LOWER AIRWAY DISEASES

1. LOWER AIRWAY DISEASES Author: N. Pham, MDAuthor: N. Pham, MD

2. Categories: Bronchiolitis Asthma Epidemiology Etiology Pathophysiology Clinical manifestations Treatment Objectives

3. Population <2yr: 1-3.5% admissions; 1-2% ER visits Risk factors: prematurity, CLD or BPD, CHD, age 3-6 mos at the onset of the epidemic Other risk factors: older sibs, day care, male, exposure to smoke & breast feeding < 2 months (lower socioeconomic pop) RSV constituted ~ ½ of the cases; 20-25%- others; 9-27% co-viral infections Other viruses: rhinovirus, adenovirus, metapneumovirus, influenza, parainfluenza, enterovirus and bocavirus RSV causes more symptoms with wheezing and retractions, longer duration of respiratory symptoms and oxygen therapy associated with lower use of antibiotics Concensus conference on acute bronchiolitis; An Pediatri, 2010 Bronchiolitis: Etiology ?bacterial superinfection?bacterial superinfection

4. Bronchiolitis: a specific clinical symptom complex <12 months old Brief prodrome of URI followed by wheezing, dyspnea, respiratory distress, tachypnea, hyperinflation on CXR Premature Apneic spells, atelectasis/infiltrates and hyperinflation May require oxygen supplementation and mechanical ventilation Bronchiolitis ?bacterial superinfection?bacterial superinfection

5. First identified >50 yrs ago 2 epidemics in the 1930s &1940s: describing the seasonal variability and physical and pathological manifestations of the disease without identified organisms 1955: Walter Reed researchers isolated a virus from the nasal secretions of young chimpanzees ? named chimpanzee coryza agent (CCA) 1956 Robert Chanock isolated CCA from 2 infants ? with characteristic mutinucleated giant cells within a large syncytium ? renamed “respiratory syncytial virus” Respiratory Syncytial Virus (RSV)

6. Single strand RNA virus: Paramyxoviridae family, 10 genes encoding 11 proteins 2 surface glycoproteins Surface glycoprotein (G): mediates attachment to the host cells Fusion protein (F): promotes aggregation of mutinucleated cells through fusion of their plasma membranes Two distinct antigenic subgroups: A&B G protein is responsible with 53% homology Controversy over which subgroup caused more severe symptoms RSV: Microbiology Currently subgroup A is indicated to cause more problemCurrently subgroup A is indicated to cause more problem

7. #1 cause of pediatric bronchiolitis & asthma: 60% of all and 80% of <1yr old with acute LRTI; 10x mortality rate compared to influenza Seasonal outbreak: in winter months, endemic in sub-tropic regions All children have been infected by 2 yrs of age with 50% of >2 infections; infection doesn’t provide long term immunity 40% infected develop LRTI; 2-5% required mechanical ventilation Health burden world wide with mortality of 5% Significant morbidity in premies (<35 week EGA, lacking placental IgG transfer), CLD and CHD Peak incidence of severe illness is between 2-3 months of age Also affect immunocompromized adults and the elderly RSV: Epidemiology CLD: BPD or CF Peak incidence due to decrease maternal IgG LRTI: lower respiratory tract infectionCLD: BPD or CF Peak incidence due to decrease maternal IgG LRTI: lower respiratory tract infection

8. Mortality 0.005-0.02% in healthy children; 1-3% in hospitalized patients Increase correlation with SIDS (25% of post mortem) probably related to prolonged apnea Chronic sequelae: early life RSV infection is an independent risk factor for recurrent wheeze and asthma: 30-40% of likelihood of recurrent asthma-like episodes Stein et al.: tapered off after 6 yrs and became insignificant after 13 yrs Sigurs et al.: showed increased risk beyond 13 yrs RSV: Epidemiology CLD: BPD or CFCLD: BPD or CF

9. Transmission Direct contact of respiratory secretions to nasopharyngeal or conjunctival mucous membrane Viable on hard surface (6 hrs); rubber gloves (90 min); skin (20 min) Incubation: 2-8 days Shedding 3 weeks in immunocompetent Several months in immunocompromised Replication: in nasopharyngeal but most efficient in the bronchiolar epithelium Direct spread Hematogenously via monocytes Causes: necrosis of the bronchiolar epithelium ? lymphocytic peribronchiolar infiltration & subsequent submucosal edema; mucus secretions increase in both quantity and viscosity RSV: Pathophysiology End result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflationEnd result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflation

10. “Master switch” of genetic control RSV induce specific cell-mediated immune response: lymphocyte transformation, cytotoxic T-cell responses, & antibody-dependent cellular cytotoxicity responses RSV: Immune Response

11. Anatomy: direct tissue damage to the mucosa ?sloughing of the epithelium ? activate of irritant receptors ? neurogenic stimulation of bronchial smooth ms & development of spasm Up regulate substance P (neuropeptides) & density of its receptors (NK1) ? significant bronchoconstriction Nerve growth factor (NGF) regulate the development of peripheral afferent and efferent neurons ?change in the distribution and reactivity of sensory & motor nerves ? non specific airway hyper-reactivity Early respiratory infections may contribute to early systemic sensitization to other antigens & allergens Neuro-immune interaction via neurotrophic pathway ? resistant to corticosteroids RSV: Immune response End result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflationEnd result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflation

12. Infection produce both serum and mucosal IgM, IgA, IgG: act in protective role IgM: 5-10 days, lower titers in <6mos; persist up to 1-3 months IgG: max in 20-30 days, lower response in <6mos; subclasses IgG1 & 3; booster effect after re-infection with highest level in 5-7 days IgA Serum IgA: several days after IgG and IgM Freed and cell-bound IgA in nasopharyngeal secretions; free anti-RSV IgA appears 2-5 days after infection and peaks 8-14 days Greater response in >6 months Primary & secondary infection with group-A can induce cross-reactive to group-B Antibody responses to the F protein are cross reactive with both strains, whereas with G protein, the response is subgroup specific RSV: Immune Response

13. RSV specific IgE: cell bound to the mucosal epithilial of the respiratory tract, not much free detected in the secretions Amount, persistency and duration are critical in determining the severity of the disease (bronchiolitis and wheezing) RSV: Immune Response

14. Cell-mediated: CD4+ & CD8+ cells and Th1 and Th2 types of CD4+ IgE + mast cells ? inflammatory mediators release RSV + epithelium ? mediators release to mobilize other cells Leukotrienes, eosinophil degranulation byproducts Epithelial cell-derived cytokines & chemokines Cell adhesion molecules and homing ligants (CD11B, ICAM-1, E-selectin) ? mobilize inflammatory and immune cells to the site, to rollover, bind and stick to the virus-infected tissues Expression of antigen-presenting molecules (HLA class I & II) Wright, M and Peidimone, G. RSV Prevention and Therapy: Past. Present and Future. Ped Pulm. RSV: Immune Response End result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflationEnd result: widespread mucus plugging with increased expiratory resistance and partial airway obstruction ? clinical triad of wheezing, atelectasis, and hyperinflation

15. Severity of illness depending on age, co-morbidities, environmental exposure & h/o previous infection 2-4 days URI ? LRTI with cough, wheeze, increased WOB, cyanosis CXR: patchy infiltration/atlectasis, hyperinflation, & peribronchial thickening Apnea: 20% in <6mos hospitalized patients Highest incidence in premies and <1mos Self-limited, does not recur with subsequent infection Prolongs reflex central apnea triggered by peripheral sensorineural stimulation Sabogal et al, Effect of RSV on apnea in weanling rats. Pediatr res 2005 RSV: Manifestations Specific blockade of the central GABA A receptors or of the high affinity substance P (NK1) receptors abolishes the influence of RSV infection on the apnea triggered by sensorineural stimulation. - Subs P released from primary sensory neurons withing the nodose ganglia activates second-order GABAergic interneurons in the spinal dorsal horsn, which in turn inhibit the function of medullary inspiratory neurons resulting in apneaSpecific blockade of the central GABA A receptors or of the high affinity substance P (NK1) receptors abolishes the influence of RSV infection on the apnea triggered by sensorineural stimulation. - Subs P released from primary sensory neurons withing the nodose ganglia activates second-order GABAergic interneurons in the spinal dorsal horsn, which in turn inhibit the function of medullary inspiratory neurons resulting in apnea

16. 165 PICU admissions with RSV bronchiolitis 42% mechanically intubated patients in PICU with lower airway secretions positive for bacteria Required longer ventilatory support WBC, neutrophil & CRP are non-conclusive Organisms: H. influenza, S. aureus, M. catarrhalis, S. penumoniae, S. pyogens Rare: Pseudomonas, B. pertussis, K. pneumoniae, E. coli Thornburn, K et al. High incidence of pulmonary bacterila co-infection in children with severe respiratory sysncytial virus (RSV) bronchiolitis. Thorz 2006; 61:611-615 RSV: Co-infection

17. Supportive care: fluid, nutrition and hydration Oxygen supplementation: non-invasive to CMV, to HFOV to ECMO Deep nasal suction CPT: administered to mobilize secretions and recruit atelectatic lungs: not beneficial (Cochrane systemic review) RSV: Treatment Infants are obligated nose breathers, need to clear nasal passageInfants are obligated nose breathers, need to clear nasal passage

18. Bronchiodilators Beta-agonists: minimally significant improvement in clinical scores but not likely to be clinically significant. No statistically significant improvement in oxygenation, admission rate or LOS (Gadomski and Basale in Cochrane review). Levoalbuterol may have better anti-inflammatory effect than racemic epi in animal model, no clinical trial Epinephrine: no benefit in in-patient settings but may produce a modest short-term improvement in out patient Anticholinergic: not effective in RSV RSV: Pharm. Interventions Use of bronchodilators and epinephrine as needed. Discontinued if no benefitUse of bronchodilators and epinephrine as needed. Discontinued if no benefit

19. Corticosteroids: Systemic: not statistically significant in clinical scores, respiratory rate, oxygen saturation, admission rate and LOS (Patel et al.; Teeratakulpisarn et al.; Corneli et al.) Inhaled: No difference in reduction in wheezing, readmission rate, use of systemci corticosteroids or use of bronchiodilators (Cochrane review; Ermers et al.) Combination: oral dexamethasone + inhaled racemic epi ? significantly less likely to require hospitalization (Plint AC, et al. Epinephrine and dexamethasone in children with bronchiolitis.. N Engl J med 2009;360:2079-2089) RSV: Pharm. Interventions Use of bronchodilators and epinephrine as needed. Discontinued if no benefitUse of bronchodilators and epinephrine as needed. Discontinued if no benefit

20. Antivirals: Ribavirin: synthetic nucleoside analog. Inhibits RSV replication in vitro, not in vivo Expensive, difficult to administer, possibly a teratogen Controversies in inhaled Ribavirin Recommended either alone or in combination with anti-RSV antibodies to treate infection in select immunocompromised hosts Antibiotics: co-infections 0.2% in all bronchiolitis 40% in intubated patients Most common sites of co-infections: UTI, OM RSV: Pharm. Interventions First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

21. Recombinant Human Deoxyribonuclease (DNAse) No demonstrable benefits (Boogaard, R. et al. Recombinant human deoxyribonuclease in infants with RSV bronchiolitis. Chest 2007;131:788-795) Hypertonic saline Nebulized HTS could reduced LOS without any adverse effects (ZhangL, et al. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Databse Syst Rev 2008:(4):CD006458) 5% nebulized HTS is safe, superior to current treatment (Khalid A., et al. Nebulized 5% or 3% hypertonic or 0.9% saline for the treating acute bronchiolitis in infants. J Ped:2010) RSV: Pharm. Interventions First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

22. Surfactant Decrease surface tension; protein components (A & D) gthat bind viral and bacterial surface markers and facilitate their immune-mediated elimination. Protein D promote alveolar macrophage production of free radicals Exogenous surfactant decrease ventilation and PICU LOS, improvement of pulm mechanics and gas exchange (Ventre K. et al. Surfactant therapy for bronchiolitis in critically ill infants. Cochrane Database Syst Rev. 2006:(3):CD005150) RSV: Pharm. Interventions First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

23. Heliox No improvement in ventilation or oxygenation (Liet et al.) Anti-Leukotrienes Controversies in using monolukast (leukotrienes antagonist) RSV: Pharm. Interventions First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

24. RSV Immunoglobulin (RSV-IVIG) Pooled polyclonal human immunoglobuline, administered monthly Decreased hospitalization and LOS of high risk infant: premies and CLD Associated with an increase in surgical morbidity and mortality in infants with CHD Interfere with immune response to live virus, delayed MMR until 9mths Disadvantages: Large volume 15ml’kg, infuse over 4-6 hrs ? fluid overload Transfer of blood born pathogens RSV: Immnunoprophylaxis First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

25. Palivizumab (Synagis) Humanized monoclonal IgG1 abs produced by recombinant DNA: >95% human with minimally immunogenic, broadly reactive activity to both subtypes; 15ml/kg IM monthly Preventing infection of upper respiratory tract but also limiting downward spread Protection for premies without BPD and acyanotic CHD patients Also decrease risk of long term wheezing Titers dropped below protective level after first dose and increase after subsequent dose, still with risk of RSV infection after the first 2 doses Low level in nasal mucosa ? doesn’t prevent infection but reduces downward spreading RSV: Immnunoprophylaxis First clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lungFirst clinical sx (coryza) usually appear toward the end of the expoential viral replication in the lung

26. Motavizumab (Rezied) Second generation IgG1 monoclonal antibody 70x higher affinity for the RSV F protein. It inhibits RSV replication in upper respiratory tract and fully humanized Phase III with 26% reduction in hospitalization compared to palivizumab, 50% reduces in outpatient medical management Not yet approved by FDA RSV: Immnunoprophylaxis