RSV bronchiolitis in 2002 John Evered, MD, MPH

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Bronchiolitis in 2006 John Evered, MD, MPH

• Pathophysiology
• Guidelines for Management
• New Strategies and Therapies

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Epidemiology

• RSV is the most common cause in neonates and
  infants of lower respiratory tract illness
  (LRTI), including bronchiolitis and pneumonia.
  Other causes of bronchiolitis include
  parainfluenza, adenovirus, influenza, and the
  recently identified metapneumovirus or MPV.
• 90-100,000 child hospital admissions/year, at a
  cost of over 300 million
• Main risk from 6 weeks to 2 years more than half
  of the hospitalized children with RSV
  bronchiolitis are 1-3 months, in whom mortality
  rate is 0.5- 1.5 . Most children are between
  2-6 months. Glezen WP, Taber LH, Frank AL, et
  al. Risk of primary infection and reinfection
  with respiratory syncytial virus. Am J Dis Child
  1986140543546.
• Morbidity and mortality is focused on children
  with underlying chronic diseases, including
  congenital heart disease, cystic fibrosis,
  chronic lung disease, and immune deficiency.
• The risk of death for high-risk children is as
  high as 3.5 for admission to ICU, 3136 and
  need for mechanical ventilation, 1119. Navas
  L, Wang E, de Carvalho V, et al. Improved outcome
  of respiratory syncytial virus infections in a
  high-risk hospitalized population of Canadian
  children. J Pediatr 1992121348354

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Pathophysiology

• RSV is a single-stranded RNA paramyxovirus, with
  two key surface glycoproteins, G (attachment) and
  F (fusion)
• The G (grab) protein enables attachment to
  cells, and F protein allows the viral particles
  to fuse with host cells and also to fuse infected
  cells to nearby uninfected cells, forming a
  syncytium
• Syncytium formation leads to epithelial cell
  necrosis and then peribronchiolar inflammation
  involving lymphocytes, plasma cells and
  macrophages, resulting in submucosal edema and
  mucus plugging (more than bronchospasm)
• Air trapping and atelectasis result, and lead to
  V/Q mismatch and hypoxemia, and possibly alveolar
  filling with a mononuclear infiltrate

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Points of interest

• Average incubation period for RSV is 5 days
• 2-3 weeks to recover full mucociliary function
  after an infection
• Easily spread by direct contact with secretions
  and contaminated objects, but not by small
  airborne secretions
• Stays on countertops for 6 hours, on hands for 25
  minutes and on rubber gloves for 1 hour and 30
  minutes
• Hansen et al. Recovery of RSV from stethoscopes
  by conventional viral culture and PCR. Peds
  Infect Dis J, 1999 18(2), 164-5. RSV is able to
  survive on stethoscopes for more than 6 hrs in
  dried secretions, can be eliminated by alcohol
  wiping

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What else comes with that?

• Up to 62 of children with RSV either have AOM
  or develop it within 10 days of the infection.
  Andrade et at. AOM in children with
  bronchiolitis. Pediatrics, 1998 Apr, 101(4 pt
  1)6l7-9
• Whats the risk that a baby with RSV will also
  have SBI?
• Early study Antonow et al. Sepsis evaluations
  in hospitalized infants with bronchiolitis. Peds
  Infect Dis J, 199817231-6.
• 5 of 282 (1.8) infants who had bronchiolitis
  also had SBI. Three had apnea, fever, shock or
  cyanosis (bacteremia, meningitis, and UTI), one
  was hypothermic with respiratory distress (UTI),
  and one had only a cough and a "resolving
  pneumonia" on film (UTI)

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SBI and RSV (continued)

• Risk of serious bacterial infection in young
  febrile infants with respiratory syncytial virus
  infections.Levine DA, Platt SL, Dayan PS,
  Macias CG, Zorc JJ, Krief W, Schor J, Bank D,
  Fefferman N, Shaw KN, Kuppermann N Multicenter
  RSV-SBI Study Group of the Pediatric Emergency
  Medicine Collaborative Research Committee of the
  American Academy of Pediatrics. Pediatrics, Jun
  2004 113 1728 - 1734.
• 1248 patients enrolled, including 269 (22) with
  RSV infections.
• The rate of SBIs in the RSV-positive infants was
  7.0 (17 of 244 95 CI 4.1-10.9) compared
  with 12.5 (116 of 925 95 CI 10.5-14.8) in
  the RSV-negative infants (risk difference 5.5
  95 CI 1.7-9.4).
• The rate of UTI in the RSV-positive infants was
  5.4 (14 of 261 95 CI 3.0-8.8) compared with
  10.1 (98 of 966 95 CI 8.3-12.2) in the
  RSV-negative infants (risk difference 4.7 95
  CI 1.4-8.1).
• The RSV-positive infants had a lower (though
  similar) rate of bacteremia compared to the
  RSV-negative infants (1.1 vs 2.3 risk
  difference 1.2 95 CI -0.4 to 2.7).
• No RSV-positive infant had bacterial meningitis
  (0 of 251 95 CI 0-1.2).
• Conclusion Febrile infants who are lt or 60
  days of age and have RSV infections are at
  significantly lower risk of SBI than febrile
  infants without RSV infection. Nevertheless, the
  rate of SBIs, particularly as a result of UTI,
  remains appreciable in febrile RSV-positive
  infants.
• Bottom line It probably makes sense to evaluate
  neonates and infants with significant fever with
  a CBC and urine if appropriate LPs should be
  done based on clinical appearance and age.

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RSV Jeopardy Immunity for 200, please

• Because neonates have high levels of maternal
  IgG from placental transfer.

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RSV Jeopardy Immunity for 200, please

• Because neonates have high levels of maternal
  IgG from placental transfer.
• Why do relatively few neonates get severe
  bronchiolitis?

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RSV Jeopardy Immunity for 200, please

• Because neonates have high levels of maternal
  IgG from placental transfer.
• Why do relatively few neonates get severe
  bronchiolitis?
• RSV-specific IgE, leukotriene C4, and the A1(3)
  allele for surfactant protein A.

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RSV Jeopardy Immunity for 200, please

• Because neonates have high levels of maternal
  IgG from placental transfer.
• Why do relatively few neonates get severe
  bronchiolitis?
• RSV-specific IgE, leukotriene C4, and the A1(3)
  allele for surfactant protein A.
• What are some biochemical risk factors for RSV?

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RSV Jeopardy Immunity for 200, please

• Because neonates have high levels of maternal
  IgG from placental transfer.
• Why do relatively few neonates get severe
  bronchiolitis?
• RSV-specific IgE, leukotriene C4, and the A1(3)
  allele for surfactant protein A.
• What are some genetic risk factors for RSV?
• High levels of RSV-specific IgE and leukotriene
  C4 are found in children with severe disease.
  The A1(3) allele for SP-A is overrepresented in
  children with severe RSV compared with controls
  (5 vs 0.5) Lofgren et al., Association between
  surfactant protein A gene locus and severe RSV
  infection in infants. J Infect Dis 2002 Feb
  1185(3)283-9

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Clinical diagnosis of bronchiolitis Gestalt

• A child up to 3 years old (most less than 2) with
  no history (or FH) of asthma or atopy who has
  wheezing and often crackles.
• Many infants are cheerful and well- appearing
  despite evidence of respiratory compromise
  (retractions, hypoxemia), though some are
  severely ill, with dramatic hypoxemia, lethargy,
  and shock.
• One study shows an average O2 sat of 87 in
  infants upon hospital admission.
• Neonates may present with poor feeding,
  irritability, apnea and cyanosis only (ALTE)

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Supporting evidence usually not necessary

• Bronchiolitis is a clinical diagnosis and many
  different viruses can cause it, so testing for
  the cause is unlikely to be useful, except in
  trying to rule in or out other serious illnesses
  (e.g., sepsis or bacterial pneumonia in a
  critically ill infant), or as sentinel testing
  at the beginning of the RSV season.
• RSV DFA testing probably 80-90 sensitive and
  specific.
• CBC unpredictable and unhelpful as a rule, may
  show viral/ lymphocyte shift
• CXR Hyperinflation, peribronchial cuffing,
  scattered atelectasis lobar consolidation
  uncommon
• Blood, urine, CSF cultures again, unlikely to
  be helpful (see Antonow reference above) in
  absence of signs of other systemic illness

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Differential diagnosis

• Asthma can be difficult to distinguish from RSV
  and pts may have both ask about PMH/FH of
  wheezing or other atopy, past use of and response
  to bronchodilators
• Pertussis consider in unimmunized pts less
  common in winter harsh paroxysmal cough (RSV
  more barking and intermittent) which in infants
  lt6m leads to frequent apnea 2 weeks of
  rhinorrhea prior to distress (RSV incubation is 5
  days) no fever, often normal CXR
• Pneumonia often tachypneic with less retraction
  but more ill-appearing high fever focal
  crackles without wheezes. Consider chlamydia in
  infants 1-4 months
• Others croup, GERD, foreign body, epiglottitis,
  tracheiitis

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Guidelines I

• Perlstein et al. Evaluation of an Evidence-Based
  Guideline for Bronchiolitis. Pediatrics 104(6),
  Dec 1999. Using an evidence-based guideline, a
  peds hospital in Ohio decreased admissions by
  29 LOS by 17 RSV tests by 52 use of
  beta-agonists by 30 mean costs by 37.
• Treats RSV as usually "self-limited disease
  characterized by airway edema and not
  bronchospasm" and emphasizes oxygenation and
  hydration
• SCMC Guidelines See printout

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Guidelines II Hydration and oxygen

• Oxygen as necessary to maintain normal (gt92-94)
  saturation and relieve respiratory distress
• Hydration IV or oral fluids as needed to
  maintain normal perfusion and to treat signs of
  dehydration (tachycardia, tenting, anuria or
  oliguria, lethargy).

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Guidelines III Racemic epinephrine

• Recommended Consider trial of racemic
  epinephrine. Some studies show vapo is more
  effective than albuterol, e.g. Kristjansson et
  al. Nebulized racemic adrenaline in the treatment
  of acute bronchiolitis in infants and toddlers.
  Arch Dis Child 199369650-4. Vapo achieved
  higher O2 sat with lower HR.
• An Australian multi-center, randomized,
  double-blind controlled trial of nebulized
  epinephrine showed no significant reduction in
  length of hospital stay or time until infant
  ready for discharge. Wainwright et al. A
  multicenter, randomized, double-blind, controlled
  trial of nebulized epinephrine in infants with
  acute bronchiolitis. NEJM 2003349127-35.
  However, vapo did significantly decrease
  short-term respiratory distress (a calculated
  number based on retractions and flaring, oxygen
  saturation on room air, and respiratory rate) (p
  0.04)

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Guidelines III Steroids

• Most RCTs have shown minimal or no benefit from
  oral or inhaled corticosteroids in bronchiolitis
  e.g., Cade A, Brownlee KG, Conway SP. Randomised
  placebo-controlled trial of nebulised
  corticosteroids in acute respiratory syncytial
  viral bronchiolitis. Arch Dis Child
  200082126130 No acute or chronic benefit
  from inhaled budesonide. Most studies of oral or
  IV steroids have shown the same findings.
• But a 2002 study with 70 children between 8 wks
  and 23 months old (no previous wheezing episodes)
  compared oral dexamethasone (1 mg/kg) versus
  placebo in the ER, along with nebulised
  albuterol. After 4 hours, pts if stable were sent
  home to receive either daily oral dexamethasone
  (0.6 mg/kg/dose) or placebo for 5 days, as well
  as inhaled albuterol. Pts in the dexamethasone
  group had significantly better respiratory scores
  than the placebo group (means difference 1.8,
  95 CI 0.175 to 3.425), but no significant
  difference was found at day 7 (difference in
  means 0.4, 95 CI 2.1 to 2.8). Admission rates
  were significantly reduced with dexamethasone
  (7/36 19 v 15/34 44 with placebo RR 0.44,
  95 CI 0.21 to 0.95).
• Recommended Consider use of 1 mg/kg decadron
  (oral if possible, or IM/IV) in the acute
  setting. Home course unlikely to provide
  benefit.

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PICU Management I Heliox

• Heliox (helium-02 mixture) has been shown to
  improve respiratory distress scores in children
  with at least moderate bronchiolitis, over just
  02. Hollman et al. Helium oxygen improves
  clinical asthma scores in children with acute
  bronchiolitis. Critical care medicine, 1998 Oct,
  26(10)1731-6.
• Also, Martinon-Torres et al. Heliox therapy in
  infants with acute bronchiolitis. Pediatrics
  2002 1091. In this study (n38), clinical score
  improved during therapy and PICU LOS was
  significantly reduced (3.5 /- 1.1 days vs. 5.4
  /- 1.6 days).
• Mechanism of action lower density of a 7030
  heliox mixture vs. a normal air/oxygen mixture,
  which decreases driving pressure required for air
  movement and enhances laminar flow.
• Logistics Non-rebreather mask, 10-15 LPM.
  Extra oxygen can be titrated in with NC if O2
  sats below 90. Nebulized meds can be given with
  the heliox. Weaning can be done if respiratory
  score remains stable.

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PICU Management II Surfactant

• Several good-sized studies have now shown
  significant benefit from use of surfactant in
  critically ill, ventilated infants with
  bronchiolitis
• Luchetti M et. Al. Multicenter, randomized,
  controlled study of porcine surfactant in severe
  respiratory syncytial virus-induced respiratory
  failure. Pediatr Crit Care Med. 2002
  Jul3(3)261-268.  
• Single dose of 50 mg/kg Curosurf
• In the treatment group, increased PaO2/FiO2 and
  decreased PaCO2
• Peak inspiratory pressure and static compliance
  were similar at baseline in the two groups.
• Decrease in PIP required and increased
  compliance.
• Duration of CMV and length of stay in the
  intensive care unit were significantly shorter in
  the treated group (4.6 /- 0.8 and 6.4 /- 0.9
  days, respectively) compared with the control
  group (5.8 /- 0.7 and 8.2 /- 1.1 days,
  respectively) (p lt.0001).

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PICU Management III DNAse (Pulmozyme) and
Ribavirin

• Thick, tenacious mucus in several disorders,
  including cystic fibrosis, is in part caused by
  the presence of highly polymerized
  deoxyribonucleic acid (DNA). Recombinant human
  deoxyribonuclease (rhDNase) can dissolve the
  polymers and liquefy this mucus.
• In small case series, several infants treated
  with DNAse avoided intubation or otherwise
  rapidly improved. Merkus PJ, et al. DNase
  treatment for atelectasis in infants with severe
  respiratory syncytial virus bronchiolitis. Eur
  Respir J. 2001 Oct18(4)734-7. Larger scale
  studies are needed.
• Ribavirin a synthetic nucleoside RSV
  antiviral. Studies in the early 1990s suggested
  its efficacy for children with RSV and serious
  underlying disease, with decreases in duration of
  mechanical ventilation, need for 02 and hospital
  stay. Ribavirin has fallen severely out of favor
  because of its potential toxicity and because
  more recent studies have not shown the same
  benefits e.g., Guerguerian et al., Ribavirin in
  Ventilated Respiratory Syncytial Virus
  Bronchiolitis A Randomized, Placebo-controlled
  Trial. Am. J. Respir. Crit. Care Med., Volume
  160, Number 3, September 1999, 829-834

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Prevention I Palivizumab

• Palivizumab (Synagis) is an anti-RSV human
  monoclonal antibody, given IM monthly to
  high-risk infants during RSV season (usually
  November or December to March). An RCT (the
  IMpact-RSV trial) demonstrated a 55 decrease in
  the rate of hospitalization among children with a
  history of preterm birth and/or CLD a second
  trial which enrolled pts with hemodynamically
  significant CHD showed a 45 decrease in the rate
  of RSV-associated hospitalization compared with
  placebo.
• The AAP currently recommends considering monthly
  IM Synagis for children who
• Are younger than 2 years of age with CLD and have
  required medical therapy (supplemental oxygen,
  bronchodilator, diuretic or corticosteroid
  therapy) for CLD within 6 months before the
  anticipated start of the RSV season
• Were born at 28 weeks gestation or less, even
  without CLD, up to 12 months prior to RSV season,
  or from 29-32 weeks, up to 6 months prior to RSV
  season
• Were born at 32-35 weeks and have special risk
  factors, including child care attendance,
  school-aged siblings, exposure to environmental
  air pollutants, congenital abnormalities of the
  airways, or severe neuromuscular disease.
• Are 24 months or younger and have hemodynamically
  significant CHD (e.g, Tetralogy, VSD with CHF),
  either cyanotic or non-cyanotic

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Prevention II Is Synagis worth its weight in
gold, and Hey! You! Wash your _at_ hands!!
(and your stethoscope, your scale, your baby toys
. . . )

• Synagis is expensive an average estimate is
  2700-3000 to treat a 3-kg child with five doses
  during an RSV season.
• Most cost-benefit analyses have not shown that
  the money saved on hospitalization justifies the
  cost e.g., Joffe et al. Cost-effectiveness of
  Respiratory Syncytial Virus Prophylaxis Among
  Preterm Infants. Pediatrics Vol. 104 No. 3
  September 1999, pp. 419-427. Cost to avert one
  hospitalization with synagis ranged from 12,000
  for the highest risk group to over 35,000 for
  other groups. NNT to prevent one hospitalization
  ranged from 7.4 to over 100.
• Five randomized, controlled clinical trials have
  failed to demonstrate a significant decrease in
  rate of mortality attributable to RSV infection
  in infants
• Washing hands, wiping down equipment and toys
  cheap, effective, painless
• Other preventable risk factors for high-risk pts
  day care, tobacco smoke, contact with
  school-aged siblings

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Long-term prognosis

• Of children with RSV, 30-50 go on to develop
  recurrent wheezing or asthma.
• Chicken and egg does RSV trigger future asthma,
  or are kids with future asthma more likely to get
  severe RSV?
• Prognosis varies among studies. One small
  prospective study of two matched cohorts (25
  children with bronchiolitis 25 children without)
  found no evidence that bronchiolitis requiring
  outpatient treatment is associated with an
  increased risk of asthma in the long term.
  McConnochie KM, Mark JD, McBride JT, et al.
  Normal pulmonary function measurements and airway
  reactivity in childhood after mild bronchiolitis.
  J Pediatr 19851075458.
• One study with n 50 showed asthma incidence at
  five years after RSV doubled compared with the
  general population. Sly PD, Hibbert ME.
  Childhood asthma following hospitalization with
  acute viral bronchiolitis in infancy. Pediatr
  Pulmonol 19897153158
• Steroids have been extensively studied for
  prevention of post-RSV wheezing and have not been
  found effective.
• Montelukast (Singulair) has been found in at
  least one small RCT to reduce post-RSV cough and
  wheezing. Bisgaard H Am J Respir Crit Care Med.
  2003 Feb 1167(3)379-83.

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Conclusion

• Bronchiolitis is a viral LRTI that is usually
  self-limited but causes most infant
  hospitalizations in the U.S., and major morbidity
  and mortality, especially for children with
  chronic disease
• The pathogenesis, different from asthma, involves
  viral and immune-mediated damage to airway
  epithelium, with subsequent inflammation, mucus
  plugging and air trapping
• Treatment following evidence-based guidelines can
  decrease hospital admissions, LOS, and
  unnecessary tests and therapies
• Evidence for standard treatment supports the use
  of oxygen and proper hydration. Bronchodilators
  such as vaponefrin and albuterol and steroids
  such as dexamethasone may be effective in some
  children
• PICU therapy includes these options plus IMV,
  surfactant, heliox, DNAse and (rarely) ribavirin
• Monthly Synagis is the main preventive therapy
  for high-risk infants, though its benefits are
  limited and it is very costly

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RSV Jeopardy 2 Review

• This commonly used beta-agonist has no strong
  evidence to recommend its routine therapy in
  bronchiolitis, though it may reasonably be tried
• Answer What is albuterol?
• This once highly-regarded synthetic nucleoside
  antiviral has fallen out of favor due to
  potential toxicity and lack of evidence of
  benefit
• Answer What is ribavirin?
• This cost range is, in one study, the money
  required, using Synagis, to prevent a single
  hospitalization for RSV
• Answer What is 12,000 - 35,000?
• This formerly common and deadly bacterial illness
  can mimic bronchiolitis, but is less common in
  winter, and may be associated with a more harsh,
  paroxysmal cough and gasping stridor
• Answer What is pertussis?

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