2

Manuel R. Amieva, M.D., Ph.D.Department of Pediatrics, Infectious DiseasesDepartment of Microbiology & ImmunologyStanford University School of Medicine

Viral Lower Respiratory Tract Infections

2

Sharon F. Chen, M.D.Department of Pediatrics, Infectious DiseasesStanford University School of Medicine

Charles G. Prober, M.D.Department of Pediatrics, Infectious DiseasesDepartment of Microbiology & ImmunologyStanford University School of Medicine

3

Learning Objectives

• Recognize the clinical characteristics of bronchitis and bronchiolitis

• Describe how the clinical characteristics of bronchiolitis relates to the pathogenesis of RSV infection.

• Discuss potential complications, management and prevention strategies for RSV-induced bronchiolitis.

• Compare the clinical manifestations of RSV to that of human metapneumovirus

Major Human Pathogens

Helminths

Taenia saginata(Beef Tapeworm)Taenia Solium(Pig Tapeworm)Diphyllobothrium(Fish Tapeworm)Echinococcus(Dog Tapeworm)

Schistosoma (Schistosomiasis)Clonorchis & Fasciola (Liver Flukes)Paragonimus (Lung Fluke)

Enterobius (Pinworm)Trichuris (Whipworm)Ascaris (Giant worm)Ancylostoma & Necator (Hookworm)Strongyloides (Strongy)Toxocara (Dog Ascaris) Trichinella (Trichinosis)Onchocerca (River Blindness)Loa Loa (Eye Worm)Wuchereria & Brugia (Elephantiasis)

Nematodes(Roundworms)

Trematodes (Flukes)

Cestodes (Tapeworms)

ProtozoaEntamoebaGiardiaCryptosporidiumTrichomonas

TrypanosomaLeishmaniaToxoplasma

GI/GUBlood

Tissue

PlasmodiumBabesia

Fungi

YeastMold

Dimorphic

Dermatophytes

CandidaCryptococcusPneumocystisMalasseziaMicrosporidia

AspergillusMucorRhizopusFusarium

CoccidioidesHistoplasmosisBlastomycesParacoccidioidesSporothrix

StaphylococcusStreptococcusEnterococcus

ListeriaBacillusClostridiumCorynebacteriumGardnerellaPropionibacterium

Cocci

Gram positive BacteriaRods Branching

ActinomycesNocardia

Mycoplasma

No cell wall Pleomorphic

Acid Fast BacilliMycobacterium tuberculosisMycobacterium lepraeNon-tuberculous Mycobacteria

Rods

E. coliKlebsiellaProteusSerratiaEnterobacter

SpiralCampylobacterHelicobacter

CommaVibrio

DiplococciNeisseriaMoraxella

ZoonoticBrucellaFrancisellaCampylobacterPasteurellaBartonellaYersiniaCoxiellaChlamydophila psittaciRickettsiaEhrlichiaAnaplasmaBorreliaLeptospira

Respiratory PathogensHaemophilusBordatellaLegionella

OpportunisticPseudomonas

BacteroidesPrevotellaFusobacterium

IntracellularChlamydiaChlamydophilaRickettsiaCoxiellaLegionellaEhrlichiaAnaplasmaBartonellaBrucellaFrancisellaShigellaSalmonella

Spirochaetes

TreponemaBorreliaLeptospira

Enteric flora

Enteric pathogensShigellaSalmonellaYersinia

Anaerobic

Gram negative Bacteria

Viruses

DNAAdenovirusHerpes simplexVaricella zosterCytomegalovirusEpstein Barr virus HHV6, HHV7, HHV8SmallpoxMolluscum contagiosumHepatitis BParvovirusHuman papillomavirusBK polyomavirus

RhinovirusCoxsackieEnterovirusesPoliovirusRotavirusNorovirusHepatitis AHepatitis CHIVHTLV-1MeaslesMumpsRubella

RNAInfluenza A, B ParainfluenzaRSVHuman metapneumovirusCoronavirus (MERS, SARS)EbolaRabiesVector borneWest NileDengueChickengunyaYellow Fever

Ticks Vectors of: Lyme borreliosis, Relapsing Fever, RMSF, other Rickettsia, Babesia, Anaplasma, EhrlichiaLice (pediculosis)Vectors of: Epidemic typhus, Trench FeverMites (scabies)Vectors of: Scrub typhus, Rickettsialpox Mosquitoes Vectors of: Malaria, Dengue, Chikungunya, West Nile, Yellow FeverFleas Vectors of: Cat-scratch fever, Murine typhus, Bubonic plague, Tularemia

Arthropods

Microsporum, Epidermophytum Trichophytum

Major Human Pathogens

Helminths

Taenia saginata(Beef Tapeworm)Taenia Solium(Pig Tapeworm)Diphyllobothrium(Fish Tapeworm)Echinococcus(Dog Tapeworm)

Schistosoma (Schistosomiasis)Clonorchis & Fasciola (Liver Flukes)Paragonimus (Lung Fluke)

Enterobius (Pinworm)Trichuris (Whipworm)Ascaris (Giant worm)Ancylostoma & Necator (Hookworm)Strongyloides (Strongy)Toxocara (Dog Ascaris) Trichinella (Trichinosis)Onchocerca (River Blindness)Loa Loa (Eye Worm)Wuchereria & Brugia (Elephantiasis)

Nematodes(Roundworms)

Trematodes (Flukes)

Cestodes (Tapeworms)

ProtozoaEntamoebaGiardiaCryptosporidiumTrichomonas

TrypanosomaLeishmaniaToxoplasma

GI/GUBlood

Tissue

PlasmodiumBabesia

Fungi

YeastMold

Dimorphic

Dermatophytes

CandidaCryptococcusPneumocystisMalasseziaMicrosporidia

AspergillusMucorRhizopusFusarium

CoccidioidesHistoplasmosisBlastomycesParacoccidioidesSporothrix

StaphylococcusStreptococcusEnterococcus

ListeriaBacillusClostridiumCorynebacteriumGardnerellaPropionibacterium

Cocci

Gram positive BacteriaRods Branching

ActinomycesNocardia

Mycoplasma

No cell wall Pleomorphic

Acid Fast BacilliMycobacterium tuberculosisMycobacterium lepraeNon-tuberculous Mycobacteria

Rods

E. coliKlebsiellaProteusSerratiaEnterobacter

SpiralCampylobacterHelicobacter

CommaVibrio

DiplococciNeisseriaMoraxella

ZoonoticBrucellaFrancisellaCampylobacterPasteurellaBartonellaYersiniaCoxiellaChlamydophila psittaciRickettsiaEhrlichiaAnaplasmaBorreliaLeptospira

Respiratory PathogensHaemophilusBordatellaLegionella

OpportunisticPseudomonas

BacteroidesPrevotellaFusobacterium

IntracellularChlamydiaChlamydophilaRickettsiaCoxiellaLegionellaEhrlichiaAnaplasmaBartonellaBrucellaFrancisellaShigellaSalmonella

Spirochaetes

TreponemaBorreliaLeptospira

Enteric flora

Enteric pathogensShigellaSalmonellaYersinia

Anaerobic

Gram negative Bacteria

Viruses

DNAAdenovirusHerpes simplexVaricella zosterCytomegalovirusEpstein Barr virus HHV6, HHV7, HHV8SmallpoxMolluscum contagiosumHepatitis BParvovirusHuman papillomavirusBK polyomavirus

RhinovirusCoxsackieEnterovirusesPoliovirusRotavirusNorovirusHepatitis AHepatitis CHIVHTLV-1MeaslesMumpsRubella

RNAInfluenza A, B ParainfluenzaRSVHuman metapneumovirusCoronavirus (MERS, SARS)EbolaRabiesVector borneWest NileDengueChickengunyaYellow Fever

Ticks Vectors of: Lyme borreliosis, Relapsing Fever, RMSF, other Rickettsia, Babesia, Anaplasma, EhrlichiaLice (pediculosis)Vectors of: Epidemic typhus, Trench FeverMites (scabies)Vectors of: Scrub typhus, Rickettsialpox Mosquitoes Vectors of: Malaria, Dengue, Chikungunya, West Nile, Yellow FeverFleas Vectors of: Cat-scratch fever, Murine typhus, Bubonic plague, Tularemia

Arthropods

Microsporum, Epidermophytum Trichophytum

ParainfluenzaRSVHumanmetapneumovirusCoronavirus(MERS, SARS)

Rhinovirus

Adenovirus

6

LRTTracheaBronchi

BronchiolesLung Bronchiolitis

RSV, Influenza, Metapneumovirus

Adenovirus

Bronchitis

Laryngotracheo-bronchitis

CroupParainfluenza

URTNasal CavityNasopharynxOropharynx

Larynx

PharyngitisSore ThroatLaryngitis

AdenovirusParainfluenza

RhinitisCommon Cold

RhinovirusCorona Virus

Parainfluenza, InfluenzaAdenovirus, Metapneumovirus

RSV, Corona

Pneumonia All

Bronchitis and Bronchiolitis

7

• Productive cough for to 10-20 days

Bronchitis clinical manifestations & pathogenesis

7

• Productive cough for to 10-20 days

Bronchitis clinical manifestations & pathogenesis

• Predominantly viral; few bacterial causes • Fever is unusual

• Purulent sputum - 50% of patients; does not mean bacterial infection

8

Bronchiolitis

LRTTracheaBronchi

BronchiolesLung Bronchiolitis

RSV, Influenza, Metapneumovirus

Adenovirus

BronchitisParainfluenza, Influenza

Adenovirus, MetapneumovirusRSV, Corona

Pneumonia All

9

• Affects mostly infants and young children• 4-6 day incubation period most common in

Winter• Begins with URI symptoms and fever• Progress to tachypnea, cough, respiratory

distress with retractions and wheezing

BronchiolitisClinical Manifestations

11

Swelling

Mucus &debris

• RSV infects respiratory epithelial cells• Innate immune sensors detect PAMPs

and produce interferon and other cytokines and chemokines

• Inflammatory cells recruited• Increased vascular flow, permeability

and increased mucus production• Apoptosis and sloughing of epithelial

cells

RSV- Pathogenesis

12

• Outpouring of mucus & inflammatory cells leads to•Small airway plugging with air trapping•Impeded gas exchange

Bronchiolitis Pathogenesis &Clinical Manifestations

13

• Respiratory failure• Apnea in newborns and/or premature infants

Bronchiolitis Complications

• Increased severity in:•newborns and the elderly•congenital heart disease•chronic lung disease•immune compromised

14

• Assess the severity and progression • Determine risks factors • Treatment is supportive• Drugs to overcome airway obstruction?

Bronchiolitis Treatment

15

• RSV is the most important viral pathogen during the first year of life.

• Two important surface proteins (F-fusion & G-attachment)

GF

ParamyxoviridaeParainfluenzaMetapneumovirus

MumpsMeaslesHendraNipah

enveloped

1 serotype

RSVRespiratory Syncytial Virus

Syncy'um

17

Protective immunity is incomplete and short-lived• G-protein is heavily glycosylated• G-protein can be produced in a soluble

form and act as a decoy• RSV can infect dendritic cells and

reduce antigen presentation to T-cells

RSV- Mechanisms of Immune evasion

G

F

17

Protective immunity is incomplete and short-lived• G-protein is heavily glycosylated• G-protein can be produced in a soluble

form and act as a decoy• RSV can infect dendritic cells and

reduce antigen presentation to T-cells

RSV- Mechanisms of Immune evasion

G

F

17

Protective immunity is incomplete and short-lived• G-protein is heavily glycosylated• G-protein can be produced in a soluble

form and act as a decoy• RSV can infect dendritic cells and

reduce antigen presentation to T-cells

RSV- Mechanisms of Immune evasion

G

F

G

18

• After age 2 most children do not develop severe disease from RSV

• Smaller airways and less respiratory capacity and reserve

• Immature infant immune system• Innate and adaptive responses may be deficient compared to adults

Host Factors Involved in RSV disease

19

• Immunopathology• recurrent wheezing in some infants after RSV

• association with asthma later in life

Host Factors Involved in RSV disease

20

•No vaccine available•Passive immunity•Palivizumab- Monoclonal Antibody against F-Protein

•Used in children < 2 years with cyanotic congenital heart disease, chronic lung disease, or prematurity < 35 weeks

GF

Prevention of RSV disease

Human Metapneumovirus

21

• One serotype • Similar structure to RSV • Mimics RSV epidemiology

& clinical diseaseParamyxoviridaeParainfluenzaRSV

MumpsMeaslesHendraNipah

enveloped

1 serotype

22

LRTTracheaBronchi

BronchiolesLung Bronchiolitis

RSV, Influenza, Metapneumovirus

Adenovirus

Bronchitis

Laryngotracheo-bronchitis

CroupParainfluenza

URTNasal CavityNasopharynxOropharynx

Larynx

PharyngitisSore ThroatLaryngitis

AdenovirusParainfluenza

RhinitisCommon Cold

RhinovirusCorona Virus

Parainfluenza, InfluenzaAdenovirus, Metapneumovirus

RSV, Corona

Pneumonia All

Bronchitis and Bronchiolitis

23

Slide 6: Respiratory Tract diagram modified from:http://commons.wikimedia.org/wiki/File:Respiratory_system_complete_numbered.svg

Slide 7: Coughing adult. Patient Education © ExitCare® Patient Information ©2014 ExitCare, LLC.https://www.clinicalkey.com

Slide 9: Infant recovering from RSV bronchiolitis with nasal canula O2 shows tachypnea and retractions. Edited from:https://www.youtube.com/watch?v=1Dp3N0tzDns

Slide 14: Ventilation mask diagram. Karlowicz, M. Gary, MD, FAAP, Karotkin, Edward H., MD, FAAP,Goldsmith, Jay P., MD, FAAP - Assisted Ventilation of the Neonate, 71-93© 2011 Copyright © 2011, 2003, 1996, 1988, 1981 by Saunders, an imprint of Elsevier Inc.https://www.clinicalkey.com

Slide 15: RSV syncytium in cell culture. From: Tian J et al. J Gen Virol 2013;94:1691-1700https://www.clinicalkey.com

Slide 19: Asthma inhaler Patient Education © ExitCare® Patient Information ©2014 ExitCare, LLChttps://www.clinicalkey.com

Credits: Viral Lower Respiratory Tract Infections