilmen, wikimedia commons
Slide23Sialic acid linkages determines influenza virus HA receptor binding
a
2,3-linkagea2,6-linkageCell surfaceglycoprotein orglycolipid
Human influenza
virus specificity(H1N1, H3N2)Avian influenzavirus specificity(H5N1, H7N7)Humans and pigsBirds and pigsSource Undetermined
Slide24Different human airway epithelial cells can express either
a2,3- or a2,6-linked sialic acid residues
Human influenza virus (a2,6)Avian influenza virus (a2,3)Ciliated cellNon-ciliatedcellCiliated cell
Matrosovich
et al., PNAS 101:4620, 2004
Slide25Origin of 2009 pandemic H1N1 influenza strain“quadruple reassortant”
Trifonov
et al., NEJM 361:115, 2009Xu et al., Sciencexpress, 25 March 2010Wei et al., Sci. Transl. Med. 2, 24ra21, 2010
Slide26Influenza Clinical Manifestations
Transmission
Airborne dropletsPrimary symptoms Acute onset fevers, chills, headache, myalgiasNon-productive coughPotentially severe even in generally health patientsComplicationsYoung and elderly most susceptibleViral and secondary bacterial pneumoniaEncephalitisReye syndrome (aspirin use)James Gathany, CDC Public Health Image Library #11162
Slide27Influenza Diagnosis, Treatment, and Prevention
Diagnosis
Clinical suspicionVirus detection (nasal swab)Culture, antigen (DFA), or genome (RT-PCR) detectionTreatmentSymptomaticM2 channel blockersAmantidine and rimantadineNeuraminidase inhibitorsOseltamivir (oral) and zanamivir (inhaled)Peramivir (IV) – CDC issued EAU in late fall, 2009NO ANTIBIOTICS (unless concern for bacterial superinfection present)PreventionProphylaxisVaccination
Slide28TRUE or FALSE?
There is very small yet scientifically validated link between childhood vaccination and autism.
Slide29Pre-vaccine
annual U.S.
cases/deaths150,000/15,0001,000/2003,500,000/500200,000/10060,000/rare4,000,000/100200,000/10,00025,000/2,000
20,000/1,000
(500,000 deaths worldwide)Smallpox (total 300-500 million deathsduring 20th century worldwide)U.S. Pharmacist
Slide30Influenza Vaccines
Three general types
Killed virus (TIV – trivalent inactivated influenza vaccine) Live virus (LAIV – live attenuated influenza vaccine)Genetically engineered, subunit (in development)Very effective (70-80%)Dependent on virus match (only 40% in 2007-2008)Contain three different viruses2 influenza A subtypes, 1 influenza B strain2008-2009 vaccine: A/Brisbane/59/2007 (H1N1), A/Brisbane/10/2007 (H3N2), and B/Florida/4/20062009-2010 vaccine: A/Brisbane/59/2007 (H1N1), and A/Brisbane/10/2007 (H3N2), B/Brisbane/60/20082010-2011 vaccine: A/California/7/2009 (pandemic H1N1), A/Perth/16/2009-like (H3N2), and B/Brisbane/60/2008 Changes (possible) every yearShould be administered yearly
Slide31Influenza Vaccine Recommendations – Children (prior to 2010)
All
children aged 6 months to 18 years (new recommendation for 2008-2009 season)High priority populationsVery young (age 6 months to 4 years)Chronic pulmonary, cardiovascular, renal, hepatic, hematologic, or metabolic disordersIncludes children with asthma and diabetesImmunosuppressionAspiration risk (e.g. seizure disorder, spinal cord injury)Long-term aspirin therapyChronic care facility residentsAnticipated pregnancy during influenza seasonCDC/ACIP. Prevention and control of seasonal influenza with vaccines.MMWR 58 (RR-8), 2009; http://www.cdc.gov/mmwr/pdf/rr/rr5808.pdf
Slide32Influenza Vaccine Recommendations – Adults (prior to 2010)
Anyone
who wants itExceptions: egg allergies and previous adverse reactions to vaccineHigh risk populations Persons aged ≥ 50 yearsChronic pulmonary, cardiovascular, renal, hepatic, hematologic, or metabolic disordersIncludes children with asthma and diabetesImmunosuppressionAspiration risk (e.g. seizure disorder, spinal cord injury)Chronic care facility residentsAnticipated pregnancy during influenza seasonHealth care workersClose contacts/caregivers of children < 5 years and adults ≥ 50 years and patients with high risk medical conditionsCDC/ACIP. Prevention and control of seasonal influenza with vaccines.MMWR 58 (RR-8), 2009; http://www.cdc.gov/mmwr/pdf/rr/rr5808.pdf
Slide33Influenza Vaccine Options
TIV (inactivated) approved for
ALL patientsLAIV (attenuated) exceptionsPersons age <2 or ≥ 50 yearsChildren 2-4 years old with history of possible reactive airway diseaseHigh risk for influenza-related complicationsCaregivers of severely immunosuppressed patients (e.g. BMT)PregnancyCDC/ACIP. Prevention and control of seasonal influenza with vaccines.MMWR 58 (RR-8), 2009; http://www.cdc.gov/mmwr/pdf/rr/rr5808.pdf
Slide34Influenza Vaccine Recommendations
CDC
Slide3542 year old generally healthy male student returned from
Christmas break and developed acute onset of clearrhinorrhea, mild sore throat, and low grade fevers. He
had very minimal cough and no myalgias, and felt well enough to return to classes. Symptoms spontaneously resolved within a week.
Slide36729:512,
flickr
Mcfarlandmo, flickr
Slide3742 year old generally healthy male student returned from
Christmas break and developed acute onset
of clearrhinorrhea, mild sore throat, and low grade fevers. Hehad very minimal cough and no myalgias, and felt well enough to return to classes. Symptoms spontaneously resolved within a week.Diagnosis?
Slide38Rhinovirus
Family:
PicornaviridaeOther members: coxsackie viruses, poliovirus, hepatitis A virusNon-envelopedNon-segmented positive (+) strand RNA genome> 100 serotypes knownSource Undetermined
Slide39Rhinovirus life cycle
RNA replication
factoryNucleusCellular receptor (species barrier)ICAM-1 (90%)VLDL receptor (10%)Entirely cytoplasmicReplication most
efficient at 33°C
****Antiviral drug targetsSource Undetermined
Slide40Rhinovirus Pathogenesis
Minimal direct virus-induced cell damage
Primarily upper respiratory tractRole of immune responseInflammatory response correlates with symptomsResponsible for COPD and asthma exacerbationsInduces serotype-specific immunity
Slide41Rhinovirus Clinical Manifestations
Transmission
Aerosol (sneezing)Direct transmission (fomites)Primary symptoms Rhinorrhea, sore throat, minimal cough, low grade feverGenerally mildComplicationsAsthma/COPD exacerbations
Slide42Rhinovirus Diagnosis, Treatment, and Prevention
Diagnosis
Clinical suspicionTreatmentSymptomaticEnormous market for “alternative” medicationsNO ANTIBIOTICSPreventionVaccine development unlikely (mild disease, serotypes)“Wash your hands!”
Slide4383 year old male nursing home resident with history of
coronary artery disease, hypertension, and emphysemain April developed low grade fever, nasal congestion,
and a non-productive cough. There were numerous otherresidents with similar symptoms over the past month. Hiscough progressed over two weeks and was keeping his roommate awake at night. He was eventually taken to thehospital when he began having trouble breathing, and despite being given numerous antibiotics he died withina week due to respiratory failure.
Slide44Source Undetermined
Slide4583 year old male nursing home resident
with history ofcoronary artery disease, hypertension, and emphysema
in April developed low grade fever, nasal congestion, and a non-productive cough. There were numerous otherresidents with similar symptoms over the past month. Hiscough progressed over two weeks and was keeping his roommate awake at night. He was eventually taken to thehospital when he began having trouble breathing, and despite being given numerous antibiotics he died withina week due to respiratory failure.Diagnosis?
Slide46Respiratory syncytial virus (RSV)
Family:
ParamyxoviridaeParainfluenza virus, human metapneumovirusMeasles (rubeola) and mumps virusesEnvelopedNon-segmented negative (-) strand RNA genomeNo reassortmentTwo major groups (A and B)
Slide47RSV Structure
G protein (HN)
Hemagglutinin and neuraminidase Receptor binding (target unknown)Group determinantF proteinPromotes virus-cell and cell-cell fusionCandidate vaccine targetTarget for palivizumab (preventive monoclonal antibody)Source Undetermined
Slide48RSV Pathogenesis
Extensive direct virus-induced damage
Primarily epithelial cells in lower respiratory tractIntense inflammatory responseSkewed inflammatory response (TH2-like) may contribute to severe diseaseInduces only partially effective immunityHallmark of RSV pathologyis “bronchiolitis”Alveoli
Peribronchiole inflammation
Bronchiole obstruction with mucus and necrotic cellsSource Undetermined
Slide49RSV Clinical Manifestations
Transmission
Aerosol (sneezing)Direct transmission (fomites, contagious secretions)Highly infectious and ubiquitous (~100% children infected by 2 yo)Primary symptoms (mild to severe) URI (rhinorrhea, sore throat, minimal cough, low grade fever)Bronchitis (cough)Bronchiolitis (wheezing, dyspnea)Pneumonia (severe dyspnea, tachypnea, hypoxemia)High risk groups for complicationsPremature infantsCardiopulmonary diseaseImmunocompromised patients
Slide50RSV Diagnosis, Treatment, and Prevention
Diagnosis
Clinical suspicionCulture, antigen (DFA), or genome (RT-PCR) detectionTreatmentSymptomaticRibavirin of questionable utilityNO ANTIBIOTICSPreventionPassive immunization (Palivizumab)EXPENSIVE (~$77,000 to prevent one hospitalization annually)Live attenuated vaccine development underwayDeaths associated with inactivated vaccine in 1960’s
Slide51Other respiratory viruses
Coronaviruses (e.g. SARS)
Enveloped, positive (+) strand RNA virusesTypically cause mild respiratory tract symptomsAdenovirusesNon-enveloped DNA virusesMany (~50) serotypesAssociated with mild URI symptoms, pharyngoconjunctivitis, and GI diseaseCan cause severe pneumonia“Source Undetermined
Slide52Source Undetermined
Slide53Slide 6: Source Undetermined
Slide 8: Iconicphotos,
http://iconicphotos.wordpress.com/2009/05/19/1918-spanish-flu/ Slide 9: Source UndeterminedSlide 11: Source UndeterminedSlide 12: David MillerSlide 13: Computational Systems Biology Lab, http://camd.yonsei.ac.kr/1160 Slide 14: YK Times, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Virus_Replication_large.svg, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/deed.en Slide 16: Source UndeterminedSlide 19: Centers for Disease Control and Prevention, http://www.cdc.gov/Slide 22: Nevit Dilmen
, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:Crowd_04379.JPG
, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/deed.en; titanium 22, Flickr, http://www.flickr.com/photos/nagarazoku/20867122/, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/deed.en; Herr Kriss, Wikimedia Commons, http://commons.wikimedia.org/wiki/File:The_pair_of_ducks.jpg, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/deed.enSlide 23: Source UndeterminedSlide 24: Matrosovich et al., PNAS 101:4620, 2004Slide 25: Trifonov et al., NEJM 361:115, 2009; Xu et al., Sciencexpress, 25 March 2010, Wei et al., Sci. Transl. Med. 2, 24ra21, 2010Slide 26: James Gathany, CDC Public Health Image Library #11162Slide 29: U.S. Pharmacist, http://uspharmacist.com/content/d/feature/i/783/c/14501/ Slide 34: Centers for Disease Control and Prevention, http://www.cdc.gov/Slide 36: mcfarlandmo, Flickr, http://www.flickr.com/photos/mcfarlandmo/4014611539/, CC:BY, http://creativecommons.org/licenses/by/2.0/deed.en; 729:512, Flickr, http://www.flickr.com/photos/tummysak/5716692/, CC:BY-NC, http://creativecommons.org/licenses/by-nc/2.0/deed.en Slide 38: Source UndeterminedSlide 39: Source UndeterminedSlide 44: Source UndeterminedSlide 47: Source Undetermined
Slide 48: Source Undetermined
Slide 51: Source Undetermined
Slide 52: Source Undetermined
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