LOWER AIRWAY DISEASES Pediatric Critical Care Medicine Emory

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LOWER AIRWAY DISEASES
Pediatric Critical Care Medicine Emory
University Childrens Healthcare of Atlanta
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Objectives

• Categories
• Bronchiolitis
• Asthma
• Epidemiology
• Etiology
• Pathophysiology
• Clinical manifestations
• Treatment

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Bronchiolitis Etiology

• Population lt2yr 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 lt 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

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Bronchiolitis

• Bronchiolitis a specific clinical symptom
  complex
• lt12 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

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Respiratory Syncytial Virus (RSV)

• First identified gt50 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

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RSV Microbiology

• 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 AB
• G protein is responsible with 53 homology
• Controversy over which subgroup caused more
  severe symptoms

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RSV Epidemiology

• 1 cause of pediatric bronchiolitis asthma 60
  of all and 80 of lt1yr 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 gt2 infections infection doesnt
  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 (lt35 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

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RSV Epidemiology

• 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

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RSV Pathophysiology

• 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

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RSV Immune Response

• Master switch of genetic control
• RSV induce specific cell-mediated immune
  response lymphocyte transformation, cytotoxic
  T-cell responses, antibody-dependent cellular
  cytotoxicity responses

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RSV Immune response

• 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

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RSV Immune Response

• Infection produce both serum and mucosal IgM,
  IgA, IgG act in protective role
• IgM 5-10 days, lower titers in lt6mos persist up
  to 1-3 months
• IgG max in 20-30 days, lower response in lt6mos
  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 gt6 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

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RSV Immune Response

• 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)

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RSV Immune Response

• 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.

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RSV Manifestations

• 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 lt6mos hospitalized patients
• Highest incidence in premies and lt1mos
• 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

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RSV Co-infection

• 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 61611-615

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RSV Treatment

• 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)

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RSV Pharm. Interventions

• 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

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RSV Pharm. Interventions

• 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 20093602079-2089)

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RSV Pharm. Interventions

• 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

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RSV Pharm. Interventions

• Recombinant Human Deoxyribonuclease (DNAse)
• No demonstrable benefits (Boogaard, R. et al.
  Recombinant human deoxyribonuclease in infants
  with RSV bronchiolitis. Chest 2007131788-795)
• 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 Ped2010)

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RSV Pharm. Interventions

• 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)

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RSV Pharm. Interventions

• Heliox
• No improvement in ventilation or oxygenation
  (Liet et al.)
• Anti-Leukotrienes
• Controversies in using monolukast (leukotrienes
  antagonist)

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RSV Immnunoprophylaxis

• 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 15mlkg, infuse over 4-6 hrs ? fluid
  overload
• Transfer of blood born pathogens

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RSV Immnunoprophylaxis

• Palivizumab (Synagis)
• Humanized monoclonal IgG1 abs produced by
  recombinant DNA gt95 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 ? doesnt prevent
  infection but reduces downward spreading

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RSV Immnunoprophylaxis

• 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