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Sneeze or Wheeze? The Role of Infections in Pediatric Asthma

Sneeze or Wheeze? The Role of Infections in Pediatric Asthma. E. Kathryn Miller, M.D., M.P.H. Pediatric Allergy and Immunology Vanderbilt Children’s Hospital. Financial: no conflicts of interest to disclose

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Sneeze or Wheeze? The Role of Infections in Pediatric Asthma

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  1. Sneeze or Wheeze?The Role of Infections in Pediatric Asthma E. Kathryn Miller, M.D., M.P.H. Pediatric Allergy and Immunology Vanderbilt Children’s Hospital

  2. Financial: no conflicts of interest to disclose Research: funded by NIH K23, NIH R03, March of Dimes Basil O’Conner, and VCTRS K12 awards Organizational: AAAAI, AAP Gifts: nothing to disclose Legal Consult/Expert Witness: nothing to disclose Other: nothing to disclose Employment: Vanderbilt University Disclosures:E. Kathryn Miller

  3. Case: “She can’t breathe!” • 2 y/o “asthmatic” with wheezing in September • 2 day h/o rhinorrhea and cough • 1 day h/o wheezing and increased work of breathing • Social/Family History • + daycare, + smoking, + maternal asthma • Physical Exam • Tachypnea, hypoxia • Expiratory wheezes bilaterally, subcostal retractions

  4. Chest X-Ray

  5. Hospital Course • In Emergency Room • Continuous albuterol, oral steroids, O2, Mg • No improvement in 4+hrs, increased respiratory distress • In Pediatric ICU • Terbutaline drip, Solu-Medrol q6h, Atrovent q6h • Weaned over 5 days • Home • Pulmicort bid, prn albuterol, prednisone taper, smoking education

  6. What is the most likely infectious trigger? • RSV (respiratory syncytial virus) • Streptococcus pneumonia • Influenza • HRV (human rhinovirus)

  7. RT-PCR of Nasal Swabs RSV A and B: negative Influenza A and B: negative Human Rhinovirus (HRV): positive • VP4/VP2 sequencing:HRVC

  8. What infection during infancy is most associated with the subsequent development of childhood asthma? • RSV (respiratory syncytial virus) • Streptococcus pneumonia • Influenza • HRV (human rhinovirus)

  9. Which of the following appears to be associated with asthma? A) Influenza B) HRV (human rhinovirus) C) hMPV (human metapneumovirus) D) Chlamydia pneumonia E) All of the above

  10. Overview:Infections and Asthma in Pediatrics • Viral Infections: Ontogeny of Asthma • Viral Infections: Exacerbation of Asthma • Infant and Toddler Wheezing Phenotypes • Treatment of Recurrent Wheezing

  11. Ontogeny of Asthma:Viral infections are important in the development of asthma.

  12. Changes in Society ( family size, improved sanitation, etc…) Decreased Childhood Infections Cytokine Imbalance Th1>>>Th2 phenotype (favors atopic disease, asthma) Ontogeny of Asthma: Infections Helpful? Hygiene Hypothesis Strachan 1989

  13. Ontogeny of Asthma: Infections Harmful? Bronchiolitis-to-Asthma • RSV bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7.1 • HRV hospitalizations during infancy are an early predictor of subsequent asthma development. 2 • 1st year wheezing with HRV is the strongest viral predictor of wheezing at 3 yrs age (OR 6.6). 3 1. Sigurs AJRCCM 2000; ; 2. Kotaneimi-Syrjanen JACI 2003; 3. Lemanske JACI 2005

  14. EarlyHRV Wheezing Is Most Associated With Childhood Asthma Jackson AJRCCM 2008

  15. EarlyHRV Wheezing Is Most Associated With Childhood Asthma • In Year 3: • HRV (OR 25.6) >> AE sensitization (OR 3.4) • as risk factor for asthma at age 6 • *90% of children who wheezed with HRV in Yr 3 • had asthma at age 6 Jackson AJRCCM 2008

  16. Differential Effect of Infant RSV vs. HRV Bronchiolitis on Early Childhood Asthma N = 1,676 N = 8,544 Dec – Feb RSV predominant months May, August & Sept HRV predominant months Proportion developing asthma Tennessee Asthma and Bronchiolitis Study Carroll JACI 2009

  17. Does Bronchiolitis Severity Predict Risk of Asthma? • Severity score: high score by age 2 years may predict asthma at age 10 yrs Devulapalli Thorax 2008

  18. Exacerbation of Asthma:Many viruses are important in asthma exacerbations.

  19. Exacerbation of Asthma • ~85% of children with asthma flare have virus. 1,2 • Among children hospitalized for wheezing, respiratory syncytial virus (RSV), influenza virus, and human rhinovirus (HRV) are most common in those <3 years; HRV in older. 3 • Bacterial causes: Atypical bacteria and sinusitis • Johnston BMJ 1995; 2. Nicholson BMJ 1993; • 3. Heymann JACI 2004

  20. Emerging Knowledge: Viruses • Human Metapneumovirus (hMPV) • Human Coronaviruses (hCoV) • Human Rhinovirus C (HRVC)

  21. The New Vaccine Surveillance Network (NVSN) Prospective, population-based surveillance: 2000-2006 Children <5 yrs hospitalized with acute respiratory illness (ARI) or fever Sites Rochester, NY Nashville, TN Cincinnati, OH (2001)

  22. NVSN Year 1: Viruses Identified in 70% of Hospitalized Children With ARI or Fever No Virus 30% HRV 26% EV AdV Flu RSV 29% hMPV 4% PIV hCoV Iwane Pediatrics 2004; Mullins EID 2004; Miller JID 2007; Dare, unpublished data

  23. HMPV Causes Fever/ARI in Young Children URI RSV Bronchiolitis Asthma Pneumonia 26/668 (4%) hMPV+ Mullins EID 2004 In various studies, 14-67% of children with hMPV have been diagnosed with asthma exacerbation, vs. 0-15% with other viruses.

  24. Coronaviruses (HCoV) in 2-5% of Hospitalized Children in NVSN Study Year 1: 27/551 (4.9%) Primarily OC43 and 229E Croup Bronchiolitis Other Asthma Pneumonia • Years 2-3: 23/1048 (2.2%) • Primarily NL63 Dare et al Talbot et al

  25. HRV Associated With Significant Burden in Hospitalized Children (18) (6) (2)

  26. HRV Species Have Different Clinical Phenotypes Seasonality of HRV Clades • HRVC (new): • More cough* • More wheezing* • More discharge diagnoses • of asthma* • HRVA(classic): • More dual infections* • Fever* *p<0.05

  27. Mechanisms of Viral Wheeze • Airway epithelial cells1 • Normal: apoptosis • Asthma: viral replication • Immune dysregulation1-5 • Altered innate immune responses • Type 1-3 interferons (, , , ) • Genetic polymorphisms6, 7 • CD14_159 and Toll 3 receptors 1. Contoli M et al. Nat Med 12:1023, 2006 2. Wark PA et al. J Exp Med 201:937, 2005 3. Copenhaver CC et al. AJRCCM 170:175, 2004 4. Parry DE et al. JACI 105:692, 2000 5. Miller EK et al. AJRCCM, 2011 6. Hewson CA et al. J Virol 79:12273 7. Martin AC et al. AJRCCM 173:617, 2006

  28. Viral Wheezing <2 Years Age • Viral etiologies • RSV > HRV > influenza, HMPV, coronavirus, PIV • Risk factors: • Environmental tobacco smoke exposure • Reduced lung function • (Lack of breastfeeding)

  29. Viral Wheezing in Older Children • HRV >>>> others • September “asthma epidemic” • Often have • elevated IgE • inhalant allergen sensitization • maternal asthma

  30. Infection and Susceptibility • Patients with asthma do not appear to be more susceptible to infection with HRV • They are more likely to have lower respiratory symptoms with more protracted and severe course

  31. Infant and Toddler Wheezing Phenotypes

  32. Childhood Wheezing • 50% of kids reported to have wheezing in 1st year of life • 15% outpatient visits, 3% hospitalizations for wheezing • 20% continue to later childhood Martinez NEJM 1995

  33. Wheezing Phenotypes • 51% never wheeze • Of those who wheeze: • Early, transient wheeze (60%) - began by 3, resolved by 6 • Non-atopic persistent wheeze (20%) - began by 1, persisted to 6, fade by adolescence • Atopic (IgE-associated) persistent wheeze (20%) – often begin after age 1, persist to late adolescence Tuscon Classification (n=1246)

  34. Risk Factors for Persistent Wheezers • Non-atopic: • Lower lung function, enhanced airway reactivity, low socioeconomic status • Atopic: • Parental asthma, male sex, atopic dermatitis, eosinophilia at 9 months, h/o wheeze with LRI, early sensitization to food, aeroallergens, symptoms between exacerbations

  35. Asthma Risk Factors • Atopy • Food/inhalant sensitization associated with persistent wheezing age 6 • Alternaria allergy associated with chronic asthma age 22 • Reduced lung function (age uncertain) • Tuscon study: normal function as infant, reduced by age 6 in asthmatics at age 22 • Norway/Australia studies: reduced function in infancy in persistent wheezers age 10-11 • Viral Infections: HRV synergistic

  36. Will My Child Get Asthma? (PPV 47.5-51.5%, NPV 91.6% for asthma age 6-13) Adapted from Guilbert et al JACI 2004

  37. Approach to the Infant/Toddler with Persistent Wheezing

  38. Medical History • Timing, pattern of wheezing • Cough or limitation outside of exacerbations • Association with feeding, failure to thrive, unresponsive to B2-adrenergics: other diagnosis? • Comorbidities: GER, rhinitis, sinusitis

  39. Therapy for Infant/Toddler Recurrent Wheeze • Based on 2007 NAEPP asthma guidelines for 0-4 years old if “asthma-like” • Sx’s <2d/wk: prn short acting B agonist • Persistent sx’s >2d/wk: low dose ICS • Consider RISK for step-up therapy: • 2+ oral steroids in 6 months? • 4+ episodes/yr >1 day wheeze and risk factors for persistent asthma?

  40. Classifying Severity in Patients 0-4 Years of Age Not Currently Taking Long-Term Controllers EIB- exercise-induced bronchospasm; SABA= short-acting beta agonist; National Asthma Education and Prevention Program. Expert Panel Repot 3: Guidelines for the Diagnosis and Management of Asthma (EPR 3-2007). U.S. Department of Health and Human Services. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  41. Assessing Asthma Control in Patients 0-4 Years of Age National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR 3-2007). U.S. Department of Health and Human Services. Available at L http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.

  42. Stepwise Approach for Managing Asthma in Children 0-4 Years of Age http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm

  43. Treatment for Recurrent Viral Wheeze in Young Children • Important: ICS may control symptoms, do not alter lung function or subsequent symptoms1,2 • In subset with recurrent wheeze, daily low dose ICS not superior to intermittent high-dose ICS in reducing exacerbations3 1. Guilbert NEJM 2006; 2. CAMP NEJM 2000; 3. Zeiger NEJM 2011

  44. Intermittent Medications for Viral-Induced Wheeze

  45. Inhaled Short-Acting Beta-Agonists • First-line therapy • Effective rescue from symptoms, especially if established asthma • Not shown to improve clinical outcomes, decrease hospitalization, or decrease duration of hospitalization in children with bronchiolitis Gadomski Cochrane Database 2006

  46. ? Inhaled Hypertonic Saline Plus B-Agonist ? • Hypothesis: viral infection (HRV) leads to dehydration of airway surface liquid and impaired mucous clearance1-3 • Small trial: 41 aged 1-6 with wheeze in ER randomly assigned albuterol plus 5% vs 0.9% saline. LOS, hospitalization lower in HS. 4 1. Daviskas J Aerosol Med 2006; 2. Randell AJRCMB 2006; 3. Mandelberg Pediatr Pulmonol 2010; 4. Ater Pediatrics 2012

  47. Intermittent HIGH Dose Inhaled Corticosteroids (ICS) • Started at onset of URI and continued up to 10 days may decrease symptoms and need for oral steroids (fluticasone 750mcg bid1, budesonide 1mg bid2 studied, and others3-5) • Maybe slight growth deficits? • Unsure if effective if started after wheezing begins? • Perhaps good in patient with asthma risk 1. Ducharme NEJM 2009; 2. Zeiger NEJM 2011; 3. Connett Arch Dis Child 1993; 4. McKean Cochrane Review 2000; 5. Papi Allergy 2009

  48. Intermittent STANDARD (low-medium) Dose ICS • Intermittent dosing NOT effective in this population • Particularly not if started after wheezing begins • Daily use effective to prevent episodes (discussed later)

  49. Intermittent Systemic Corticosteroids • Mixed data for treating virus-induced wheeze in preschoolers, but overall NOT EFFECTIVE • Alternatively, initiating systemic CS at earliest signs of viral URI MAY prevent wheeze • Response may differ by virus • Unsure if response differs by atopy status? Jarrti PAI 2007

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