Viral Upper Infections

Manuel R. Amieva, M.D., Ph.D. Department of Pediatrics, Infectious Diseases Department of Microbiology & Immunology Stanford University School of Medicine

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

Charles G. Prober, M.D. Department of Pediatrics, Infectious Diseases Department of Microbiology & Immunology Stanford University School of Medicine

2 Learning Objectives

• Describe a general model for the pathogenesis of viral respiratory tract infections that explains the symptoms and clinical manifestations. • Relate the epidemiology and clinical manifestations to the pathogenesis of viral respiratory tract infections caused by: Rhinoviruses Coronaviruses Adenoviruses Parainfluenza viruses

3 Major Human Pathogens Viruses Fungi Gram positive Bacteria RNA A, B Mold Rods Rhinovirus Branching Coxsackie Parainfluenza DNA Yeast Aspergillus Dimorphic Listeria Actinomyces RSV Coccidioides Cocci Enteroviruses Adenovirus Candida Mucor Bacillus Nocardia Human Histoplasmosis Poliovirus Herpes simplex Cryptococcus Rhizopus Staphylococcus Clostridium metapneumovirus Blastomyces Rotavirus Varicella zoster Pneumocystis Fusarium Streptococcus Corynebacterium Coronavirus Paracoccidioides Norovirus Cytomegalovirus Malassezia Enterococcus Gardnerella (MERS, SARS) Sporothrix Hepatitis A Epstein Barr virus Microsporidia Propionibacterium Hepatitis C Ebola HHV6, HHV7, HHV8 Dermatophytes HIV Rabies Smallpox Microsporum, Epidermophytum Trichophytum HTLV-1 Vector borne Molluscum contagiosum No cell wall Acid Fast Bacilli Measles West Nile Hepatitis B Mumps Parvovirus Pleomorphic Dengue Protozoa Tissue Mycobacterium tuberculosis Rubella Human papillomavirus Chickengunya Trypanosoma Mycoplasma Mycobacterium leprae Yellow Fever BK polyomavirus GI/GU Non-tuberculous Mycobacteria Entamoeba Blood Leishmania Toxoplasma Giardia Plasmodium Cryptosporidium Babesia Trichomonas Gram negative Bacteria Zoonotic Spirochaetes Arthropods Brucella Rods Francisella Campylobacter Treponema Ticks Helminths Enteric flora Pasteurella Borrelia Vectors of: Lyme borreliosis, Trematodes (Flukes) Nematodes E. coli Respiratory Pathogens Bartonella Leptospira Relapsing Fever, RMSF, Haemophilus other Rickettsia, Babesia, Schistosoma (Roundworms) Klebsiella Yersinia (Schistosomiasis) Bordatella Spiral Anaplasma, Ehrlichia Enterobius (Pinworm) Proteus Coxiella Clonorchis & Fasciola Legionella Campylobacter Intracellular Lice (pediculosis) Trichuris (Whipworm) Serratia Chlamydophila (Liver Flukes) Helicobacter Chlamydia Vectors of: Epidemic typhus, Ascaris (Giant worm) Enterobacter psittaci Paragonimus (Lung Fluke) Trench Fever Ancylostoma & Necator Opportunistic Rickettsia Chlamydophila Mites (scabies) (Hookworm) Pseudomonas Ehrlichia Rickettsia Coxiella Vectors of: Scrub typhus, Cestodes (Tapeworms) Strongyloides (Strongy) Anaplasma Rickettsialpox Enteric pathogens Legionella Taenia saginata Toxocara (Dog Ascaris) Comma Borrelia Mosquitoes (Beef Tapeworm) Trichinella (Trichinosis) Shigella Leptospira Ehrlichia Vectors of: Malaria, Dengue, Salmonella Vibrio Anaplasma Taenia Solium Onchocerca (River Anaerobic Chikungunya, West Nile, (Pig Tapeworm) Yersinia Bartonella Blindness) Yellow Fever Diphyllobothrium Loa Loa (Eye Worm) Bacteroides Brucella Fleas Diplococci (Fish Tapeworm) Wuchereria & Brugia Prevotella Francisella Vectors of: Cat-scratch fever, Neisseria Echinococcus (Elephantiasis) Fusobacterium Shigella Murine typhus, Bubonic Moraxella (Dog Tapeworm) Salmonella plague, Tularemia Major Human Pathogens Viruses Fungi Gram positive Bacteria RNA Influenza A, B Mold Rods Rhinovirus Branching Coxsackie Parainfluenza DNA Yeast Aspergillus Dimorphic Listeria Actinomyces RSV Coccidioides Cocci Enteroviruses RSV Adenovirus Candida Mucor Bacillus Nocardia Human Histoplasmosis Poliovirus Human Herpes simplex Cryptococcus Rhizopus Staphylococcus Clostridium metapneumovirus Blastomyces Rotavirus Varicella zoster Pneumocystis Fusarium Streptococcus Corynebacterium Coronavirus Paracoccidioides Norovirus Cytomegalovirus Malassezia Enterococcus Gardnerella (MERS, SARS)SARS) Sporothrix Hepatitis A Epstein Barr virus Microsporidia Propionibacterium Hepatitis C Ebola HHV6, HHV7, HHV8 Dermatophytes HIV Rabies Smallpox Microsporum, Epidermophytum Trichophytum HTLV-1 Vector borne Molluscum contagiosum No cell wall Acid Fast Bacilli Measles West Nile Hepatitis B Mumps Parvovirus Pleomorphic Dengue Protozoa Tissue Mycobacterium tuberculosis Rubella Human papillomavirus Chickengunya Trypanosoma Mycoplasma Mycobacterium leprae Yellow Fever BK polyomavirus GI/GU Non-tuberculous Mycobacteria Entamoeba Blood Leishmania Toxoplasma Giardia Plasmodium Cryptosporidium Babesia Trichomonas Gram negative Bacteria Zoonotic Spirochaetes Arthropods Brucella Rods Francisella Campylobacter Treponema Ticks Helminths Enteric flora Pasteurella Borrelia Vectors of: Lyme borreliosis, Trematodes (Flukes) Nematodes E. coli Respiratory Pathogens Bartonella Leptospira Relapsing Fever, RMSF, Haemophilus other Rickettsia, Babesia, Schistosoma (Roundworms) Klebsiella Yersinia (Schistosomiasis) Bordatella Spiral Anaplasma, Ehrlichia Enterobius (Pinworm) Proteus Coxiella Clonorchis & Fasciola Legionella Campylobacter Intracellular Lice (pediculosis) Trichuris (Whipworm) Serratia Chlamydophila (Liver Flukes) Helicobacter Chlamydia Vectors of: Epidemic typhus, Ascaris (Giant worm) Enterobacter psittaci Paragonimus (Lung Fluke) Trench Fever Ancylostoma & Necator Opportunistic Rickettsia Chlamydophila Mites (scabies) (Hookworm) Pseudomonas Ehrlichia Rickettsia Coxiella Vectors of: Scrub typhus, Cestodes (Tapeworms) Strongyloides (Strongy) Anaplasma Rickettsialpox Enteric pathogens Legionella Taenia saginata Toxocara (Dog Ascaris) Comma Borrelia Mosquitoes (Beef Tapeworm) Trichinella (Trichinosis) Shigella Leptospira Ehrlichia Vectors of: Malaria, Dengue, Salmonella Vibrio Anaplasma Taenia Solium Onchocerca (River Anaerobic Chikungunya, West Nile, (Pig Tapeworm) Yersinia Bartonella Blindness) Yellow Fever Diphyllobothrium Loa Loa (Eye Worm) Bacteroides Brucella Fleas Diplococci (Fish Tapeworm) Wuchereria & Brugia Prevotella Francisella Vectors of: Cat-scratch fever, Neisseria Echinococcus (Elephantiasis) Fusobacterium Shigella Murine typhus, Bubonic Moraxella (Dog Tapeworm) Salmonella plague, Tularemia Anatomical Location of Viral Syndromes

URT Nasal Cavity Nasopharynx Oropharynx

6

airway Pathogenesis

mucus

goblet cell respiratory epithelium

blood vessel

smooth muscle

8 airway Pathogenesis

mucus

goblet cell respiratory epithelium

blood vessel

smooth muscle

8 Pathogenesis

Attach through receptor mediated endocytosis Cellular and tissue Tropism

Replicate rapidly in cytosol (RNA viruses)

9 Pathogenesis

Local spread of virus stimulation to epithelial cells of mucus production Innate immune and sensing of PAMPs release Interferon, cytokines & chemokines

Recruitment of inflammatory cells extravasation

10 Increase in Mucus & airway mucus debris

Death of epithelial cells by lysis and exit (non-enveloped viruses)

Swelling Increased vascular permeability & inflammatory cell infiltration

11 Mucus & debris

normal Swelling

12 Anatomical Location of Viral Syndromes

Rhinitis Rhinovirus URT Corona Virus Nasal Cavity Nasopharynx Oropharynx Larynx

13 Anatomical Location of Viral Syndromes

Rhinitis Rhinovirus URT Common Cold Corona Virus Nasal Cavity Nasopharynx Oropharynx Larynx

13 Rhinovirus & Coronavirus Clinical Manifestations

• Incubation period, 2 to 3 days • Mild symptoms for 5 to 7 days • Fever & systemic symptoms are not common • May cause exacerbation of chronic lung disease • More severe in smokers, elderly • Immunocompromised may develop

14 Rhinovirus & Coronavirus are RNA viruses Virus

II

(+) DNA

III I (+/-) DNA

(+/-) DNA (+/-) RNA

VII IV (+/-) gapped (+/-) DNA (+) RNA DNA mRNA

(+/-) DNA (-) RNA V (-) DNA

PROTEIN (+) RNA VI 15 Rhinovirus & Coronavirus are RNA viruses Virus

II

(+) DNA

III I (+/-) DNA

(+/-) DNA (+/-) RNA

VII IV (+/-) gapped (+/-) DNA (+) RNA DNA mRNA

(+/-) DNA (-) RNA V (-) DNA

PROTEIN (+) RNA VI 15 Rhinovirus & Coronavirus Viral Characteristics

>100 serotypes at least 6 serogroups naked capsid enveloped Picornaviridae Coronaviridae Poliovirus Enteroviruses SARS Coxackievirus MERS Hepatitis A 16 Coronavirus SARS Global Mortality

Deaths Cases

17 Coronavirus SARS Global Mortality

Deaths Cases

17 Coronavirus MERS Global Cases

18 Coronavirus MERS Global Cases

18 Anatomical Location of Viral Syndromes

Rhinitis Rhinovirus URT Common Cold Corona Virus Nasal Cavity Nasopharynx Adenovirus Sore Throat Oropharynx Parainfluenza Larynx

19 Adenovirus Clinical Manifestations

Typical clinical manifestations • Acute febrile pharyngitis • Pharyngoconjunctival fever

• Can be deadly in immunocompromised hosts

20 Adenovirus Viral Characteristics

• Double-stranded DNA virus >50 serotypes naked capsid Adenoviridae

none

21 Anatomical Location of Viral Syndromes

Rhinitis Rhinovirus URT Common Cold Corona Virus Nasal Cavity Nasopharynx Pharyngitis Adenovirus Sore Throat Oropharynx Parainfluenza Larynx Laryngitis

22 Anatomical Location of Viral Syndromes

Laryngotracheo- LRT Parainfluenza Bronchi Bronchioles Lung

23 Parainfluenza virus Clinical Manifestations

Croup is distinctive • Barking cough with inspiratory stridor • Fever and hoarseness common • Often improves with exposure to cold air or steam • Common in Fall months (Type 1)

24 Subglottic Stenosis

Steeple Sign

25 Parainfluenza virus Viral Characteristics

4 serotypes • Enveloped single stranded RNA enveloped • 4 major serotypes (1,2,3,4) Paramyxoviridae • Reinfections are common RSV Metapneumovirus

Mumps Measles Hendra

Nipah 26 Anatomical Location of Viral Syndromes

Rhinitis Rhinovirus URT Common Cold Corona Virus Nasal Cavity Nasopharynx Pharyngitis Adenovirus Sore Throat Oropharynx Parainfluenza Larynx Laryngitis Laryngotracheo- LRT bronchitis Parainfluenza Croup Trachea Bronchi Parainfluenza Bronchitis Adenovirus Bronchioles RSV, Corona Lung RSV, Influenza, Metapneumovirus Adenovirus 27 Credits: Viral Upper Respiratory Tract Infections

Slide 6: Respiratory Tract diagram modified from: http://commons.wikimedia.org/wiki/File:Respiratory_system_complete_numbered.svg Slide 13: Clear, watery nasal secretions with swollen, reddish turbinates seen via fiberoptic rhinoscopy in a patient during the first few days of viral rhinitis. Often, the secretions become mucopurulent after several days. (From Fireman P: Atlas of Allergies and Immunology, 3rd ed. St. Louis, Mosby, 2006.) Ferri, Fred F., M.D., F.A.C.P. - Ferri's Color Atlas and Text of Clinical Medicine, 318-319 © 2009 Copyright © 2009 by Saunders, an imprint of Elsevier Inc. https://www.clinicalkey.com Slide 16: A) Molecular surface of the capsid of human rhinovirus 16. Modified from: Wikimedia Commons, the free media repository. Created using the data from entry 1AYM in the Protein Data Bank, and the following free software: Chimera, the free trial of AccuTrans and Anim8or. http://commons.wikimedia.org/wiki/File:Rhinovirus.PNG B)Coronavirus- Colorized transmission electron micrograph of the novel coronavirus that emerged in 2012 National Institute of Allergy and Infectious Diseases (NIAID)- Public Domain. http://commons.wikimedia.org/wiki/Category:Coronavirus#mediaviewer/File:Coronavirus.jpg

28 Credits: Viral Upper Respiratory Tract Infections

Slide 17: Map of deaths due to SARS Co-V infection: From Wikimedia Commons, the free media repository. WHO Data from 2008. Author: Maximilian Dorrbecker. http://commons.wikimedia.org/wiki/File:SARS_map.svg Slide 18: Map of cases of MERS Co-V infection. From Wikimedia Commons, the free media repository. Author: Renzoy16. http://commons.wikimedia.org/wiki/File:MERS-CoV_map.png Slide 20: Adenovirus pharyngitis and nonpurulent conjunctivitis. Courtesy Michael Sherlock, MD, Lutherville, Md. From: Michaels, Marian G.,Nowalk, Andrew J. - Atlas of Pediatric Physical Diagnosis, 469-529 © 2012 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. https://www.clinicalkey.com Slide 21: Adenovirus Structure. From Wikimedia Commons, the free media repository. 24 July 2006. Author: Pico en el Ojo. http://commons.wikimedia.org/wiki/File:Adenovirus_structure.png Slide 25: Croup Steeple Sign. From: Smith's Anesthesia for Infants and Children , 8th Edition Davis PJ, Cladis FP, Motoyama EK. Chapter 24, 786-820, 2011.

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