Viral Diseases of the Respiratory System

1. Viral Diseases of the Respiratory System MMI 205 Fall 2003 Louise S. Thai, M.D.

2. Learning Objectives For the following viruses: Influenza v. Parainfluenza v. Respiratory syncytial v. Rhinovirus You need to know: General characteristics Epidemiology Pathogenesis Clinical manifestations Treatment & Prevention

3. Impact on Public Health Infectious diseases of the respiratory system are among the most common human diseases Cause up to 5 million deaths worldwide. One million of these are due to viral illnesses Flu pandemic in 1918 caused 20 million deaths

4. Economic and Social Burden of VRI Adults average ~2 to 4 colds Children average 3 to 8 colds per year In 1998, 25 million office visits to primary care providers for upper respiratory infections (URIs) Costs associated with VRIs estimated at ~$25 billion annually

5. Childhood Lower Respiratory Tract Infections 10-13 viral respiratory infections/child in the first year of life - higher in day care Majority - upper respiratory infections Most of the URI viruses can also cause LRI - the boundaries blur 0.5-2.5% of infants will require hospitalization for viral pneumonia or bronchiolitis

6. Childhood Lower Respiratory Tract Infections Estimated 4 million children die worldwide from pneumonia each year Another 1.2 million deaths from measles and its complications (pneumonia). Although bacteria can cause of pneumonia, viruses are the MAJOR cause of childhood pneumonia in the USA.

7. Pneumonia in Children: Primarily Viral Agents Usual causes of pneumonia in this age group: Respiratory Syncytial Virus Influenza Parainfluenza Virus 3 Parainfluenza Viruses 1 & 2 Adenovirus Atypical presentation of Bordetella pertussis or other bacterial causes The primary causes of lower respiratory tract disease in childrenThe primary causes of lower respiratory tract disease in children

8. Why so many? Constant exposure: 21,000 L of air/day RT is a favorable environment for viruses: Warm, moist, and dark Plenty of cell types (25), which are good �tissue culture media� Optimal temperature Easy transmission via: Sneezing � aerosol 100-200 ?m particles at 100 ft/sec Cough � disperses nasopharyngeal content at 850 ft/sec Intimate and non-intimate contact

9. Airway Filters Pollens 10-100 ?m Spores 6-60 ?m Fungus 3-100 ?m Bacteria 0.15-0.45 ?m Viruses 0.01-1 ?m Tobacco smoke 0.0001-0.0006?m

10. Determinants of Viral Respiratory Disease Viral Factors Tissue tropism Route of infection Stability of the virus Replication and release of viruses into aerosols Host Factors Age Immune status Underlying disease adaptation Environmental Factors Dosage Exposure Occupation Life Style: Occupation Day care setting Public transport

11. Replication Sites and Clinical Manifestations

12. In order to understand the pathophysiology of bronchiolitis and why certain treatment modalities are not universally effective in treating this disease, we need to focus on 3 major areas: The dissociation between viral shedding or viral infection and �disease� The contributions or reversible and irreversible airway obstruction to the pathophysiology of bronchiolitis Host factors that modulate the response to virus This figure illustrates the relationship between viral shedding and �disease�. Note that 1. The curves intersect but do not entirely overlap 2. �Disease� can develop as the viral shedding is decreasing 3. This feature is why antivirals do not alter the clinical course of hospitalized patientsIn order to understand the pathophysiology of bronchiolitis and why certain treatment modalities are not universally effective in treating this disease, we need to focus on 3 major areas: The dissociation between viral shedding or viral infection and �disease� The contributions or reversible and irreversible airway obstruction to the pathophysiology of bronchiolitis Host factors that modulate the response to virus This figure illustrates the relationship between viral shedding and �disease�. Note that 1. The curves intersect but do not entirely overlap 2. �Disease� can develop as the viral shedding is decreasing 3. This feature is why antivirals do not alter the clinical course of hospitalized patients

13. Types of Viral Respiratory Infections Acute/confined (~two weeks) Influenza virus, rhinovirus, RSV, coronavirus Persistent Adenoviruses Herpesviruses Systemic Measles virus Smallpox virus

14. Influenza A and B Viruses Genome: 8-strand segmented (-) sense RNA Enveloped Spikes: Hemagglutinin (H) Neuraminidase (N) Attachment: through hemagglutinin Replication: in the nucleus

15. Influenza Virus

16. Epidemiology Winter epidemics Yearly antigenic drift due to minor mutations in H, N or both (influenza A and B) Epidemic antigenic shifts due to re-assortment, leading to major changes in H, N, or both ? new strain (influenza A only): 1918 H1N1 �Spanish flu� 1957 H2N2 �Asian flu� 1968 H1N2 �Hong Kong flu� 1977 H1N1 �Swine flu�

18. Pathogenesis Infection of the cells lining URT, trachea and bronchi Viral replication Budding Cell death ? Sloughing of the cells ? Breakdown products enter the bloodstream ? Systemic Symptoms Secondary bacterial infection major cause of death

19. Influenza A and B: Clinical Features Adults: Shivering, fever, headache, myalgia, sore throat, cough Fever 38-40� C Cough persists 1-2 weeks Children: Symptoms similar to adults Fever higher ? febrile seizures Non-pulmonary complications

20. Lab Diagnosis Cell culture in monkey kidney: Cytopathic effect Hemagglutination IFA ELISA Serology

21. Treatment and Prevention Amantadine and rimantadine ? inhibit un-coating of influenza A Zanamivir and oseltamivir ? inhibit neuraminidase of both influenza A and B viruses Influenza A and B Vaccines

22. Paramyxoviruses Parainfluenza Virus Respiratory Syncytial Virus (RSV)

23. Parainfluenza virus Single-stranded (-) sense RNA virus Enveloped with spikes Types based on spike proteins Entry = Orthomyxoviruses (influenza v.) Replication: in the cytoplasm

24. Epidemiology Humans are the only host Transmission via aerosol Who is at risk? Children � mild disease and croup (obstruction of the upper airway, barking cough) Adults � mild disease Where? Worldwide When? Types 1&2 cause croup in the fall; type 3 � year round

25. Pathogenesis

27. RSV Paramyxovirus (-) sense single-stranded RNA Enveloped 90throughout life

28. Pathogenesis of RSV Infection The most common cause of severe acute LRI in infants, young children, elderly and immunocompromised 50% of infected babies < 8-mo-old will develop lower respiratory tract disease Viral invasion of host cells ? fusion ? syncytium Immune mediated cell injury ? cell debris plug the small airways (bronchioli)

29. RSV-Bronchiolitis First episode of wheezing Infant less than one year of age Typical in presentation and clinical course: Incubation period of 4-7 days URI symptoms with low-grade fever Progresses to LRI symptoms

30. Bronchiolitis Early Symptoms Mild rhinorrhea Cough Low-grade T Later Symptoms Difficulty breathing Wheezing, cough Fussiness, lethargy Poor Feeding

31. RSV Pulmonary Obstruction Syncytia formation Inflammatory cell infiltrate Sloughing of respiratory epithelium

33. Viral Pneumonia

34. Lab Diagnosis IFA Enzyme Immunoassays Detect viral antigen in infected cells and nasal washings

35. Treatment and Prevention O2 Ribavirin Passive immunization of premature babies with anti-RSV antibodies No vaccine Hand-washing! Masks etc.

36. Rhinovirus Picornavirus >100 serotypes (+) sense RNA virus Naked capsid Acid labile Optimum T = 33� C

37. Epidemiology Responsible for half of all URI Transmission: Via aerosol and infected hands and fomites Who is at risk? Everybody When? Early fall and late spring

38. Pathogenesis and Clinical Manifestations Portal of entry: nose, mouth, eyes Replication: in the nose Primarily infects upper airway ? common cold Binds to ICAM-1 as cellular receptors Causes lysis of cells Infected cells release bradykinin and histamine ? rhinitis & rhinorrhea Sore throat, cough, headache, malaise Immunity is serotype specific

39. Lab Diagnosis Usually not necessary Can be cultured from nasal washings ID: Cytopathic effect Acid lability

40. Treatment and Prevention Decongestants Various antivirals (arildone, rhodanine, disoxaril) No vaccine Washing Hands

41. Important Message Wash Your Hands!

42. SARS Cause: SARS-associated corona (RNA) virus Respiratory illness with onset 2-1-2003 T > 100.5�F (>38� C) Cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome Travel within 10 days of onset of symptoms to an area with documented or suspected community transmission of SARS Close contact with a person with SARS within 10 days of onset