1. Viral Respiratory Infections in the Morbidity and Mortality of Airway Diseases and Immunocompromised States Acute and Chronic Bronchitis, COPD, Asthma, Cystic Fibrosis, and Immunocompromised Cancer Patients Viral Respiratory Infections in the Morbidity and Mortality of Airway Diseases and Immunocompromised States Acute and Chronic Bronchitis, COPD, Asthma, Cystic Fibrosis, and Immunocompromised Cancer Patients

2. Frequency, Seasonality, and Characteristics of Viral Respiratory Infections (VRIs)

3. Recognized for the last century as the most common infectious illness in humans Terminology has varied –Common respiratory infection –Common cold –Rhinosinusitis Rhinoviruses (RVs) cause a majority of these infections Impact of VRIs Monto AS et al. Clin Ther. 2001;1615.

4. Adults average ~2 to 4 colds 1,2 and children average 3 to 8 colds 3 per year In 1996, colds were associated with ~148 million days restricted activity, 20 million days missed work, 22 million days missed school, 45 million days bedridden 4 In 1998, 25 million office visits to primary care providers for upper respiratory infections (URIs) 5 Costs associated with VRIs estimated at ~$25 billion annually 6 1. Turner RB. Pediatr Ann. 1998;27:790. 2. Monto AS et al. Clin Ther. 2001;23:1615. 3. Rosenstein N et al. Pediatrics. 1998;101:181 4. Adams PF et al. Vital Health Stat. 1999;10 (200). 5. Gonzales R et al. Clin Infect Dis. 2001;33:757. 6. Fendrick AM et al. Value in Health. 2001;4:412. Economic and Societal Burden of VRIs

5. Mean annual illness incidence Reprinted from Monto AS, Ullman BM. JAMA. 1974;227:164. Age group (yr) 7654321076543210 11 1–23–45–910–1415–1920–2425–2930–3940–4950–59  60 Mean Annual Incidence of Respiratory Illnesses per Person-Year, Tecumseh, Michigan, 1965–1971 Females Males

6. 30 25 20 15 10 5 0 Percent RVParainfluenza viruses Percent Respiratory syncytial virus (RSV)Influenza virus 30 25 20 15 10 5 0 JanAprSepOctNovDecJanFebMarAprMayJunJanAprSepOctNovDecJanFebMarAprMayJun Reprinted from Br J Prev Soc Med, 1977;31:101-108, with permission from the BMJ Publishing Group. Seasonality of Respiratory Agents: Proportion Isolated in Each Calendar Month During 6 Years of Tecumseh, Michigan, Study

7. Transmission of viruses differs Influenza –Airborne transmission 1 –Widespread outbreaks RVs –Closer contact required –Aerosol and direct 2,3 –Households and schools are sites of transmission 4 Transmission of Respiratory Viruses 1. Goldman DA. Pediatr Infect Dis J. 2000;19(10 suppl):S97. 2. Gwaltney JM Jr, Hendley JO. Am J Epidemiol. 1982;116:828. 3. Dick EC et al. J Infect Dis. 1987;156:442. 4. Gwaltney JM Jr. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:1940.

8. Sore throat Cough Activity restriction Lower respiratory symptomsHeadache Coryza Percent RVRSV Parainfluenza virus Hemolytic streptococci Influenza AInfluenza B 0 20 40 60 80 100 Characteristics of VRIs of Known Etiology Reprinted from Br J Prev Soc Med, 1977;31:101-108, with permission from the BMJ Publishing Group.

9. Reprinted with permission from Monto AS et al. J Infect Dis. 1987;156:43. ©1987 by The University of Chicago. All rights reserved. Characteristics of RV-Associated Illnesses Illness with indicated syndrome (%)Percent with Age group (years) No. of isolates Lower respiratory Upper respiratory Laryngo- pharyngeal Other Median duration (days) Activity restriction Physician consultation 0–46114.883.61.6—12016.4 5–19395.174.415.45.1756.415.4 20–395933.959.36.8—1311.915.3  40 1764.729.45.9—2035.3 Total17623.868.26.81.21219.917.6

10. Adapted with permission from Arruda E et al. J Clin Microbiol. 1997;35:2864. Clinical feature RV % positive First symptom (% of subjects) Sore throat Stuffy nose Runny nose Sneezing 39 17 8 Most bothersome symptom (% of subjects) Runny nose Stuffy nose Sore throat Malaise 36 20 19 10 Median duration of symptoms (days) Cold episode Sleep disturbance Interference with daily activities 11 4 7 Clinical Features and Duration of Illness in Adults with RV Colds (n=276, RV confirmed by PCR or culture)

11. Reproduced with permission from Pediatrics, Vol. 102, Pages 291-295, Table 2. Copyright 1998. Virus RV RSV HCV Total positive Middle ear fluid, *No. (%) 22 (24%) 17 (18%) 7 (8%) 44 (48%) Nasopharyngeal aspirate, † No. (%) 28 (30%) 21 (23%) 14 (15%) 57 (62%) Infected children, No. (%) 32 (35%) 26 (28%) 16 (17%) 69 (75%) Detection of Viruses by RT-PCR in Middle Ear Fluid and Nasopharyngeal Aspirates from 92 Children with Acute Otitis Media *2 samples had both HRV and RSV RNA; † 2 aspirates had both HRV and RSV RNA, and 1 had both RSV and HCV RNA. RV=rhinovirus; RSV=respiratory syncytial virus; HCV=human coronavirus.

12. Sinusitis is an extremely common part of the common cold syndrome RV has been detected in 50% of adult patients with sinusitis by RT-PCR of maxillary sinus brushings or nasal swabs 1 Frequency of association of RV infection with sinusitis suggests the common cold could be considered a rhinosinusitis 2 RV in Acute Sinusitis 1.Pitkäranta A et al. J Clin Microbial. 1997;35:1791. 2.Gwaltney JM Jr. Clin Infect Dis. 1996;23:1209.

13. Respiratory viruses are common pathogens in acute bronchitis 1 Respiratory virus infection associated with cough 1 –Influenza virus: 75%–93% of cases –Adenovirus: 45%–90% –RVs: 32%–60% –Coronavirus: 10%–50% 40% of nonasthmatic patients with acute bronchitis had FEV 1  80% of predicted 2 Bronchial reactivity remained increased up to 5 weeks after episode of acute bronchitis 2,3 VRIs and Acute Bronchitis 1. Gwaltney JM Jr. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone; 2000:703. 2. Williamson HA Jr. J Fam Pract. 1987;25:251. 3. Hallett JS, Jacobs RL. Ann Allergy. 1985;55:568.

14. In persons 60–90 years of age with RV infection, median duration of illness was 16 days 19% were confined to bed; 26% had restriction of daily activities 63% had lower respiratory tract symptoms; 43% consulted their physician Burden of RV infection in the elderly appears to exceed that of influenza Nicholson KG et al. BMJ. 1996;313:1119. RV Infection in the Elderly

15. Reprinted from Wald TG et al. Ann Intern Med. 1995;123:588. Upper respiratory Cough Coryza Nasal or sinus congestion Sore throat Total Lower respiratory Productive cough Dyspnea Hoarseness Total Gastrointestinal Anorexia Nausea, vomiting, or diarrhea Total Systemic Malaise or fatigue Myalgia Sweating or chills Total 34 (97) 31 (89) 21 (60) 18 (51) 35 (100) 19 (54) 8 (23) 5 (14) 23 (66) 11 (31) 4 (11) 12 (34) 23 (66) 8 (23) 5 (14) 25 (71) SymptomNo. of patients (%) Symptoms of RV Infection in 35 Culture-Documented Illnesses in a Long-Term Care Facility

16. VRIs are the most common infectious diseases worldwide RVs are predominant cause of VRIs in all age groups Transmission requires relatively close contact Family and school major sites of transmission RV infections peak in autumn, with minor spring peaks RVs cause AOM, sinusitis, and bronchitis in otherwise healthy people Summary

17. Role of VRIs in Asthma Exacerbations

18. Poor underlying control Environmental factors –VRIs –Allergen exposure –Air pollution –Bacterial infections –Stress –Exercise/cold air –Occupational exposure Causes of Asthma Exacerbations

19. Reprinted from BMJ. 1995;310:1225-1229, with permission from the BMJ Publishing Group. Virus Picornaviruses14647147 Coronavirus17142138 Influenza viruses14102021 Parainfluenza viruses 1, 2, and 3661821 RSV661212 Other212 3 Method of detection Viruses Detected During Asthma Exacerbations in Children *84 identified as RV on further testing. ELISA=enzyme-linked immunosorbent assay. PCRCulture Immuno- fluorescence Antibody rise by ELISA Total *

20. Hospital admissions for asthma correlate with virus isolation peaks and school terms. Adapted with permission from Johnston SL et al. Am J Respir Crit Care Med. 1996;154:654. Official Journal of the American Thoracic Society. ©American Lung Association. VRIs and Hospitalizations for Asthma Total pediatric and adult hospitalizations School holidays URIs

21. Comparison of wheezing and nonwheezing (control) children –Age, atopic status, eosinophil markers In wheezing children <2 years old –Respiratory viruses detected in 82% (18/22) –RSV predominant, 68% (15/22) In wheezing children  2 years old –Respiratory viruses detected in 83% (40/48) –RV predominant, 71% (34/48) –+PCR for RV and nasal eosinophilia or elevated nasal ECP, 48% (23/48) Rakes GP et al. Am J Respir Crit Care Med. 1999;159:785. Children with Wheezing Presenting to the ER

22. RV=rhinovirus; HCV=human coronavirus; RSV=respiratory syncytial virus. Nicholson KG et al. BMJ. 1993;307:982. Pathogen RV HCV OC43 HCV 229E Influenza B Parainfluenza RSV Chlamydia psittaci Dual infection Number 76 21 15 2 5 2 3 5 Percent of all episodes 33.2 9.2 6.6 0.9 2.2 0.9 1.3 2.2 Viruses Detected in 229 Symptomatic Asthma Episodes in Adults

23. Data from Teichtahl H et al. Chest. 1997;112:591. Viruses Detected in Adult Patients Hospitalized with Asthma 54.5% 6.1% 27.3% 3% Influenza A Influenza B RV Adenovirus RSV Herpes 33 organisms isolated; 5 subjects had >1 virus detected and some viruses were detected by >1 test. 6.1%

24.  2 episodes of “common cold” before age 1 yr decrease risk of asthma by age 7 by ~50% Other viral infections—eg, herpes, varicella, measles—also protective Reported LRI with wheeze in the first 3 years of life increases risk of asthma Illi S et al. BMJ. 2001;322:390. Respiratory Infections in Infancy May Protect Against Development of Asthma

25. Children who had  2 older siblings or attended day care during first 6 mo of life had increased risk of wheeze early in life but decreased risk later. Reprinted with permission from Ball TM et al. N Engl J Med. 2000;343:538. Copyright ©2000 Massachusetts Medical Society. All rights reserved. P=0.01 P=0.03 P=0.001 P<0.001 2.7 1.0 0.4 1234567891011121314 Adjusted relative risk of frequent wheezing Age (yr) 0.1 Effect of Day Care in Infancy and Number of Older Siblings on Asthma Risk

26. Viral infections (esp. RV) frequently cause exacerbations of asthma Possible mechanisms –Extension into the lower airway 1-3 –Inflammation 2,3 Immunologic Mechanisms of VRI- Induced Asthma Exacerbations 1. Gern JE et al. Am J Respir Crit Care Med. 1997;155:1159. 2. Gern JE, Busse WW. J Allergy Clin Immunol. 2000;106:201. 3. Fraenkel DJ et al. Am J Respir Crit Care Med. 1995;151:879.

27. Adapted from Gern JE, Busse WW. J Allergy Clin Immunol. 2000;106:201. RV-Induced Airway Inflammation

28. VRIs (especially RV infections in children >2 yr old) and atopy synergistically enhance the risk of wheezing 1 –Antigen-specific IgE –Eosinophilic inflammation Cytokine production pattern is related to outcomes of experimental infection 2 High IFN-  /IL-5 ratio=Th1-type (antiviral) response 2 Low IFN-  /IL-5 ratio=Th2-type (allergic) response 2 1. Rakes GP et al. Am J Respir Crit Care Med. 1999;159:785. 2. Gern JE et al. Am J Respir Crit Care Med. 2000;162:2226. What Is Different About VRIs in Asthma?

29. PBMC IFN-  secretion –Reduced peak viral shedding Sputum IFN-  /IL-5 mRNA ratio correlates with –Lower symptom scores –More rapid viral clearance Parry DE et al. J Allergy Clin Immunol. 2000;105:692. Reprinted from Gern JE et al. Am J Respir Crit Care Med. 2000;162:2226. Immunologic Risk Factors for More Severe VRIs Virus detected at 14 days? NoYes IFN  /IL-5 ratio (units) 10 0 10 1 10 2 10 3 10 4Th1 Th2

30. Viruses cause asthma exacerbations in adults and children RVs cause ~60% of virus-induced exacerbations of asthma RVs directly infect the bronchial airways The response to viral infection is shaped by the host’s antiviral response VRIs in early childhood may protect against the development of asthma Summary

31. Role of VRI and RV in Acute Exacerbations of Chronic Bronchitis

32. Cost of Acute Exacerbations of Chronic Bronchitis (AECB) Hospitalization (500,000 episodes) –Total cost, $1.6 billion –Mean LOS, 6 days –Mean cost, $5500/patient Outpatient office visits –  65 yr: 331,000, cost $24.9 million –<65 yr: 237,000, cost $15.1 million Indirect costs –Days lost from work –Lost productivity. Niederman MS et al. Clin Ther. 1999;21:576-591

33. Infectious, 80% –Bacterial pathogens, 40%–50% –Viruses, 30%–40% –Atypical bacteria, 5%–10% Noninfectious, 20% –Environmental factors –Noncompliance with medical therapy Sethi S. Chest. 2000;117(suppl):380S. AECB: Etiology

34. Data from Greenberg SB et al. Am J Respir Crit Care Med. 2000;162:167. Viral AECB: Pathogens 0 5 10 15 20 25 30 35 Picorna- viruses Para- influenza viruses Corona- viruses Influenza viruses RSVAdeno- viruses Control FEV 1  50% FEV 1 <50% % of total identified

35. Virus-Associated Illness in Controls and COPD Patients 2600% LRT symptoms alone 0.520.380.54No. VRIs/yr 31.81.4No. respiratory illnesses/yr 323055No. patients FEV 1 <50% FEV 1  50% Controls LRT = lower respiratory tract. Data from Greenberg SB et al. Am J Respir Crit Care Med. 2000;162:167.

36. FEV 1 <50% predicted –52 hospitalizations in 12 patients –82% acute exacerbations, 22% pneumonia –5 of 6 deaths were COPD related ER=emergency room. Data from Greenberg SB et al. Am J Respir Crit Care Med. 2000;162:167. Viral AECB: Medical Resource Utilization % VRI 0 10 20 30 40 50 60 70 80 OfficeERHospital Control FEV 1  50% predicted FEV 1 <50% predicted 100

37. AECB manifestations –Increased dyspnea, 76% –Increased sputum volume, 62% –Increased sputum purulence, 39% Anthonisen type –Type 1 (all 3 of above symptoms), 20% –Type 2 (2 of above symptoms), 46% –Type 3 (1 of above symptoms), 34% 64% of AECB associated with prior cold (18 days) Seemungal T et al. Am J Respir Crit Care Med. 2001;164:1618. Viral AECB: Clinical Presentation

38. 39.2% of AECB associated with viral infection Cold, increased dyspnea with cold, and sore throat associated with viral isolation Data from Seemungal T et al. Am J Respir Crit Care Med. 2001;164:1618. 0 5 10 15 20 25 % of reported exacerbations RVCoronaInfl AInfl BParainflAdenoRSV AECB: Viral Detection and Symptoms

39. AECB are associated with considerable morbidity, mortality, and health care costs VRIs are an important cause of AECB RVs are frequently detected in the airway secretions of patients with AECB Summary

40. VRIs in Patients with Cystic Fibrosis

41. Cause exacerbations and LRIs Contribute to long-term pulmonary deterioration, morbidity, mortality Strongly associated with every measure of CF disease progression 1 Contribute to initial bacterial colonization 2 1. Wang EEL et al. N Engl J Med. 1984;311:1653. 2. Armstrong et al. Pediatr Pulmonol. 1998;26:371. Cystic Fibrosis (CF): Respiratory Viruses

42. Infection of epithelial cells –Release of proinflammatory mediators –Attraction and activation of inflammatory cells –Neutrophil release of prostaglandins and oxygen radicals Altered endothelial permeability Promotion of edema, enhanced cell recruitment Stimulation of mucus secretion Airway smooth muscle contraction Prober CG. Clin Rev Allergy. 1991;9:87. CF: Proposed Mechanisms of Virus-Induced Exacerbation

43. VRIs are associated with clinical exacerbations of CF with disease progression Inflammatory response most likely mechanism by which VRIs exacerbate CF Viruses predispose to bacterial colonization and infection Summary

44. VRIs in Immunosuppressed Cancer Patients

45. Impairments in Viral Immunity in BMT Recipients with Cancer B lymphocytes –Reduced response to stimulatory cytokines (IL-4) –Reduced serum immunoglobulins –Depressed primary and secondary responses to antigens T lymphocytes –Reduced CD4 lymphocyte numbers –Reduced helper cell activity –Increased suppressor cell activity –Reduced proliferative responses –Reduced CD8 lymphocyte cytotoxic function Mucositis Reduced IgA secretion Couch RB et al. Am J Med. 1997;102(suppl 3A):2.

46. Allogeneic transplant Hematologic malignancy Graft-vs-host disease Corticosteroid therapy ? Conditioning regimen Lymphopenia (<200/mL) Age >65 years <100 days post-transplant Risk Factors Associated with Serious Morbidity from VRIs in BMT Recipients Sable CA, Donowitz GR. Clin Infect Dis. 1994;18:273.

47. Important Features of VRIs in Immunocompromised Patients High potential for nosocomial acquisition 1 Prolonged shedding of virus, even with treatment 2 High frequency of pneumonia and death 1 Viral pneumonia often associated with other infections 1 Outbreaks can occur in absence of community epidemic 1 1. Couch RB et al. Am J Med. 1997;102(suppl 3A):2. 2. Bodey GP. Am J Med. 1997;102(suppl 3A):77.

48. 1. Data from Couch RB et al. Am J Med. 1997;102(suppl 3A):2. 2. Data from Ghosh et al. Clin Infect Dis. 1999;29:528. No. of infections leading to pneumonia Pneumonia (% of infections) Death (% of those with pneumonia)* Leukemia BMT 22 33 59 61 32 36 27 20 78 70 33 25 9 45 67 58 44 22 32100 Progression of VRIs in Leukemia and BMT RSV 1 Influenza Parainfluenza RV 2 Leukemia BMT Leukemia BMT *Other pulmonary infections often present.

49. VRIs are an important cause of morbidity and mortality in immunosuppressed cancer patients Underlying disease and immunosuppressive therapy contribute to the high mortality rate in BMT patients with VRIs Summary

50. Acute Respiratory Infections and Antibiotic Use: A Primary Care and Health Services Research Perspective

51. Reprinted from Gonzales R et al. Clin Infect Dis. 2001;33:757. Office visits (  1000) 0 5000 10,000 15,000 20,000 25,000 Office visits Antibiotic prescription Bacterial prevalence Acute Respiratory Infections (ARIs): Primary Care Office Visits, Antibiotic Use, and Bacterial Prevalence in US, 1998 30% 76% 70% 62% 59% URIOtitis media Sinusitis PharyngitisBronchitis 0 20 40 60 80 100 Antibiotic Rx and estimated bacterial prevalence (% of visits)

52. Adapted from Gonzales R et al. Clin Infect Dis. 2001;33:757. Estimated 55% of prescriptions (22.6 million) for ARIs are unnecessary, at a cost of $726 million. No. of prescriptionsCost estimate ARI diagnosis (millions)(millions) Otitis media9.6$280 Pharyngitis8.7$215 URI7.4$227 Sinusitis7.9$310 Bronchitis7.8$289 Total 41.4 $1322 Estimated Annual Cost of Antibiotic Use for ARIs in US, 1998

53. Adapted from Stone S et al. Ann Emerg Med. 2000;36:320. Emergency Department Visits and Antibiotic Use for ARIs in US, 1996 ConditionVisits (millions)Antibiotic use URIs, all2.026% URIs only*1.624% Bronchitis, all 2.142% Bronchitis only* 1.242% Otitis media 2.755% Pharyngitis 1.552% Total ARIs8.144.5% *Excludes patients with additional diagnoses of asthma, COPD, chronic bronchitis, pneumonia, otitis, pharyngitis, sinusitis, HIV.

54. Patients who expect antibiotics receive them more often 1-3 Strongest predictor of receipt of antibiotics for ARI is MD perception of patient expectation 1,3 Patient satisfaction more closely related to quality of communication (explanations, contingency plans) than receipt of antibiotics 1,3,4 Public beliefs about antibiotic effectiveness 5 –Useful for VRI: 55% –Useful for bacterial but not viral illness: 21% 1. Hamm RM et al. J Fam Pract. 1996;43:56. 2. Bauchner H et al. Pediatrics. 1999;103:395. 3. Mangione-Smith R et al. Pediatrics. 1999;103:711. 4. Mangione-Smith R et al. Arch Pediatr Adolesc Med. 2001;155:800. 5. Wilson AA et al. J Gen Intern Med. 1999;14:658. Use of Antibiotics: Patient Expectations, Physician Perceptions, Public Beliefs

55. Pre-, post-intervention trial to decrease antibiotic use in acute, uncomplicated bronchitis in HMO sites Full intervention: household and office-based patient-education materials; clinician education, profiling, and academic detailing Limited intervention: office-based patient education materials Antibiotic use declined from 74% to 48% only at site with full intervention No differences in revisits, other prescriptions, other diagnoses Gonzales R et al. JAMA. 1999;281:1512. Decreasing Antibiotic Overuse Is Hard But Possible

56. “Just Say No” to unnecessary antibiotics for ARI –Community and patient education –Office-based interventions –Clinician-oriented interventions Better technology for rapid diagnostic testing to identify bacterial vs viral illness Possible development of antiviral medications Summary

57. VRIs are an important cause of morbidity and increased health care costs RVs are the most common cause of VRIs RVs are also an important cause of morbidity in patients with asthma, COPD, and CF, and in immunocompromised patients In immunocompromised cancer patients, VRIs increase mortality and morbidity from pneumonia The mechanism of exacerbation of asthma, chronic bronchitis, and CF is related to the host inflammatory response Patients with VRIs are often prescribed antibiotics Program Summary

58. Contributors Gerald P. Bodey, Sr., MD The University of Texas M. D. Anderson Cancer Center Houston Ethan A. Halm, MD, MPH Mount Sinai School of Medicine New York James E. Gern, MD University of Wisconsin Madison Sebastian L. Johnston, MD Imperial College of Science, Technology and Medicine London, UK Sanjay Sethi, MD State University of New York Buffalo Homer A. Boushey, Jr., MD, Editor University of California San Francisco Arnold S. Monto, MD University of Michigan School of Public Health Ann Arbor Harley A. Rotbart, MD University of Colorado Health Sciences Center Denver