Viral Respiratory Viral Respiratory Infections in the Infections in the Morbidity and Morbidity and Mortality Mortality of Airway Diseases of Airway Diseases and and Immunocompromised Immunocompromised States States Acute and Chronic Acute and Chronic Bronchitis, Bronchitis, COPD, Asthma, Cystic COPD, Asthma, Cystic Fibrosis, Fibrosis, and Immunocompromised and Immunocompromised
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Viral Respiratory Infections in the Morbidity and Mortality of Airway Diseases and Immunocompromised States Acute and Chronic Bronchitis, COPD, Asthma,
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Viral Respiratory Viral Respiratory Infections in theInfections in theMorbidity and MortalityMorbidity and Mortalityof Airway Diseases andof Airway Diseases and Immunocompromised Immunocompromised StatesStatesAcute and Chronic Bronchitis,Acute and Chronic Bronchitis,COPD, Asthma, Cystic Fibrosis,COPD, Asthma, Cystic Fibrosis,and Immunocompromisedand ImmunocompromisedCancer PatientsCancer Patients
Frequency, Seasonality, Frequency, Seasonality, and Characteristics of and Characteristics of Viral Respiratory Viral Respiratory Infections (VRIs)Infections (VRIs)
• 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 VRIsImpact of VRIs
Monto AS et al. Clin Ther. 2001;1615.
• Adults average ~2 to 4 colds1,2 and children average 3 to 8 colds3 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 bedridden4
• In 1998, 25 million office visits to primary care providers for upper respiratory infections (URIs)5
• Costs associated with VRIs estimated at ~$25 billion annually6
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 BurdenEconomic and Societal Burdenof VRIsof VRIs
Mea
n a
nn
ual
illn
ess
inci
den
ce
Reprinted from Monto AS, Ullman BM. JAMA. 1974;227:164.
Mean Annual Incidence of Respiratory Mean Annual Incidence of Respiratory Illnesses per Person-Year, Tecumseh, Illnesses per Person-Year, Tecumseh, Michigan, 1965–1971Michigan, 1965–1971
0Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jan Apr Sep Oct Nov Dec Jan Feb Mar Apr May Jun
Reprinted from Br J Prev Soc Med, 1977;31:101-108, with permission from the BMJ Publishing Group.
Seasonality of Respiratory Agents: Proportion Seasonality of Respiratory Agents: Proportion Isolated in Each Calendar Month During Isolated in Each Calendar Month During 6 Years of Tecumseh, Michigan, Study6 Years of Tecumseh, Michigan, Study
• Transmission of viruses differs• Influenza
– Airborne transmission1
– Widespread outbreaks
• RVs– Closer contact required– Aerosol and direct2,3
– Households and schools are sites of transmission4
Transmission of Respiratory Transmission of Respiratory VirusesViruses
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.
Characteristics of RV-Associated Characteristics of RV-Associated IllnessesIllnesses
Illness with indicated syndrome (%) Percent with
Age group (years)
No. of isolates
Lower respiratory
Upper respiratory
Laryngo- pharyngeal Other
Medianduration(days)
Activity restriction
Physician consultation
0–4 61 14.8 83.6 1.6 — 12 0 16.4
5–19 39 5.1 74.4 15.4 5.1 7 56.4 15.4
20–39 59 33.9 59.3 6.8 — 13 11.9 15.3
40 17 64.7 29.4 5.9 — 20 35.3 35.3
Total 176 23.8 68.2 6.8 1.2 12 19.9 17.6
Adapted with permission from Arruda E et al. J Clin Microbiol. 1997;35:2864.
Clinical featureRV %
positive
First symptom (% of subjects) Sore throat Stuffy nose Runny nose Sneezing
391717
8
Most bothersome symptom (% of subjects) Runny nose Stuffy nose Sore throat Malaise
36201910
Median duration of symptoms (days) Cold episode Sleep disturbance Interference with daily activities
1147
Clinical Features and Duration of Clinical Features and Duration of Illness in Adults with RV ColdsIllness in Adults with RV Colds(n=276, RV confirmed by PCR or culture)(n=276, RV confirmed by PCR or culture)
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%)
Infectedchildren, No. (%)
32 (35%)
26 (28%)
16 (17%)
69 (75%)
Detection of Viruses by RT-PCR in MiddleDetection of Viruses by RT-PCR in MiddleEar Fluid and Nasopharyngeal AspiratesEar Fluid and Nasopharyngeal Aspiratesfrom 92 Children with Acute Otitis Mediafrom 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.
• 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 swabs1
• Frequency of association of RV infection with sinusitis suggests the common cold could be considered a rhinosinusitis2
RV in Acute SinusitisRV in Acute Sinusitis
1. Pitkäranta A et al. J Clin Microbial. 1997;35:1791.2. Gwaltney JM Jr. Clin Infect Dis. 1996;23:1209.
• Respiratory viruses are common pathogens in acute bronchitis1
• Respiratory virus infection associated with cough1
• 40% of nonasthmatic patients with acutebronchitis had FEV1 80% of predicted2
• Bronchial reactivity remained increased up to 5 weeks after episode of acute bronchitis2,3
VRIs and Acute BronchitisVRIs 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.
• In persons 60–90 years of age with RV infection, median duration of illness was16 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 ElderlyRV Infection in the Elderly
Reprinted from Wald TG et al. Ann Intern Med. 1995;123:588.
Upper respiratoryCoughCoryzaNasal or sinus congestionSore throat
TotalLower respiratory
Productive coughDyspneaHoarseness
TotalGastrointestinal
AnorexiaNausea, vomiting, or diarrhea
TotalSystemic
Malaise or fatigueMyalgiaSweating 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)
Symptom No. of patients (%)
Symptoms of RV Infection in Symptoms of RV Infection in 35 Culture-Documented Illnesses 35 Culture-Documented Illnesses in a Long-Term Care Facilityin a Long-Term Care Facility
• VRIs are the most common infectious diseases worldwide
• RVs are predominant cause of VRIs in allage 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
SummarySummary
Role of VRIs in Asthma Role of VRIs in Asthma Exacerbations Exacerbations
• Poor underlying control
• Environmental factors– VRIs
– Allergen exposure
– Air pollution
– Bacterial infections
– Stress
– Exercise/cold air
– Occupational exposure
Causes of Asthma ExacerbationsCauses of Asthma Exacerbations
Reprinted from BMJ. 1995;310:1225-1229, with permission from the BMJ Publishing Group.
Virus
Picornaviruses 146 47 147
Coronavirus 17 14 21 38
Influenza viruses 14 10 20 21
Parainfluenza viruses 1, 2, and 3 6 6 18 21
RSV 6 6 12 12
Other 2 1 2 3
Method of detection
Viruses Detected During Asthma Viruses Detected During Asthma Exacerbations in ChildrenExacerbations in Children
*84 identified as RV on further testing.ELISA=enzyme-linked immunosorbent assay.
PCR CultureImmuno-
fluorescenceAntibody rise
by ELISA Total
*
Hospital admissions for asthma correlate with virus isolation peaks and school terms.
VRIs and Hospitalizations VRIs and Hospitalizations for Asthmafor Asthma
Total pediatric andadult hospitalizations
School holidays
URIs
0
5
10
15
20
Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
• 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 Children with Wheezing Presenting to the ERPresenting to the ER
RV=rhinovirus; HCV=human coronavirus; RSV=respiratory syncytial virus.Nicholson KG et al. BMJ. 1993;307:982.
Effect of Day Care in Infancy and Effect of Day Care in Infancy and Number of Older Siblings onNumber of Older Siblings onAsthma RiskAsthma Risk
• Viral infections (esp. RV) frequently cause exacerbations of asthma
• Possible mechanisms– Extension into the lower
airway1-3
– Inflammation2,3
Immunologic Mechanisms of VRI-Immunologic Mechanisms of VRI-Induced Asthma ExacerbationsInduced 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.
AirwayHyperresponsiveness
Plasmaleakage
Mucus hypersecretion
Inflammatorycell recruitmentand activation
Neural activation
Virus-infected epithelium
Adapted from Gern JE, Busse WW. J Allergy Clin Immunol. 2000;106:201.
• 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
SummarySummary
VRIs in VRIs in Immunosuppressed Immunosuppressed Cancer PatientsCancer Patients
Impairments in Viral ImmunityImpairments in Viral Immunityin BMT Recipients with Cancerin BMT Recipients with Cancer
• B lymphocytes– Reduced response to stimulatory cytokines (IL-4)– Reduced serum immunoglobulins– Depressed primary and secondary responses to antigens
Risk Factors Associated withRisk Factors Associated withSerious Morbidity from VRIs inSerious Morbidity from VRIs inBMT RecipientsBMT Recipients
Sable CA, Donowitz GR. Clin Infect Dis. 1994;18:273.
Important Features of VRIs in Important Features of VRIs in Immunocompromised PatientsImmunocompromised Patients
• High potential for nosocomial acquisition1 • Prolonged shedding of virus, even with
treatment2
• High frequency of pneumonia and death1
• Viral pneumonia often associated with other infections1
• Outbreaks can occur in absence of community epidemic1
1. Couch RB et al. Am J Med. 1997;102(suppl 3A):2.2. Bodey GP. Am J Med. 1997;102(suppl 3A):77.
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)*
LeukemiaBMT
BMT
2233
5961
3236
2720
7870
3325
945
6758
4422
22 32 100
Progression of VRIs inProgression of VRIs inLeukemia and BMTLeukemia and BMT
RSV1
Influenza
Parainfluenza
RV2
LeukemiaBMT
LeukemiaBMT
*Other pulmonary infections often present.
• 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
SummarySummary
Acute Respiratory Acute Respiratory Infections and Antibiotic Infections and Antibiotic Use: A Primary Care andUse: A Primary Care andHealth Services Health Services Research PerspectiveResearch Perspective
Reprinted from Gonzales R et al. Clin Infect Dis. 2001;33:757.
Off
ice
visi
ts (
1000
)
0
5000
10,000
15,000
20,000
25,000
Office visits
Antibiotic prescription
Bacterial prevalence
Acute Respiratory Infections (ARIs):Acute Respiratory Infections (ARIs):PrimaryPrimary Care Office Visits, Antibiotic Use, Care Office Visits, Antibiotic Use, and Bacterial Prevalence in US, 1998and Bacterial Prevalence in US, 1998
30%
76%
70%
62%
59%
URI Otitis media Sinusitis Pharyngitis Bronchitis0
20
40
60
80
100
An
tibio
tic Rx an
d estim
atedb
acterial prevalen
ce (% o
f visits)
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 prescriptions Cost estimate
ARI diagnosis (millions) (millions)
Otitis media 9.6 $280
Pharyngitis 8.7 $215
URI 7.4 $227
Sinusitis 7.9 $310
Bronchitis 7.8 $289
Total 41.4 $1322
Estimated Annual Cost of Antibiotic Estimated Annual Cost of Antibiotic Use for ARIs in US, 1998Use for ARIs in US, 1998
Adapted from Stone S et al. Ann Emerg Med. 2000;36:320.
Emergency Department Visits and Emergency Department Visits and Antibiotic Use for ARIs in US, 1996Antibiotic Use for ARIs in US, 1996
Condition Visits (millions) Antibiotic use
URIs, all 2.0 26%
URIs only* 1.6 24%
Bronchitis, all 2.1 42%
Bronchitis only* 1.2 42%
Otitis media 2.7 55%
Pharyngitis 1.5 52%
Total ARIs 8.1 44.5%
*Excludes patients with additional diagnoses of asthma, COPD, chronic bronchitis, pneumonia, otitis, pharyngitis, sinusitis, HIV.
• Patients who expect antibiotics receive them more often1-3
• Strongest predictor of receipt of antibiotics for ARI isMD perception of patient expectation1,3
• Patient satisfaction more closely related to quality of communication (explanations, contingency plans) than receipt of antibiotics1,3,4
• Public beliefs about antibiotic effectiveness5
– 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 Use of Antibiotics: Patient Expectations, Physician Perceptions, Expectations, Physician Perceptions, Public BeliefsPublic Beliefs
• 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