Transcript 2011 RSV - Emory University Department of Pediatrics

LOWER AIRWAY DISEASES
Pediatric Critical Care Medicine
Emory University
Children’s Healthcare of Atlanta
Objectives
• Categories:
– Bronchiolitis
– Asthma
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Epidemiology
Etiology
Pathophysiology
Clinical manifestations
Treatment
Bronchiolitis: Etiology
• 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% coviral 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
• 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
Respiratory Syncytial Virus
(RSV)
• 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”
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: A&B
– G protein is responsible with 53% homology
– Controversy over which subgroup caused more severe symptoms
RSV: Epidemiology
• #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
• 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: 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
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
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
RSV: Immune Response
 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
• 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
• 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, Eselectin)  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: 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 <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: 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; 61:611-615
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)
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
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.
and dexamethasone in children with bronchiolitis.. N Engl J med 2009;360:2079-2089)
Epinephrine
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
RSV: Pharm. Interventions
• 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
• 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
• Heliox
– No improvement in ventilation or oxygenation (Liet et al.)
• Anti-Leukotrienes
– Controversies in using monolukast (leukotrienes antagonist)
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 15ml’kg, infuse over 4-6 hrs  fluid overload
» Transfer of blood born pathogens
RSV: Immnunoprophylaxis
• 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
• 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