What 2012 pulmonology

WHAT YOU SHOULD HAVE READ BUT….2012  pulmonologyAttilio BonerUniversity ofVerona, Italy

Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis Belderbos Pediatrics 2011;127:e1513 156 healthy term Cord blood concentrations of 25-OHD in neonates. neonates who subsequently developed RSV LRTI (n=18) and those who did not (n=138) 25-hydroxyvitamin D (25-OHD) in cord blood plasma. Lower respiratory tract infection (LRTI) caused by Respiratory Syncytial Virus (RSV) in the first year of life, defined as LRTI symptoms and presence of RSV RNA in a nose-throat specimen.

Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis Belderbos Pediatrics 2011;127:e1513 156 healthy term Risk of RSV LRTI per quartile of 25-OHD levels. neonates. Because of the limited number of cases, the lower quartiles (25 nmol/L, n=7; and 25–49 nmol/L, n=29) were pooled 25-hydroxyvitamin D (25-OHD) in cord blood plasma. Lower respiratory tract infection (LRTI) caused by Respiratory Syncytial Virus (RSV) in the first year of life, defined as LRTI symptoms and presence of RSV RNA in a nose-throat specimen.

Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis Belderbos Pediatrics 2011;127:e1513 156 healthy term Risk of RSV LRTI per quartile of 25-OHD levels. neonates. Because of the limited number of cases, the lower quartiles Vitamin D (25 nmol/L, n=7; and 25–49 nmol/L, n=29) were pooled 25-hydroxyvitamin D deficiency in (25-OHD) in cord blood healthy neonates is plasma. associated with Lower respiratory tract increased risk of infection (LRTI) caused RSV LRTI in the by Respiratory Syncytial Virus (RSV) in year first the first of life. year of life, defined as LRTI symptoms and presence of RSV RNA in a nose-throat specimen.

Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis Belderbos Pediatrics 2011;127:e1513 156 healthy term Risk of RSV LRTI per quartile of 25-OHD levels. neonates. Because of the limited number of cases, the lower quartiles Intensified (25 nmol/L, n=7; and 25–49 nmol/L, n=29) were pooled 25-hydroxyvitamin D D routine vitamin (25-OHD) in cord blood supplementation plasma. during pregnancy may be a useful Lower respiratory tract infection (LRTI) caused strategy to prevent by Respiratory Syncytial RSV LRTI Virus (RSV) in the first year during defined as of life, infancy. LRTI symptoms and presence of RSV RNA in a nose-throat specimen.

Lung function prior to viral lower respiratory tract infections in prematurely born infants Drysdale Thorax 2011;66:468ObjectivePrematurely born infants who develop respiratory syncytial virus(RSV) lower respiratory tract infections (LRTIs) have lungfunction abnormalities at follow-up.The aim of this study was to determine whether prematurely borninfants who developed symptomatic RSV, or other viral LRTI(s),had poorer premorbid lung function than infants who did notdevelop LRTIs during the RSV season. ?

Lung function prior to viral lower respiratory tract infections in prematurely born infants Drysdale Thorax 2011;66:468 Functional residual capacity (FRC), compliance (Crs) and resistance (Rrs) of the respiratory system measured % infants developing LRTs at 36 weeks postmenstrual age. 50 – Nasopharyngeal aspirates whenever the infants had an LRTI. RSV A and RSV B, rhinovirus, 40 – 46% influenza A and B, 30 – 73/159 parainfluenza 1, 2 and 3, human metapneumovirus and 20 – adenovirus. 159 infants with a median gestational 10 – age of 34 (range 23-36) weeks prospectively followed. 0

Lung function prior to viral lower respiratory tract infections in prematurely born infants Drysdale Thorax 2011;66:468 Functional residual capacity (FRC), compliance (Crs) and resistance (Rrs) of the respiratory system measured Overall, there were at 36 weeks postmenstrual age. no significant differences Nasopharyngeal aspirates whenever in the FRC (p=0.54), the infants had an LRTI. Crs (p=0.11) or RSV A and RSV B, rhinovirus, Rrs (p=0.12) results influenza A and B, between those who parainfluenza 1, 2 and 3, developed an RSV human metapneumovirus and or other viral LRTI adenovirus. and those who did not 159 infants with a median gestational develop an LRTI. age of 34 (range 23-36) weeks prospectively followed. …but…

Lung function prior to viral lower respiratory tract infections in prematurely born infants Drysdale Thorax 2011;66:468 Functional residual capacity (FRC), compliance (Crs) and resistance (Rrs) of the respiratory system measured at 36 weeks postmenstrual age. Infants with RSV or other viral LRTIs Nasopharyngeal aspirates whenever the infants had an LRTI. who were admitted to hospital compared RSV A and RSV B, rhinovirus, with those who influenza A and B, parainfluenza 1, 2 and 3, were not had higher human metapneumovirus and Rrs results (p=0.033 and adenovirus. p=0.039, respectively). 159 infants with a median gestational age of 34 (range 23-36) weeks prospectively followed.

Lung function prior to viral lower respiratory tract infections in prematurely born infants Drysdale Thorax 2011;66:468 Functional residual capacity (FRC), compliance (Crs) and resistance (Rrs) Diminished of the respiratory system measured at 36premorbid lung weeks postmenstrual age. Infants with RSV or other viral LRTIs function Nasopharyngeal aspirates whenever who were admitted to the infants had an LRTI. may predispose hospital compared RSV A and RSV B, rhinovirus, prematurely born influenza A and B, with those who parainfluenza 1, to severe were not had higher infants 2 and 3, and human metapneumovirus Rrs results (p=0.033 and adenovirus. LRTIs in viral p=0.039, respectively). infancy. 159 infants with a median gestational age of 34 (range 23-36) weeks prospectively followed.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550RationaleRespiratory syncytial virus (RSV) is a major cause of lower respiratorytract infections in children, for which no specific treatment or vaccineis currently available.We have previously shown that RSV induces reactive oxygen species incultured cells and oxidative injury in the lungs of experimentallyinfected mice. The mechanism(s) of RSV-induced oxidative stress invivo is not known.ObjectivesTo measure changes of lung antioxidant enzymes expression/activityand activation of NF-E2-related factor 2 (Nrf2), a transcription factorthat regulates detoxifying and antioxidant enzyme gene expression, inmice and in infants with naturally acquired RSV infection.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Superoxide dismutase 1 (SOD 1), SOD 2, SOD 3, catalase, glutathione peroxidase, and glutathione S-transferase, RSV infection induced a as well as NF-E2-related factor significant decrease in the 2 (Nrf2 )expression, expression and/or activity were measured in murine bronchoalveolar lavage, cell of SOD, catalase, extracts of conductive airways, Glutathione S-transferase, and/or inhumannasopharyngeal and glutathione peroxidase secretions. in murine lungs and in the Antioxidant enzyme activity and airways of children with markers of oxidative cell injury severe bronchiolitis. were measured in either murine bronchoalveolar lavage or nasopharyngeal secretions.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Superoxide dismutase 1 (SOD 1), SOD 2, SOD 3, catalase, glutathione peroxidase, and glutathione S-transferase, Markers of oxidative as well as NF-E2-related factor 2 (Nrf2 )expression, damage correlated with were measured in murine severity of clinical illness bronchoalveolar lavage, cell in RSV infected infants. extracts of conductive airways, Nrf2 expression was also and/or inhumannasopharyngeal significantly reduced in secretions. the lungs of viral-infected Antioxidant enzyme activity and mice. markers of oxidative cell injury were measured in either murine bronchoalveolar lavage or nasopharyngeal secretions.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550  Superoxide dismutase 1 (SOD 1), RSV infection SOD 2, SOD 3, catalase, glutathione peroxidase, and induces glutathione S-transferase, Markers of oxidative significant as well as Nrf2 expression, damage correlated with down-regulation were measured in murine severity of clinical illness bronchoalveolar lavage, cell in RSV infected infants. of the airway extracts of conductive airways, Nrf2 expression was also antioxidant and/or inhumannasopharyngeal secretions. significantly reduced in system in vivo, the lungs of viral-infected  Antioxidant enzyme activity and likely oxidative cell injury markers of resulting in mice. lung oxidative were measured in either murine damage. bronchoalveolar lavage or nasopharyngeal secretions.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550  Superoxide dismutase 1 (SOD 1), Modulation of SOD 2, SOD 3, catalase, oxidative stress glutathione peroxidase, and Markers of oxidative glutathione S-transferase, as may paveexpression, well as Nrf2 the way damage correlated with toward important were measured in murine severity of clinical illness bronchoalveolar lavage, cell advances in the extracts of conductive airways, in RSV infected infants. therapeutic and/or inhumannasopharyngeal Nrf2 expression was also significantly reduced in approach of secretions. the lungs of viral-infected RSV-induced  Antioxidant enzyme activity and mice. markers of oxidative cell injury were measured in lung murine acute either disease. bronchoalveolar lavage or nasopharyngeal secretions.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Antioxidant enzymes are reduced in bronchoalveolar lavage (BAL) of respiratory syncytial virus (RSV)-infected mice.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Western blots were performed using antibodies against superoxide dismutase (SOD) 1, SOD 2, SOD 3, catalase, and glutathione S-transferase (GST)-mu. The figure is representative of 3 independent experiments, each experiment with 4 mice per group at each time point.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550Superoxide dismutase (SOD) 1, SOD 2, and SOD 3 in conductive airway epithelial cells. Proteins of conductive airway epithelial Densitometric analysis of cells were obtained by lysis lavage from Western blot band intensities using respiratory syncytial virus (RSV)-infected Alpha Ease software. or control mice (Day 1 after infection) * p<0.05 ***p<0.001 and analyzed by Western blot.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550  Respiratory syncytial virus (RSV) infection inhibits antioxidant enzyme activity in the lung.  Total superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione S- transferase (GST) activity in bronchoalveolar lavage of groups of mice that were RSV infected or sham inoculated. *p<0.05; **p< 0.01 and ***p<0.001 relative to control mice.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Respiratory syncytial virus (RSV) infection is associated with decreased levels of nuclear Nrf2 in the lung 12 and 24 hours after infection with RSV *p<0.05; **p<0.01 relative to control mice.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550 Concentrations of the oxidative stress markers in nasopharyngeal secretions (NPS) of infants with naturally acquired respiratory syncytial virus (RSV) infections. F2-isoprostane concentration Malondialdehyde concentration **p < 0.01 and ***p < 0.001 compared with upper respiratory tract infection

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550Antioxidant enzyme expression in nasopharyngeal secretions (NPS) of infants with naturally acquired respiratory syncytial virus (RSV) infections.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550Antioxidant enzyme expression in nasopharyngeal secretions (NPS) of infants with naturally acquired respiratory syncytial virus (RSV) infections.Western blot analysis of superoxide dismutase (SOD) 1, SOD 2, and SOD 3, catalase, and glutathione S-transferase (GST)-mu in NPS of children with: • upper respiratory tract infections (URTI), • bronchiolitis (BR), • bronchiolitis with hypoxia (BR 1 H), and • patients on ventilatory support (VS).b-actin was used as a control for protein integrity and equal loading of the samples.

Viral-mediated Inhibition of Antioxidant Enzymes Contributes to the Pathogenesis of Severe RespiratorySyncytial Virus Bronchiolitis Hosakote AJRCCM 2012;183:1550ConclusionRSV infection induces a significant decrease in the expression ofmost antioxidant enzyme involved in maintaining cellularoxidant–antioxidant balance in mice and children.The exception is SOD 2, for which levels are reduced in the BALof infected mice but not in epithelial cell proteins of the conductiveairways or in nasopharyngeal secretions of infected children,suggesting that airway epithelial cells may not be the only cellularsource of the lung antioxidant response measured in BAL of mice.Other tissue resident cells, such as alveolar macrophages, whichare early targets of RSV infection, could contribute to theobserved BAL findings.

Rhinovirus-induced bronchiolitis and asthma development Jartti Pediat Allergy Immunol 2011;22:350The association between any sensitization The association between log10 numberand of sensitizations andsole rhinovirus [human rhinovirus (HRV);n= 58], sole HRV,sole respiratory syncytial virus [respiratory sole RSV,syncytial virus (RSV); n = 35], sole EV,sole enterovirus (EV; n = 34), sole HBoV,sole human bocavirus (HBoV; n = 12), sole other virus (the only child wassole other virus (n = 8), sensitized; not computable),mixed virus (n = 87) and mixed virus, andnon-virus (n = 13) non-virusassociated wheezing in hospitalized children. associated wheezing in hospitalized children.

Rhinovirus-induced bronchiolitis and asthma development Jartti Pediat Allergy Immunol 2011;22:350The association between any sensitization The association between log10 numberand of sensitizations andsole rhinovirus [human rhinovirus (HRV);n= 58], sole HRV,sole respiratory syncytial virus [respiratory sole RSV, Low interferon responses have beensyncytial virus (RSV); n = 35], sole EV, sole HBoV,sole enterovirus (EV; associated with HRV bronchiolitis. n = 34),sole human bocavirus (HBoV; n = 12), sole other virus (the only child wassole other virus (n = 8), sensitized; not computable),mixed virus (n = 87) and mixed virus, andnon-virus (n = 13) non-virusassociated wheezing in hospitalized children. associated wheezing in hospitalized children.

Rhinovirus-induced bronchiolitis and asthma development Jartti Pediat Allergy Immunol 2011;22:350The association between any sensitization The association between log10 numberand of sensitizations andsole rhinovirus [human rhinovirus (HRV);n= 58], sole HRV, Although recurrent wheezing is common aftersole respiratory syncytial virus [respiratory sole RSV,syncytial virus (RSV);both RSV and HRV bronchiolitis, HRV n = 35], sole EV,sole enterovirus (EV; n = 34), sole HBoV, bronchiolitis carries a markedly higher riskonly child was sole other virus (the ofsole human bocavirus (HBoV; n = 12), persistent wheezing until 6 years of age andsole other virus (n = 8), sensitized; not computable),mixed virus (n = 87) and for childhood asthma. and mixed virus,non-virus (n = 13) non-virusassociated wheezing in hospitalized children. associated wheezing in hospitalized children.

Rhinovirus-induced bronchiolitis and asthma development Jartti Pediat Allergy Immunol 2011;22:350 Possible mechanisms of interactions between rhinovirus and allergy in causing more severe asthma or asthma-like illnesses.

Rhinovirus bronchiolitis and recurrent wheezing: 1-year follow-up. Midulla F, Eur Respir J 2012;39:396 Rate of recurrent wheezing 60 - 313 infants aged <12 months 50 – 52.7% hospitalised for their p<0.001 40 – first episode of bronchiolitis. 30 – 14 respiratory viruses assayed in nasal washings. 20 – 10.3% 10 – Recurrent wheezing. 0 A 12-month follow-up. controls bronchiolitis

Rhinovirus bronchiolitis and recurrent wheezing: 1-year follow-up. Midulla F, Eur Respir J 2012;39:396 OR for recurrent wheezing Recurrent wheezing. 4 – A 12-month follow-up. 313 infants 3 – 3.3 aged <12 months 3.2 hospitalised for their 2 – 2.5 first episode of bronchiolitis. 1 – 14 respiratory viruses 00 assayed in nasal washings. rhinovirus family history infection for asthma

Preschool asthma after bronchiolitis in infancy Koponen P, Eur Respir J 2012;39:76 % children with current asthma at age 6.5 205 infants hospitalised for bronchiolitis at 20 – < 6 months of age. Control visit at a mean age of 6.5 yrs. 10 – 12.7% Viral aetiology of bronchiolitis, on admission by antigen detection. 0

Preschool asthma after bronchiolitis in infancy Koponen P, Eur Respir J 2012;39:76 % children with current asthma according to viral etiology of bronchiolitis 205 infants hospitalised 30 – for bronchiolitis at < 6 months of age. 20 – 24% Control visit at a mean age of 6.5 yrs. p=0.01 10 – Viral aetiology of bronchiolitis, 8.2% on admission by 0 antigen detection. RSV non-RSV

Preschool asthma after bronchiolitis in infancy Koponen P, Eur Respir J 2012;39:76 % children with current asthma according to viral etiology of bronchiolitis The risk of asthma 205 infants hospitalised 30 – forwas lower after bronchiolitis at < 6RSV bronchiolitis months of age. than after 20 – 24% Control visit atcaused bronchiolitis a meanother viruses in by age of 6.5 yrs. p=0.01 children hospitalised 10 – Viral aetiology of age at <6 months of bronchiolitis, 8.2% on admission by 0 antigen detection. RSV non-RSV

Clinical Impact of RT-PCR for Pediatric Acute Respiratory Infections: A Controlled Clinical Trial Wishaupt Pediatrics 2011;128:e1113 Real-time polymerase chain reaction (RT-PCR) testing is a quick sensitive method for detecting respiratory pathogens. There were no Nasal wash specimens from patients significant differences 12 years of age with suspected between the groups acute respiratory infections. with respect to The RT-PCR results were hospital admissions, communicated to the clinicians within 12 to 36 hours in the length of hospital stay intervention group and after 4 or duration of weeks in the control group. antibiotic use. 583 patients: 298 in the intervention group and 285 in the control group.

Clinical Impact of RT-PCR for Pediatric Acute Respiratory Infections: A Controlled Clinical Trial Wishaupt Pediatrics 2011;128:e11131. Although a positive viral diagnosis could be established for many patients, the numbers of hospital admissions and the lengths of hospital stays did not differ between the groups.2. The need for hospitalization depends primarily on clinical parameters, such as the degree of clinical illness, the need for supplemental oxygen therapy, and the need for bronchodilator nebulization therapy, rather than a confirmed viral diagnosis.

Clinical Impact of RT-PCR for Pediatric Acute Respiratory Infections: A Controlled Clinical Trial Wishaupt Pediatrics 2011;128:e11133. The duration of antibiotic treatment was not significantly influenced by RTPCR testing. This is partly explained by physicians‘ concerns regarding bacterial superinfection in patients with ARIs.4. Unfortunately, positive RT-PCR results do not exclude the possibility of bacterial superinfection; therefore, physicians are unlikely to change the antibiotic treatment that has been initiated. In addition, viral infection was reported previously to predispose patients to bacterial superinfection. In our study, the majority of patients with proven bacterial pneumonia also had positive RT-PCR results for a virus.

Observational study of two oxygen saturation targets for discharge in bronchiolitis Cunningham, Arch Dis Child 2012;97:361 To assess the potential effect of discharge oxygen saturation (SpO2) ≥ 90% and ≥ 94% 1. Feeding problems in bronchiolitis. resolved at 68 infants aged ≤ 18 mo a median of 11 h. requiring therapeutic oxygen for SpO2 ≤ 93%. 2. SpO2 became stable for at least 4h at: SpO2 assessed in air every 2 h. - 17 h for ≥ 90% Time from admission - 63 h for ≥ 94%. to re-establish feeding (>75% normal) and for SpO2 to become stable for 4h at ≥ 90% and ≥ 94%.

Observational study of two oxygen saturation targets for discharge in bronchiolitis Cunningham, Arch Dis Child 2012;97:361 Time difference (hours) Time to resolve feeding,≥90% to ≥94% SpO2 in air for 4h. SpO2 ≥90% and ≥94% in air in infants with bronchiolitis.

Observational study of two oxygen saturation targets for discharge in bronchiolitis Cunningham, Arch Dis Child 2012;97:361 Time difference (hours) Time to resolve feeding, ≥90% to ≥94% SpO2 in air for 4h. SpO2 ≥90% and ≥94% in air in infants with bronchiolitis. The median lag between stable oxygen at ≥90% and ≥94% for 3 observations32 (≥4h) was 32h.

Observational study of two oxygen saturation targets for discharge in bronchiolitis Cunningham, Arch Dis Child 2012;97:361 Time difference (hours) Time to resolve feeding,≥90% to ≥94% SpO2 in air for 4h. SpO2 ≥90% and ≥94% in air in infants with bronchiolitis. The time for all study infants to achieve a stable SpO2≥90% and resolve feeding difficulties was a median of 22h. 22

Observational study of two oxygen saturation targets for discharge in bronchiolitis Cunningham, Arch Dis Child 2012;97:3611. This study identifies that stopping therapeutic oxygen for acute recovering viral bronchiolitis at stable 90% SpO2 rather than 94% SpO2 could result in a median discharge from hospital 22h earlier.2. With an average length of stay of 3 days, this difference represents a significant potential gain.3. The clinical and safety effects of this policy have yet to be assessed.

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 % infants admitted 449 infants 40 – presenting with acute bronchiolitis. 30 – 20 – 36% 10 – 0

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 % infants admitted 449 infants 40 – presenting with The 5 best predictors of acute bronchiolitis. 30 – admission were: 1) age, 20 – 36% 2) respiratory rate, 3) heart rate, 10 – 4) oxigen saturations 5) duration of symtomps. 0

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 Bronchiolitis risk of admission score

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 Distribution of scores across admitted and discharged children with sensitivity and specificity at each score cut-off

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 Distribution of scores across admitted and discharged children with sensitivity and Scoring system couldcut-off specificity at each score be a useful addition to the safety net scoring systems and be employed effectively in the emergency department, particularly by inexperienced clinicians.

Clinical predictors of admission in infants with acute bronchiolitis Marlais Arch Dis Child 2011;96:648 Distribution of scores across admitted and discharged children with sensitivity and specificity at each score cut-off The score is simple to use and takes into account objective data. A score of 3 or over could direct the clinician to seek a review of the child by a senior colleague before allowing that child to be discharged.

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis. A systematic review Ralston APAM 2011;165:951 Rate of urinary tract 11 studies reporting infections 4 – rates of serious bacterial infection in infants younger than 90 days with clinical 3 – 3.3% bronchiolitis and/or 2 – respiratory syncytial virus infection. 1 – 0

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis. A systematic review Ralston APAM 2011;165:951 Bacteremia rates in infants with bronchiolitis or respiratory syncytial virus infection.

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis. A systematic review Ralston APAM 2011;165:951 Bacteremia rates in infants with bronchiolitis or respiratory syncytial virus infection. No case of bacteremia was reported in 8 of 11 studies. No case of meningitis was reported in any of the studies.

Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis. A systematic review Ralston APAM 2011;165:951 Bacteremia rates in infants with bronchiolitis or respiratory syncytial virus infection. A screening approach to culturing for serious bacterial infections in febrile infants presenting with bronchiolitis or respiratory syncytial virus infection is very low yield.

Impact of PCR for respiratory viruses on antibiotic use:Theory and Practice. van de Pol Pediatr Pulmonol 2011;46:428  Real-time polymerase chain reaction (PCR) for respiratory viruses is more sensitive, yet more expensive, than conventionally used direct immunofluorescence (DIF).  We determined the impact of real-time PCR, additional to DIF, on antibiotic prescription in ventilated children with lower respiratory tract infection (LRTI) at admission to the pediatric intensive care unit (PICU). The multicenter survey study (94 respondents) showed that PCR decreased antibiotic use (P < 0.001).

Impact of PCR for respiratory viruses on antibiotic use:Theory and Practice. van de Pol Pediatr Pulmonol 2011;46:428 In a prospective study, children (≤5 years) with LRTI % children DIF (+) tested at admission by DIF and PCR. 50 – Positive DIF results were 40 – 50% reported at the end of the first working day. 30 – 19/38 PICU physicians reported 20 – antibiotic treatment on the second working day. 10 – After informing them of the PCR result antibiotic treatment 00 was reevaluated.

Impact of PCR for respiratory viruses on antibiotic use:Theory and Practice. van de Pol Pediatr Pulmonol 2011;46:428 In a prospective study, children (≤5 years) with LRTI % children DIF (+) testedthe admissionnegative and Of at 19 DIF by DIF PCR.patients 12 (63%) were 50 – treated with antibiotics Positive DIF results were before revealing the PCR 40 – 50% reported at the end of the result; the PCR test was 19/38 first working day. 30 – positive in 9 out of 12. PICU physicians reporteddid Revealing PCR results 20 – antibioticalter antibiotic not treatment on the second working day. treatment. 10 – After informing them of the PCR result antibiotic treatment 00 was reevaluated.

Impact of PCR for respiratory viruses on antibiotic use:Theory and Practice. van de Pol Pediatr Pulmonol 2011;46:428 In a prospective study, children (≤5 years) with LRTI % children DIF (+) tested at admission by DIF and In contrast to their PCR.responses to the survey 50 – Positive DIF real-life PICU study, in results were physicians did not let their 40 – 50% reported at the end of the first workingprescription be antibiotic day. 30 – 19/38 influenced by respiratory PICU physicians reported 20 – antibiotic treatmentchildren real-time PCR in on the second working for LRTI. ventilated day. 10 – After informing them of the PCR result antibiotic treatment 00 was reevaluated.

Impact of PCR for respiratory viruses on antibiotic use:Theory and Practice. van de Pol Pediatr Pulmonol 2011;46:428 Flow chart of viral test results and antibiotic use of patients enrolled in the prospective study

Unnecessary Care for Bronchiolitis Decreases With Increasing Inpatient Prevalence of Bronchiolitis Van Cleve Pediatrics 2011;128:e11061. Efforts to improve the quality of care for bronchiolitis have focused on decreasing utilization through implementation of prespecified “pathways” of care delivery: lack of utility of routine use of laboratory testing, steroids, radiography, and antibiotics for patients with uncomplicated viral bronchiolitis. American Academy of Pediatrics, Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4): 1774.2. If high-quality care for bronchiolitis is defined in part on the basis of what physicians choose not to do, why do patients continue to receive unnecessary care?

Unnecessary Care for Bronchiolitis Decreases With Increasing Inpatient Prevalence of Bronchiolitis Van Cleve Pediatrics 2011;128:e11063. The clinical presentation of viral bronchiolitis includes fever, tachypnea, and respiratory distress, all of which also can be symptoms of more- serious bacterial illnesses.4. Although diagnosis of a viral infection decreases the probability of other illnesses, it does not exclude other causes of illness among infants.5. To accept a clinical hypothesis that a patient has bronchiolitis and to provide high-quality, evidence-based care, physicians must integrate a patient‟s clinical presentation with contextual information that includes the ―pretest‖ probability of illness.

Unnecessary Care for Bronchiolitis Decreases With Increasing Inpatient Prevalence of Bronchiolitis Van Cleve Pediatrics 2011;128:e11066. Failure to incorporate such information might lead to an inappropriatelylow degree of faith in a clinical diagnosis, which might contribute tooveruse of diagnostic tests and empirical therapeutic measures.7.In this study, we hypothesized that an important determinant of caredelivery to patients with eventual diagnoses of bronchiolitis would be theinpatient bronchiolitis prevalence (IBP) in the hospital in which their care isbeing delivered. A priori, we postulated that an elevated IBP would increasephysician/care team confidence that a patient‘s illness was caused bybronchiolitis and therefore would decrease the likelihood that the patientwould receive care that is generally thought to provide little or no benefitfor bronchiolitis.

Unnecessary Care for Bronchiolitis Decreases With Increasing Inpatient Prevalence of Bronchiolitis Van Cleve Pediatrics 2011;128:e1106 During winter months, with each 1% absolute All patients increase in inpatient 2 months to 2 years of age hospitalized bronchiolitis prevalence with bronchiolitis (IBP), patients were less during 2004–2008 likely to receive: at pediatric hospitals. 1. steroids (P<0.001), 2. radiographs (P<0.001), 3. laboratory tests (P<0.001).

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Infants aged 2-12 months with a Modified Wood‘s Mean change in M-WCAS Clinical Asthma Score from baseline to 240 minutes. (M-WCAS) of 3 or higher. 0 Randomized to the -0.31 helium-oxygen (n=34) -0.5 – or oxygen (n=35) p<0.001 and received nebulized -1.0 – racemic epinephrine via a -1.84 face mask. -2.0 – Helium-oxygen Oxygen group group

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Infants aged 2-12 months with a Modified Wood‘s The mean M-WCAS was Mean change in M-WCAS Clinical Asthma Score for significantly improved from baseline to 240 minutes. the helium-oxygen group (M-WCAS) of 3 or higher. compared with the 0 Randomized to the at oxygen group -0.31 helium-oxygen (n=34) 60 minutes (p=0.005), -0.5 – oxygen (n=35) or120 minutes (p<0.001), p<0.001 and received nebulized 180 minutes (p<0.001), -1.0 – racemic epinephrine via a 240 minutes (p<0.001). -1.84 face mask. -2.0 – Helium-oxygen Oxygen group group

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Lowell Pediatrics 1987;79:939.

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Mean Modified Wood‟s Clinical Asthma Scores (M-WCASs) vs time.

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Mean Respiratory Distress Assessment Instrument (RDAI) scores vs time.

Helium-Oxygen Therapy for Infants With Bronchiolitis Kim APAM 2011;165:1115 Nebulized racemic epinephrine delivered by helium-oxygenRespiratory helium-oxygen inhalation therapy Mean followed by Distress Assessment Instrument (RDAI) scores vs time. was associated with a greater degree of clinical improvement compared with that delivered by oxygen among infants with bronchiolitis.

Clinical predictors of nasal continuous positive airway pressure requirement in acute bronchiolitis Evans Pediatr Pulmonol 2012;47:3811) Two to three percent of infants under 1 year of age are admitted each year with bronchiolitis caused by RSV.2) A small percentage of those admitted go on to require ventilatory support.3) There is an increasing awareness of the potential benefits that non-invasive ventilation, such as nasal continuous positive airway pressure (nCPAP) may confer over basic supportive care in reducing the need for invasive ventilation in severely affected infants.

Clinical predictors of nasal continuous positive airway pressure requirement in acute bronchiolitis Evans Pediatr Pulmonol 2012;47:381 To identify clinical % children requiring factors in infants with nasal CPAP 20 – acute bronchiolitis in the emergency department (ED), which might predict 15 – 17% 10 – a requirement for nCPAP 28/163 following admission. 05 – 163 admitted infants. 00

Clinical predictors of nasal continuous positive airway pressure requirement in acute bronchiolitis Evans Pediatr Pulmonol 2012;47:381 Statistically Significant Predictors % %1Continuous variables presented as mean values and binary variables presented as percentages.2Univariate binary logistic regression was used for statistical analysis and provides an odds ratio for a 1 pointchange in the independent variable, i.e., odds ratio for a 1 point change in the unit of measurement forcontinuous variable and odds ratio associated with the presence of a binary variable.

Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial de Betue Arch Dis Child 2011;96:817 Rates of protein kinetics (g/kg/24 h) 18 infants admitted to the paediatric intensive care unit in both study groups on day 5 with respiratory failure due to viral bronchiolitis. p<0.05 Continuous enteral feeding p<0.05 with protein and energy enriched formula (PE-formula) (n=8; 3.1±0.3 g protein/kg/24 h, 119±25 kcal/kg/24 h) or standard formula (S-formula) p<0.05 (n=10; 1.7±0.2 g protein/kg/24 h, Whole body Whole body Whole body 84±15 kcal/kg/24 h. protein protein protein breackdown balance synthesis

Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial de Betue Arch Dis Child 2011;96:817 A positive 18 infants admitted to the Rates of protein kinetics (g/kg/24 h) Whole body paediatric intensive care unit in both study groups on day 5 protein balance with respiratory failure due to viral bronchiolitis. was achieved p<0.05 in the Continuous enteral feeding p<0.05 with protein and energy PE-group, enriched formula (PE-formula) which was (n=8; 3.1±0.3 g protein/kg/24 significantly h, 119±25 kcal/kg/24 h) or p<0.05 standard formula (S-formula) higher than in (n=10; 1.7±0.2 g the S-group. protein/kg/24 h, Whole body Whole body Whole body 84±15 kcal/kg/24 h. protein protein protein breackdown balance synthesis

Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial de Betue Arch Dis Child 2011;96:817 Rates of protein kinetics (g/kg/24 h) Increasing protein 18 infants admitted to the in both study groups on day 5 and energy intakes paediatric intensive care unit with respiratory failure due promotes protein to viral bronchiolitis. anabolism in p<0.05 Continuous enteralill infants. critically feeding p<0.05 Increased protein with protein and energy enriched formula (PE-formula) and energy intakes (n=8; 3.1±0.3 g protein/kg/24 should be preferred h, 119±25 kcal/kg/24 h) or above standard intakes standard formula (S-formula) p<0.05 in these infants. (n=10; 1.7±0.2 g protein/kg/24 h, Whole body Whole body Whole body 84±15 kcal/kg/24 h. protein protein protein breackdown balance synthesis

Discharged on Supplemental Oxygen From anEmergency Department in Patients With Bronchiolitis Halstead, Pediatrics 2012;129;e6051) The primary reasons for admission include respiratory distress, poor feeding, and hypoxia or the need for supplemental oxygen (O2).2) Practitioners are influenced by small changes in pulse-oximetry data in the decision to admit patients with bronchiolitis.3) With the increased use of pulse-oximetry, patients also remain in the hospital for supplemental O2 for longer periods of time after other parameters such as work of breathing and feeding have returned to normal.

Discharged on Supplemental Oxygen From an Emergency Department in Patients With Bronchiolitis Halstead, Pediatrics 2012;129;e605 The American Academy of Pediatrics1) The primary reasons for admission include respiratory distress, poor feeding, and hypoxia or the need for be initiatedoxygen recommends that O2 therapy supplemental (O2). judiciously when O saturations 2 levels fall < 90% and that the intensity2) Practitioners are influenced by small changes in pulse-oximetry of monitoring O2 saturation levels data in the decision to admit patients with bronchiolitis. be reduced as the infant improves.3) With the increased use of pulse-oximetry, patients also remain in the hospital for of Pediatrics Subcommitteeof for longer periods of time American Academy supplemental O2onbronchiolitis. Pediatrics. of Bronchiolitis; Diagnosis and management Diagnosis and Management after other parameters such as work of breathing and feeding 2006;118(4): 1774–1793 have returned to normal.

Discharged on Supplemental Oxygen From an Emergency Department in Patients With Bronchiolitis Halstead, Pediatrics 2012;129;e605 % patients 60 – Retrospective chart review of 4194 patients with 57% bronchiolitis between 2005 40 – and 2009. Patients requiring baseline 20 – 28% O2 were excluded. Patients admitted after 15% home O2 for adverse 0 on O2 room air admitted outcomes. discharged

Discharged on Supplemental Oxygen From an Emergency Department in Patients With Bronchiolitis Halstead, Pediatrics 2012;129;e605 % patients 60 – Retrospective chart review of 4194 patients with on Those discharged 57% room air, 4% were bronchiolitis between 2005 40 – and 2009. subsequently admitted, and 6% of those Patients requiring baseline discharged on O2 20 – 28% O2 were excluded. were admitted. Patients admitted after 15% home O2 for adverse 0 on O2 room air admitted outcomes. discharged

Discharged on Supplemental Oxygen From an Emergency Department in Patients With Bronchiolitis Halstead, Pediatrics 2012;129;e605 % patients 60 – Retrospective chartan Home O2 is review of 4194 patients with effective way to 57% bronchiolitis between 2005 anddecrease hospital 40 – 2009. admissions in a select group Patients requiring baseline 20 – 28% O2 were excluded.with of patients bronchiolitis. Patients admitted after 15% home O2 for adverse 0 on O2 room air admitted outcomes. discharged

Pulmonary surfactant in respiratory syncytial virus bronchiolitis: The role in pathogenesis and clinical implications. Barreira Pediatr Pulmonol 2011;46:415 Besides the well-known importance of pulmonary surfactant in maintenance of pulmonary homeostasis and lung mechanics, the surfactant proteins SP-A and SP-D are essential components of the pulmonary innate immune system. Deficiencies of such proteins, which develop in severe RSV bronchiolitis, may be related to impairment in viral clearance, and exacerbated inflammatory response.

Pulmonary surfactant in respiratory syncytial virus bronchiolitis: The role in pathogenesis and clinical implications. Barreira Pediatr Pulmonol 2011;46:415The immune response to RSV infection includes the componentsof innate and acquired immunity. Innate immune responserepresents the first line of defense against pathogens, and playsthree important functions:a) detection of pathogens and expression of biological factors for their eradication,b) signaling and attraction of immune cells to the site of infection,c) trigger of the adaptive immune response. In RSV infection, innate immune system constitutes the main defense mechanism against the disease. Krishnan Viral Immunol 2004; 17: 220

Pulmonary surfactant in respiratory syncytial virus bronchiolitis: The role in pathogenesis and clinical implications. Barreira Pediatr Pulmonol 2011;46:415•Pulmonary surfactant proteins SP-A and SP-D represent the firstmean of interaction between the virus and the innate pulmonarydefense.•Following the disruption of the immune barrier represented by thelung surfactant proteins, interaction of RSV with the respiratorytract cells—in particular the epithelial and dendritic cells—triggersthe pulmonary inflammatory response.•After binding to epithelial cells, RSV is recognized by Toll LikeReceptors (TLR) 3 and 4. The linkage between TLR and RSV throughF glycoprotein induces NFκ-β factor activation, and the subsequenttranscription of genes related to antiviral response.•Such process induces the release of cytokines and chemokines, andthe recruitment of eosinophils, natural killer, and CD4 lymphocytesinto the airways.

•cough

An objective study of acid reflux and cough in children using an ambulatory pHmetry–cough logger A B Chang Arch Dis Child 2011;96:468 pHmetry-cough logger with attachments Children (aged <14 yrs) with chronic cough. pHmetry using a specifically built ambulatory pHmetry–cough logger that enabled the simultaneous ambulatory recording of cough and pH with a fast (10 Hz) capture rate. Coughs within (before & after) 10, 30, 60 and 120s of a reflux episode (pH<4 for >0.5 s).

An objective study of acid reflux and cough in children using an ambulatory pHmetry–cough logger A B Chang Arch Dis Child 2011;96:468 Cough preceding a pH drop followed by another cough Children (aged <14 yrs) with chronic cough. pHmetry using a specifically built ambulatory pHmetry–cough logger that enabled the simultaneous ambulatory recording of cough and pH with a fast (10 Hz) capture rate. Coughs within (before & after) 10, 30, 60 and 120s of a reflux episode (pH<4 for >0.5 s).

An objective study of acid reflux and cough in children using an ambulatory pHmetry–cough logger A B Chang Arch Dis Child 2011;96:468 Cough preceding a pH drop followed by another cough Recording from the Children (aged <14 yrs) with pHmetry–cough logger chronic cough. pHmetry using astudy, used in this specifically built ambulatory which has a capture pHmetry–cough logger rate of 10 Hz that enabled the simultaneous (40 times the usual ambulatory recording of cough commerciallyfast (10 Hz) and pH with a available systems, capture rate. which has a capture Coughs within (before & after) 10, 30, 60 and 120s of a reflux rate of 0.25 Hz). episode (pH<4 for >0.5 s).

An objective study of acid reflux and cough in children using an ambulatory pHmetry–cough logger A B Chang Arch Dis Child 2011;96:468 Children (aged <14 yrs) with There were: chronic cough. • 5628 coughs in 20 pHmetry using a specifically children. built ambulatory pHmetry–cough logger • Most coughs (83.9%) that enabled the simultaneous were independent of a ambulatory recording of cough reflux event. and pH with a fast (10 Hz) capture rate. • The temporal Coughs within (before & after) relationship between 10, 30, 60 and 120s of a reflux acid reflux and cough episode (pH<4 for >0.5 s). is unlikely causal.

An objective study of acid reflux and cough in children using an ambulatory pHmetry–cough logger A B Chang Arch Dis Child 2011;96:468 Children (aged <14 yrs) with There were: Effect of chronic cough. • 5628 coughs in 20 pHmetry using a specifically anti-reflux built ambulatory children. • Most coughs (83.9%) therapy theloggerto pHmetry–cough that enabled has simultaneous were independent of a be strictly ambulatory recording of cough reflux event. and pH with a fast (10 Hz) evaluted in capture rate. • The temporal relationship betweenindividual 120s of a reflux 10, 30, 60 and patient Coughs within (before & after) acid reflux and cough episode (pH<4 for >0.5 s). is unlikely causal.

Pnumonia

Community-acquired pneumonia in children: what‟s new? Thomson Thorax 2011;66:9271) The guideline confirms that no diagnostic tests are necessary in the community but emphasises the importance of providing families with information, including advice on management, identifying any deterioration and the importance of reassessment.2) Infant vaccination with PCV 7 (seven-valent pneumococcal conjugate vaccination) started in the UK in 2007 has shown a 19% decrease in admission rates between 2006 and 2008. In countries such as the USA where PCV 7 has been available for longer, a decrease in hospital admissions of≈30% is reported.3) Streptococcus pneumoniae remains by far the most common bacterial cause and is found in 30-40% of cases as a single or co-pathogen. Group A Streptococcus contributes 1-7% of cases. Mycoplasma and Chlamydia pneumoniae are found with variable frequency and are not uncommon in the preschool child. Harris M, Clark J, Coote N, et al. BTS guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 2011. doi:10.1136/thoraxjnl-2011-200598

Community-acquired pneumonia in children: what‟s new? Thomson Thorax 2011;66:9274) Overall viruses account for 30-67% of cases and are most frequent in children <1 year of age.5) In the 2002 guidance, clinicians were encouraged to search for a pathogen in all cases, but this has been revised to more practical guidance that aetiological investigation be restricted to those with either severe or complicated disease.6) The WHO produced a method for standardising the interpretation of chest radiographs in children, but, even using this, the concordance rate between trained reviewers was only 48%.7) Investigation of the use of acute phase reactants as a means of differentiating aetiology and/or severity of CAP are not of clinical utility in distinguishing viral from bacterial infections and should not be a routine test. Harris M, Clark J, Coote N, et al. BTS guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 2011. doi:10.1136/thoraxjnl-2011-200598

Community-acquired pneumonia in children: what‟s new? Thomson Thorax 2011;66:9278) Oxygen saturation <92% is an indicator of severity and the need for oxygen therapy.9) With the introduction of PCV 13 the likelihood of bacterial pneumonia in a fully vaccinated child will fall further. Fully vaccinated children <2 years old presenting with mild symptoms of LRTI need not be treated with antibiotics, but should be reviewed if symptoms persist.10)The evidence is that bacterial and viral pneumonia cannot reliably be distinguished and therefore all other children with a clear clinical diagnosis of pneumonia should receive antibiotics. Harris M, Clark J, Coote N, et al. BTS guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 2011. doi:10.1136/thoraxjnl-2011-200598

Community-acquired pneumonia in children: what‟s new? Thomson Thorax 2011;66:92711) Amoxicillin is effective, well tolerated and cheap. Macrolide antibiotics should not be first line but can be added at any age if there is no response to first-line empirical therapy.12) Over the age of 6 months to either oral amoxicillin or intravenous penicillin, and the outcomes were equivalent (with a shorter duration of hospital stay in the oral group). Oral amoxicillin is therefore the antibiotic of choice both in the community and in hospital. Intravenous antibiotics should be reserved for children unable to absorb oral drugs or those presenting with septicaemia or complicated pneumonia.13) Now: no intravenous line, no tests, no physiotherapy. Simple oral antibiotics and supportive care will be effective for the majority of children with CAP, who will also escape from hospital faster. Harris M, Clark J, Coote N, et al. BTS guidelines for the management of community acquired pneumonia in children: update 2011. Thorax 2011. doi:10.1136/thoraxjnl-2011-200598

Prediction of Pneumonia in a Pediatric Emergency Department. Mark, Pediatrics 2011;128:246 A prospective cohort % PATIENTS WITH study in an urban pediatric RADIOGRAPHIC PNEUMONIAE emergency department 20 – of patients who had a chest radiograph performed for suspicion 16% of pneumonia (n=2574). 10 – Radiologist interpretation equivocal cases of pneumonia and definite pneumonia. 0

Prediction of Pneumonia in a Pediatric Emergency Department. Mark, Pediatrics 2011;128:246 A prospective cohort % PATIENTS WITH study in an urban pediatric RADIOGRAPHIC PNEUMONIAE emergencyof chest pain, 20 – History department of patients who had a focal rales, chest radiographfever, duration of performed for suspicion and oximetry levels 16% of pneumonia (n=2574). at triage 10 – were significant Radiologist interpretation predictors equivocal pneumonia. of cases of pneumonia and definite pneumonia. 0

Prediction of Pneumonia in a Pediatric Emergency Department. Mark, Pediatrics 2011;128:246 A prospective cohort OR FOR PNEUMONIAE study in an urban pediatric 4 – emergency department of patients who had a chest radiograph 3 – 3.6 performed for suspicion of pneumonia (n=2574). 2 – Radiologist interpretation 1 – equivocal cases of pneumonia and definite pneumonia. 00 OXIGEN SATURATION ≤92%

Prediction of Pneumonia in a Pediatric Emergency Department. Mark, Pediatrics 2011;128:246 A prospective cohort Among subjects with OR FOR PNEUMONIAE study inSaO >92%, an urban pediatric 2 4 – emergency department no history of fever, of patients who had a no focal decreased chest breath sounds, radiograph 3 – 3.6 performed focal rales, and no for suspicion of pneumonia (n=2574). 2 – the rate of radiographic pneumonia Radiologist interpretation was 7.6% 1 – equivocal cases of pneumoniaand and definite pneumonia definite pneumonia. 00 OXIGEN SATURATION ≤92% was 2.9%

Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections Schuetz P, Chest 2012;141:1055 A growing body of evidence supports the use of procalcitonin (PCT) to differentiate bacterial from viral respiratory diagnoses, to help risk stratify patients, and to guide antibiotic therapy decisions about initial need for, and optimal duration of, therapy. A series of randomized controlled trials have evaluated PCT protocols for antibiotic-related decision making and have included patients from different clinical settings and with different severities of respiratory infection. In these trials, initial PCT levels were effective in guiding decisions about the initiation of antibiotic therapy in lower-acuity patients, and subsequent measurements were effective for guiding duration of therapy in higher-acuity patients, without apparent harmful effects.

Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections Schuetz P, Chest 2012;141:1055 A growing body of evidence supports the use of procalcitonin (PCT) to differentiate bacterial from viral respiratory diagnoses, to help risk stratify with any other laboratory test, PCT about  As patients, and to guide antibiotic therapy decisions initial should not optimal durationa stand-alone basis. need for, and be used on of, therapy.  Rather, it must be integrated into clinical A series of randomized controlled trials have evaluated PCT protocols protocols, together with clinical, for antibiotic-related decision making and have included patients from different clinical settings and with different severities of respiratory microbiologic data and with results from infection. clinical risk scores. In these trials, initial PCT levels were effective in guiding decisions about the initiation of antibiotic therapy in lower-acuity patients, and subsequent measurements were effective for guiding duration of therapy in higher-acuity patients, without apparent harmful effects.

Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections Schuetz P, Chest 2012;141:1055 Use of PCT

Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections Schuetz P, Chest 2012;141:1055 Use of PCT The evidence suggests that using PCT for patients with respiratory infections can lead to more parsimonious antibiotic use and de-escalation, without safety concerns

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD Bafadhel CHEST 2011;139:1410 62 patients with pneumonia, 96 with asthma and 161 with COPD were studied Serum procalcitonin (PCT) and C-reactive protein (CRP) were assayed in these patients

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD Bafadhel CHEST 2011;139:1410 Patients with pneumonia had increased PCT and CRP levels compared with those with asthma and COPD

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD Bafadhel CHEST 2011;139:1410 62 patients with A CRP value >48 pneumonia, 96 with mg/L had a asthma and 161 sensitivity of with COPD were 91% and studied specificity of Serum procalcitonin 93% for (PCT) and C-reactive identifying protein (CRP) were patients with assayed in these pneumonia

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD Bafadhel CHEST 2011;139:1410 62 patients with CRP levels could pneumonia, 96 with be used to guide asthma and 161 antibiotic therapy with COPD were and reduce studied antibiotic overuse Serum procalcitonin in hospitalized (PCT) and C-reactive patients with protein respiratory acute (CRP) were assayed in these illness

Procalcitonin and C-reactive protein in hospitalized adult patients with community-acquired pneumonia or exacerbation of asthma or COPD Bafadhel CHEST 2011;139:1410 Serum Pct and CRP concentrations were strongly correlated p<0.001 r=0.56

PnumoniaRisk factors

Alcohol drinking and risk of subsequent hospitalisation with pneumonia. Kornum J.B, Eur Respir J 2012;39:1491) Alcohol abuse has been associated with a 2-to 9-fold higher risk of pneumonia.2) Abuse of alcohol may increase susceptibility to pneumonia for several reasons: alcohol intake may cause alterations in neutrophil and macrophage function and abnormalities in ciliary and surfactant functioning in the lung . Alcohol overuse also can increase the risk of aspiration and suppress the normal cough reflex .3) Finally, chronic alcohol intake is closely associated with malnutrition and other chronic diseases that may affect pneumonia risk.

Alcohol drinking and risk of subsequent hospitalisation with pneumonia. Kornum J.B, Eur Respir J 2012;39:149 HR for pneumonia 2 – * 1.81 22,485 males and * 1.49 24,682 females from Denmark * 1.15 (aged 50–64 yrs). 1 – * 1.0 * 0.88 * 0.87 follow-up of 12 yrs. 1,091 (males) and 944 (females) had 0 pneumonia-related 0 1-6 7-20 21-34 34-50 > 50 hospitalisation. drinks for week

Alcohol drinking and risk of subsequent hospitalisation with pneumonia. Kornum J.B, Eur Respir J 2012;39:149 HR for pneumonia Regular moderate 2 – alcohol intake is * 1.81 not associated 22,485increased risk with males and * 1.49 24,682 females from of hospitalisation Denmark * 1.15 for pneumonia. 1 – (aged High weekly 50–64 yrs). * 1.0 * 0.88 alcohol consumption * 0.87 follow-up of 12 yrs. and infrequent heavy drinking may 1,091 (males) and increase pneumonia 944 (females) had risk 0 pneumonia-related 0 1-6 7-20 21-34 34-50 > 50 hospitalisation. drinks for week

Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter Mushtaq JACI 2011;127:1236 Background Epidemiologic studies report an association between pneumonia and urban particulate matter (PM) less than 10 microns (μm) in aerodynamic diameter (PM10). Streptococcus pneumoniae is a common cause of bacterial pneumonia worldwide. To date, the mechanism whereby urban PM enhances vulnerability to S pneumoniae infection is unclear. Adhesion of S pneumoniae to host cells is a prerequisite for infection. Host-expressed proteins, including the receptor for platelet-activating factor (PAFR), are co-opted by S pneumoniae to adhere to lower airway epithelial cells.

Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter Mushtaq JACI 2011;127:1236 1) Cultured with PM10 and PM2.5 2) Then infected with S pneumoniae Airway epithelial cells A 549 PM10 and PM2.5 increased S pneumoniae adhesion

Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter Mushtaq JACI 2011;127:1236 1) Cultured with PM10 and PM2.5 2) Then infected with S pneumoniae Airway epithelial cells A 549 PM10 and PM2.5 increased S pneumoniae adhesion Adhesion was attenuated by N-acetyl cysteine antioxidant

Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter Mushtaq JACI 2011;127:1236 1) Cultured with PM10 and PM2.5 2) Then infected with S pneumoniae Airway epithelial cells A 549 PM10 and PM2.5 increased PM The ability of combustion to induce oxidative stress in S pneumoniae adhesion airway cells is considered to be an important factor in the initiation of adverse health Adhesion was attenuated effects. by N-acetyl cysteine antioxidant

Influenza Coinfection and Outcomes in ChildrenWith Complicated Pneumonia. Williams APAM 2011;165:506 A bacterial pathogen was identified in 1201 cases (35.5%). The most commonly identified 3382 children bacteria were discharged from Staphylococcus aureus hospitals with in children with complicated influenza coinfection pneumonia (22.9% of cases) requiring a and pleural drainage. Streptococcus pneumoniae in children without coinfection (20.0% of cases).

Influenza Coinfection and Outcomes in ChildrenWith Complicated Pneumonia. Williams APAM 2011;165:506 Multivariable analysis comparing outcomes between patients with complicated pneumonia with and without influenza

Influenza Coinfection and Outcomes in ChildrenWith Complicated Pneumonia. Williams APAM 2011;165:506 Multivariable analysis comparing outcomes between patients with complicated pneumonia with and without influenza Influenza coinfection was associated with higher odds of intensive care unit admission, mechanical ventilation, vasoactive infusions, blood product transfusions, higher costs and a longer hospital stay.

Influenza vaccination is associated with reduced severityof community-acquired pneumonia Tessmer ERJ 2011;38:147 Pneumonia is an important cause of influenza-associated morbidity and mortality. Influenza vaccination has been shown to reduce morbidity and mortality during influenza seasons. Protection from severe pneumonia may contribute to the beneficial effect of influenza vaccination. Therefore, we investigated the impact of prior influenza vaccination on disease severity and mortality in patients with community-acquired pneumonia (CAP).

Influenza vaccination is associated with reduced severityof community-acquired pneumonia Tessmer ERJ 2011;38:147 During the influenza season in vaccinated subjects OR 1.0 –  Patients were analysed separately as an influenza 0.76 0.53 season (2.368 0.5 – patients) and off-season cohort.  Vaccination status. 0 Severe Procalcitonin pneumonia ≥2.0 ng/ml

Influenza vaccination is associated with reduced severityof community-acquired pneumonia Tessmer ERJ 2011;38:147 During the influenza season in vaccinated subjects OR These patients 1.0 –  Patients were a showed analysed separately significantly as an influenza 0.76 better overall 0.53 season and 2.368 0.5 – survival within the off-season cohort. 6-month  Vaccination status. follow-up period. 0 Severe Procalcitonin pneumonia ≥2.0 ng/ml

Influenza vaccination is associated with reduced severityof community-acquired pneumonia Tessmer ERJ 2011;38:147 During the influenza season in vaccinated subjects OR 1.0 – Within the  Patients were cohort off-season analysed separately (2,632 patients) as an influenza 0.76 there was no 0.53 season (2.368 0.5 – patients) and influence significant of vaccination off-season cohort. status on CAP  Vaccination status. severity 0 Severe Procalcitonin pneumonia ≥2.0 ng/ml

Microbial evaluation of proton-pump inhibitorsand the risk of pneumonia Meijvis ERJ 2011;38:1165Recent initiation of proton-pump inhibitor (PPI) treatment may increase the risk of community-acquired pneumonia (CAP), hypothetically by allowing colonisation of the oropharynx by gastrointestinal bacteria.

Microbial evaluation of proton-pump inhibitors and the risk of pneumonia Meijvis ERJ 2011;38:1165 OR for community acquired pneumonia. 3.1 3 – 430 cases with 2 – pneumonia. 1720 controls. 1 – 0 Recent initiation of PPI treatment (<30 days).

Microbial evaluation of proton-pump inhibitors and the risk of pneumonia Meijvis ERJ 2011;38:1165 OR for community acquired pneumonia. Gastrointestinal 3.1 3 – bacteria were identified in only 5 430 cases with (1.2%) patients with pneumonia. 2 – pneumonia 1720 controls. (2 current users and 1 – 3 nonusers). 0 Recent initiation of PPI treatment (<30 days).

Microbial evaluation of proton-pump inhibitors and the risk of pneumonia Meijvis ERJ 2011;38:1165 OR for community acquired pneumonia. PPIs is associated with 3.1 an increased risk of 3 – CAP, especially when 430 cases with recently2 – treatment has pneumonia. started been 1720 controls. in microbial but no shifts aetiology seem 1 – to explain the associations. 0 Recent initiation of PPI treatment (<30 days).

Increased incidence of bronchopulmonary fistulas complicating pediatric pneumonia McKee Pediatr Pulmonol 2011;46:717BackgroundThe frequency of complicatedpneumococcal disease, including necrotizingpneumonia, has increased over the lastdecade.During 2008–2009, we noted an increase inthe number of children whose empyemawas complicated by the development of abronchopleural fistula and air leak.We studied these children to see if therewas an associated cause.

Increased incidence of bronchopulmonary fistulas complicating pediatric pneumonia McKee Pediatr Pulmonol 2011;46:717 % children with fistula 35 – 33% Retrospective review of 30 – children admitted with a parapneumonic effusion 25 – or empyema from 20 – p<0.0001 2002 to 2007, compared 15 – with 2008 to 2009. 10 – 310 children. 05 – 00 1% 2002-2007 2008-2009

Increased incidence of bronchopulmonary fistulas complicating pediatric pneumonia McKee Pediatr Pulmonol 2011;46:717 % children with fistula 35 – 33% Retrospective review of Pneumococcal serotype 30 – children admitted with a 3 was identified in parapneumonic effusion 10/16 (63%) children 25 – orwith a bronchopleural empyema from 20 – p<0.0001 2002 to 2007, compared fistula and 1/33 (3%) 15 – withwithout (<0.0001). 2008 to 2009. 10 – 310 children. 05 – 00 1% 2002-2007 2008-2009

Increased incidence of bronchopulmonary fistulas complicating pediatric pneumonia McKee Pediatr Pulmonol 2011;46:717 % children with fistula 35 – 33% Retrospective review of Pneumococcal serotype 30 – children admitted with a 3 infection, was not parapneumonic effusion covered by the 25 – or empyema from 20 – p<0.0001 heptavalent 2002 to 2007, compared pneumococcal 15 – with 2008 to 2009. vaccine Prevenar. 10 – 310 children. 05 – 00 1% 2002-2007 2008-2009

Combined treatment for child refractoryMycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Lu Pediatr Pulmonol 2011;46:1093 Mycoplasma pneumoniae (M. pneumoniae) is one of the major pathogens causing community-acquired respiratory tract infections in children. Although M. pneumoniae pneumonia (MP) is usually a benign self-limited disease, it may develop into a severe life-threatening pneumonia in rare cases. These cases are defined as refractory MP showing clinical and radiological deterioration after macrolide antibiotic therapy for 7 days or more.

Combined treatment for child refractoryMycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Lu Pediatr Pulmonol 2011;46:1093 Mycoplasma pneumoniae (M. pneumoniae) is one of the major pathogens causing community-acquired respiratory tract infections in children. Refractory MP may be related to emergency Although M. pneumoniae pneumonia (MP) pneumoniae benign of macrolide (ML) resistant M. is usually a self-limited disease, it may develop into a severe life-threatening pneumonia in rare cases. These cases are defined as refractory MP showing clinical and radiological deterioration after macrolide antibiotic therapy for 7 days or more.

Combined treatment for child refractoryMycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Lu Pediatr Pulmonol 2011;46:1093 In children, macrolide antibiotics are the first-choice agents for M. pneumoniae infections, and these antibiotics have been thought to have excellent effectiveness against M. pneumoniae for many years. However, in recent years, many isolates of M. pneumoniae from clinical samples showed resistance to macrolides. Mutations in domain V of 23S rRNA of M. pneumoniae are proved as main mechanism of resistance.

Combined treatment for child refractoryMycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Lu Pediatr Pulmonol 2011;46:1093 In children, macrolide antibiotics are the first-choice agents for M. pneumoniae infections, and these antibiotics have been thought to have excellent effectiveness against M. pneumoniae Fluoroquinolones have a broad spectrum of for many years. activity against Gram-positive, Gram-negative, and other organisms such as Mycoplasma However, in recent years, many isolates of M. pneumoniae and Chlamydia. from clinical samples showed resistance to macrolides. Mutations in domain V of 23S rRNA of M. pneumoniae are proved as main mechanism of resistance.

Combined treatment for child refractoryMycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Lu Pediatr Pulmonol 2011;46:1093 In children, macrolide antibiotics are the first-choice agents for M. pneumoniae infections, and these antibiotics have been thought to have excellent effectiveness against M. pneumoniae Many clinical studies show that corticosteroids for many years. dramatically benefit patients with severe MP, However, in recent years, many isolates of immunity in which is related to cell-mediated M. pneumoniae from clinical samplespneumoniae infections. M. showed resistance to macrolides. Mutations in domain V of 23S rRNA of M. pneumoniae are proved as main mechanism of resistance.

Pnumoniaassesment

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336• Currently the best predictor of pneumonia mortality risk is arterial oxygen saturation, measured by pulse oximetry (saturation of peripheral oxygen, SpO2).• Lactate is a product of anaerobic cellular metabolism. It is used as a marker of poor tissue oxygen delivery, and cell hypoxia in high-income settings to monitor critically ill children, including those with severe infections, low cardiac output and acute respiratory distress syndrome.• Elevated blood lactate may occur as an end result of: - hypoxaemic respiratory failure - cardiovascular or cellular failure from associated sepsis.

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336 % deaths 20 – 233 children 18% 15 – with pneumonia. Serum lactate 13% 10 – concentration. 05 – 00 2.1 – 4.0 > 4.0 Lactate concentration (mmol/l)

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336 RR of death 8 – 233 children 7 – 6 – 7.48 with pneumonia. 5 – Serum lactate 4 – concentration. 3 – 2 – 1 – 0 Lactate level >2 mmol/l

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336 Log-likelihood model of saturation of peripheral oxygen (SpO2) according to normal and elevated lactate concentrations. 233 children with pneumonia. Serum lactate concentration.

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336 Log-likelihood model of saturation of peripheral oxygen (SpO2) according to Used in conjunction normal and elevated lactate concentrations. with clinical risk factors 233 children and pulse oximetry with pneumonia. , lactate could play Serum lactate role an important concentration. the in identifying sickest patients with pneumonia in developing countries.

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336• Hypoxaemia occurs in pneumonia because of ventilation–perfusion mismatching in the lungs, right to left intrapulmonary shunts, and in very severe and late stages due to inadequate minute volume.• Tissue hypoxaemia and high blood lactate can occur because of low partial pressure of arterial oxygen, or impaired perfusion, impaired oxygen delivery or impaired oxygen extraction from a septic state that exists in some children with bacteraemia.• Hypoxaemia may lead to increased serum lactate, though the hypoxemic threshold for hyperlactataemia will differ between individuals. 65 out of 87 children with hypoxaemia by definition (SpO2 <90%) had normal lactate concentrations.

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia. Ramakrishna, Arch Dis Child 2012;97:336• Children with radiographic consolidation or effusion had lower risk of mortality when compared to children with evidence of interstitial infiltrate and hyperinflation.• Radiographic findings of interstitial infiltrate, peribronchial thickening, small areas of atelectasis and hyperinflation are features of Pneumocystis jirovecii pneumonia, as well as being consistent with viral pneumonia.

Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia Newman, Pediatrics 2012;129;e5971) Studies have identified Streptococcus pneumoniae as the most common bacterial pathogen in children.2) The recently published pediatric CAP guideline recommends the use of ampicillin or ceftriaxone for children admitted with uncomplicated CAP (community-acquired pneumonia). Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25–e763) Generally, the need for broad-spectrum antibiotics to treat CAP is unnecessary. S.pneumoniae resistance occurs by changing its penicillin-binding proteins, which can be overcome by high levels of ampicillin.

Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia Newman, Pediatrics 2012;129;e597 % of pneumonia treated with 80 – Retrospective study 70 – of discharged patients 72% for pneumonia. 60 – 50 – 12 months before and 40 – after the community- 30 – acquired pneumonia (CAP) clinical practice guideline 20 – (CPG) was introduced. 10 – 13% 0 1033 patients: 530 (51%) ceftriaxone ampicilline before the CPG. preguidelines

Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia Newman, Pediatrics 2012;129;e597 % of pneumonia treated with 80 – Retrospective study 70 – of discharged patients 63% for pneumonia. 60 – 50 – 12 months before and 40 – after the community- 30 – acquired pneumonia (CAP) clinical practice guideline 20 – (CPG) was introduced. 10 – 0 1033 patients: 530 (51%) ampicilline before the CPG. postguidelines

Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia Newman, Pediatrics 2012;129;e597 % of pneumonia treated with 80 – Retrospective study 70 – of discharged patients The effect of the 63% for pneumonia. 60 – clinical practice 50 – guideline (CPG) 12 months before and 40 – was associated with after the community- 30 – acquired pneumonia (CAP) a 34% increase clinicalampicillin use in practice guideline 20 – (CPG) was introduced. (P ‹ 0.001). 10 – 0 1033 patients: 530 (51%) ampicilline before the CPG. postguidelines

Impact of a Guideline on Management of Children Hospitalized With Community-Acquired Pneumonia Newman, Pediatrics 2012;129;e597 % of pneumonia treated with 80 – Retrospective study 70 – of discharged patients Discharge 63% for pneumonia. 60 – antibiotics also 50 – 12changed post-CPG, months before and 40 – showing a significant after the community- 30 – increase in amoxicillin acquired pneumonia (CAP) use (P ‹ 0.001). clinical practice guideline 20 – (CPG) was introduced. 10 – 0 1033 patients: 530 (51%) ampicilline before the CPG. postguidelines

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21Background: Although antibiotics are recommended for the primarycare management of community-acquired pneumonia, a recent UKstudy reported that most children admitted to hospital had notreceived antibiotics.Objective: To describe primary care antibiotic use for childrensubsequently hospitalised with community-acquired pneumonia.

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21 % of children who had received an antibiotic before hospital admission 50 – 280 children <5 years, 40 – hospitalised with 39% pneumonia in 30 – 108/280 New Zeland 20 – Receipt of antibiotics 10 – 0

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21 % of children who had received an antibiotic before hospital admission 50 – For 60 children 280 children <5(21%) there had years, 40 – been no opportunity hospitalised with to prescribe because 39% pneumonia in 30 – the illness evolved 108/280 New Zeland rapidly, resulting in 20 – Receipt of early hospital antibiotics admission 10 – 0

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21 % of children for whom there was the opportunity to have a prescription (112/280) but did not have the treatment 30 – 20 – 25% 21% 21% 10 – 0 Parents failed Pneumonia was The diagnosis to obtain the diagnosed but was not made antibiotic no antibiotic prescribed prescribed

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21 Missed opportunities to prescribe were not associated with for whom thereof symptoms % of children overall severity was the opportunity at hospital presentation (112/280) to have a prescription BUT… but did not have the treatment 30 – 20 – 25% 21% 21% 10 – 0 Parents failed Pneumonia was The diagnosis to obtain the diagnosed but was not made antibiotic no antibiotic prescribed prescribed

Why do children hospitalised with pneumonia not receive antibiotics in primary care? Grant, Arch Dis Child 2012;97:21 …were associated with an increased risk of: 1) Focal chest radiological abnormalities (RR=2.14) % of children for whom there was the 2) Peripheral leucocytosis >15x109/L (RR=2.29) opportunity toBacteraemia (RR=6.68)(112/280) 3) have a prescription but did not have the treatment 30 – 20 – 25% 21% 21% 10 – 0 Parents failed Pneumonia was The diagnosis to obtain the diagnosed but was not made antibiotic no antibiotic prescribed prescribed

Empirical treatment of influenza-associated pneumonia in primary care: antimicrobial susceptibility of lower respiratory tract bacteria Blackburn Thorax 2011;66:389 % organism susceptible to 100 – Sentinel microbiology laboratories in England, 90 – 80 – 96% 92% Wales and 70 – Northern Ireland. 60 – Adults who had an 96% 92% 50 – LRT specimen taken between 40 – January 2007 and 30 – March 2010. 20 – Antimicrobial susceptibility. 10 – 0 tetracyclines co-amoxiclav

Empirical treatment of influenza-associated pneumonia in primary care: antimicrobial susceptibility of lower respiratory tract bacteria Blackburn Thorax 2011;66:389 % organism susceptible to 100 – Sentinel microbiology laboratories in England, 90 – 80 – 96% 92% Wales and The data support 70 – Northern Ireland. the use of doxycycline 60 – or Adults who had an 96% 92% 50 – co-amoxiclav LRT specimen taken between 40 – January 2007 and empiric as appropriate 30 – Marchtreatment for 2010. 20 – LRT infection Antimicrobial susceptibility. 10 – 0 tetracyclines co-amoxiclav

Empirical treatment of influenza-associated pneumonia in primary care: antimicrobial susceptibility of lower respiratory tract bacteria Blackburn Thorax 2011;66:389 Percentage susceptibility from lower respiratory tract isolates. S.pneumoniae H.influenzae S.aureus

Nebulized Ceftazidime and Amikacin inVentilator-associated Pneumonia Caused by Pseudomonas aeruginosa Lu AJRCCM 2012;184:10640 patients with ventilator-associated pneumonia caused by After 8 days of Pseudomonas. antibiotic administration, aerosol and intravenous groupsNebulized ceftazidime were similar in terms of (15 mg•kg-1•3 h-1) and successful treatment(70 vs. 55%), amikacin* (25 mg•kg-1•d-1). treatment failure (15 vs. 30%),Intravenous ceftazidime and superinfection with other (90 mg•kg-1•d-1 continuous microorganisms (15 vs. 15%). administration) and amikacin (15 mg•kg-1•d-1). * BB-K8 2mL=100-250-500 mg

Macrolide-resistant Mycoplasma pneumoniae in paediatric pneumonia Cardinale ERJ 2011;37:1522  The mechanism of M. Pneumoniae macrolide resistance is related to point mutation in domain V of the 23S rRNA gene of M.Pneumoniae and macrolide resistance is usually detected at disease onset.  Here describe the first case of macrolide-resistant M.Pneumoniae detected during treatment with clarithromycin in an otherwise healthy child with CAP (community acquired pneumonia).

Macrolide-resistant Mycoplasma pneumoniae in paediatric pneumonia Cardinale ERJ 2011;37:1522  Despite the broad-spectrum antibiotic therapy (clarithromicin, meropenem and teicoplanin) the child remained severely ill and, on day 10, nasopharyngeal aspiration was repeated and a bronchoalveolar lavage sample was obtained: real-time PCR revealed M. Pneumoniae DNA in both samples.  A macrolide-resistant M.Pneumoniae infection was hypotesised and clarithromycin was replaced by ciprofloxacin (40mg/kg/die in two doses). The child‘s clinical condition subsequently improved, as did the results of routine and radiological examinations.

Macrolide-resistant Mycoplasma pneumoniae in paediatric pneumonia Cardinale ERJ 2011;37:1522  DNA extracted from the respiratory samples was pretested by means of real-time PCR targeting a conserved inter-repetitive region of the P1 gene of M. pneumoniae.  Mutations of the 23S rRNA gene of M.Pneumoniae at positions were relevant for most cases of macrolide resistance (2.063 and 2.064) were detected.

Treatment failure in pneumonia: impact of antibiotic treatment and cost analysis Hauptmeier, Eur Respir J 2012;39:6111) Community-acquired pneumonia (CAP) is a frequent disease with important implications for healthcare systems worldwide.2) Only ~20% of all CAP patients require in-patient treatment.3) Initial treatment with a fluoroquinolone has shown to be associated with a faster resolution of signs and symptoms of CAP and probably reduces the risk of treatment failure (TF) in comparison with nonstandardised therapies.

Treatment failure in pneumonia: impact of antibiotic treatment and cost analysis Hauptmeier, Eur Respir J 2012;39:611 % patients with treatment failure 1,236 (mean±SD age 69.6) 30 – community-acquired pneumonia (CAP) patients. Moxifloxacin (MFX) or a 20 – nonstandardised antibiotic 20.6% p<0.001 therapy. treatment failure (TF) = any 10 – change in antibiotic therapy 10.9% after ›72h of treatment to a OR = 0.43 broadened antibiotic spectrum. 0 Moxifloxacin Β lactam monotherapy

•POLMONITE necrotizzante

PLEURITE EMPIEMAepidemiologia e diagnosi

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663 Trends in parapneumonic empyema-related hospitalisations in the USA. Hospitalisation data (1996-2008) Incidence rate ratios (IRR)

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663 Trends in parapneumonic empyema-related hospitalisations in the USA. Hospitalisation data Overall, (1996-2008) national parapneumonic empyema-related hospitalisation ratios Incidence rate rates (IRR) increased 2.0-fold

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663 incidence rate ratio fold increase 2 – 1.9 2.0 Hospitalisation data 1.8 (1996-2008) 1.7 Incidence rate ratios 1 – (IRR) 0 children adults adults aged adults aged 18-39 40-64 aged ≥ 65

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663 Trends in parapneumonic empyema-related hospitalisations by different pathogens in the USA, 1996-2008. Overall, pneumococcalempyema rates remained relatively stable in all age groups

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663 Trends in parapneumonic empyema-related hospitalisations by different pathogens in the USA, 1996-2008. whereas streptococcal-(non-pneumococcal)and staphylococcal- related empyema rates increased 1.9-fold and 3.3- fold, respectively, with consistent increases across age groups

Emergence of parapneumonic empyema in the USA Grijalva Thorax 2011;66:663ConclusionsAlthough parapneumonic empyema-related hospitalisationsremained relatively rare, they increased substantially duringthe study period. A number of pathogens, especiallystaphylococcus, contributed to this increase.

Predictive factors, microbiology and outcome of patients with parapneumonic effusion Falguera ERJ 2011;38:1173 4.715 consecutive patients with 20 – community-acquired Of whom 261 met 19% pneumonia. criteria for empyema/complicated Patients classified parapneumonic into 3 groups: effusion. 10 – -no pleural effusion, -uncomplicated 882/4715 parapneumonic effusion and -empyema/complicated 0 parapneumonic Radiological evidence effusion. of pleural fluid.

Predictive factors, microbiology and outcome of patients with parapneumonic effusion Falguera ERJ 2011;38:1173 4.715 consecutive Five independent baseline patients with characteristics could predict community-acquired the development of pneumonia. empyema/complicated parapneumonic effusion: Patients classified into 3 groups: 1. Age<60 yrs (p=0.012), -no pleural effusion, 2. Alcoholism (p=0.002), -uncomplicated 3. Pleuritic pain (p=0.002), parapneumonic 4. Tachycardia >100 effusion and beats/min (p=0.006) -empyema/complicated 5. Leukocytosis >15,000 mm-3 parapneumonic effusion. (p<0.001).

Predictive factors, microbiology and outcome of patients with parapneumonic effusion Falguera ERJ 2011;38:1173 4.715 consecutive Five independent baseline patients with characteristics could predict A higher community-acquired incidence the development of pneumonia. empyema/complicated of anaerobes and parapneumonic effusion: Patients classified into 3 groups: + cocci was Gram 1. Age<60 yrs (p=0.012), -no pleural found , in this effusion 2. Alcoholism (p=0.002), -uncomplicated 3. Pleuritic pain (p=0.002), subgroup of parapneumonic 4. Tachycardia >100 effusion and patients. beats/min (p=0.006) -empyema/complicated 5. Leukocytosis >15,000 mm-3 parapneumonic effusion. (p<0.001).

Predictive factors, microbiology and outcome of patients with parapneumonic effusion Falguera ERJ 2011;38:1173 This Five independent baseline 4.715 consecutive should be condition patients with characteristics could predict suspected in the presence the development of community-acquired pneumonia. of some baseline empyema/complicated characteristics and parapneumonic effusion: Patients classified by using managed into 3 groups: antimicrobials active 1. Age<60 yrs (p=0.012), -no pleural effusion, 2. Alcoholism (p=0.002), against Gram + cocci -uncomplicated 3. Pleuritic pain (p=0.002), (50% of cases S. parapneumonic 4. Tachycardia >100 effusion and pneumoniae) beats/min (p=0.006) and anaerobes. -empyema/complicated 5. Leukocytosis >15,000 mm-3 parapneumonic effusion. (p<0.001).

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 Background Pleural infection is common, and has a >30% major morbidity and mortality-particularly when infection is caused by Gram-negative, Staphylococcus aureus or mixed aerobic pathogens. Standard pleural fluid culture is negative in ~ 40% of cases. Culturing pleural fluid in blood culture bottles may increase microbial yield, and is cheap and easy to perform.Objectives To determine whether inoculating pleural fluid into bloodculture bottles increases the culture positivity of pleural infectionover standard laboratory culture, and to assess the optimum volume ofinoculum to introduce.

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 % increase of patients with identifiable pathogens by the addition of blood culture bottle culture to standard culture 62 patients with 30 – pleural infection. Aerobic and anaerobic blood culture bottles were 20 – inoculated at the bedside 20.8% with 2,5 or 10 ml of pleural fluid. p<0.001 10 – 2 pleural fluid specimens were sent for standard culture. 0

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 % increase of patients with identifiable pathogens by the addition of blood culture bottle culture to standard culture 62 patients with 30 – pleural infection. The culture inoculum Aerobic and anaerobic volume did not blood culture bottles were influence 20 – inoculated at the bedside 20.8% with 2,5 or 10 ml isolation bacterial of pleural frequency fluid. p<0.001 10 – 2 pleural fluid specimens were sent for standard culture. 0

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 % increase of patients with identifiable pathogens by the addition of blood culture Blood culture bottle bottle culture to standard culture 62 patients with of culture 30 – pleural infection. infected pleural fluid increases Aerobic and anaerobic microbial yield blood culture bottles were 20 – inoculatedused in bedside when at the addition 20.8% with to standard culture. 2,5 or 10 ml of pleuraltechnique should This fluid. p<0.001 10 – be part 2 pleural fluid specimens of routine care were sent for standard culture. 0

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 % increase of patients with identifiable pathogens by the second standard culture 62 patients with pleural infection. 10 – Aerobic and anaerobic blood culture bottles were inoculated at the bedside with 2,5 or 10 ml 15 – 6.1% of pleural fluid. p= 0.08 2 pleural fluid specimens were sent for standard culture. 0

Blood culture bottle culture of pleural fluid in pleural infection. Menzies Thorax 2011;66:658 The value of adding different culture methods to standard culture in the additional detection of pathogens.

Computed tomography measurements of parapneumonic effusion indicative of thoracentesis Moffett ERJ 2011;38:1406 Parapneumonic effusions (PPE) result from inflammation of the visceral pleura as a consequence of infection of the lung parenchyma by bacterial or viral pathogens. These effusions occur in up to 45% of patients with community-acquired pneumonia (CAP) and have a 10% chance of progressingto an empyema with associated increased morbidity and mortality. An important step in the management of PPE is to ascertain which effusions require further diagnostic evaluation.Aspiration is recommended in patients with a PPE> 1 cm measured by lateral decubitus radiograph (LDR), or in patients with a PPE> 5 cm measured by lateral erect radiograph (LER).

Computed tomography measurements of parapneumonic effusion indicative of thoracentesis Moffett ERJ 2011;38:1406 Techniques for measuring effusion using: Lateral decubitus Lateral erect Chest computed radiograph. radiograph. tomography.

Computed tomography measurements of parapneumonic effusion indicative of thoracentesis Moffett ERJ 2011;38:1406 Measurements of patients with parapneumonic effusion PPE measurements (PPE) using lateral decubitus of 1cm and 5cm radiograph (LDR), by LDR and LER, lateral erect radiograph (LER) and chest computed respectively, tomography (CCT). correlated with a measurement Correlated by linear regression analysis. of 2.5cm by CCT. PPE was identified in 419 out of 1.460 patients with possible pneumonia.

Computed tomography measurements of parapneumonic effusion indicative of thoracentesis Moffett ERJ 2011;38:1406 Measurements of patients with parapneumonic effusion PPE measurements (PPE) using lateral decubitus of 1cm and 5cm Community-acquired radiograph (LDR), by LDR and LER, pneumonia and a PPE lateral erect radiograph (LER) chest computed and measuring <2.5cm by respectively, tomography (CCT). managed correlated with a CCT can be measurement Correlated bythe need for without linear of 2.5cm by CCT. thoracentesis. regression analysis. PPE was identified in 419 out of 1.460 patients with possible pneumonia.

An Update on the causes, investigation and management of empyema in childhood: Review Walker Arch Dis Child 2011;96:482 The incidence of empyema has been increasing constantly over the last decade. Serotype 1 Streptococcus pneumoniae is the commonest cause of childhood empyema. The possibility of a developing parapneumonic effusion should be considered in all children presenting with pneumonia. Initial investigations should include urine for pneumococcal antigen testing, if available. Chest ultrasound is the central radiological investigation.

An Update on the causes, investigation and management of empyema in childhood: Review Walker Arch Dis Child 2011;96:482 Learning points:  Empiric intravenous antibiotics are the first line of treatment in the absence of respiratory compromise.  Chest drain insertion and intrapleural urokinase installation should be considered if there is an inadequate response to antibiotics.  Video-assisted thoracoscopic surgery procedure should be reserved for failure of medical management.

An Update on the causes, investigation and management of empyema in childhood: Review Walker Arch Dis Child 2011;96:482

An Update on the causes, investigation and management of empyema in childhood: Review Walker Arch Dis Child 2011;96:482 Ultrasound appearances of PPE/empyema Large anechoic effusion Echoic effusion without Complex effusion with with collapsed underlying evidence of septation multiple septations lung

An Update on the causes, investigation and management of empyema in childhood: Review Walker Arch Dis Child 2011;96:482 Proposed algorithm for management of parapneumonic effusion and empyema

An 11-year-old boy with respiratory failure and massive pleural fluid drainage Tse CHEST 2011;140:1659 An 11-year-old boy was admitted to the pediatric ICU for respiratory failure. Nine months prior to presentation, he developed right-sided pneumonia complicated by a 4-cm pleural rind. Because of persistent shortness of breath and a restrictive pattern on pulmonary function tests, he was taken for an elective decortication of the pleural rind. Postoperatively, the chest tubes drained excessive amounts of serosanguinous fluid (25 L/d), and the patient subsequently developed respiratory failure.

An 11-year-old boy with respiratory failure and massive pleural fluid drainage Tse CHEST 2011;140:1659 The patient had a congenital erythematous patch covering his right shoulder and upper chest.

An 11-year-old boy with respiratory failure and massive pleural fluid drainage Tse CHEST 2011;140:1659 Extracorporeal membrane oxygenation was initiated shortly after the patient‘s arrival to the pediatric ICU. Three chest tubes continued to drain up to 20 L of fluid per day over the next several days. Analysis of the pleural fluid showed a predominance of lymphocytes (59%) and the following laboratory values: triglycerides 35 mg/dL, glucose 123 mg/dL, total protein 2.4 g/dL, albumin 2.2 g/dL and lactate dehydrogenase 1.241 U/L. There was no growth of bacteria.

An 11-year-old boy with respiratory failure and massive pleural fluid drainage Tse CHEST 2011;140:1659 What is the diagnosis? Lymphangiomatosis is characterized by the presence of multifocal lymphangiomas that may involve the lungs, bone, liver, spleen and mediastinum. Lymphangiomatosis is a developmental abnormality of the lymphatic system.

An 11-year-old boy with respiratory failure and massive pleural fluid drainage Tse CHEST 2011;140:1659 What is the diagnosis? Thoracic lymphangiomatosis may present with a pulmonary or mediastinal mass, resulting in symptoms of dyspnea, cough, chest pain and wheezing, which may be misdiagnosed as asthma. Chylous pleural effusions are common and may be associated with chylopericardium and chylous ascites.

Linezolid vs Glycopeptide antibiotics for the treatmentof suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia Walkey CHEST 2011;139:1148 Methicillin-resistant Staphilococcus aureus (MRSA) is an important cause of nosocomial pneumonia. Societal guidelines suggest linezoild may be the preferred treatment of MRSA nosocomial pneumonia. We investigated the efficacy of linezolid compared with glycopeptide antibiotics (vancomycin or teicoplanin) for nosocomial pneumonia.

Linezolid vs Glycopeptide antibiotics for the treatmentof suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia Walkey CHEST 2011;139:1148  Linezolid was not superior to glycopeptide antibiotics. 8 trials encompassing  Randomized controlled 1641 subjects trials do not support superiority of linezolid over glycopeptide antibiotics (vancomycin, teicoplanin) for the treatment of nosocomial pneumonia.

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364WHAT‟S KNOWN ON THIS SUBJECT: Chronic wet cough is a common symptom well recognized by pediatricians. Protracted bacterial bronchitis is defined as > 4 weeks of wet cough that responds to antibiotic treatment. Diagnosis of protracted bacterial bronchitis is not readily accepted by pediatricians.WHAT THIS STUDY ADDS: Children with chronic wet cough often have bronchitis, which is evident during bronchoscopy. Purulent bronchial secretions suggest the presence of bacterial infection. Children with chronic wet cough frequently have a bacterial infection of the lower airway.

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364OBJECTIVES: Protracted bacterial bronchitis is defined asthe presence of more than 4 weeks of chronic wet cough that resolves with appropriate antibiotic therapy, in the absence of alternative diagnoses. The diagnosis of protracted bacterial bronchitis is not readily accepted within the pediatric community, however, and data on the incidence of bacterial bronchitis in children are deficient. The objective of this study was to determine the frequency of bacterial bronchitis in children with chronic wet cough and to analyze their bronchoscopic findings.

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364 % children who were 0 to 3 years of age with Retrospective review of 40 – 197 charts of children who presented with chronic wet 30 – cough, unresponsive to therapy, before referral to 20 – 30.3% the pediatric pulmonary clinic. 10 – 0 Laryngomalacia and/or tracheomalacia

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364 % children with 60 - Retrospective review of 197 charts of children who 50 – 56% presented with chronic wet cough, unresponsive to 40 – 44% therapy, before referral to 30 – the pediatric pulmonary 20 – clinic. 10 – 000 YES NO Purulent bronchitis

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364 % children with BAL (+) bacterial cultures Retrospective review of 50 – 197 charts of children who presented with chronic wet cough, unresponsive to 40 – 46% therapy, before referral to 30 – the pediatric pulmonary 20 – clinic. 10 – 000

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364 % children with BAL Bronchoalveolar lavage (+) bacterial cultures bacterial cultures Retrospective review of 50 – 197 charts ofnontypable showed children who Haemophilus influenzae wet presented with chronic (49%),Streptococcus pneumoniae (20%), cough, unresponsive to 40 – 46% Moraxella catarrhalis (17%), therapy, before referral to 30 – Staphylococcus aureus (12%), the pediatric pulmonary 20 – clinic. Klebsiella pneumoniae and in 1 patient. 10 – 000

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364 % children with BAL (+) bacterial cultures Positive bacterial cultures Retrospective review of 50 – occurred more frequently 197 charts of children who in children with purulent presented with chronic wet bronchitis (69.8%) cough, unresponsive to 40 – 46% than in children therapy, before referral to 30 – with non-purulent bronchitis the pediatric pulmonary 20 – clinic. (19.8%) (P‹.001). 10 – 000

Bronchoscopic Findings in Children With Chronic Wet Cough Zgherea, Pediatrics 2012;129;e364CONCLUSIONS: Children who present with chronicwet cough are often found to have evidence ofpurulent bronchitis on bronchoscopy.This finding is often indicative of a bacterial lowerairway infection in these children.

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 70 children (infancy-60months). ≥104 CFU per ml of Streptococcus pneumoniae, With protracted Haemophilus influenza cough, wheeze, or Moraxella catarrhalis, and/or noisy separately or in combination, breathing. were found in BAL. BAL for potential pathogenic bacteria.

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 % BAL with neutrophils 100 – 70 children 90 – (infancy-60months). 87% 80 – 70 – With protracted 60 – cough, wheeze, 50 – and/or noisy 40 – breathing. 30 – BAL for potential 20 – pathogenic bacteria. 10 – 0

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 % of children with tracheomalacia, bronchomalacia or both 100 – 70 children 90 – (infancy-60months). 80 – 74% 70 – With protracted 60 – cough, wheeze, 50 – and/or noisy 40 – breathing. 30 – BAL for potential 20 – pathogenic bacteria. 10 – 0

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 % of children with tracheomalacia, bronchomalacia or both 100 – 70 children 90 – (infancy-60months). The predominance 80 – of airway malacia 74% 70 – With protractedin cough, wheeze, suggests these patients 60 –anand/or noisy etiologic role for those 50 – breathing.anomalies. airway 40 – 30 – BAL for potential 20 – pathogenic bacteria. 10 – 0

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 % of children with tracheomalacia, bronchomalacia or both 100 – 70 children 90 – (infancy-60months). The potential 80 – With protracted damage 74%for chronic airway 70 – from protracted cough, wheeze, 60 – bacterial bronchitis and/or noisy 50 – warrants breathing. 40 – further investigation. 30 – BAL for potential 20 – pathogenic bacteria. 10 – 0

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 Quantification of bacteria cultured from BAL fluid (cfu/ml)

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:88 Quantification of bacteria cultured from BAL fluid (cfu/ml) More than 1 organism was present in many cases.

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:881) On the basis of our observation of airway malacia in 74% of our patients, we hypothesize pthat tracheal malacia, bronchial malacia, or both is a predisposing anomaly for protracted bacterial bronchitis.2) Airway collapse decreases effectiveness of cough and can interfere with normal mucous flow, an important mechanism for clearing bacteria from the airway.3) Airway malacia might result in impairment of normal pulmonary defense.4) Children with airway malacia have increased frequency of respiratory illness, severity of illness, and tendency for delayed recovery.

Protracted Bacterial Bronchitis in Young Children: Association with Airway Malacia Kompare, J Pediatr 2012;160:881) On the basis of our observation of airway malacia in 74% of our patients, we hypothesize pthat tracheal malacia, bronchial malacia, or both Although bacterial infection might in is a predisposing anomaly for protracted bacterial bronchitis. some cases be a primary event that2) Airway collapse decreases effectiveness of damage causes tracheal or bronchial cough and can interfere with normal mucous it is more likely mechanism resulting in malacia, flow, an important for clearing bacteria from the airway. that the malacia is generally the3) Airway malacia might result in impairment of normal primary factor that results in pulmonary defense. protracted bacterial bronchitis.4) Children with airway malacia have increased frequency of respiratory illness, severity of illness, and tendency for delayed recovery.

Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms De Baets F, Eur Respir J 2012;39:392 % subjects with a structural abnormality of the central airways 124 children with 50 – persistent respiratory symptoms despite 40 – 47% regular anti-asthma inhalation treatment. 30 – 24-h oesophageal pH 20 – measurement. 10 – Fibreoptic bronchoscopy with BAL. 0

Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms De Baets F, Eur Respir J 2012;39:392 % subjects with a definite macroscopic mucosal inflammation 124 children with 70 – persistent respiratory 64% 60 – symptoms despite regular anti-asthma 50 – inhalation treatment. 40 – 24-h oesophageal pH 30 – measurement. 20 – 10 – Fibreoptic bronchoscopy with BAL. 0 with a significantly higher percentage of neutrophils in the BALF

Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms De Baets F, Eur Respir J 2012;39:392 % subjects with (+) BALF culture 70 – 124 children with 60 – persistent respiratory 50 – 62% p<0.016 symptoms despite regular anti-asthma 40 – inhalation treatment. 30 – 24-h oesophageal pH measurement. 20 – 25% 10 – Fibreoptic bronchoscopy 0 with BAL. YES NO Mucosal inflammation at bronchoscopy

Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms De Baets F, Eur Respir J 2012;39:392 In children with persistent respiratory symptoms, nearly half have anatomical anomalies of the central airways. In 62% of the children with mucosal inflammation, a positive BAL culture and a significantly higher percentage of BALF neutrophils were detected.

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317BackgroundChronic wet cough strongly suggests endobronchial infection, which,if left untreated, may progress to established bronchiectasis.Our aim was to compare the effectiveness of chesthigh-resolution CT (HRCT) scanning and flexible bronchoscopy(FB) in detecting airway abnormalities in children with chronicwet cough and to explore the association between radiologic andbronchoscopic/BAL findings.

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317 93 children (0.6- 16.4 years) with wet cough for >6 weeks HRTC scans scored with Bhalla method Bronchoscopic findings of bronchitis were grouped into 5 grades severity Bhalla score in the three groups of cough duration

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317 93 children (0.6- A positive 16.4 years) with wet correlation cough for >6 weeks was found HRTC scans scored between with Bhalla method Bhalla score Bronchoscopic and duration findings of of cough bronchitis were grouped into five (P= 0.028) grades severity Bhalla score in the three groups of cough duration

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317 HRTC scanning 93 children (0.6- detected airway wall 16.4 years) with wet cough for >6and thickening weeks brochiectasis, that HRTC scans scoredcorrelated positively with Bhalla method with length of Bronchoscopic symptoms and findings of of intensity neutrofhilic bronchitis were inflammation in grouped into five the airways grades severity Bhalla score in the three groups of cough duration

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317 93 children (0.6- The bronchoscopic findings 16.4 years) with wet were grouped into five types cough for >6 weeks according to the classification proposed by Chang*: HRTC scans scored • type I: mucosal abnormality/ with Bhalla method inflammation only; Bronchoscopic • type II: bronchomalacia; findings of • type III: obliterative-like; bronchitis were • type IV: malacia/obliterative- grouped into 5 like combination; grades severity • type V: no abnormality. *Chang AB et al. Thorax 2002;57( 11 ):935-938

Bronchoscopic and high-resolution CT scan findings in children with chronic wet cough Douros CHEST 2011;140:317 93 children (0.6- 16.4 years) with wet The Bhalla score correlated cough for >6 weeks positively with type III (OR 5.44;P= 0.001) HRTC scans scored and with Bhalla method type IV (OR 8.91; P= 0.001) Bronchoscopic bronchoscopic lesions. findings of bronchitis were It also correlated positively with grouped into 5 the percentage of neutrophils in grades severity the BAL (P= 0.036)

Resolution of bronchomalacia presenting as severe asthma by endoscopic intervention Andregnette Ann Allergy Asthma Immunol 2011;106:443 Bronchoscopy revealed a A 42-year-old female with bronchial collapsibility, FEV1, 50% predicted and with significant loss of persisting dyspnea despite airway caliber in the left optimal treatment. main bronchus, resulting in severe bronchomalacia.

Resolution of bronchomalacia presenting as severe asthma by endoscopic intervention Andregnette Ann Allergy Asthma Immunol 2011;106:443 Days later, the bronchoscopist placed a Dumon prosthesis inthe left main bronchus using anEfer-Dumon rigid bronchoscope. In subsequent monthly visits, thepatient reported good tolerance to the prosthesis and demonstrated clinical improvement. Placement of the prosthesis in the left bronchus

bronchiectasis

What Is in a Name? The Dilemma of “Prebronchiectasis” Rubin B,Chest 2011;140;278-279•Flexible bronchoscopy has safely facilitated spelunkingin an ever-increasing number of airways, and highresolutionCT scanning using low radiation doses and incremental scanninghas increased resolution while decreasing radiation exposure tolevels comparable to a standard chest radiograph, making high-resolution CT scanning almost a routine diagnostic test in somepatients with chronic lung disease.•We are recognizing that more airways than we suspected containbacteria, inflammatory cells, or both and that more patientswith chronic lung problems and relatively normal chestradiographs have high-resolution CT scanning evidence ofbronchiectasis.

What Is in a Name? The Dilemma of “Prebronchiectasis” Rubin B,Chest 2011;140;278-279―Chronic Suppurative Lung Disease‖ (CSLD) is part of a continuumstarting in the young child with protracted bacterial bronchitis,which can become CSLD and finally progress to bronchiectasis.Douros and colleagues (Chest 2011;140:317) speculated that earlytherapy with antibiotics can stop this progression.We now need con trolled prospective studies with sufficiently longobservation periods and unambiguous end points in order to betteridentify which of these children can truly benefi t from earlyintervention.

Bronchoarterial ratio on high-resolution CT Scan of the chest in children without pulmonary pathology Kapur CHEST 2011;139:1445BackgroundThe radiologic definition of airway dilatation and bronchiectasisin children has substantial limitations.Bronchoarterial (BA) ratio is a commonly used criterion to defineairway dilatation despite the lack of normative pediatric data.The objective of our study was to determine the range of normalbronchial to accompanying arterial diameter ratio onhigh-resolution CT scan of the chest in children and compare it withthe available adult.

Bronchoarterial ratio on high-resolution CT Scan of the chest in children without pulmonary pathology Kapur CHEST 2011;139:1445 41 children undergoing CT scan of the chest for nonpulmonary conditions Airway lumen and vassels diameters in the upper and lower lobes of both lungs Mean bronchoarterial (BA) ratio CT image showing electronic caliper marking and measurements of bronchus (E) and adjoining vessel (F). Note vessel G does not have an adjoining airway.

Bronchoarterial ratio on high-resolution CT Scan of the chest in children without pulmonary pathology Kapur CHEST 2011;139:1445 41 children undergoing CT scan of the chest The mean BA ratio was for nonpulmonary 0.626 (SD 0.068). conditions This ratio was lower than Airway lumen and comparable adult data vassels diameters in (mean 0.676; SD 0.12) the upper and lower (P=0.01). lobes of both lungs There was no differences in the ratio based on laterality Mean bronchoarterial or lobe. (BA) ratio

Bronchoarterial ratio on high-resolution CT Scan of the chest in children without pulmonary pathology Kapur CHEST 2011;139:1445 41 children undergoing CT scan of the chest In the pediatric The mean BA ratio was for nonpulmonary age group the 0.626 (SD 0.068). conditions This ratio was lower than airway is Airway lumen and comparable adult data significantly vassels diameters in (mean 0.676; SD 0.12) smaller than the upper and lower (P=0.01). lobes ofadjoining the both lungs There was no differences in vessel. Mean bronchoarterial the ratio based on laterality or lobe. (BA) ratio

Bronchoarterial ratio on high-resolution CT Scan of the chest in children without pulmonary pathology Kapur CHEST 2011;139:1445 Airway lumen and Using the radiologic vassels diameters in criteria of BA The mean BA ratio was the upper anddefine ratio >1 to lower 0.626 (SD 0.068). lobes of both lungs bronchial dilatation This ratio was lower than would understimate Mean bronchoarterial comparable adult data the presence and (BA) ratio (mean 0.676; SD 0.12) extent of (P=0.01). bronchectasis, There was no differences in leading to delayed the ratio based on laterality and missed or lobe. diagnosis

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 the median interquartile range of PC-QOL scores and DASS scores Parents of 69 children 30 – (median age 7 yrs) with non-CF bronchiectasis. p<0.001 2 questionnaires: parent-proxy cough-specific 20 – 22 quality of life (PC-QOL) and the Depression, Anxiety, and Stress Scale (DASS). 10 – At stable and exacerbation states. 0 4.6 PC-QOL scores DASS scores

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 Comparative analysis showing effect of pulmonary exacerbation on PC-QOL total and sub-component scores stable exacerbations

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 Comparative analysis showing effect of pulmonary exacerbation on PulmonaryPC-QOL total and sub-component scores exacerbation significantly worsened the total PC-QOL scores and all three subscales when compared with stable-state scores stable exacerbations

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 Comparative analysis showing effect of pulmonary exacerbation on DASS-21 total and subcomponent scores stable exacerbations

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 Comparative analysis showing effect of pulmonary exacerbation on The DASS-21and subcomponent and DASS-21 total total scores scores the depression, anxiety, and stress subscores were all significantly worse during an stable exacerbation than in the stable state exacerbations

The Burden of Disease in Pediatric Non-Cystic Fibrosis Bronchiectasis Kapur N, Chest 2012;141:1018 Comparative analysis showing effect of pulmonary exacerbation on There is a DASS-21 total and subcomponent scores significant burden of disease, especially during exacerbation, on parents of children with bronchiectasis. Prevention, early detection, and stable appropriate treatment of exacerbations are likely to reduce psychologic morbidity in this group exacerbations

Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis Kapur Pediatr Pulmonol 2012;47:68 Wet cough and cough severity (score ≥2) over 72-hr were 69 children with non-CF the best predictors of an bronchiectasis. exacerbation with area under the curve (AUC) of 0.85 Prospectively followed (95% CI 0.79–0.92) and 0.84 for 900 child-months. (95% CI 0.77–0.91), respectively.

Defining pulmonary exacerbation in children with non-cystic fibrosis bronchiectasis Kapur Pediatr Pulmonol 2012;47:68Chang AB, Newman RG, Carlin JB, Phelan PD, Robertson CF.Subjective scoring of cough in children: parent-completed vschild-completed diary cards vs an objective method.Eur Respir J 1998; 11: 462–466

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis Kapur Pediatr Pulmonol 2012;47:300 % children with positive BAL cultures for respiratory bacterial pathogens 70 – 113 children with non- 68% 60 – cystic fibrosis (CF) 50 – bronchiectasis. 40 – 77/113 Bronchoalveolar lavage 30 – (BAL) within 4 weeks of diagnosis. 20 – 10 – 00

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis Kapur Pediatr Pulmonol 2012;47:300 % children with 50 – 40 – 47% 113 children with non- cystic fibrosis (CF) 30 – bronchiectasis. 20 – Bronchoalveolar lavage (BAL) within 4 weeks of diagnosis. 10 – 12% 00 6% Haemophilus P. aeruginosa Respiratory influenzae viruses

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis Kapur Pediatr Pulmonol 2012;47:300 % children with 50 – 40 – 47% (63%) had more 113 children with non- than one pathogen cystic fibrosis (CF) 30 – present. bronchiectasis. 20 – Bronchoalveolar lavage (BAL) within 4 weeks of diagnosis. 10 – 12% 00 6% Haemophilus P. aeruginosa Respiratory influenzae viruses

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis Kapur Pediatr Pulmonol 2012;47:300 % children with 50 – 5 out of 7 patients with 47% P. aeruginosa isolation40 113 children with non- – (63%) had more had an underlying than one pathogen cystic fibrosis (CF) 30 – present. disorders and isolation bronchiectasis. of P. aeruginosa may 20 – Bronchoalveolarserious suggest a lavage co-morbidity in this 10 (BAL) within 4 weeks group. of diagnosis. – 12% 00 6% Haemophilus P. aeruginosa Respiratory influenzae viruses

Lower airway microbiology and cellularity in children with newly diagnosed non-CF bronchiectasis Kapur Pediatr Pulmonol 2012;47:300Comorbidities in Seven Children With P. aeruginosa and Newly Diagnosed BronchiectasisTCC, total cell count; ANC, absolute neutrophil count; ND, not done.1Co-pathogen = ≥105 colony forming units/ml of H. influenzae.2Co-pathogen = Respiratory syncytial virus.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 We present an unusual type of broncholithiasis complicated with cystic bronchiectasis. Chest CT scans showed cystic bronchiectasis with fluid collection in the right lower lobe and calcification was also detected in the right lower bronchus. Bronchoscopy showed a ‗coral‘ broncholith arising from the right lower bronchus. Broncholithiasis is commonly caused by erosion and extrusion of a calcified adjacent lymph node into the bronchial lumen, a finding usually associated with tuberculosis or histoplasmosis.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 Chest CT.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 Chest CT. Calcified lesion is seen in the lower bronchus. Cystic lesion is evident in the right lower lobe.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 Chest CT. Cystic bronchiectasis are seen in the right lower lobe.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 Bronchoscopy.

Coral broncholith associated with cystic bronchiectasis. Kadowaki Thorax 2011;66:1111 Bronchoscopy. “Coral” broncholith arising from the right lower bronchus.

Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease Maekawa CHEST 2011;140:723Background:Mycobacterium avium-intracellulare complex (MAC) is a ubiquitouspathogen found in soil and water.Environmental exposure is the primary route for MAC infection.However, specific environmental risk factors have beenpoorly determined in immunocompetent patientswith pulmonary MAC disease.

Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease Maekawa CHEST 2011;140:723 OR for high soil exposure 106 patients with (≥2 per week) pulmonary MAC disease. 6 – 53 age-matched control patients 5.9 with bronchiectasis but 5 – p=0.015 not pulmonary MAC infection. 4 – Environment exposures: 1) soil exposure (farming, gardening); 3 – 2) water exposure (bathing, showering, hot tub use, dishwashing, 2 – swimming, drinking water); 3) pet exposure. cases vs controls 1 –

Environmental Risk Factors for Pulmonary Mycobacterium avium-intracellulare Complex Disease Maekawa CHEST 2011;140:723 OR for high soil exposure 106 patients with (≥2 per week) pulmonary MAC disease. 6 – Environmental 53 age-matched control patients soil exposure 5.9 with bronchiectasis but 5 – p=0.015 is a likely risk factor not pulmonary MAC infection. 4 – for the development of Environment exposures: 1) soil pulmonary MAC exposure (farming, gardening); 3 – disease. 2) water exposure (bathing, showering, hot tub use, dishwashing, 2 – swimming, drinking water); 3) pet exposure. cases vs controls 1 –

Clinical Efficacy and Safety of Budesonide-Formoterol in Non-Cystic Fibrosis Bronchiectasis Martínez-García, CHEST 2012;141:461 BDI/TDI dyspnea indexes 12-mo parallel-groups in the studied groups. clinical trial. 40 patients with non-CF bronchiectasis. Formoterol-budesonide combined treatment (18/640 µg) daily or budesonide treatment (1600 µg) daily. BDI=basal dyspnea index; TDI=transition dyspnea index; 640 µg budesonide delivered dose = 800 µg budesonide metered dose.

Clinical Efficacy and Safety of Budesonide-Formoterol in Non-Cystic Fibrosis Bronchiectasis Martínez-García, CHEST 2012;141:461 BDI/TDI dyspnea indexes 12-mo parallel-groups in the studied groups. Inhaled medium-dose clinical trial. formoterol-budesonidecombined treatment in a 40 patients single inhaler is more with non-CF bronchiectasis. effective and safe Formoterol-budesonidecompared with high-dose combined treatment budesonide treatment in (18/640 µg) daily or patients with non-CF budesonide treatment bronchiectasis in reducing (1600 µg) daily. dyspnoea. BDI=basal dyspnea index; TDI=transition dyspnea index; 640 µg budesonide delivered dose = 800 µg budesonide metered dose.

Clinical Efficacy and Safety of Budesonide-Formoterol in Non-Cystic Fibrosis Bronchiectasis Martínez-García, CHEST 2012;141:461 Changes in health-related quality of life 12-mo parallel-groups in the studied groups. clinical trial. 40 patients with non-CF bronchiectasis. Formoterol-budesonide combined treatment (18/640 µg) daily or budesonide treatment (1600 µg) daily. 640 µg budesonide delivered dose = 800 µg budesonide metered dose.

•COPD•generalità

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467 Molecular mechanisms involved in chronic obstructive pulmonary disease (COPD) progression. Three major host alterations characteristic of COPD progression, fibrosis, emphysema and mucus hypersecretion, are shown.

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467A fourth characteristic of COPD progression, lower airway colonisation by opportunisticpathogens, is stated (bottom). Microbial persistency is relevant because it greatlycontributes to deleterious amplification of COPD features. The main host cells involved inCOPD patient airways, epithelial cells, alveolar macrophages (AMs), neutrophils and CD8+lymphocytes, are shown. Cigarette smoke activates epithelial cells to produce inflammatorymediators, activating and/or recruiting AMs and neutrophils. Epithelial cells also secretethe local fibrosis inducer transforming growth factor (TGF)-β. Chemokines produced byepithelial cells and AMs activate CD8+ lymphocytes, which release the emphysemamediators perforin and granzyme. AMs secrete neutrophil chemoattractants and releaseproteases. Matrix metalloproteinase (MMP)-9 activates the fibrosis inducer TGF- β andcauses elastolysis, either directly or by α1-antitrypsin (AT) inactivation. Proteasesproduced by AMs and neutrophils promote emphysema. Together with proteases,neutrophils secrete inflammatory mediators and granule contents. Neutrophilchemoattractants are produced directly by AMs and epithelial cells, and by enzymaticactivity of the AM protease MMP-9. COPD patient airways display oxidative stress.Cigarette smoke itself contains high levels of reactive oxygen species (ROS), and bothAMs and neutrophils increase their respiratory burst in response to cigarette smoke. Highconcentrations of ROS and reactive nitrogen species have multiple consequences: 1)decreased antiprotease defences and proteolysis; 2) activation of nuclear factor (NF)-kBand neutrophil recruitment; 3) steroid resistance; 4) increased isoprostanes production;and 5) mucus hypersecretion. SLPI: secretory leukoprotease inhibitor.

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467 The vicious circle hypothesis of chronic obstructive pulmonary disease (COPD) progression

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467 Cigarette smoke is an external insult that damages respiratory tract immunity, allowing lower respiratory tract colonisation by microorganisms. Such colonisation is a starting point for a cyclic sequence of events that progressively contribute to a high level of chronic inflammation, tissue damage and fibrosis, together with persistent bacterial infection of the lower airways. Together, these processes continuously contribute to the nonreversible progression of the chronic respiratory disease.

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467 Cigarette smoke and host insensitivity to corticoids

Impact of cigarette smoke exposure on host–bacterialpathogen interactions. Garmendia J, Eur Respir J 2012;39:467Histone deacetylase (HDAC) reduction caused by cigarette smoke may accountfor an amplification of the inflammatory response (right) and insensitivity to theanti-inflammatory effect of corticoids (left).Cigarette smoke activates nuclear factor (NF)-kB in alveolar macrophages (right).Gene expression is activated by histone acetyltransferase (HAT)-mediated corehistone acetylation; histone acetylation of inflammatory gene promotersactivated by NF-kB is increased in chronic obstructive pulmonary disease.The increase in acetylation is due to a reduction of HDACs. HDACs reversehistone acetylation and switch off gene transcription. HDACs are inactivated byoxidative and nitrosative stress. Oxidative and nitrosative stress lead to theformation of peroxynitrite, which nitrosylates HDAC, leading to its degradation,resulting in low HDAC levels and, subsequently, in an amplification of theinflammatory response. HDAC reduction by cigarette smoke-induced oxidativestress impairs the response to corticoids. Glucocorticoids (GCs) bind GC receptor(GR) and recruit HDAC to activated inflammatory genes; by reversing theacetylation of those genes, their transcription is switched off and theinflammation is reduced (left). IL: interleukin; TNF: tumour necrosis factor;ROS: reactive oxygen species; NO: nitric oxide.

Defective Phagocytosis in Airways Disease Donnelly L, Chest 2012;141:1055 In patients with COPD, phagocytosis of several bacterial species and removal of apoptotic cells (efferocytosis) by alveolar macrophages are significantly reduced; however, these cells can remove inert beads normally. Attenuated phagocytosis is also apparent in monocyte-derived macrophages from the same patients, suggesting an inherent defect in these cells. Reduced expression of cell surface recognition receptors has been suggested as one mechanism for these observations.

Defective Phagocytosis in Airways Disease Donnelly L, Chest 2012;141:1055 Defective phagocytosis in COPD In COPD, particulate matter appears to be phagocytosed normally; however, removal of bacteria and apoptotic cells is attenuated. This allows bacterial species to propagate and colonize the airways, contributing to exacerbations. Failure to clear apoptotic cells results in increased necrotic material being released into the airway, thus contributing to damage and remodeling

Defective Phagocytosis in Airways Disease Donnelly L, Chest 2012;141:1055Effects of neutrophil elastase (NE) on phagocytosis NE is abundant in the airways of patients with COPD. This enzyme cleaves cell surface complement receptors, thus reducing uptake of opsonized bacteria and also the phosphatidylserine receptor that recognizes apoptotic cells. This results in reduced clearance of bacterial species.

Defective Phagocytosis in Airways Disease Donnelly L, Chest 2012;141:1055 In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. In asthma and other airways diseases, there are also reports of defective phagocytosis of bacterial pathogens, although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies.

Defective Phagocytosis in Airways Disease Donnelly L, Chest 2012;141:1055 In cystic fibrosis, a similar defect is also observed in both airway neutrophils and macrophages, leading to ineffective bacterial uptake and subsequent killing. other mechanisms The identification of this and underlying phagocyte dysfunction may present novel therapeutic opportunities for the In asthma and other airways diseases, there are also reports treatment ofphagocytosis of bacterial pathogens, of defective many of these intractable diseases and improve patient morbidity and mortality although the relevance to disease pathophysiology is not understood. Oxidative stress is emerging as a common mechanism that may be altering both macrophage and neutrophil functions that can be reversed by various antioxidant strategies.

•COPD•epigenetica

Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function Qiu AJRCCM 2012;185:373 1) 349 CpG sites significantly associated with the presence and severity of COPD with the majority of CpG sitesArray-based relatively hypomethylated. methylation 2) Gene analysis on these 349 CpGs screens. (330 genes) suggested the involvement of a number of genes responsible for: • immune and inflammatory system pathways, • responses to stress and external stimuli, • wound healing, • coagulation cascades.

Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function Qiu AJRCCM 2012;185:373 1) 349 CpG sites significantly associated with the presence and severity of COPD with the majority of CpG sites DNAArray-based relatively hypomethylated. methylation methylation 2) Gene analysis on these 349 CpGs screens. may be a (330 genes) suggested the involvement biomarker of of a number of genes responsible for: • immune and inflammatory system COPD. pathways, • responses to stress and external stimuli, • wound healing, • coagulation cascades.

•COPD•Red-ox

Outdoor air pollution and respiratory health in patients with COPD Peacock Thorax 2011;66:591 Objectives Time series studies have shown adverse effects of outdoor air pollution on mortality and hospital admissions in patients with chronic obstructive pulmonary disease (COPD) but panel studies have been inconsistent. This study investigates short-term effects of outdoor nitrogen dioxide, ozone, sulfur dioxide, particulate matter (PM10) and black smoke on exacerbations, respiratory symptoms and lung function in 94 patients with COPD in east London.

Outdoor air pollution and respiratory health in patients with COPD Peacock Thorax 2011;66:591 Daily diary cards; Median follow-up 518 days; 1) Symptoms but not lung function Recording exacerbations, showed symptoms and lung associations with function, and the amount of raised pollution time spent outdoors; levels. Air pollution exposure 2) Dyspnoea was from local background significantly monitoring stations. associated with PM10.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Isoprostanes are formed by to very severe COPD. free-radical-catalyzed lipid 8-Isoprostane levels in peroxidation of arachidonic exhaled breath condensate acid on cell membrane (EBC) measured by phospholipids. enzyme immunoassay. 8-isoprostane may represent COPD severity classified a reliable biomarkers of according to: oxidative stress 1) GOLD (Global Initiative for in patients with COPD. Chronic Obstructive Lung Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Box-and-whisker plots of the EBC concentration to very severe COPD. of 8-isoprostane distribution in patients with COPD according to the GOLD stage. 8-Isoprostane levels in exhaled breath condensate (EBC) measured by enzyme immunoassay. COPD severity classified according to: 1) GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Box-and-whisker plots of the EBC concentration to very severe COPD. of 8-isoprostane distribution in patients with Significant COPD according to the GOLD stage. 8-Isoprostane levels in severity-related exhaled breath condensate differences (EBC) measured by were not enzyme immunoassay. identified COPD severity classified according to according to: GOLD stage 1) GOLD (Global Initiative for (p=0.052), Chronic Obstructive Lung but… Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Box-and-whisker plots of the EBC concentration to very severe COPD. of 8-isoprostane distribution in patients with COPD according to the BODE index. 8-Isoprostane levels in exhaled breath condensate (EBC) measured by enzyme immunoassay. COPD severity classified according to: 1) GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, andAirway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Box-and-whisker plots of the EBC concentration to very severe COPD. of 8-isoprostane distribution in patients with COPD according to the BODE index. 8-Isoprostane levels in …severity-related exhaled breath condensate (EBC) measured by differences enzyme immunoassay. were identified according to COPD severity classified according to: index. the BODE 1) GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Comparison of the EBC 8-isoprostane level to very severe COPD. between patients with COPD with and without dynamic hyperinflation. 8-Isoprostane levels in exhaled breath condensate (EBC) measured by enzyme immunoassay. COPD severity classified according to: 1) GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage; 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Comparison of the EBC 8-isoprostane level Concentration of between patients with COPD with and to very severe COPD. 8-isoprostane without dynamic hyperinflation. 8-Isoprostane levels in in the EBC was exhaled breath condensate quite a bit higher (EBC) measured by in those patients enzyme immunoassay. who developed COPD severity classified dynamic according to: hyperinflation 1) GOLD (Global Initiative for than in those Chronic Obstructive Lung Disease) stage; not who did 2) BODE 0.0003). (p= (BMI, obstruction, dyspnea and exercise) index.

Dynamic Hyperinflation, Arterial Blood Oxygen, and Airway Oxidative Stress in Stable Patients With COPD García-Rio CHEST 2011;140:961 76 men with moderate Comparison of the EBC 8-isoprostane level to very severe COPD. between patients with COPD with and without dynamic hyperinflation. Dynamic 8-Isoprostane levels in hyperinflation and exhaled breath condensate arterial blood oxygen (EBC) measured by are related enzyme immunoassay. to the level of COPD severity classified airway oxidative according to: stress 1) GOLD (Global Initiative for Chronic patients with in Obstructive Lung Disease) stage; COPD. 2) BODE (BMI, obstruction, dyspnea and exercise) index.

Oxidative Stress–induced Antibodies toCarbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease Kirkham AJRCCM 2012;184:796RationaleThere is increasing evidence for the presence of autoantibodiesin chronic obstructive pulmonary disease (COPD).Chronic oxidative stress is an essential component in COPDpathogenesis and can lead to increased levels of highly reactivecarbonyls in the lung, which could result in the formation ofhighly immunogenic carbonyl adducts on ―self‖ proteins.

Oxidative Stress–induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease Kirkham AJRCCM 2012;184:796 Antibody titer againstBlood and peripheral lung carbonyl-modified self-protein from patients with COPD, was significantly increased in age-matched smokers, and patients with Global Initiative nonsmokers with normal for Chronic Obstructive Lung lung function, as well as Disease stage III COPD patients with severe compared with control subjects. persistent asthma. Antibody levels inverselyAntibody titers correlated with disease severity measured by ELISA. and showed a prevalence toward an IgG1 isotype.

Oxidative Stress–induced Antibodies toCarbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease Kirkham AJRCCM 2012;184:796 Antibody titers against human serum albumin (HSA) Unmodified Modified by cigarette Cumulative titers against all the antibody smoke extract different carbonyl- modified HSAs tested

Identification of Novel Diagnostic Biomarkers for Asthma and Chronic Obstructive Pulmonary Disease Verrills AJRCCM 2012;183:1633 Four biomarkers: •a2-macroglobulin,Proteomics of peripheral •haptoglobin, blood proteins. •ceruloplasmin,Subjects with asthma •hemopexin and COPD. was able to discriminate with statistical significanceMass spectrometry between the clinical groups and immunoassay. of patients with asthma, COPD, and control subjects.

Identification of Novel Diagnostic Biomarkers forAsthma and Chronic Obstructive Pulmonary Disease Verrills AJRCCM 2012;183:1633 Prothrombin Ceruloplasmin Haptoglobin Antithrombin III

Identification of Novel Diagnostic Biomarkers forAsthma and Chronic Obstructive Pulmonary Disease Verrills AJRCCM 2012;183:1633 Ceruloplasmin Haptoglobin Hemopexin

Identification of Novel Diagnostic Biomarkers forAsthma and Chronic Obstructive Pulmonary Disease Verrills AJRCCM 2012;183:1633• The biomarker panel comprises three positive acute-phase proteins (a2-macroglobulin, ceruloplasmin, and haptoglobin) and one type II acute-phase protein (hemopexin).• These are predominantly liver-synthesized proteins that can have important antiinflammatory activity through inhibition of oxidative stress, and iron sequestration resulting in antimicrobial activity.• As such, they may function to modulate the systemic inflammatory response to inflammation and be involved in tissue repair through fibrosis and angiogenesis.

Identification of Novel Diagnostic Biomarkers for Asthma and Chronic Obstructive Pulmonary Disease Verrills AJRCCM 2012;183:1633• The acute-phase response is an innate body defense observed during infection, physical trauma, malignancy, and tissue damage that aims to minimize on-going tissue damage by isolating and destroying infective agents while activating repair processes.• It is an antigen-nonspecific, innate response that aims to eliminate microbes and hence prevent infection.• Cytokines travel through the bloodstream and stimulate hepatocytes in the liver to synthesize and secrete acute-phase proteins.

•COPD•terapia

Antibiotic prescribing for discoloured sputum in acute cough/lower respiratory tract infection Butler ERJ 2011;38:119 OR for antibiotic 4 – prescription Whether discoloured sputum and feeling 3.2 3 – unwell were with antibiotic prescription. 2 – 3.402 adults 1 – in 13 countries. 0 Patients producing discoloured sputum

Antibiotic prescribing for discoloured sputum in acute cough/lower respiratory tract infection Butler ERJ 2011;38:119 OR for antibiotic Antibiotic prescription 4 – prescription Whether discoloured with was not associated sputum and feeling a greater rate 3.2 3 – unwell were with symptom or magnitude of antibiotic resolution score prescription. (as measured by 2 – a 13-item questionnaire 3.402 adults by patients completed 1 – ineach day) among those 13 countries. who produced yellow or green sputum. 0 Patients producing discoloured sputum

The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-Agonist Therapy in COPD Short, CHEST 2012;141:81 Retrospective cohort study. Patients with COPD 996 patients between 2001 and 2010. ICS + LABA Impact of the addition of tiotropium (Tio) to inhaled corticosteroids (ICS) + long-acting β-agonists (LABA) on: 1) mortality; 2) hospital admissions for respiratory disease; 3) emergency oral corticosteroid 1857 patients bursts. ICS + LABA + Tio Mean follow-up was 4.65 yrs.

The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-Agonist Therapy in COPD Short, CHEST 2012;141:81 Retrospective cohort study. Patients with COPD HR in ICS+LABA+Tio vs between 2001 and 2010. ICS+LABA for Impact of the addition of 1.0 – tiotropium (Tio) to inhaled corticosteroids (ICS) + 0.85 long-acting β-agonists (LABA) on: p=0.04 0.71 1) mortality; 0.65 p<0.001 2) hospital admissions for p<0.001 respiratory disease; 0.5 – 3) emergency oral corticosteroid p=0. bursts. mortality hospital oral Mean follow-up was 4.65 yrs. admissions corticosteroid bursts

The Impact of Tiotropium on Mortality and Exacerbations When Added to Inhaled Corticosteroids and Long-Acting β-Agonist Therapy in COPD Short, CHEST 2012;141:81 Retrospective cohort study. Patients with COPD HR in ICS+LABA+Tio vs between 2001 of tiotropium Addition and 2010. ICS+LABA for to ICSs and LABA Impact of the addition of 1.0 – may confer benefits tiotropium (Tio) to inhaledin reducing: corticosteroids (ICS) + 0.85 1) mortality, long-acting β-agonists (LABA) on: p=0.04 0.71 2) hospital admissions, 1) mortality; 0.65 p<0.001 3) oral corticosteroid 2) hospital admissions for p<0.001 bursts. respiratory disease; 0.5 – 3) emergency oral corticosteroid p=0. bursts. mortality hospital oral Mean follow-up was 4.65 yrs. admissions corticosteroid bursts

•fibrosi cistica

Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening Rock Pediatr Pulmonol 2011;46:1166 Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF. 14 factors can account for a missed diagnosis of CF. Care providers should maintain a high suspicion for CF if there are compatible symptoms, regardless of the results of the newborn screening test. These factors in newborn screening programs leading to a missed diagnosis of CF present opportunities for quality improvement in specimen collection, laboratory analysis of immunoreactive tryspinogen (IRT) and CF mutation testing, communication, and sweat testing.

Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening Rock Pediatr Pulmonol 2011;46:1166Factors Accounting for a Missed/Delayed Diagnosis of Cystic Fibrosis After Newborn Screening

Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study. Langen, Thorax 2012;67:289Context:Newborn screening for cystic fibrosis (CF)is included in many routine programmes but current strategieshave considerable drawbacks, such as false-positive tests,equivocal diagnosis and detection of carriers.Objective:To assess the test performance of 2 CF newborn screening strategies.Design, setting and participants:In 2008 and 2009, CF screening was added to the routine screeningprogramme as a prospective study in part of the Netherlands.

Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study. Langen, Thorax 2012;67:289 Concentrations of: - immunoreactive trypsinogen ll(IRT) - pancreatitis associated protein The IRT/PAP approach ii(PAP) showed: Samples with IRT ≥ 60 µg/litre : 1) Sensitivity=95.0% - analysed for 36 CFTR mutations 2) Specificity=99.89% - sequencing when a single mutation was detected. 3) Positive predictive value (PPV)=12.3%. Tests were positive only with 2 identified CFTR mutations. • Sensitivity = the percentage of sick people who are correctly identified as having the condition; 145499 infants • Specificity = the percentage of healthy people who were screened. are correctly identified as not having the condition • PPV = proportion of subjects with positive test results who are correctly diagnosed.

Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study. Langen, Thorax 2012;67:289 Concentrations of: - immunoreactive trypsinogen ll(IRT) - pancreatitis associated protein Test properties for the ii(PAP) IRT/ DNA/sequencing strategy: Samples with IRT ≥ 60 µg/litre : - analysed for 36 CFTR mutations 1) Sensitivity=100% - sequencing when a single mutation 2) Specificity=100% was detected. 3) PPV=64.9%. Tests were positive only with 2 identified CFTR mutations. • Sensitivity = the percentage of sick people who are correctly identified as having the condition; 145499 infants • Specificity = the percentage of healthy people who were screened. are correctly identified as not having the condition • PPV = proportion of subjects with positive test results who are correctly diagnosed.

Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study. Langen, Thorax 2012;67:289 Concentrations of: - immunoreactive trypsinogen ll(IRT) Combining - pancreatitis associated protein Test properties for the ii(PAP) both strategies IRT/ DNA/sequencing (IRT/PAP/DNA/sequencing) strategy: Samples with IRT ≥ 60 µg/litre : led to: - analysed for 36 CFTR mutations 1) Sensitivity=100% 1) Sensitivity=95.0% - sequencing when a single mutation 2) Specificity=100% 2) Specificity=100% was detected. 3) PPV=64.9%. Tests were PPV=87.5%. 3) positive only with 2 identified CFTR mutations. • Sensitivity = the percentage of sick people who are correctly identified as having the condition; 145499 infants • Specificity = the percentage of healthy people who were screened. are correctly identified as not having the condition • PPV = proportion of subjects with positive test results who are correctly diagnosed.

Age of Pseudomonas aeruginosa acquisition andsubsequent severity of cystic fibrosis lung disease Pittman Pediatr Pulmonol 2011;46:497RationalePseudomonas aeruginosa (Pa) is associated with poor pulmonaryoutcomes in cystic fibrosis (CF), but the association betweenage of Pa infection and severity of subsequent lung diseasehas not been thoroughly investigated.ObjectiveOur goal was to determine the association between age ofPa acquisition and subsequent severity of CF lung disease.

Age of Pseudomonas aeruginosa acquisition and subsequent severity of cystic fibrosis lung disease Pittman Pediatr Pulmonol 2011;46:497 Cumulative percentage of subjects ever reported positive for Pseudomonas aeruginosa (Pa) by age and lung disease severity. 629 ΔF508 homozygotes. Association between age of Pa acquisition and lung disease severity.

Age of Pseudomonas aeruginosa acquisition and subsequent severity of cystic fibrosis lung disease Pittman Pediatr Pulmonol 2011;46:497 Cumulative percentage of subjects ever reported positive for Pseudomonas aeruginosa (Pa) by age and lung disease severity. Subjects were considered Pa 629 ΔF508 homozygotes. positive at a given age if they had a Association between age history of at least of Pa acquisition and lung one culture positive disease severity. for Pa by that age.

Age of Pseudomonas aeruginosa acquisition andsubsequent severity of cystic fibrosis lung disease Pittman Pediatr Pulmonol 2011;46:497 Association Between Age of Pseudomonas aeruginosa Infection and Severity of Lung Disease

Age of Pseudomonas aeruginosa acquisition andsubsequent severity of cystic fibrosis lung disease Pittman Pediatr Pulmonol 2011;46:497 Association Between Age of Pseudomonas aeruginosa Infection and Severity of Lung Disease by Gender

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469BackgroundThe Vitamin D deficiency is common in patients with cystic fibrosis(CF), and guidelines recommend 25-hydroxyvitamin D (25OHD)levels ≥30 ng/mL.This threshold was selected because serum parathyroid hormone(PTH) rises in healthy individuals when the 25OHD level falls below30 ng/mL.PTH levels >50 pg/mL are associated with an increased risk of boneloss. However, the relationship between 25OHD and PTH has notbeen studied in CF.We sought to determine the appropriate goal 25OHD level inpatients with CF by identifying the level below which the risk ofPTH >50 pg/mL begins to increase.

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469 Mean vit D level (ng/mL) 30 –  25OHD and PTH in 216 individuals with CF 25.7 20 –  Individuals with ng/mL 25OHD <30 ng/mL were treated with 10 – vitamin D2 and levels were reevaluated 0

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469 % of patients with 70 –  25OHD and PTH in 60 – 216 individuals with 63% CF 50 –  Individuals with 40 – 25OHD <30 ng/mL 30 – 38% were treated with vitamin D2 and levels 20 – were reevaluated 10 – 0 25OHD level 25OHD level <30 ng/mL <20 ng/mL

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469 r=-0.25, p=0.0003 Relationship between 25OHD Quartiles of 25OHD levels and and PTH levels correlating PTH levels

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469 Low 25OHD levels were significanly associated with elevated PTH levels r=-0.25, p=0.0003 Relationship between 25OHD Quartiles of 25OHD levels and and PTH levels correlating PTH levels

Appropriate goal level for 25-hydroxyvitamin D in cystic fibrosis West CHEST 2011;140:469ConclusionsInadequate serum 25OHD levels are common in adults with CF andare associated with elevated PTH levels.Aiming to maintain 25-OHD levels ≥35 ng/mLin individuals with CF decreases the riskof having a PTH level associatedwith secondary hyperparathyroidismand bone loss.

Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term tolerability, adherence, and safety. Rosenfeld Pediatr Pulmonol 2011;46:666  At the enrollment visit, one participant was withdrawn after <1 min of the test dose due to maternal concern regarding fussiness with facemask placement.  Of the remaining 19 participants. 7% HS administered - only 1 was intolerant of the test dose twice daily for 14 days based on a drop in oxygen saturation of in 20 children with CF >5% from baseline for more than 2 min 12–30 months of age. (from 97% to 89%), and an increase of ≥10 breaths per minute in the respiratory rate compared to baseline for more than 2 min (from 29 to 41 breaths per minute). This patient also underwent infant lung function testing and had a 29% decline in FEV0.5.

Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term tolerability, adherence, and safety. Rosenfeld Pediatr Pulmonol 2011;46:666 1) Home symptom diaries demonstrated cough as the main symptom in the hour following 7% HS administered twice daily for 14 days inhalation, which decreased in in 20 children with CF frequency over the study period. 12–30 months of age. 2) 7% HS appears well tolerated for up to 14 days in infants and toddlers with CF, with high adherence.

Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term tolerability, adherence, and safety. Rosenfeld Pediatr Pulmonol 2011;46:666 Respiratory rate and oxygen saturationFor time, B refers to versus time in study participantsbaseline. Subsequent tickmarks are at 10 min afterbaseline (oxygen saturationsonly), completion of the HStest dose (C), 20 and 30 minlater, and the final studyvisit (day 14).Gray indicates subjects whowere tolerant to the testdose. Black indicatessubjects who were intolerantto test dose. X indicatessubject who withdrew after<1 min of test dose exposure.

Physician Practices for Communicating With Patients With Cystic Fibrosis About the Use of Noninvasive and Invasive Mechanical Ventilation Dellon E, Chest 2012;141:1010Background: Many patients with advanced cystic fibrosis (CF)lung disease receive intensive treatments such as noninvasiveand invasive mechanical ventilation for respiratory failure afterlittle or no communication with physicians.

Physician Practices for Communicating With Patients With Cystic Fibrosis About the Use of Noninvasive and Invasive Mechanical Ventilation Dellon E, Chest 2012;141:1010 Physicians at two major % of physician report of CF care centers. optimal timing for first discussion about intensive treatment Surveys and follow-up 60 – interviews. 40 – 55% Practices for discussing intensive treatment 45% 20 – preferences with patients with CF. 0 medical stability During acute illness or a Barriers and facilitators to major decline in health communication.

Physician Practices for Communicating With Patients With Cystic Fibrosis About the Use of Noninvasive and Invasive Mechanical Ventilation Dellon E, Chest 2012;141:1010Content of discussions about preferences for the use of intensive treatments

Physician Practices for Communicating With Patients With Cystic Fibrosis About the Use of Noninvasive and Invasive Mechanical Ventilation Dellon E, Chest 2012;141:1010 Barriers to discussions about intensive treatment preferences

Physician Practices for Communicating With Patients With Cystic Fibrosis About the Use of Noninvasive and Invasive Mechanical Ventilation Dellon E, Chest 2012;141:1010 Facilitators to discussions about intensive treatment preferences

Complementary and Alternative Therapies: Use in Pediatric Pulmonary Medicine Chung Pediatr Pulmonol 2011;46:530 Several individual herbs with relevance to pulmonary disease are of particular interest.1. Boswellia serrata have been shown to inhibit pro-inflammatory processes by their effects on 5-lipoxygenase and cyclo-oxygenase and on the complement system.2. Tylophora indica is thought to have antiinflammatory activity.3. Curcumin is probably the most recognized of herbs with potential use in Cystic Fibrosis, largely due to studies showing that it can open cystic fibrosis transmembrane conductance regulator chloride channels. Immunomodulatory effects include down regulation of various proinflammatory cytokines.

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 Height standard deviation score (SDS) by visit (as randomized subjects) 68 prepubertal children <14 years with CF. Daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18).

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 Height standard deviation score (SDS) by visit (as randomized subjects) Mean height standard 68deviation score (SDS) in prepubertal children <14 years with CF. increased the rhGH group Daily0.5 ± 0.4 at 12 months by rhGH (Nutropin (mean ± SD, P < 0.001); the AQ) or no treatment control group height SDS (control) for 12 months, remained unchanged. followed by a 6-month observation (month 18).

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 Weight and lean body mass (LBM) change from baseline to Month 12 (as randomized subjects) 68 prepubertal children <14 years with CF. Daily rhGH (Nutropin AQ) or no treatment (control) for 12 months, followed by a 6-month observation (month 18).

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 Weight and lean body mass (LBM) change from baseline to Month 12 (as randomized subjects) Weight increased by 3.8 ± 1.8 versus 68 prepubertal children 2.8 ± 1.5 kg, <14 years with CF. (mean ± SD, P = 0.0356) Daily rhGH (Nutropin by and LBM increased 3.8 ± 1.8 vs 2.1 ± 1.4 kg AQ) or no treatment (P = 0.0002) in the rhGH (control) for 12 months, group vs controls. followed by a 6-month observation (month 18).

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 350 – Increase in FVC (ml) 68 prepubertal children 300 – 325 p=0.032 <14 years with CF. ml 250 – Daily rhGH 200 – (Nutropin AQ) or no treatment (control) for 150 – 178 12 months, followed by 100 – ml a 6-month observation 150 – (month 18). 150 Rh GH Controls

A multi-center controlled trial of growth hormone treatment in children with cystic fibrosis Stalvey Pediatr Pulmonol 2012;47:252 Mean increase in FEV1 (ml) 300 – 68 prepubertal children 250 – <14 years with CF. p=0.004 Daily rhGH (Nutropin 200 – 224 AQ) or no treatment 150 – ml (control) for 12 months, 100 – followed by a 6-month 108 observation (month 18). 150 – ml 150 Rh GH Controls

Ciliopathies: The Central Role of Cilia in a Spectrum of Pediatric Disorders. Ferkol, J Pediatr 2012;160:366 Cilia are found on the surface of most cells. These hair-like appendages, anchored by a basal body to the apical cytoplasm and extending from the cell surface into the extracellular space, consist of hundreds of proteins organized around a microtubular scaffold, which makes up the basic axonemal structure. On the basis of the arrangement of these longitudinal microtubules, cilia have historically been segregated in motile or primary (or sensory) cilia. The terminology can be confusing, but currently there are 3 broad classes of cilia: motile „„9 + 2‟‟, motile „„9 + 0‟‟, and non-motile „„9 + 0‟‟.

Ciliopathies: The Central Role of Cilia in a Spectrum of Pediatric Disorders. Ferkol, J Pediatr 2012;160:366 Schematic diagram showing the structural elements ofnon-motile „„9 + 0‟‟, motile „„9 + 0‟‟, and motile „„9 + 2‟‟ ciliary axonemes.

Ciliopathies: The Central Role of Cilia in a Spectrum of Pediatric Disorders. Ferkol, J Pediatr 2012;160:366 Classification and sites of different cilia, showing the coordinated synchronousmotion of motile ‗‗9 + 2‘‘ cilia, the rotary motion of motile ‗‗9 + 0‘‘ nodal monocilium, and non-motile ‗‗9 + 0‘‘ primary monocilium.

Ciliopathies: The Central Role of Cilia in a Spectrum of Pediatric Disorders. Ferkol, J Pediatr 2012;160:366

Diagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children withPrimary Ciliary Dyskinesia Mateos-Corral, J Ped 2011;159:420 Objectives: Nasal nitric oxide (nNO) is a reliable non-invasive screening test for primary ciliary dyskinesia (PCD), but the recommended technique, exhalation against resistance (ER), requires cooperation limiting its use in young children. Our objectives were to determine whether easier non-velum closure techniques have the ability to discriminate PCD and longitudinal reproducibility.

Diagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children withPrimary Ciliary Dyskinesia Mateos-Corral, J Ped 2011;159:420 5 breathing techniques: 1) 4) 1) exhalation against resistance, 2) breath hold, 3) tidal breathing mouth open, 2) 5) 4) tidal breathing mouth closed, 5) humming PCD compared with 3) control subjects (cystic fibrosis [CF], non-PCD non-CF bronchiectasis, and healthy.

Diagnostic Value of Nasal Nitric Oxide Measured with Non-Velum Closure Techniques for Children withPrimary Ciliary Dyskinesia Mateos-Corral, J Ped 2011;159:420 5 breathing techniques: 1) 4) 1) Non-velum closure exhalation against resistance, techniques 2) breath hold, (2,3,4,5) are 3) tidal breathing mouth reproducible and open, 2) 5) valid to 4) tidal breathing mouth discriminate PCD; closed, 5) humming however, they generally yield PCD compared with lower values than 3) control subjects (cystic exhalation against fibrosis [CF], non-PCD non-CFresistance bronchiectasis, and healthy. (1)

Cooling of Cilia Allows Functional Analysis of the Beat Pattern for Diagnostic Testing. Smith CHEST 2011;140:186Background:Reports of the effect of low temperatureson ciliary beat frequency (CBF) are conflicting, and the effecton ciliary beat pattern has not been reported.We aimed to clarify this association and determine whethercooling of cilia may allow ciliary function to be assessedwithout the need of expensive high-speed video microscopy.

Cooling of Cilia Allows Functional Analysis of the Beat Pattern for Diagnostic Testing. Smith CHEST 2011;140:186 CBF decreased with cooling 14 nasal brush biopsy samples and were collected, and increased with warming. the CBF and beat pattern Ciliary function of undisrupted ciliated edges was unaffected were evaluated. by the direction of temperature change Rapid transitory measurements and was maintained during cooling and warming down to 2°C. or maintaining accurate low The percentage of dyskinetic cilia temperatures over longer observed at 2°C or 4°C periods of time. was unchanged from that at 37°C.

Cooling of Cilia Allows Functional Analysis of the Beat Pattern for Diagnostic Testing. Smith CHEST 2011;140:186 The association between 14 nasal brush biopsy samples exposure temperature and CBF. were collected, and the CBF and beat pattern of undisrupted ciliated edges were evaluated. Rapid transitory measurements during cooling and warming or maintaining accurate low temperatures over longer periods of time. ○ (and dashed lines)= measurements taken during decreasing temperature; ●(and solid line)= measurements during increasing temperature.

Cooling of Cilia Allows Functional Analysis of the Beat Pattern for Diagnostic Testing. Smith CHEST 2011;140:186 The association between 14 nasal brush biopsy samples exposure temperature and CBF. were collected,previous research, Contrary to and our data show that the CBF and beatto beat with a cilia continue pattern of undisrupted ciliated at normal pattern edges were temperatures as low as 2°C. evaluated. Rapid transitorycilia by cooling Slowing of measurements may allow detailed analysis during cooling and warming of ciliary beat pattern or maintaining accurate low without the need of expensive temperatures over longer high-speed video microscopy. periods of time. ○ (and dashed lines)= measurements taken during decreasing temperature; ●(and solid line)= measurements during increasing temperature.

Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required O‘Callaghan ERJ 2011;38:603Primary ciliary dyskinesia (PCD) results in chronic nasal symptoms and chest disease leading to bronchiectasis. We noted a number of patients referred for diagnostic testing whose initial results suggested PCD due to an inner dynein arm or radial spoke defect but in whom no abnormality was found on retesting.

Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required O‘Callaghan ERJ 2011;38:603 On repeat testing, 5 patients initially suspected of an inner dynein arm 21 patients referred for diagnostic testing for PCD defect and 1 with a suspected of an inner dynein radial spoke defect arm defect and 6 suspected had normal EM and of a radial spoke defect on initial EM and beat pattern beat pattern. analysis. Repeat testing.

Inner dynein arm defects causing primary ciliary dyskinesia: repeat testing required O‘Callaghan ERJ 2011;38:603 Patients suspected of PCD due to an inner On repeat testing, dynein arm defect or radial spoke defect 5 patients initially should have the suspected of an diagnosis reassessed inner dynein arm 21 patients referred for if it has testing based on diagnostic been for PCD defect and 1 with a only one diagnostic suspected of an inner dynein radial spoke defect sample. arm defect and 6 suspected had normal EM and of a radial spoke defect on initial EM and beat pattern beat pattern. analysis. Repeat testing.

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483•Examination of ciliary ultrastructure remains the cornerstonediagnostic test for primary ciliary dyskinesia (PCD), a diseaseof abnormal ciliary structure and/or function.•Obtaining a biopsy with sufficient interpretable cilia andproducing quality transmission electron micrographs (TEM) ischallenging.•Methods for processing tissues for optimal preservation ofaxonemal structures are not standardized.•This study describes our experience using a standard operatingprocedure (SOP) for collecting nasal scrape biopsies andprocessing TEMs in a centralized laboratory.

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483•Nasal scrape biopsies were performed using a curettage techniquewhereby ciliated epithelial cells were obtained from the inferiorsurface of the inferior nasal turbinate.•The curettes (Rhino-Pro®; Arlington Scientific, Inc., Springville,UT) were immediately immersed in a cold fixative consisting of2% glutaraldehyde, 2% paraformaldehyde, and 0.5% tannic acid.This fixative was prepared by thawing and mixing a vial of frozenglutaraldehyde and paraformaldehyde with a vial of frozen tannicacid just prior to the specimen collection.•Tissue specimens were stored refrigerated and shipped to acentralized laboratory at the University of North Carolina ChapelHill.

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483 Distribution of ciliary biopsy results from all sites 448 specimens were obtained

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483 Distribution of ciliary biopsy results from all sites 88% of all biopsies 448 specimens were adequate for were obtained formal interpretation.

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483 Percentage of nasal scrape biopsies by age that was adequate for formal interpretation 448 specimens were obtained

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483Distribution of TEM diagnoses among interpretable nasal scrape biopsies

Diagnostic yield of nasal scrape biopsies in primary ciliary dyskinesia: A multicenter experience Olin Pediatr Pulmonol 2011;46:483Distribution of TEM diagnoses among interpretable nasal scrape biopsies ODA defects were the most common abnormality. Note the low frequency of central apparatus defects.

Ventilation Inhomogeneity in Children with Primary Ciliary Dyskinesia. Green, Thorax 2012;67:49Background:• The lung clearance index (LCI) derived from the multiple breath inert gas washout (MBW) test reflects global ventilation distribution inhomogeneity.• It is more sensitive than FEV1 for detecting abnormal airway function and correlates closely with structural lung damage in children with cystic fibrosis, which shares features with primary ciliary dyskinesia (PCD).• Normalised phase III slope indices Scond and Sacin reflect function of the small conducting and acinar airways, respectively.

Ventilation Inhomogeneity in Children with Primary Ciliary Dyskinesia. Green, Thorax 2012;67:49 % children with ABNORMAL 100 – 90 – 96% 27 children and adolescents 80 – 85% with PCD. 70 – 78% 60 – lung clearance index LCI, 50 – Scond (n=23), Sacin (n=23) 40 – derived from MBW 30 – using a mass spectrometer 20 – and sulfur hexafluoride 10 – as inert marker gas. 0 lung Scond Sacin clearance index Normalised phase III slope indices

Ventilation Inhomogeneity in Children with Primary Ciliary Dyskinesia. Green, Thorax 2012;67:49 % children with NORMAL FEV1 but with ABNORMAL 100 – 90 – 27 children and adolescents 80 – 93% with PCD. 70 – 81% 79% 60 – lung clearance index LCI, 50 – Scond (n=23), Sacin (n=23) 40 – derived from MBW 30 – using a mass spectrometer 20 – and sulfur hexafluoride 10 – as inert marker gas. 0 lung Scond Sacin clearance index Normalised phase III slope indices

Ventilation Inhomogeneity in Children with Primary Ciliary Dyskinesia. Green, Thorax 2012;67:49 % children with NORMAL FEV1 but with ABNORMAL 100 – PCD is characterised 90 – 93% by marked 27 children and adolescents 80 – with PCD. 81% 79% peripheral airway 70 – 60 – dysfunction. lung clearance index LCI, 50 – Scond (n=23), Sacin (n=23) MBW seems promising derived from MBW 40 – using the early detection in a mass spectrometer 30 – of lung damage, and sulfur hexafluoride 20 – as even in younggas. inert marker patients 10 – with PCD. 0 lung Scond Sacin clearance index Normalised phase III slope indices

•TBC•Epidemiology•Clinical X-ray of a patient with tuberculosis. A cavity-like aspects lesion is visible on the upper- right lobe of the lung.

Spontaneous pneumothorax and tuberculosis: long-term follow-up Freixinet ERJ 2011;38:126 % of patients with TB 46 cases Spontaneous 6 – antecedents pneumothorax (SP) were treated with pleural is a well-known complication 5 – 4 – 5.4% drainage. of pulmonary 47/872 3 – tuberculosis (TB). 2 – 872 patients treated for SP 1 – between 1989 and 0 2010. had SP

Spontaneous pneumothorax and tuberculosis: long-term follow-up Freixinet ERJ 2011;38:126 % of patients with TB The mean SD 46 cases Spontaneous 6 – antecedents lenght of PD pneumothorax (SP) were treated treatment was with pleural is a well-known complication 5 – 4 – 5.4% 12.9 11.3 drainage. of pulmonary 47/872 days. 3 – tuberculosis (TB). 2 – 872 patients treated for SP 1 – between 1989 and 0 2010. had SP

Spontaneous pneumothorax and tuberculosis: long-term follow-up Freixinet ERJ 2011;38:126 % cases in whom it was necessary to carry out a resection (atypical segmentectomy) Spontaneous 30 – pneumothorax (SP) 28% is a well-known complication of pulmonary 20 – tuberculosis (TB). 13/47 872 patients 10 – treated for SP between 1989 and 2010. 0

Spontaneous pneumothorax and tuberculosis: long-term follow-up Freixinet ERJ 2011;38:126 % cases in whom it was necessary to carry out a resection (atypical segmentectomy) Treatment of SP Spontaneous 30 – pneumothorax (SP) with secondary to TB 28% is a well-known a sound PD is usually complication response, with a good 20 – of pulmonary general prognosis and tuberculosis (TB). a low percentage of 13/47 872 patients cases (28%) that 10 – treated for SP between 1989surgical require and 2010. treatment. 0

•TBC•diagnosis

Tuberculosis screening of migrants to low-burden nations: insights from evaluations of UK practice Pareek ERJ 2011;37:1175 Flow chart of pathway for tubercolosis (TB) screening of new entrants to the UK. CRX:chest radography, PCO:primary care organisation.

Tuberculosis screening of migrants to low-burden nations: insights from evaluations of UK practice Pareek ERJ 2011;37:1175 Flow chart of pathway for tubercolosis (TB) screening of new entrants to the UK. CRX:chest radography, PCO:primary care organisation. UK policy advocates identification, chest radiography (CXR) and medical examination by port-of-entry Health Control Units for all new arrivals intending to stay for >6 months from countries with a TB incidence >40 cases per 100,000 p.a.

Tuberculosis screening of migrants to low-burden nations: insights from evaluations of UK practice Pareek ERJ 2011;37:1175 Flow chart of pathway for tubercolosis (TB) screening of new entrants to the UK. CRX:chest radography, PCO:primary care organisation. NICE recommends step-wise diagnosis of LTBI beginning with a CXR that, if normal, is followed by a tuberculin skin test (TST) that, if positive, requires a confirmatory test with interferon-γ release assays (IGRAs) prior to chemoprophylaxis.

Tuberculosis screening of migrants to low-burden nations: insights from evaluations of UK practice Pareek ERJ 2011;37:1175 % PCOs screened new entrants for LTBI. 60 - How UK primary care organisations (PCOs) screen new entrants 50 – 60.4% and wheter this differs 40 – according to TB burden in the PCOs 30 – (incidence <20 or ≥20 cases 20 – per 100.000 per annum). Questionnaire was sent to 10 – all 192 UK PCOs. 0

Tuberculosis screening of migrants to low-burden nations: insights from evaluations of UK practice Pareek ERJ 2011;37:1175 % PCOs screened new entrants for LTBI. How UKConsiderable primary care 60 - heterogeneity and organisations (PCOs) deviation from national screen new entrants 50 – 60.4% and wheter this exist guidance differs 40 – throughout according to TB burden in thethe UK new entrant PCOs 30 – (incidence <20 process, screening or ≥20 cases with high-burden regions per 100.000 per annum). 20 – undertaking the least Questionnaire was sent to 10 – screening. all 192 UK PCOs. 0

Who misses the second step of evaluation in tuberculosis contact screening? Soares ERJ 2011;38:474  Assessment of people likely to have been recently infected with Mycobacterium tuberculosis is important because of the risk to these people of progressing to active tuberculosis (TB) within 1-2 yrs.  Contact investigation is an integral part of the TB control programme, enabling the identification and treatment of individuals with latent TB infection (LTBI), thus preventing active TB.  Guidelines require a two-step evaluation of pulmonary TB contacts, with the first step being performed at the moment the index case is diagnosed and the second performed 10-12 weeks later if the first evaluation was negative.

Who misses the second step of evaluation in tuberculosis contact screening? Soares ERJ 2011;38:474 Retrospective cohort study % subjects diagnosed with of 226 pulmonary TB contacts. 20 – Individuals testing negative 17.7% being offered a second TST 12 weeks later. 10 – Individuals testing positive were offered an IGRA test. Individual positive on both 0.9% TST and IGRA were offered preventive treatment, after 0 exclusion of risk factors for Active TB LTBI hepatotoxicity.

Who misses the second step of evaluation in tuberculosis contact screening? Soares ERJ 2011;38:474 % subjects with Retrospective cohort study 40 – initially negative tests of 226 pulmonary TB contacts. Individuals testing negative 30 – 35% being offered a second TST 12 weeks later. 20 – Individuals testing positive were offered an IGRA test. 18.4% 10 – Individual positive on both TST and IGRA were offered 0 preventive treatment, after Missed the Diagnosed with exclusion of risk factors for second evaluation LTBI at the 2nd hepatotoxicity. evaluation

Who misses the second step of evaluation in tuberculosis contact screening? Soares ERJ 2011;38:474 4 – OR for missing the second evaluation 3.2 3 – 2 – 2.9 1 – 1.8 00 Male Summer Comorbidities

Concordance between tuberculin skin test and interferon-γ assay and interferon-γ response to mitogen in pediatric tuberculosis contacts Thomas Pediatr Pulmonol 2011;46:1225 Concordance between N° of children with latent tuberculosis infection and positive tuberculin skin test 40 – (TST) and QuantiFERON®-TB Gold in-tube (QFT-GIT) 30 – 36 test, when used in contact screening to 20 – 27 diagnose LTBI in 10 – asymptomatic children. 00 283 children. TST IGRA

Concordance between tuberculin skin test and interferon-γ assay and interferon-γ response to mitogen in pediatric tuberculosis contacts Thomas Pediatr Pulmonol 2011;46:1225 Concordance between N° of children with latent tuberculosis infection and positive tuberculin skin test 40 – (TST) and 18 children Of the in this group with QuantiFERON®-TB Gold an indeterminate in-tube (QFT-GIT) 30 – 36 test, when used in result, QFT-GIT test all except one were contact screening to 20 – 27 <5-yrs-old. diagnose LTBI in 10 – asymptomatic children. 00 283 children. TST IGRA

Concordance between tuberculin skin test and interferon-γ assay and interferon-γ response to mitogen in pediatric tuberculosis contacts Thomas Pediatr Pulmonol 2011;46:1225 Correlation between age and IFN-γ release Concordance between response to the mitogen in 282 children tuberculin skin test (TST) and QuantiFERON®-TB Gold in-tube (QFT-GIT) test, when used in contact screening to diagnose LTBI in (r = 0.47) asymptomatic children. 283 children.

Concordance between tuberculin skin test and interferon-γ assay and interferon-γ response to mitogen in pediatric tuberculosis contacts Thomas Pediatr Pulmonol 2011;46:1225 Correlation between age and IFN-γ release Concordance between response to the mitogen in 282 children tuberculin skin test (TST)low IFN-γ response The and to the mitogen seen in QuantiFERON®-TB young children raise Gold in-tube (QFT-GIT) some concerns about the test, when used in performance of IGRAs contact screening to diagnose LTBIgroup. in this in (r = 0.47) asymptomatic children. 283 children.

Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting? Ling ERJ 2011;38:649Although interferon-γ release assays (IGRAs) are intended fordiagnosing latent tuberculosis (TB), we hypothesised thatin a high-burden setting :1) the magnitude of the response when using IGRAscan distinguish active TB from other diagnoses;2) IGRAs may aid in the diagnosis of smear-negative TB;3) IGRAs could be useful as rule-out tests for active TB.

Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting? Ling ERJ 2011;38:649 In a high-burden setting, 2 IGRAs IGRAs alone do not have (QuantiFERON®-TB value as rule-in or -out tests Gold In-tube for active TB. (QFT-GIT) and TSPOT1®.TB). In smear-negative patients, chest radiography 395 patients had better NPV even (27% HIV-infected) in HIV-infected patients. with suspected TB.

Diagnosing TB infection in children: analysis ofdiscordances using in vitro tests and the tuberculin skin test Altet-Gómez ERJ 2011;37:1166 % of children with 80 – active TB and (+) A prospective study. 70 – 78.6% 98 children 60 – 64.3% from contact-tracing 50 – studies. 40 – 68 children 30 – with TST indurations ≥5mm 20 – recruited during public 10 – health screenings. 0 T-SPOT.TB QFT-G-IT

Diagnosing TB infection in children: analysis ofdiscordances using in vitro tests and the tuberculin skin test Altet-Gómez ERJ 2011;37:1166 % of children with 80 – active TB and + A prospective study. 70 – 78.6% 98 children 60 – 64.3% from contact-tracing 50 – studies. 40 – 68 children 30 – with TST indurations ≥5mm 20 – recruited during public 10 – health screenings. QuantiFERON-TB 0 gold in-tube T-SPOT.TB QFT-G-IT

Diagnosing TB infection in children: analysis ofdiscordances using in vitro tests and the tuberculin skin test Altet-Gómez ERJ 2011;37:1166 % of children with IFN-γ assays 80 – active TB and + are not able to distinguish A prospective study. active TB. 70 between LTBI and – 78.6% 98No significant differences 60 children – 64.3% from contact-tracing were detected between 50 – studies. and diseased children 40 infected – in the number of responding 68 children 30 – withT-cells and the amount TST indurations ≥5mm 20 – recruited during public after of IFN-γ released healthantigen stimulation. 10 – screenings. 0 T-SPOT.TB QFT-G-IT

Diagnosing TB infection in children: analysis ofdiscordances using in vitro tests and the tuberculin skin test Altet-Gómez ERJ 2011;37:1166 % of children with 80 – active TB and + The use of IFN-γ tests A prospective study. the is helpful for 70 – 78.6% 98 children of TB infection. diagnosis 60 – 64.3% from contact-tracing 50 – studies. use eliminates Its 40 – the cross-reactions 68 children 30 – with BCG immunisation with TST indurations ≥5mm 20 – and may help to exclude recruited during public health NTM infections. 10 – screenings. 0 T-SPOT.TB QFT-G-IT

Performance of Confirmatory Interferon-γ Release Assays in School TB Outbreaks Song S , Chest 2012;141:983Background: Interferon-γ release assays (IGRAs) have beenincorporated into several national guidelines for latent TB infection(LTBI) diagnosis.The aim of this study is to evaluate the performance ofconfirmatory IGRAs in addition to tuberculin skin tests (TSTs)in high school students with TST-positive resultswho have had contact with another student who had TB (―contacts‖)in TB outbreaks in a high BCG-vaccinated population.

Performance of Confirmatory Interferon-γ Release Assays in School TB Outbreaks Song S , Chest 2012;141:983 % of progression to TB in the untreated groups Retrospective observational 10 – study. P< 0.001 5 school TB outbreaks in South Korea. 05 – 6.1% Groups based on the results of TSTs and QuantiFERON- TB gold assays (QFT-Gs). 0.6 % 0 TST(+) TST (-)

Performance of Confirmatory Interferon-γ Release Assays in School TB Outbreaks Song S , Chest 2012;141:983 % of progression to TB in the TST (+) contacts Retrospective observational 20 – study. 18.75% P < 0 .001 Five school TB outbreaks in South Korea. 10 – Groups based on the results of TSTs and QuantiFERON- TB gold assays (QFT-Gs). 0% 0 QFT-G (+) QFT-G(-)

Performance of Confirmatory Interferon-γ Release Assays in School TB Outbreaks Song S , Chest 2012;141:983 % of progression to TB The addition of a in the TST (+) contacts Retrospective observational 20 – confirmatory IGRA for study. + contacts could TST effectively focus the 18.75% P < 0 .001 Five school TBof latent in targeting outbreaks South infection treatment TB Korea. to fewer contacts in an 10 – intermediate-incidence Groups based on the results setting in a high of TSTs and QuantiFERON- BCG-vaccinated TB gold assays (QFT-Gs). population 0% 0 QFT-G (+) QFT-G(-)

Time interval to conversion of interferon-γ release assays after exposure to tuberculosis Lee ERJ 2011;37:1447 % soldiers initially with a (+) Platoon of 32 soldiers, 80 – 4 active pulmonary tuberculosis patients, 70 – 77.8% 60 – in addition to 1 index 50 – 63% patient. 40 – For the other 27 30 – contacts, a tuberculin skin test (TST) and 20 – QuantiFERON TB-Gold 10 – In-Tube (QTF-GIT) 0 assay were performed. QFT-GIT TST

Time interval to conversion of interferon-γ release assays after exposure to tuberculosis Lee ERJ 2011;37:1447 Among 10 participants with initially negative QFT-GIT results, 3 showed conversion at 2 weeks, 3 at 4 weeks and 3 at 14 weeks. Conversion did not occur during the 30-week observation period in 1 contact. Based on the tuberculosis exposure time-points among the contacts, IGRA conversion generally occurred 4-7 weeks after exposure, although it could occur as late as 14-22 weeks after exposure.

Time interval to conversion of interferon-γ release assays after exposure to tuberculosis Lee ERJ 2011;37:1447 Among 10 participants with initially negative QFT-GIT results, 3 showed conversion at 2 weeks, 3 at 4 weeks and 3 at 14 weeks. Conversion did not occur during the 30-week observation period in 1 contact. Based on the tuberculosis exposure time-points among the contacts, IGRA conversion generally occurred 4-7 weeks after exposure, although it could occur as late as 14-22 weeks after exposure. IFN-γ release assays

Time interval to conversion of interferon-γ release assays after exposure to tuberculosis Lee ERJ 2011;37:1447 Among 10 participants with initially negative QFT-GIT results, 3 showed conversion at 2 weeks, 3 at 4 weeks and 3 at 14 For close contacts with an weeks. Conversion did not occur during the 30-week initially negative IGRA result, observation period in one contact. the appropriate time over which Based on the tuberculosis exposure time-points among the to repeat the IGRA contacts, IGRA conversion generally occurred 4-7 weeks after may be longer occur the as 14-22 weeks after exposure, although it couldthan as latecurrently exposure. recommended 6–10 weeks. IFN-γ release assays

Serial interferon-γ release assay in children with latent tuberculosis infection and children with tuberculosis Nenadić Pediatr Pulmonol 2012;47:401 Background •Interferon-γ (IFN-γ) release assay (IGRA) is used for diagnosis of latent tuberculosis infection (LTBI), and for serial testing of active tuberculosis (TB). •The aim of this study was to evaluate the results of IGRA for diagnosis and treatment monitoring of children with LTBI and children with TB. IGRA was performed in BCG vaccinated children before and six months after the beginning of treatment.

Serial interferon-γ release assay in children with latent tuberculosis infection and children with tuberculosis Nenadić Pediatr Pulmonol 2012;47:401 59 BCG vaccinated children (4–18 yrs) investigated due to exposure to active TB. There was no significant Group 1, children with LTBI difference in IFN-γ (N = 41), and Group 2, concentrations between children with TB (N = 18). Group 1 and Group 2 IGRA (QuantiFERON-TB Gold subjects either before In-Tube) was performed twice, or after the treatment. i.e., before treatment and at the end of prophylaxis and therapy.

Serial interferon-γ release assay in children with latent tuberculosis infection and children with tuberculosis Nenadić Pediatr Pulmonol 2012;47:401 59 BCG vaccinated children (4–18 yrs) investigated due to exposure to active TB. During follow-up, children with LTBI did Group 1, children with LTBI not develop active TB. (N = 41), and Group 2, In addition, in children children with TB (N = 18). with TB, signs and IGRA (QuantiFERON-TB Gold symptoms of TB In-Tube) was performed twice, improved with i.e., before treatment and at anti-TB therapy. the end of prophylaxis and therapy.

Serial interferon-γ release assay in children with latent tuberculosis infection and children with tuberculosis Nenadić Pediatr Pulmonol 2012;47:401 Conclusion •This study showed that the concentrations of IFN-γ did not differ in children with LTBI and TB either before or at the end of treatment. •IGRA may remain positive over a long period of time. •It seems that IGRA is not useful for monitoring treatment of children with LTBI and children with TB.

Serial interferon-γ release assay in children with latent tuberculosis infection and children with tuberculosis Nenadić Pediatr Pulmonol 2012;47:401 •Close contact was defined as a household contact with aggregate exposure to a TB patient of not less than 40 hr in closed rooms, whereas distant contact was defined as occasional or undefined exposure time of less than 40 hr during the presumed period of infectiousness. •LTBI subjects were treated with isoniazid for 6 months and monitored on an outpatient basis. •Children with TB were treated at hospital with four anti- tuberculotics (isoniazid, rifampicin, ethambutol, streptomycin) for 2 months. After discharge, the therapy was continued at home for 4 months with isoniazid and rifampicin.

CD81+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children Lancioni AJRCCM 2012;185:206RationaleThe immunologic events surrounding primary Mycobacteriumtuberculosis infection and development of tuberculosis remaincontroversial.Young children who develop tuberculosis do so quickly afterfirst exposure, thus permitting study of immune responseto primary infection and disease.We hypothesized that M. tuberculosis–specific CD81+ T cellsare generated in response to high bacillary loads occurringduring tuberculosis.

CD81+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children Lancioni AJRCCM 2012;185:206 Proportion of positive Mycobacterium tuberculosis– specific T-cell responses in young children with Determine if M.tuberculosis probable TB (pro-TB) and confirmed TB (C-TB) –specific T cells are versus healthy exposed (HE) children generated among healthy children exposed to M. tuberculosis (n=62) and children with tuberculosis (n=96). IFN-γ production in response to M.tuberculosis –specific proteins ESAT-6/CFP-10 by peripheral blood mononuclear cells and CD81+T cells. *The differences in proportions were tested using Fisher exact test.

CD81+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children Lancioni AJRCCM 2012;185:206 Proportion of positive Mycobacterium tuberculosis– specific T-cell responses in young children with Determine proportion of The if M.tuberculosis probable TB (pro-TB) and confirmed TB (C-TB) –specific T positive cells are versus healthy exposed (HE) children generated +among healthy CD81 T-cell assays children exposed to M. tuberculosis (n=62) of and magnitude and children with responses CD81+T-cell tuberculosissignificantly were (n=96). greater among young IFN-γ production in (<5 yr) tuberculosis response to M.tuberculosis cases compared –specific proteins ESAT-6/CFP-10young with by peripheral contacts. blood mononuclear cells and CD81+T cells. *The differences in proportions were tested using Fisher exact test.

CD81+ T Cells Provide an Immunologic Signature of Tuberculosis in Young Children Lancioni AJRCCM 2012;185:206ConclusionsAmong young children, M. tuberculosis–specific CD81+T cellsdevelop in response to high bacillary loads, as occurs duringtuberculosis, and are unlikely to be found after M.tuberculosisexposure.T-cell responses measured in peripheral blood mononuclear cellsare generated after M. tuberculosis exposure alone, and thuscannot distinguish exposure from disease.In young children, IFN-γ–producing M. tuberculosis–specificCD81+T cells provide an immunologic signature of primaryM. tuberculosis infection resulting in disease.

A new potential biomarker for childhood tuberculosis Thomas T, Thorax 2011;66:7271) One of the major research areas for tuberculosis (TB) focuses not only on diagnostics but also on biomarkers that can provide prognostic data about the disease course and response to treatment.2) Young children are at increased risk of progressing to TB after exposure, and may suffer from disseminated forms of the disease.3) Due to the paucibacillary nature of paediatric disease, the current armamentarium and future pipeline of TB diagnostics that largely rely on microbial growth and/or molecular detection are unlikely to demonstrate performance equivalent to that in adults.

A new potential biomarker for childhood tuberculosis Thomas T, Thorax 2011;66:727• A novel B-cell assay called the antibodies in lymphocyte supernatant, or ALS, as a biomarker in children with culture-confirmed TB.• The ALS assay detects antibody secretion from in vivo activated plasma B cells that migrate throughout the peripheral circulation in response to TB antigens that are present during active disease but not latent TB infection.• The ALS methodology for children includes phlebotomy of 3.5 ml of blood in order to isolate 5 million PBMCs; these cells are incubated in tissue culture plates without stimulation for 48-72 h.• The supernatant is collected, placed into BCG-coated microtitre plates and IgG responses to BCG are measured by ELISA.

A new potential biomarker for childhood tuberculosis Thomas T, Thorax 2011;66:727 1) The ALS assay performed 58 hospitalised children equally well in TB cases with clinically diagnosed <5 yrs old compared TB (ages 1-14 yrs, with those ≥5 yrs. 15% confirmed by culture). 2) Notably, the BCG-specific IgG titres 58 age-matched declined after starting controls. appropriate anti-TB treatment.

A new potential biomarker for childhood tuberculosis Thomas T, Thorax 2011;66:727 Antibodies in lymphocyte supernatant (ALS) titres during the course of anti-tuberculosis (TB) therapy. The black dashed line represents the threshold value for a positive test, 0.35 optical density. Solid data lines depict changes in ALS titres for children found to have culture-confirmed drug-susceptible TB. Dotted data lines depict changes in ALS titres for children found to have drugresistant TB; red dotted lines represent children with multidrug-resistant TB (isoniazid and rifampin resistant) and green dotted lines represent children with drug-resistance to isoniazid or rifampin (but not both). ALS titres from the five children with drug-susceptible TB significantly declined after 2 months of first-line anti-TB treatment (p=0.016). However, ALS titres failed to decline significantly after 2 months of first-line anti-TB treatment among the four children who were later found to have drug resistant TB (p=0.62). After these four children initiated second-line anti-TB treatment, the ALS titres gradually declined, mirroring their clinical improvement.

Widespread use of serological tests for tuberculosis: data from 22 high-burden countries Grenier J, Eur Respir J 2012;39:5021) Currently available commercial serological (antibody detection) tests for TB are inaccurate and highly inconsistent.2) The International Standards for TB Care explicitly discourage their use.3) Use of serological tests also entails potential harm to patients (e.g. unnecessary TB therapy because of false-positive results, or morbidity and mortality because of false-negative serology results).4) The WHO recently announced its first negative policy in TB, against the use of current TB serological.5) Misdiagnosis of TB is harmful both to individual patients and to public health; every missed TB diagnosis may result in additional TB transmission.

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study Navani Thorax 2011;66:8891) While the number of cases of pulmonary TB has fallen in many developed countries over recent years, the notification of extrapulmonary disease has increased.2) In both the USA and UK, tuberculosis lymphadenitis (TBLA) is the commonest extrapulmonary manifestation among all ethnic groups.3) Clarifying the aetiology of isolated mediastinal lymphadenopathy is essential to exclude alternative diagnoses such as lymphoma, carcinoma and sarcoidosis.4) However, the lack of specific clinical and radiological features necessitates a pathological or microbiological diagnosis whenever possible.

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study Navani Thorax 2011;66:889BackgroundEndobronchial ultrasound-guided transbronchial needleaspiration (EBUS-TBNA) has emerged as an important toolfor the diagnosis and staging of lung cancer but its rolein the diagnosis of tuberculous intrathoracic lymphadenopathyhas not been established.The aim of this study was to describe the diagnostic utility ofEBUS-TBNA in patients with intrathoracic lymphadenopathydue to tuberculosis (TB).

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study Navani Thorax 2011;66:889 % of patients in whom ultrasound-guided transbronchial needle aspiration was diagnostic 156 patients with isolated 100 – intrathoracic TB lymphadenitis. 94% 90 – 80 – Only patients with a confirmed diagnosis or unequivocal clinical 70 – 146/156 and radiological response to 60 – antituberculous treatment 50 – during follow-up for a minimum 40 – of 6 months were included. 30 – CT scan prior to EBUS-TBNA. 20 – 10 – 0

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study Navani Thorax 2011;66:889 % of patients in whom ultrasound-guided transbronchial needle aspiration was diagnostic 156 patients with(6%) 10 patients isolated 100 – did not have a specific intrathoracic TB lymphadenitis. 94% 90 – diagnosis following EBUS; 80 – 4 underwent Only patients with a confirmed mediastinoscopy which diagnosis or unequivocal clinical 70 – 146/156 and radiologicaldiagnosis of confirmed the response to 60 – TB while 6 responded to antituberculous treatment 50 – empirical antituberculous during follow-up for a minimum 40 – therapy. of 6 months were included. 30 – CT scan prior to EBUS-TBNA. 20 – 10 – 0

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study Navani Thorax 2011;66:889 % of patients with 100 – 156 patients with isolated 90 – intrathoracic TB lymphadenitis. identified Only patients with a confirmed 80 – 70 – 86% 8 drug resistant cases (5%) diagnosis or unequivocal clinical 60 – and radiological response to 50 – antituberculous treatment during follow-up for a minimum 40 – 30 – 47% of 6 months were included. 20 – CT scan prior to EBUS-TBNA. 10 – 0 Pathological findings Microbiological investigation consistent with TB yielded a positive culture of TB

•TBC•treatment

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• For 2 weeks in January, India coughed and the rest of the world paid attention.• Drug resistant tuberculosis (TB), languishing from a decade of neglect by the Indian Revised National Tuberculosis Control Program (RNTCP), was headline news in every Indian newspaper and several international ones as well.• What captured local and international attention was a report documenting the isolation of the first cases of totally drug resistant TB (TDR-TB) from India.MDR = multidrug resistant, XDR = extensively drug resistant, TDR = totally drug resistant

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• For 2 weeks in January, India coughed and the rest of the world paid attention. TB exists on an epic scale• Drug resistant tuberculosis (TB), languishing from a decade of neglect by the Indian in India. Revised National Tuberculosis Control It resolutely remains India‟s Program (RNTCP), was headline news in every Indian newspaper and several international ones as well. biggest public health problem.• What captured local and international attention was a report documenting the isolation of the first cases of totally drug resistant TB (TDR-TB) from India.MDR = multidrug resistant, XDR = extensively drug resistant, TDR = totally drug resistant

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• For 2 weeks in January, India coughed and the rest of the world paid attention. India is the highest TB burden country• Drug resistant tuberculosis (TB), languishing from a decade in the world of neglect by the Indian Revised National Tuberculosis Control Program (RNTCP),300 headline news in every Indian newspaper with was million Indians infected, and several international ones as well. 21% accounting for of the global incidence.• What captured local and international attention was a report documenting the isolation of the first cases of totally drug resistant TB (TDR-TB) from India.MDR = multidrug resistant, XDR = extensively drug resistant, TDR = totally drug resistant

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• The situation is even worse when it comes to multidrug resistant TB (MDR-TB).• Here again India emerges a global hot spot with 20% of the world‘s MDR-TB burden.• These figures are a considerable underestimate because the majority of patients with MDR-TB are seen in the private sector and never notified.

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• The first Indian cases of extensively drug-resistant (XDR)-TB were described in 2006.• Inappropriate prescriptions further amplified resistance till the microorganisms were finally resistant to all first-line (isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin) and second-line drugs (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, ethionamide, para-amino salicylic acid).

MDR, XDR, TDR tuberculosis: ominous progression. Editorial Udwadia, Thorax 2012;67:286• The first Indian cases of extensively drug-resistant (XDR)-TB TDR-TB is were described in 2006. an iatrogenic disease• Inappropriate that represents amplified resistance prescriptions further a failure of physicians, public and private, till the microorganisms were finally resistant to all first-line (isoniazid, rifampicin, ethambutol, public health. and a failure of pyrazinamide, streptomycin) and second-line drugs (ofloxacin, moxifloxacin, kanamycin, amikacin, capreomycin, ethionamide, para-amino salicylic acid).MDR = multidrug resistant, XDR = extensively drug resistant, TDR = totally drug resistant

Prevalence of inappropriate tuberculosis treatment regimens: a systematic review Langendam, Eur Respir J 2012;39:1012 % studies with 37 observational studies inappropriate treatment published from 2000. regimens prescribed 70 – TB patients receiving treatment. A treatment regimen was 60 – 67% 50 – considered inappropriate if the regimen was not a WHO 40 – recommended regimen. 30 – A 4-drug short-course regimen is currently recommended by the 20 – World Health Organization (WHO). 10 – World Health Organization. Treatment of tuberculosis guidelines. 4th Edn. Geneva, WHO, 2009. 0

Prevalence of inappropriate tuberculosis treatment regimens: a systematic review Langendam, Eur Respir J 2012;39:1012 37 observational studies published from 2000. TB patients receiving treatment. A treatment regimen was considered inappropriate if the regimen was not a WHO recommended regimen. A 4-drug short-course regimen is currently recommended by the World Health Organization (WHO). World Health Organization. Treatment of tuberculosis guidelines. 4th Edn. Geneva, WHO, 2009.

Prevalence of inappropriate tuberculosis treatment regimens: a systematic review Langendam, Eur Respir J 2012;39:1012 37 observational studies published Treatment against TB may be inappropriate because: from 2000. TB patients receiving treatment duration is too short or the 1) the treatment. regimen contains too few drugs, has insufficient A treatment regimen wasor drugs in a wrong combination; dose considered inappropriate if the treatment is too long, with an 2) the duration of excessive dose or number of drugs. regimen was not a WHO recommended regimen. The first error may cause drug resistance, while A 4-drug short-course regimen error increases the risk of the second is side-effects and consequently low-treatment currently recommended by the compliance and, thus, increased treatment World Health Organization (WHO). World Health Organization. Treatment of failure. tuberculosis guidelines. 4th Edn. Geneva, WHO, 2009.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged? Migliori, Eur Respir J 2012;39:619In spite of the growing awareness of emerging drug-resistantMycobacterium tuberculosis, the extent of inappropriatetuberculosis (TB) case management may be underestimated,even in Europe.We evaluated TB case management in the European Union/European Economic Area countries, with special focus onmultidrug-resistant (MDR) and extensively drug-resistant(XDR)-TB, using a purposely developed, standardised surveytool.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged? Migliori, Eur Respir J 2012;39:619 Deviations from international standards of TB care were observed in the following National reference areas: centres in 5 countries 1) surveillance (no information available in Europe. on patient outcomes) 2) infection control (lack of respiratory 40 consecutive, isolation rooms/procedures and original clinical TB negative-pressure ventilation rooms) case records 3) clinical management of TB, MDR-TB 30 MDR/XDR-TB and HIV co-infection (inadequate cases reviewed in bacteriological diagnosis, regimen selection and treatment duration) each of the 5 countries. 4) laboratory support 5) diagnostic/treatment algorithms.

TB and MDR/XDR-TB in European Union and European Economic Area countries: managed or mismanaged? Migliori, Eur Respir J 2012;39:619 1) With regard to ensuring the prevention of nosocomial spread of drug- resistant Mycobacterium tuberculosis strains, the main area of concern was the observed lack of a comprehensive infection control strategy or plan in all the reference centres surveyed.2) From the diagnostic point of view, several findings deserve comment: reports in which bacteriological confirmation of TB cases is shown to remain suboptimal. A surprising finding was the irregular use of the rapid molecular diagnostic methods, which allow for the rapid identification of M.tuberculosis and a proxy of MDR-TB (in ‹1 day), are not routinely used. The gold standard for diagnosing drug-resistant TB remains that of culture-based DST (drug susceptibility testing). However, the rapid molecular methods offer the potential to give a first, essential indication of M. tuberculosis and drug-resistance pattern in a patient, enabling rapid, more optimised treatment choices.3) With regard to treatment practices, the choice of treatment regimens, the doses of administered anti-TB drugs and the duration of anti-TB drug treatment did not follow international recommendations in a number of the reference centres.

TB and M/XDR-TB infection control in European TB reference centres: the Achilles‟ heel? Sotgiu ERJ 2011;38:1221 Multidrug-resistant (MDR) tuberculosis (TB) is defined as in vitro resistance to isoniazid and rifampicin, and extensively drug-resistant (XDR)-TB is defined as in vitro drug resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the injectable drugs (amikacin, capreomycin or kanamycin). XDR-TB is a manmade product, resulting, in essence, from clinical mismanagement of newly diagnosed susceptible and resistant TB cases.

TB and M/XDR-TB infection control in European TB reference centres: the Achilles‟ heel? Sotgiu ERJ 2011;38:1221  Investigation of previous TB diagnosis was performed The aim of the study in 186 (93%) out of 200 was to document how TB cases admitted infection control measure to the reference centres. are implemented in the European Union,  Only 80% of their focusing on national contacts were MDR/XDR-TB reference investigated, which centres. is potentially relevant from a public health perspective.

TB and M/XDR-TB infection control in European TB reference centres: the Achilles‟ heel? Sotgiu ERJ 2011;38:1221  Healthcare workers were sufficiently protected in the majority of cases The aim of the study (99.5%). was to document how infection control measure  40 (20%) out of 200 are implemented cases were not educated in the European Union, on cough etiquette focusing on national and other important MDR/XDR-TB reference infection control issues. centres.  No negative-pressure room was identified in 4 out of 5 surveyed centres.

A Comparison between Two Strategies for Monitoring Hepatic Function during Antituberculous Therapy Singanayagam AJRCCM 2012;185:653 % patients developed drug-induced liver injury 288 adult patients 10 – undergoing therapy for active tuberculosis. Alanine transferase 7.3% 05 – measurement at baseline and 2 weeks following therapy. 0

A Comparison between Two Strategies for Monitoring Hepatic Function during Antituberculous Therapy Singanayagam AJRCCM 2012;185:653 % patients developed drug-induced liver injury 57.1%“early” 288 adult patients 10 – undergoing weeks at 2 therapy for active tuberculosis. and Alanine transferase 7.3% 42.9% “late” measurement at 05 – baselineafter and 2 weeks 2 weeks. following therapy. 0

A Comparison between Two Strategies for Monitoring Hepatic Function during Antituberculous Therapy Singanayagam AJRCCM 2012;185:653 % patients developed There were drug-induced liver injury 288 adult patients increased rates of 10 – undergoing therapy forindividuals with active tuberculosis. HIV infection Alanine transferase 7.3% in the early 05 – measurement at drug-induced baseline and 2 weeks liver injury group. following therapy. 0

A Comparison between Two Strategies for Monitoring Hepatic Function during Antituberculous Therapy Singanayagam AJRCCM 2012;185:653 Liver function testing % patients developed at 2 wks is useful drug-induced liver injury 288 adult patients for prompt 10 – undergoing therapy a identification of for active tuberculosis. subgroup who develop Alanine transferase liver early drug-induced 7.3% 05 – measurement may offer injury and at baseline and 2 weeks in better specificity ruling out late following therapy. 0 drug-induced liver injury.

•TBC•Vaccine BCG

The Influence of Bacille Calmette-Guérin Vaccine Strain on the Immune Response against Tuberculosis A Randomized Trial Ritz AJRCCM 2012;185:213 Rationale Approximately 100 million doses of bacille Calmette-Guérin (BCG) vaccine are given each year to protect against tuberculosis (TB). More than 20 genetically distinct BCG vaccine strains are in use worldwide. Previous studies suggest that BCG vaccine strain influences the immune response and protection against TB. Current data on which BCG vaccine strain induces the optimal immune response in humans are insufficient.

The Influence of Bacille Calmette-Guérin Vaccine Strain on the Immune Response against Tuberculosis A Randomized Trial Ritz AJRCCM 2012;185:213 Newborn infants Proportion of single cytokine-producing immunized at birth CD4 T-cells after in vitro stimulation with BCG. with one of three BCG vaccine strains. BCG-Denmark (n=54); BCG-Japan (n=54); BCG-Russia, (n=57). Mycobacterial specific polyfunctional CD4T-cells were measured.

The Influence of Bacille Calmette-Guérin Vaccine Strain on the Immune Response against Tuberculosis A Randomized Trial Ritz AJRCCM 2012;185:213 Newborn infants of The proportion Proportion of single cytokine-producing polyfunctional immunized at birth CD4 T-cells after in vitro stimulation with BCG. with one of T-cells CD4 three was significantly higher BCG vaccine strains. in infants immunized BCG-Denmark (n=54); with BCG-Japan (n=54); BCG-Denmark (0.013%) or BCG-Japan (0.016%) BCG-Russia, (n=57). than with Mycobacterial(0.007%) BCG-Russia specific polyfunctional and ( p=0.018 CD4T-cells were p=0.003,respectively). measured.

The Influence of Bacille Calmette-Guérin Vaccine Strain on the Immune Response against Tuberculosis A Randomized Trial Ritz AJRCCM 2012;185:213 Conclusions There are significant differences in the immune response induced by different BCG vaccine strains in newborn infants. Immunization with BCG-Denmark or BCG-Japan induced higher frequencies of mycobacterial-specific polyfunctional and cytotoxic T cells and higher concentrations of Th1 cytokines. These findings have potentially important implications for global antituberculosis immunization policies and future tuberculosis vaccine trials.

Prospects for elimination of childhood tuberculosis: the role of new vaccines Hatherill Arch Dis Child 2011;96:851Key facts about Tubrculosis1) The main route of TB transmission to children is from adults whohave infectious, often cavitary, pulmonary disease.2) There were approximately 9.4 million incident TB cases and1.8 million TB deaths worldwide in 2008.3) One third of the global population is thought to be latentlyinfected with TB.4) Global TB disease incidence has begun to fall since 2004.5) The elimination target of the Stop TB Partnership is a reductionof global incidence to less than 1 case per million per year by 2050.

Prospects for elimination of childhood tuberculosis: the role of new vaccines Hatherill Arch Dis Child 2011;96:851Key facts about Tuberculosis vaccines1) BCG protects against miliary and meningitic TB in children(disseminated forms of childhood tuberculosis), but protectionagainst pulmonary disease is inconsistent.2) WHO recommends that BCG should not be given to HIV infectedinfants.3) 14 candidate TB vaccines have entered clinical trials.4) Two viral-vectored TB vaccines have entered large proof-of-concept efficacy trialsamong infants.5) Global elimination of TB will require a new, effective pre- andpost-exposure TB vaccine to be used in conjunction with massvaccination campaigns.

TAKE HOME

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Raghu G, Eur Respir J 2012;39:242• Idiopathic pulmonary fibrosis (IPF) is a distinct clinical entity that generally affects people who are over 60 yrs of age, and median survival ranges from 3 to 5 yrs after the diagnosis is ascertained.• The natural course of IPF is well known: the majority of patients with IPF display steady decline in lung function, some patients remain stable for prolonged periods of time, a subgroup of patients rapidly decline, and a subset of patients manifest acute exacerbations of IPF preceding death.• The ultimate cause of IPF and the triggering factor(s) that injure the lung remain elusive, and none of the currently available pharmacological agents have demonstrated improved outcomes and survival in patients with IPF.

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Raghu G, Eur Respir J 2012;39:242High-resolution computed tomography (HRCT) Concepts of gastro-oesophageal reflux image of the chest in a patient with (GER) and microaspiration in the idiopathic pulmonary fibrosis pathogenesis of IPF and acute exacerbation of IPF

Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Raghu G, Eur Respir J 2012;39:242High-resolution computed tomography (HRCT) Concepts of gastro-oesophageal reflux image of the chest in a patient with (GER) and microaspiration in the Note the schematic idiopathic pulmonary fibrosis pathogenesis of IPF and representation of the acute exacerbation of IPF presence of a hiatal hernia (small) and the contents of gastric juice refluxate gaining access to the distal pulmonary parenchyma via GER and microaspiration (shown by the dots from the distal oesophagus into the proximal oesophagus and aspirating into the lung (arrowhead)

“The Cruelest Lies Are Often Told in Silence” Rubin CHEST 2011;140:5671) The term Silent Aspiration (SA) refers to aspiration before, during, or after swallowing in the absence of cough or visible signs of choking and distress.2) The ―gold standard‖ for diagnosing oropharyngeal aspiration is the videofluoroscopic swallow study (VFSS), more commonly known as the modified barium swallow.3) The only effective therapy for oropharyngeal aspiration in children is feeding modification using food thickened appropriately, based on the results of the VFSS.4) Unrecognized silent aspiration can lead to permanent recurrent pneumonia, pulmonary impairment, and substantial health-care costs.

Oropharyngeal Aspiration and Silent Aspiration in Children. Weir CHEST 2011;140:589 Oropharyngeal aspiration (OPA) % children with and silent aspiration (SA) oropharyngeal aspiration (OPA) in children. 40 – 300 children presenting with feeding difficulties. 30 – 34 % Videofluoroscopic swallow study (VFSS) for evaluation of 20 – swallowing. 10 – Swallowing performance was rated using the 00 penetration-aspiration scale.

Oropharyngeal Aspiration and Silent Aspiration in Children. Weir CHEST 2011;140:589 Oropharyngeal aspiration (OPA) % children with Of these, and silent aspiration (SA) oropharyngeal aspiration (OPA) 81% had in children. 40 – 300 silent aspiration. with children presenting feeding difficulties. 30 – 34 % Videofluoroscopic swallow study (VFSS) for evaluation of 20 – swallowing. 10 – Swallowing performance was rated using the 00 penetration-aspiration scale.

Oropharyngeal Aspiration and Silent Aspiration in Children. Weir CHEST 2011;140:589 OR for silent aspiration (SA) Oropharyngeal aspiration (OPA) and silent aspiration (SA) 5 - 4.65 4.62 in children. 4 - 300 children presenting with 3.22 feeding difficulties. 3 – Videofluoroscopic swallow 2.02 study (VFSS) for evaluation of 2 – swallowing. 1 – Swallowing performance was rated using the 0 Neurologic Developmental Aspiration Enteral penetration-aspiration scale. impairment delay lung disease feeding

Oropharyngeal Aspiration and Silent Aspiration in Children. Weir CHEST 2011;140:589 OR for silent aspiration (SA) Oropharyngeal aspiration (OPA) and silent aspiration (SA) 5 - 4.65 4.62 in SA is very common children. in children with with 300 children presenting 4 - feeding difficulties 3.22 feeding difficulties. 3 – and is most likely Videofluoroscopic swallow 2.02 to occur in study (VFSS) for evaluation of 2 – children with a swallowing. neurologic problem. 1 – Swallowing performance was rated using the 0 Neurologic Developmental Aspiration Enteral penetration-aspiration scale. impairment delay lung disease feeding

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380• A 13-year-old boy with severe respiratory distress.• Chest RX: bilateral massive pleural effusions.• He had been treated for diffuse lymphangiomatosis associated with chylothorax with regular injections of pegylated interferon α-2b.• Because of side effects (high fever, headache, and depression) the dose of interferon had been reduced and the treatment interval prolonged.• Respiratory distress recurred.• The plasma vascular endothelial growth factor (VEGF) level in this patient was very high (normal value, 38.3pg/ml).• VEGF is both an angiogenic and a lymphangiogenic factor.• Propranolol is thought to cause reduced expression of VEGF and direct induction of apoptosis in capillary endothelial cells.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380• A 13-year-old boy with severe respiratory distress.• Chest RX: bilateral massive pleural effusions.• He had been treated for diffuse lymphangiomatosis associated with We hypothesized that propranolol chylothorax with regular injections of pegylated interferon α-2b.• Because of side effects (high might inhibit lymphangiogenesis fever, headache, and depression) the dose and reduce tumor growth. of interferon had been reduced and the treatment interval prolonged.• Respiratory distress recurred.• The plasma vascular endothelial growth factor (VEGF) level in this patient was very high (normal value, 38.3pg/ml).• VEGF is both an angiogenic and a lymphangiogenic factor.• Propranolol is thought to cause reduced expression of VEGF and direct induction of apoptosis in capillary endothelial cells.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380 Effect of therapy with Interferon and Propranolol on drainage volume in diffuse lymphangiomatosiswith associated improvement as seen on chest radiography.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380 Propranolol initiated at a dose of 5 mg every 8 hours (0.5 mg of therapy with Effect per kilogram of body weight per day) Interferon and Propranolol on drainage volume in then gradually increased diffuse lymphangiomatosiswith 40 mg every 8 hours to associated improvement (4 mg per seen on per day). as kilogram chest radiography.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380 The drainage volume decreased therapy with Effect of gradually,Interferon and Propranolol and treatment with on drainage volume in pegylated interferondiffuse discontinued. was lymphangiomatosiswith associated improvement as seen on chest radiography.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380 Effect blood VEGF The of therapy with Interferon and Propranolol level decreased on drainage volume in remarkably. diffuse lymphangiomatosiswith associated improvement as seen on chest radiography.

Propranolol for Intractable Diffuse Lymphangiomatosis. Ozeki, NEJM 2011;364:1380Conclusions:• The prognosis for patients with diffuse lymphangiomatosis is poor if the condition is resistant to standard therapies.• Propranolol treatment is safe in children and may be an important alternative in the treatment of this disease in infants and children.

Congenital diaphragmatic hernia Kotecha, Eur Respir J 2012;39:820 Recommendations for the antenatal management and delivery of congenital diaphragmatic hernia (CDH) infants1)2)3)4)5)6)7)8)9)

Congenital diaphragmatic hernia Kotecha, Eur Respir J 2012;39:820Post-natal recommendations for the management of congenital diaphragmatichernia (CDH) based on the consensus statement of the CDH-EURO consortium

Congenital diaphragmatic hernia Kotecha, Eur Respir J 2012;39:820Long-term outcomes of congenitaldiaphragmatic hernia TLC: total lung capacity; FEV1: forced expiratory volume in 1 s; V‟O2,max: maximal oxygen uptake; % pred: % predicted.

Mounier-Kuhn Syndrome: Imaging in Recurrent Pulmonary Infections Lakshminarayana AJRCCM 2012;185:225A man with ahistory ofrecurrentpneumonia,asthma, andunexplainedbronchiectasis.X-rays showedtracheo-bronchomegaly.

Mounier-Kuhn Syndrome: Imaging in Recurrent Pulmonary Infections Lakshminarayana AJRCCM 2012;185:225Computedtomography scan withthree-dimensionalairway reconstructionand bronchoscopyrevealedtracheobronchomegalyinvolving the entiretrachea and mainbronchi, with nearcomplete collapse ofleft mainstembronchus duringexpiration(noted by arrows).

Mounier-Kuhn Syndrome: Imaging in Recurrent Pulmonary Infections Lakshminarayana AJRCCM 2012;185:225 Bronchoscopy: near complete collapse of left main bronchus during expiration. A diagnosis of Mounier-Kuhn syndrome was made. Treatment usually consists ofairway clearance maneuvers, antibiotics during infectious exacerbations, and in some cases, endobronchial stenting.

Bilateral Pulmonary Sequestration Enfield AJRCCM 2012;184:141Our patient (male, aged 53 yr) was referred for a pulmonary mass found on routine chest X-ray.

Bilateral Pulmonary Sequestration Enfield AJRCCM 2012;184:141Our patient (male, aged 53 yr) was referred for a pulmonary mass found on routine chest X-ray. A CT of the chest revealed two areas of pulmonary sequestration.

Bilateral Pulmonary Sequestration Enfield AJRCCM 2012;184:141Our patient (male, aged 53 yr) was referred for a pulmonary mass found on routine chest X-ray. The CT angiogram shows the left sequestration with feeding vessels coming from the left epigastric artery and the right sequestration feeding directly from the aorta, suggesting an intralobar sequestration.

Bilateral Pulmonary Sequestration Enfield AJRCCM 2012;184:141Demonstration of the arterial supply is useful to distinguish intralobar sequestration (typically arising from the aorta) from extralobar sequestration (typically supplied by aberrant vessels).This information helps with surgical planning.Pulmonary sequestration is a rare congenital malformation making up 0.15% to 6.4% of all pulmonary malformations.Intralobar sequestrations, as in this case, are often identified during the second decade of life secondary to recurrent infections and, rarely, as asymptomatic lesions in patients >50 yrs.

Alveolar Capillary Dysplasia Bishop AJRCCM 2012;184:172• The interstitial lung diseases of childhood, characterized by defective gas exchange, restrictive lung physiology, and diffuse involvement on lung imaging, include a heterogeneous group of conditions involving disordered development of the alveoli and distal airspaces.• Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV), the most common of these disorders, produces respiratory failure early in life and carries a mortality rate that approaches 100%.

Alveolar Capillary Dysplasia Bishop AJRCCM 2012;184:172Characteristic histologic features of ACD/MPV: •small pulmonary arteries with medial hyperplasia (a), • congested pulmonary veins malpositioned within the same adventitial sheath (v), •a dilated bronchiole (b).Additional findings, (i.e., neutrophilic infiltrate and hemorrhage) are consequences of the hypoxemic respiratory failure and aggressive ventilatory support.

Pediatric obstructive sleep apnea syndrome (OSAS) forthe allergist: update on the assessment and management Alkhalil Ann Allergy Asthma Immunol 2011;107:1041) Pediatric sleep-disordered breathing (SDB) may be considered a disease continuum.2) It ranges in severity from mild obstruction of the upper airway, producing primary snoring, to increased upper airway resistance syndrome (UARS), to continuous episodes of complete upper airway obstruction or OSAS.3) The degree of sleep disruption, hypoxemia, hypercapnia, and upper airway airflow reduction are main factors in determining the severity of SDB.

Pediatric obstructive sleep apnea syndrome (OSAS) forthe allergist: update on the assessment and management Alkhalil Ann Allergy Asthma Immunol 2011;107:1044) Mounting evidence implicates OSAS as a risk factor for decreased growth, impaired neurocognitive function, and cardiovascular morbidity.5) The first treatment of choice for OSAS in children remains tonsillectomy and adenoidectomy.

Pediatric obstructive sleep apnea syndrome (OSAS) forthe allergist: update on the assessment and management Alkhalil Ann Allergy Asthma Immunol 2011;107:104 Conditions in which obtaining a sleep study may be beneficial

Seasonal Variability of Sleep-Disordered Breathing in Children. Gozal Pediatr Pulmonol 2011;46:581 1051 records of all children participating in a prospective, cross- Snoring frequency and sectional community- loudness were significantly based research study higher in spring and questionnaire on summer and lowest in fall snoring frequency and (P < 0.001). loudness. An overnight sleep study.

Seasonal Variability of Sleep-Disordered Breathing in Children. Gozal Pediatr Pulmonol 2011;46:581 Obstructive apnea–hypopnea index 1051 records of all in 1,051 school-age children by season (weighted means). children participating in a prospective, cross- sectional community- based research study questionnaire on snoring frequency and loudness. An overnight sleep study.

Seasonal Variability of Sleep-Disordered Breathing in Children. Gozal Pediatr Pulmonol 2011;46:581 Obstructive apnea–hypopnea index 1051 records of all in 1,051 school-age children by season (weighted means). children participating in Both seasonal viral aand allergen burdens prospective, cross- sectional community- may contribute to based research study SDB severity and questionnaire differing may prompt on clinical referral snoring frequency and loudness. throughout patterns the year. An overnight sleep study.

Sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years Bonuck Pediatrics 2012;129:e857 OR in children with symptoms Parents in the Avon of sleep-disordered breathing with Longitudinal Study of Parents peak at 30 months that abated thereafter for and Children. 2 – Children‘s snoring, mouth breathing, and witnessed apnea at ≥2 surveys 1.85 at 6, 18, 30, 42, 57, and 69 1.60 months. Strengths and Difficulties 1 – 1.37 Questionnaire at 4 (n = 9140) and 7 (n =8098) years. Cluster analysis produced 5 ―Early‖ (6–42 months) 0 and ―Later‖ (6–69 months) Hyperreactivity Conduct Peer symptom trajectories. difficulties difficulties AT AGE 7 YRS

Sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years Bonuck Pediatrics 2012;129:e857 OR in children with symptoms Parents in the Avon of sleep-disordered breathing Longitudinal Study of Parents between 6-69 months for and Children. 2 – Children‘s snoring, mouth breathing, and 1.88 witnessed apnea at ≥2 surveys at 6, 18, 30, 42, 57, and 69 1.67 months. 1 – Strengths and Difficulties Questionnaire at 4 (n = 9140) and 7 (n =8098) years. Cluster analysis produced 5 ―Early‖ (6–42 months) 0 and ―Later‖ (6–69 months) Hyperreactivity Conduct symptom trajectories. difficulties AT AGE 7 YRS

Sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years Bonuck Pediatrics 2012;129:e857 Peak symptoms before 18 months that resolve thereafter still predicted 40% to 50% increased odds of behavior problems at 7 years. In this large, population-based, longitudinal study, early-life sleep disordered breathing symptoms had strong, persistent statistical effects on subsequent behavior in childhood. Findings suggest that SDB symptoms may require attention as early as the first year of life.

Nocturnal Enuresis in Children: Prevalence, Correlates, and Relationship with Obstructive Sleep Apnea Su, J Ped 2011;159:238 Prevalence of Nocturnal Enuresis 48 – (≥1 wet night/month) 47 – Nocturnal enuresis (NE) in 6147 primary 46 – 6.7% children with and those 45 – without obstructive 44 – sleep apnea (OSA) 43 – aged 6-11 years. 42 – 2.5% 41 – 40 boys girls

Nocturnal Enuresis in Children: Prevalence, Correlates, and Relationship with Obstructive Sleep Apnea Su, J Ped 2011;159:238 Prevalence of Nocturnal Enuresis 48 – (≥1 wet night/month) 47 – Boys had a Nocturnal enuresis (NE) in 6147 primary significantly 46 – 6.7% children with and those greater prevalence 45 – without obstructive across all age sleep apnea (OSA) 44 – groups. aged 6-11 years. 43 – 42 – 2.5% 41 – 40 boys girls

Nocturnal Enuresis in Children: Prevalence, Correlates, and Relationship with Obstructive Sleep Apnea Su, J Ped 2011;159:238 Prevalence of NE (≥1 wet night/month) in girls 20 – 18 – 20% Nocturnal enuresis 16 – (NE) in 6147 primary 14 – p=0.01 for trend children with and those 12 – without obstructive 10 – sleep apnea (OSA) aged 6-11 years. 08 – 8.8% 06 – 04 – 2.1% 02 – 00 <1 1-5 >5 Obstructive apnea hypopnea index

Nocturnal Enuresis in Children: Prevalence, Correlates, and Relationship with Obstructive Sleep Apnea Su, J Ped 2011;159:238 Prevalence of NE (≥1 wet night/month) in girls 20 – 18 – 20% Nocturnal enuresisNE Prevalence of 16 – (NE) in 6147 primary 14 – p=0.01 for trend was increased children with and those 12 – with increasing without obstructive 10 – severity of OSA sleep apnea (OSA) agedin girls only. 6-11 years. 08 – 8.8% 06 – 04 – 2.1% 02 – 00 <1 1-5 >5 Obstructive apnea hypopnea index

Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea Kimoff ERJ 2011;38:89  Pro-inflammatory In the severe OSA group, cytokine expression. expression of IL-1α, IL-6 and TGF-ß  Oxidative stress. was significantly higher in  In severe (n=25) versus mucosa-predominant tissues, mild (n=17) OSA patients. whereas in muscle-predominant  Oxidative stress specimens, RANTES assessed via protein expression was greater in carbonyl group detection severe OSA. by immunoblotting.

Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea Kimoff ERJ 2011;38:89 Representative immunoblot for carbonylated proteins from muscle-predominant samples, indicating the presence of carbonylated protein bands, which are increased in the severe obstructive sleep apnoea group.

Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea Kimoff ERJ 2011;38:89 Group mean SE optical density for carbonylated protein bands in severe versus mild obstructive sleep apnoea subjects for predominant tissues specimens. mucosa muscle

Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea Kimoff ERJ 2011;38:89 Group mean increased pro-inflammatory There is SE optical density for carbonylated and pro-fibrotic severe versus mild obstructive sleep protein bands in cytokine expression, oxidative stress, and connective tissue deposition specimens. apnoea subjects for predominant tissues in upper airway tissues from severe versus mild OSA patients. mucosa muscle

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503BackgroundLectin-like oxidized low-density lipoprotein receptor 1 (LOX-1)is the major receptor for oxidized low-density lipoproteinin endothelial cells, and its expression is enhancedin proatherogenic settings.The objective of this study was to investigate the associationbetween LOX-1 in freshly harvested human venous endothelial cellsand apoptotic circulating endothelial cells in patients with obstructivesleep apnea (OSA).

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 Box and whisker plots of e-LOX-1 expression according to OSA severity 38 patients with OSA. 12 healthy control subjects. Plasma LOX-1 (pLOX-1). Circulating apoptotic endothelial cells (CD46+, CD45-, and CD 31+) were assessed by flow cytometry.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 Box and whisker plots of e-LOX-1 expression according to OSA severity OSA is 38 patients with OSA. associated 12 healthy control subjects. with Plasma LOX-1 (pLOX-1). increased Circulating apoptotic endothelial cells levels plasma of LOX-1 (CD46+, CD45-, and CD 31+) were assessed by flow cytometry.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 Box and whisker plots of e-LOX-1 expression according to OSA severity Vascular cell 38 patients with OSA. apoptosis 12 healthy control subjects. in patients with OSA is associated with Plasma LOX-1 (pLOX-1). increased LOX-1 Circulating apoptotic endothelial cellsdensity receptor (CD46+on vascular 31+) , CD45-, and CD were assessed endothelium. by flow cytometry.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 eLOX-1 expression before and after ≥4h of CPAP 38 patients with OSA. therapy per night 12 healthy control subjects. Plasma LOX-1 (pLOX-1). Circulating apoptotic endothelial cells (CD46+, CD45-, and CD 31+) were assessed by flow cytometry.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 eLOX-1 expression before and after <4h of CPAP 38 patients with OSA. therapy per night 12 healthy control subjects. Plasma LOX-1 (pLOX-1). Circulating apoptotic endothelial cells (CD46+, CD45-, and CD 31+) were assessed by flow cytometry.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 eLOX-1 expression before and after ≥4h of CPAP before and after <4h of CPAP therapy per night therapy per night

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 eLOX-1 expression Effective therapy (≥4hours per night) withCPAP before and after ≥4h of CPAP before and after <4h of therapy per night therapy per night nCPAP reduces the expression of LOX-1.

Lectin-like oxidized low density lipoprotein receptor-1modulates endothelial apoptosis in obstructive sleep apnea Akinnusi CHEST 2011;140:1503 eLOX-1 expression before and after of sleep apnea provides an effective Treatment ≥4h of CPAP before and after <4h of CPAP means of mitigating the associated cardiovascular therapy per night therapy per night complications.

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea Kim AJRCCM 2012;185:330BackgroundPediatric obstructive sleep apnea (OSA) leads tomultiple end-organ morbidities that are mediatedby the cumulative burden of oxidative stress andinflammation.Because not all children with OSA exhibitincreased systemic inflammation, genetic andenvironmental factors may be affecting patternsof DNA methylation in genes subservinginflammatory functions.

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea Kim AJRCCM 2012;185:330 Forkhead box P3 (FOXP3) and interferon regulatoryDNA methylation factor 1 (IRF1) showed levels of 24 higher methylation in 6 inflammatory-related children with OSA and high genes. high-sensitivity C-reactive protein (hsCRP) levels47 OSA cases compared with matched children with OSA and low 31 control subjects. hsCRP levels (p<0.05).

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea Kim AJRCCM 2012;185:330 Forkhead box P3 (FOXP3) DNA Prevalence of Forkhead box P3 (FOXP3) hypermethylation in children with DNA hypermethylation in childrenobstructive sleep apnea (OSA) and control according to the categorical severity of subjects. obstructive sleep apnea (OSA). *FOXP3 DNA hypermethylation was defined as >24%.

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea Kim AJRCCM 2012;185:330 Correlation between apnea- Correlation between body masshypopnea index (AHI) and FOXP3 index (BMI) z score and FOXP3 DNA methylation levels in DNA methylation levels. children.

DNA Methylation in Inflammatory Genes among Children with Obstructive Sleep Apnea Kim AJRCCM 2012;185:330What This Study Adds to the FieldChildren with OSA with elevated systemic inflammatorymarkers were more likely to display increased DNA methylation inthe Forkhead box P3 gene.DNA methylation of this gene was also independently associatedwith the severity of OSA and with the variance in systemicinflammatory markers, suggesting that epigenetic modifications inselected genes underlie individual susceptibility components.

Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea Almendros I, Eur Respir J 2012;39:215 Tumour growth in both groups of mice A murine melanoma model consisting of tumour induction by subcutaneous injection of 106 B16F10 melanoma cells. Application of chronic intermittent hypoxia (60 events·h-1 consisting of 20 s of 5% O2 followed by 40 s of room air).

Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea Almendros I, Eur Respir J 2012;39:215 Tumour growth in both groups of mice A murine melanoma model consisting of growth Tumour can be tumour induction by subcutaneous injection of modulated by 10 6 B16F10 melanoma cells. changes in the Applicationof chronic level of tissue oxygenation intermittent hypoxia (60 events·h consisting of -1 20 s of 5% O2 followed by 40 s of room air).

Intermittent hypoxia enhances cancer progression in a mouse model of sleep apnoea Almendros I, Eur Respir J 2012;39:215 Tumour growth in both groups of mice Over-expression of A murine melanoma model hypoxia-inducible consisting of tumour induction by by factor-1α caused subcutaneoushypoxia of tissue injection triggers upregulation 106 B16F10 melanoma cells. of proangiogenic mediators, such as Application of chronic intermittentendothelial vascular hypoxia (60 events·h-1factor, growth consisting of in tumour cells 20 s of 5% O followed by 2 40 s of room air).

Elevated Blood Pressure During Sleep and Wake in Children With Sleep-Disordered Breathing Horne Pediatrics 2011;128:e85 •Blood pressure during awake before sleep onset and during 105 children referred overnight sleep was elevated for assessment of by 10 to 15 mmHg in the sleep-disordered sleep-disordered breathing breathing. compared with the control group; this finding was independent of 36 nonsnoring controls. sleep-disordered breathing severity. Routine •Blood pressure during stable sleep polysomnography with (with respiratory events and continuous blood movements excluded) was also pressure monitoring. elevated in the children with OSA compared with the control group.

Elevated Blood Pressure During Sleep and Wake in Children With Sleep-Disordered Breathing Horne Pediatrics 2011;128:e85Conclusion:•We recorded blood pressure continuously overnight andfound that sleep-disordered breathing, regardless of theseverity, was associated with increased blood pressureduring sleep and wake compared with nonsnoring controlchildren.•These findings highlight the importance of considering thecardiovascular effects of sleep-disordered breathing of anyseverity in children, and the need to review current clinicalmanagement that focuses primarily on more severe sleep-disordered breathing .

Obstructive sleep apnea in poorly controlled asthmatic children: Effect of adenotonsillectomy Kheirandish-Gozal Pediatr Pulmonol 2011;46:913 % children with OSA 92 children with poorly (i.e., AHI > 5/hrTST) controlled asthma. 70 – 63% Overnight sleep study. 60 – 50 – Adenotonsillectomy performed if OSA was 40 – 58/92 present. 30 – 20 – Total sleep time (TST). 10 – Apnea/hypopnea index (AHI). 0

Obstructive sleep apnea in poorly controlled asthmatic children: Effect of adenotonsillectomy Kheirandish-Gozal Pediatr Pulmonol 2011;46:913 % children with OSA 92 children with poorly (i.e., AHI > 5/hrTST) The maximal controlled asthma. 70 – estimated 63% Overnight sleep study. 60 – prevalence of 50 – OSA in a Adenotonsillectomy 40 – 58/92 performed if OSA was non-asthmatic present. 30 – population is 20 – ∼4%. Total sleep time (TST). 10 – Apnea/hypopnea index (AHI). 0

Obstructive sleep apnea in poorly controlled asthmatic children: Effect of adenotonsillectomy Kheirandish-Gozal Pediatr Pulmonol 2011;46:913 N° of acute asthma exacerbatione 92 children with poorly for year in children with OSA controlled asthma. 5 – 4 – Overnight sleep study. 4.1 p=0.0001 3 – Adenotonsillectomy performed if OSA was 2 – present. 1 – 1.8 Total sleep time (TST). 0 Apnea/hypopnea index PRE POST (AHI). A & T

Interactions of obstructive sleep-disordered breathing with recurrent wheezing or asthma and their effects on sleep quality. Malakasioti Pediatr Pulmonol 2011;46:1047 Enlarged tonsils and adenoid or obesity predispose to obstructive sleep apneas and hypopneas which are accompanied by arousals, restless sleep, and frequently daytime sleepiness, inattention, hyperactivity, and academic difficulties. Subjects with history of wheezing are also at risk for sleep disturbance and daytime cognitive dysfunction. Asthmatic children have more frequent snoring, apneas, and hypopneas during sleep than non-asthmatic subjects and tonsillar hypertrophy mediates at least in part this epidemiologic association.

Interactions of obstructive sleep-disordered breathingwith recurrent wheezing or asthma and their effectson sleep quality. Malakasioti Pediatr Pulmonol 2011;46:1047 Preliminary evidence indicates that treatment of sleep apnea with adenotonsillectomy results in improved control of coexisting asthma. Elevated concentrations of leukotrienes and oxidative stress markers have been detected in the exhaled breath condensate of children with asthma and probably contribute to bronchoconstriction. Moreover, sleep apneic children have increased expression of leukotrienes and leukotriene receptors in adenotonsillar tissue.

Interactions of obstructive sleep-disordered breathingwith recurrent wheezing or asthma and their effectson sleep quality. Malakasioti Pediatr Pulmonol 2011;46:1047 •Viral respiratory infections may induce inflammation and oxidative stress in the asthmatic airway enhancing not only bronchospasm, but also biosynthesis of leukotrienes within pharyngeal lymphoid tissues, which promote adenotonsillar enlargement and sleep apnea. •In conclusion, taking under consideration the epidemiologic association between obstructive SDB and asthma, when one of the two disorders is diagnosed, the possibility of the other disease being present should be entertained.

Interactions of obstructive sleep-disordered breathingwith recurrent wheezing or asthma and their effectson sleep quality. Malakasioti Pediatr Pulmonol 2011;46:1047 Some Speculative Pathogenetic Mechanisms That may Explain the Association Between Obstructive Sleep-Disordered Breathing and Recurrent Wheezing/Asthma

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment Canessa AJRCCM 2012;183:1419RationaleObstructive sleep apnea (OSA) is commonlyassociated with neurocognitive impairmentsthat have not been consistently relatedto specific brain structure abnormalities.Knowledge of the brain structures involved inOSA and the corresponding functionalimplications could provide clues to the pathogenesis of cognitiveimpairment and its reversibility in this disorder.ObjectivesTo investigate the cognitive deficits and the corresponding brainmorphology changes in OSA, and the modifications after treatment,using combined neuropsychologic testing and voxel based morphometry.

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment Canessa AJRCCM 2012;183:1419 17 patients • Pretreatment: neuropsychologic results treatment-naive showed impairments in most cognitive areas, and in mood and sleepiness that to sleep apnea. were associated with focal reductions 15 age-matched of gray-matter volume in the healthy control left hippocampus (entorhinal cortex), subjects. left posterior parietal cortex, and right superior frontal gyrus. A sleep study, cognitive tests, • After treatment: significant and magnetic improvements involving memory, attention, and executive-functioning that resonance paralleled gray-matter volume increases imaging. in hippocampal and frontal structures.

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment Canessa AJRCCM 2012;183:1419• Structural brain changes in OSA before and after continuous positive airway pressure treatment. Regions showing a gray matter volume decrease in untreated patients with OSA compared with control subjects (p<0.05).• Regions showing a GM-volume increase in post-treatment, compared with pretreatment, patients with OSA (p< 0.05).

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment Canessa AJRCCM 2012;183:1419• Left hippocampal entorhinal cortex showing both a GM- volume reduction before treatment and a GM-volume increase after treatment (p< 0.001), and the correlation between GM-volume increase in this region and cognitive improvement after treatment (p<0.05).

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682Background:• Obesity is a prominent risk factor for the development of cardiovascular disease, diabetes mellitus, dyslipidemia, hypertension, and their constellation as the metabolic syndrome.• There is now incremental evidence that the complications of obesity begin in early childhood.• OSA is a highly prevalent condition in children.• Endothelial dysfunction can develop in the context of both obesity and obstructive sleep apnea (OSA).• We assessed endothelial function in children who were obese and non-obese, with and without OSA.

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 108 prepubertal non-hypertensive children. Endothelial function was assessed using a modified hyperemic test involving cuff-induced occlusion of the radial and ulnar arteries. Blood was drawn for assessment of myeloid-related protein 8/14 (MRP8/14) levels. Overnight polysomnography defined the presence of OSA or absence of OSA (NOSA). Anthropometric measurements were performed to assign subjects to obese (OB) and non-obese (NOB) categories.

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 108 prepubertal non-hypertensive children. Endothelial function was assessed using a modified MRP 8/14, a major calcium-binding protein, hyperemic test involving cuff-induced occlusion of the radial is primarily expressed in cells of myeloid origin, and ulnar arteries. namely monocytes and neutrophils. Blood was drawn for assessment of myeloid-related protein 8/14 (MRP8/14) levels. association of these atherogenic There is an markers with endothelial dysfunction. Overnight polysomnography defined the presence of OSA Kim Eur Respir J 2010;35:843 or absence of OSA (NOSA). Anthropometric measurements were performed to assign subjects to obese (OB) and non-obese (NOB) categories.

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 % subjects with evidence of endothelial dysfunction 70 – 60 – 62.5% p<0.01 50 – 40 – 30 – 38.7% 20 – 10 – 20.0% 0.0% 0 OB + OB + OB (-) OB (-) OSA (+) OSA(-) OSA (+) OSA (-)

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 % subjects with evidence of endothelial dysfunction Both obesity and OSA can independently increase 70 – the risk for endothelial dysfunction. 60 – 62.5% p<0.01 50 – 40 – 30 – 38.7% 20 – 10 – 20.0% 0.0% 0 OB + OB + OB (-) OB (-) OSA (+) OSA(-) OSA (+) OSA (-)

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 % subjects with evidence ofpresence of both The concurrent endothelial dysfunction 70 – markedly increases such risk. 60 – 62.5% p<0.01 50 – 40 – 30 – 38.7% 20 – 10 – 20.0% 0.0% 0 OB + OB + OB (-) OB (-) OSA (+) OSA(-) OSA (+) OSA (-)

Endothelial Dysfunction in Children Without Hypertension: Potential Contributions of Obesity andObstructive Sleep Apnea. Bhattacharjee, CHEST 2012;141:682 The degree of endothelial dysfunction in all groups % subjects with evidence of endothelial dysfunction was associated with circulating MRP8/14 levels 70 – (p<0.001). 60 – 62.5% p<0.01 50 – 40 – 30 – 38.7% 20 – 10 – 20.0% 0.0% 0 OB + OB + OB (-) OB (-) OSA (+) OSA(-) OSA (+) OSA (-)

Continuous Positive Airway Pressure Reduces Postprandial Lipidemia in Obstructive Sleep Apnea A Randomized, Placebo-Controlled Crossover Trial Phillips AJRCCM 2012;184:355RationaleDyslipidemia is common in Obstructive Sleep Apnea(OSA).Postprandial lipidemia (PPL) is a strong marker of cardiovascularrisk. Evidence that OSA treatment improves PPL is lacking.ObjectivesTo investigate the effect of continuous positive airway pressure(CPAP) treatment on postprandial lipidemia (PPL) in patients withobstructive sleep apnea (OSA) in the upper moderate or severerange.

Continuous Positive Airway Pressure Reduces Postprandial Lipidemia in Obstructive Sleep Apnea A Randomized, Placebo-Controlled Crossover Trial Phillips AJRCCM 2012;184:355Effects of 2 months each of therapeutic and placebo continuous positive airway Treatment of severe OSA pressure treatment on with CPAP improves postprandial lipidemia. postprandial TAG and total cholesterol levels.Area under the 24-hour These effects may reduce triglyceride concentration the risk for cardiovascular curve (TAG-AUC24) using events. seven blood samples drawn across both the wake and sleep periods.

Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse Nair AJRCCM 2012;184:1305RationaleSleep fragmentation (SF) is one of the major characteristics ofsleep apnea, and has been implicated in its morbid consequences,which encompass excessive daytime sleepiness and neurocognitiveimpairments.We hypothesized that absence of nicotinamide adeninedinucleotide phosphate (NADPH) oxidase activity is neuroprotectivein SF-induced cognitive impairments.

Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse Nair AJRCCM 2012;184:1305 The effect of chronic Sleep Fragmentation on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters. Mice lacking Wild-type NADPH oxidase. littermates.

Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse Nair AJRCCM 2012;184:1305 The effect of chronic Sleep Fragmentation on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters. Mice lacking Wild-type NADPH oxidase. littermates.Mice displayed normal learning and were protected from the spatial learning deficits observed in wild-type littermates.

Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse Nair AJRCCM 2012;184:1305 The effect of chronic Sleep Fragmentation on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters. Mice lacking Wild-type NADPH oxidase. littermates.• Anxiety levels were increased in wild-type mice.• Significantly elevated NADPH oxidase gene expression and activity.

Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse Nair AJRCCM 2012;184:1305 The effect of chronic Sleep Fragmentation on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters. Mice lacking Wild-type Important role for NADPH oxidase in NADPH oxidase. littermates. hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease.

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018BackgroundIt is unknown whether oxygen therapy causes worseninghypercapnia in patients with obesity-associated hypoventilation(OAH), similar to the response observed in COPD.The objectives of this study were to investigate whetherbreathing 100% oxygen results in an increase in hypercapnia inpatients with OAH and the mechanisms of any effect.

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 Transcutaneous CO2 tension (PtCO2), minute ventilation (MV), and volume of dead space (VDS) to tidal volume (VT) ratio measured at baseline and at 20 min. The PtCO2 was used to estimate PaCO2 using a combined SpO2/PtCO2 monitor (TOSCA; Radiometer Medical ApS; Brønshøj, Denmark). MV was measured using a flow sensor (CO2SMO Plus! respiratory profile monitor; Respironics; Murrysville, Pennsylvania) attached to the expiratory port of the mask. The mixed expired CO2 (PECO2) was measured using volumetric capnography (CO2SMO Plus! respiratory profile monitor). With measurements of the PtCO2 and PECO2, the VDS/VT was calculated using the Bohr-Engoff equation.

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018The tidal volume (VT) was calculated by the equation VT=MV/RR;The volume of dead space (VDS) was calculated by the equationVDS=VT x VDS/VT;The alveolar volume (VA) was calculated by the equation VA=VT-VDS;and the alveolar MV (MVA) was calculated by the MVA=VA x RR.Abbreviations: MV = minute ventilation; MVa = alveolar minute ventilation;NPPV= noninvasive positive pressure ventilation; OAH = obesity-associated hypoventilation;OHS = obesity hypoventilation syndrome; Peco2 = mixed expired CO2 tension;Ptco2 = transcutaneous CO2 tension; RR = respiratory rate;SpO2 = oxygen saturation as measured by pulse oximetry; Va = alveolar volume;Vds = volume of dead space; Vt = tidal volume;Vds /Vt = volume of dead space to tidal volume ratio

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with obesity-associated hypoventialtion (OAH) inhaled 100% oxygen or The study was terminated room air for 20 min in 3 subjects breathing on 2 separate days. 100% oxygen due to a Transcutaneous CO2 PtCO2 increase ≥10mmHg, tension (PtCO2), which occurred after minute ventilation (MV), 10:35, 13:20, and volume of dead space and 15:51 min. (VDS) to tidal volume (VT) ratio measured at baseline and at 20 min.

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with obesity-associated hypoventialtion (OAH) was similar to the increase in This finding PaCO from 51 to 68 The study was terminated inhaled 100% oxygen 2or mmHg within room air for20 to 30 min of 100% oxygen three subjects 20 min in in one of on 2 separate days. obese subjects with baseline two breathing 100% oxygen due to a hypercapnia investigated in another study Transcutaneous CO2 and PtCO2 increase ≥10mmHg, tension (PtCO2), illustrates the short time period occurred after minute ventilation (MV), which in which 10:35, 13:20, thedead space rise with oxygen therapy, PaCO2 may and volume of and 15:51 min. (VDS) to tidal volume (VT) that observed in COPD. similar to ratio measured at baseline and at 20 min.

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with obesity-associated hypoventialtion (OAH) 10 – Mean increase in inhaled 100% oxygen or PtCO2 room air for 20 min on 2 separate days. Transcutaneous CO2 50 – tension (PtCO2), minute ventilation (MV), 5 mmHg and volume of dead space (VDS) to tidal volume (VT) ratio measured at 0 baseline and at 20 min. with oxigen compared with room air

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with obesity-associated hypoventialtionventilation Minute (OAH) 10 – Mean increase in decreased inhaled 100% oxygen or PtCO2 by 1.4L/min room air for 20 min (p=0.03) on 2 separate days. and volume of dead Transcutaneous to tidal space CO2 50 – tension (PtCO2), volume ratio minute ventilation (MV), 5 mmHg increased by 0.067 and volume of dead space (p<0.001) with (VDS) to tidal volume (VT) oxygen. ratio measured at 0 baseline and at 20 min. with oxigen compared with room air

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with Mean increase in obesity-associated PtCO2 hypoventialtion (OAH) 10 – Breathing 100% inhaled 100% oxygen or oxygen causes room air for 20 min worsening on 2 separate days. Transcutaneous COdue to a hypercapnia 2 50 – tension (PtCO2), in minute reduction minute ventilation in stable 5 mmHg ventilation (MV), andpatients dead space volume of with OAH. (VDS) to tidal volume (VT) ratio measured at 0 baseline and at 20 min. with oxigen compared with room air

The effect of supplemental oxigen on hypercapnia in subjects with obesity-associated hypoventilation Wijesinghe CHEST 2011;139:1018 24 outpatients with obesity-associated The change in PtCO2 (mmHg) from hypoventialtion (OAH) baseline following breathing 100% inhaled 100% oxygen or oxigen or room air. room air for 20 min on 2 separate days. Transcutaneous CO2 tension (PtCO2), minute ventilation (MV), and volume of dead space (VDS) to tidal volume (VT) ratio measured at baseline and at 20 min.

Oxygen for obesity hypoventilation syndrome: a double-edged sword? Mokhlesi CHEST 2011;139:975 The impact of oxygen supplementation in patients with obesity hypoventilation syndrome (OHS) has clinical relevance because 15% to 30% of patients are treated with supplemental oxygen during sleep due to persistent hypoxemia. The mechanism underlying such an increase in PtCO2 was primarily due to a 13% reduction in minute ventilation during oxygen administration compared with room air. In patients with COPD who retained CO2 with hyperoxia, ventilation decreased by 20%, and volume of dead space/tidal volume ratio increased by 24%.

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Apnea-hypopnea index events/h Changes in heart rate (HR) 31.9 30 – and time and frequency components of heart rate variability (HRV). 20 – Retrospectively analized during light, deep and rapid eye movement (REM) 10 – sleep in children with OSAS who underwent polysomnography before 0 4.1 and after BEFORE AFTER adenotonsillectomy (AT). AT

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after adenotonsillectomy (AT) Changes in heart rate (HR) and time and frequency p<0.005 components of heart rate variability (HRV). Retrospectively analized during light, deep and rapid eye movement (REM) sleep in children with OSAS who underwent N1,2= stage N1 polysomnography before and N2 sleep and after adenotonsillectomy (AT).

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after adenotonsillectomy (AT) Changes in heart rate (HR) and time and frequency p<0.005 components of heart rate variability (HRV). Retrospectively analized during light, deep and rapid eye movement (REM) sleep in children with OSAS who underwent Stage N3 sleep polysomnography before and after adenotonsillectomy (AT).

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after adenotonsillectomy (AT) Changes in heart rate (HR) and time and frequency p<0.005 components of heart rate variability (HRV). Retrospectively analized during light, deep and rapid eye movement (REM) sleep in children with OSAS who underwent Rapid eye movement polysomnography before and after adenotonsillectomy (AT).

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after Changes in The HR decreased after AT in adenotonsillectomy (AT) heart rate (HR) all stages of sleep and time and frequency 100 – p<0.005 heart rate components of 90 – variability (HRV). – 80 99.8 Light sleep 70 – 60 – 80.7 Retrospectively analized 50 – during light, deep– and 40 30 – rapid eye movement (REM) 20 – sleep in children with 10 – OSAS who underwent 0 BEFORE AFTER Rapid eye movement polysomnography before AT and after adenotonsillectomy (AT).

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after Changes in The HR decreased after AT in adenotonsillectomy (AT) heart rate (HR) all stages of sleep and time and frequency 100 – p<0.005 components of 90 – 100.2 heart rate variability (HRV). – 80 Deep sleep 70 – 60 – 80.5 Retrospectively analized 50 – during light, deep– and 40 30 – rapid eye movement (REM) 20 – sleep in children with 10 – OSAS who underwent 0 BEFORE AFTER Rapid eye movement polysomnography before AT and after adenotonsillectomy (AT).

Changes in heart rate variabilty after adenotonsillectomy in children with obstructive sleep apnea Muzumdar CHEST 2011;139:1050 Changes in heart rate interval after Changes in The HR decreased after AT in adenotonsillectomy (AT) heart rate (HR) all stages of sleep and time and frequency p<0.005 107 100 – heart rate components of 90 – variability (HRV). – 80 70 – 87 REM sleep 60 – Retrospectively analized 50 – during light, deep– and 40 30 – rapid eye movement (REM) 20 – sleep in children with 10 – OSAS who underwent 0 BEFORE AFTER Rapid eye movement polysomnography before AT and after adenotonsillectomy (AT).

Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea Ben-Israel ERJ 2011;37:1144 14 children with OSA Following AT, (mean age 6.4 elevation of slow-wave apnoea-hypopnoea index activity (SWA), (AHI) 10.0 events h-1) a marker of sleep who underwent AT. homeostasis, during the 6 children with OSA first two sleep cycles that did not undergo (p<0.01) treatment. and a more physiological decay of SWA Electroencephalogram across the night (p<0.0001) waveform analysis. were noted.

Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea Ben-Israel ERJ 2011;37:1144 14 children with OSA Following AT, (mean age 6.4 The slow-wave slope elevation of slow-wave apnoea-hypopnoea increased by >30% index activity (SWA), (AHI) 10.0 events h -1) a marker of sleep following AT (p<0.03). who underwent AT. homeostasis, during the 6 children with OSA first two sleep cycles No significant changes were found (p<0.01) that did not undergo treatment. in Slow Wave Activity inmore physiological and a the comparison group. decay of SWA Electroencephalogram across the night (p<0.0001) waveform analysis. were noted.

Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea Ben-Israel ERJ 2011;37:1144 14 children with OSA Following AT, (mean age 6.4 homeostasis is considerably Sleep elevation of slow-wave apnoea-hypopnoea index impaired hin pre-pubescent activity (SWA), (AHI) 10.0 events -1) children a marker of sleep who underwent AT. with OSA. homeostasis, during the 6 children with OSA first two sleep cycles that did A&T restores more not undergo physiological (p<0.01) sleep homeostasis in treatment. children with and a more physiological decay of SWA Electroencephalogram OSA. across the night (p<0.0001) waveform analysis. were noted.

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797Background Obstructive sleep apnoea (OSA)is commonly associated with obesity and canbe improved by weight loss. Changes in upperairway size related to regional fat loss maymediate the improvement in OSA.This study aimed to assess changes in upper airwaysizeand regional facial and abdominal fat with weight lossand their association with OSA improvement.

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Reduction in weight (kg) 0 Middle-aged obese men with moderate-to-severe OSA; 24-week sibutramine- -5 p<0.001 assisted weight loss trial; -7.8 Kg Polysomnography and CT of the head and neck at baseline and 24 weeks -10

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Reduction in apnoea-hypopnoea index (AHI; events/h) 0 Middle-aged obese men -05 – with moderate-to-severe OSA; -10 – 24-week sibutramine- -15 – 15.9% assisted weight loss trial; -20 – Polysomnography and CT of the head and neck at baseline and 24 weeks

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Velopharyngeal airway volume increase in cm3 Middle-aged obese men 7.5 – with moderate-to-severe OSA; 0.5 – 6.3 24-week sibutramine- 5.3 assisted weight loss trial; 2.5 – p<0.01. Polysomnography and CT of the head and neck at baseline and 24 weeks 0.0 – Baseline Post-intervention

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Velopharyngeal airway volume increase in cm3 Facial and Middle-aged obese men 7.5 – parapharyngeal with moderate-to-severe OSA; fat volume were 0.5 – 6.3 24-week sibutramine- 5.3 significantly assisted weight loss trial; reduced 2.5 – p<0.01. Polysomnography and CT of the head and neck at baseline and 24 weeks 0.0 – Baseline Post-intervention

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Upper airway volumes at baseline and after a 24-week weight loss programme Middle-aged obese men p<0.01. with moderate-to-severe OSA; 24-week sibutramine- assisted weight loss trial; Polysomnography and CT of the head and neck at baseline and 24 weeks

Effect of weight loss on upper airway size and facial fat in men with obstructive sleep apnoea Sutherland Thorax 2011;66:797 Surface reconstructions from CT scans of a single patient before and after weight loss showing (A) head and neck region and (B) the upper airway. The patient showed a 5.1 cm3 increase in upper airway volume after 19 kg weight loss (approximately 18% of body weight) associated with an improvement in apnoea- hypopnoea index (AHI) from 55.9 events/h to 15.1 events/h.

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331BackgroundMandibular advancement splints (MASs) can effectively treatobstructive sleep apnea (OSA).However, no validated and reliable prediction method for treatmentoutcome currently exists.The efficacy of MAS may relate to anatomic factors, includingcraniofacial size and upper-airway soft-tissue volume and anatomicbalance between them. We aimed to assess whether craniofacial andoral measurements are associated with MAS treatment outcome.

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Dental impressions and lateral cephalometric radiographs were obtained from patients with OSA prior to commencing mandibular advancement splints (MAS) treatment. lateral cephalogram illustrating identified cephalometric landmarks

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Intertooth distances and palatal depths were measured on dental casts, standard cephalometric analysis was performed with the addition of cross-sectional area (CSA) of the tongue and bony oral enclosure. Schematic diagram of dental arch

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Treatment outcome was determined by polysomnography. Polysomnography

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331  25 were complete responders Of 53 patients with (AHI <5/h) obstructive sleepapnea (OSA) treated  17 were partial responders with mandibular (≥50% AHI reduction)advancement splints (MASs)  11 were nonresponders (<50% AHI reduction) AHI: posttreatment apnea-hypopnea index

Influence of oral and craniofacial dimensions onmandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Chephalometric  25 were complete respondersOf 53 patientsdid not analyses with (AHI <5/h)obstructive sleep reveal anyapnea (OSA) treated significant  17 were partial responderswith mandibular differences (≥50% AHI reduction)advancement splints between(MASs)responders and  11 were nonresponders nonresponders (<50% AHI reduction) AHI: posttreatment apnea-hypopnea index

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Tongue dimension (cm2) 40 – However, 39.5 there was a trend toward 30 – p<0.09 35.5 a larger tonguecross-sectional area (CSA) 20 – in complete vs partial and nonresponders 10 – 0 Complete Partial and responders nonresponders

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Tongue dimension (cm2) Tongue/oral enclosure CSA 40 – However, 39.5 ratio, indicating p<0.09 there was a trend 30 – 35.5towardlarger tongue a a larger tongue for given oral cross-sectional area 20 – cavity size, was in complete vs partial greater in and nonresponders 10 – complete responders 0 Complete Partial and responders nonresponders

Influence of oral and craniofacial dimensions on mandibular advancement splint treatment outcome in patients with obstructive sleep apnea Mostafiz CHEST 2011;139:1331 Tongue dimension (cm2) This evidence suggests 40 – However, that MAS treatment p<0.09 there was a trend 30 – help to correct the toward a larger anatomic imbalance tongue CSA 39.5 35.5 20 – between tongue volumein complete vs partial and oral cavity size. and nonresponders 10 – 0 Complete Partial and responders nonresponders

Non-CPAP therapies in obstructive sleep apnoea Randerath ERJ 2011;37:1000Evidence supports the use of mandibular advancement devices in mild to moderate OSAS. Maxillomandibular osteotomy seems to be as efficient as continuous positive airway pressure (CPAP) in patients who refuse conservative treatment. Distraction osteogenesis is usefully applied in congenital micrognathia or midface hypoplasia. There is a trend towards improvment after weight reduction.

Non-CPAP therapies in obstructive sleep apnoea Randerath ERJ 2011;37:1000 Positional therapy is clearly inferior to CPAP and long-term compliance is poor.Drugs, nasal dilators and apnoea triggered muscle stimulation cannot be recommended as effective treatments of OSAS at the moment. Nasal surgery, radiofrequency tonsil reduction, tongue base surgery, uvulopalatal flap, laser midlineglossectomy, tongue suspension and genioglossus advancement cannot be recommended as single interventions.

Non-CPAP therapies in obstructive sleep apnoea Randerath ERJ 2011;37:1000 Uvulopalatopharyngoplasty, pillar implants and hyoid suspension should only be considered in selectedpatients and potential benefits should be weighed against the risk of long-term side-effects. Multilevel surgery is only a salvage procedure for OSA patients.

Pediatric Paradoxical Vocal-Fold Motion: Presentation and Natural History Maturo Pediatrics 2011;128:e1443Paradoxical vocal-fold motion (PVFM) is inappropriate adductionof the vocal folds during inspiration.PVFM has been known as paroxysmal vocal-cord dysfunction,episodic laryngospasm, irritable larynx syndrome, and Munchausenstridor.Abu-Hasan et al reported close to a 10% incidence in children withexercise-induced dyspnea.Reisner and Borish reported a 10% rate in patients referred forinpatient evaluation of refractory asthma.Abu-Hasan M. Ann Allergy Asthma Immunol. 2005;94:366;Reisner C. Chest. 1995;108:1477;

Pediatric Paradoxical Vocal-Fold Motion: Presentation and Natural History Maturo Pediatrics 2011;128:e1443The speech pathologist, on an individualized basis, instructs thepatient on:1. laryngeal control exercises,2. laryngeal desensitization strategies,3. laryngeal breathing techniques.If it is felt that there may be an underlying psychologicalcomponent, the child is sent to speech therapy and psychiatryconcurrently.

Pediatric Paradoxical Vocal-Fold Motion: Presentation and Natural History Maturo Pediatrics 2011;128:e1443 % success rate after an average of 3.7 treatment sessions. 70 – 63% 60 – 59 children with paradoxical 50 – vocal-fold motion 40 – mean age of 13.64 30 – years and a female-to-male 20 – ratio of 3:1. 10 – 0 Speech therapy

Pediatric Paradoxical Vocal-Fold Motion: Presentation and Natural History Maturo Pediatrics 2011;128:e1443 % success rate after an average of 3.7 treatment sessions. 70 – 30% of children – 63% 60 59 childrenultimately were with paradoxical 50 – vocal-fold motion with – diagnosed 40 mean a psychiatric age of 13.64 30 – years and condition. 20 – a female-to-male ratio of 3:1. 10 – 0 Speech therapy

Pediatric Paradoxical Vocal-Fold Motion: Presentation and Natural History Maturo Pediatrics 2011;128:e1443 % success rate after an average Children with of 3.7 treatment sessions. inspiratory stridor at – 70 63% rest had a lower initial – 60 59 children with speech success rate with paradoxical 50 – vocal-fold motiona higher therapy (56%), 40 – mean ageof underlying rate of 13.64 30 psychiatric disorders – years and a(75%), and a high rate female-to-male 20 – ratioof success after 10 of 3:1. – psychiatric treatment 0 (100%). Speech therapy

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• When an individual patient with a known pulmonary condition presents with worsening respiratory symptoms, it is inevitable that such worsening is attributed to that condition.• Sometimes another reason for the change in symptoms is present.• Vocal cord dysfunction (VCD) occurring in someone with asthma is a case in point, and in this circumstance assuming worsening symptoms to be due to asthma rather than VCD often results in inappropriately high treatment with anti-asthma medication.

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• VCD is characterized by episodes of paradoxical inspiratory /expiratory adduction of the true and/or false vocal cords.• The true prevalence of VCD is unknown, largely due to difficulties in diagnosis, although around 4 to 10% of patients referred to difficult asthma clinics were diagnosed as having VCD.• VCD is more common in females; athletes; army recruits with exercise-induced asthma, asthma, and chronic cough; and has been reported following upper respiratory tract infection, thyroid surgery, and with gastroesophageal reflux.

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• VCD is most often regarded as a conversion disorder, and the complex innervation of the larynx and the association between VCD and stress and comorbid psychology strengthens this view.• More specifically, it has been suggested that altered autonomic balance maintained by central brain activity may underlie VCD.

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• Symptoms are similar to those of asthma (wheezy breathlessness and cough), but the pattern may be different, breathlessness often being inspiratory in VCD, in which attacks are often associated with voice change.• Objective evidence to date has focused on flow–volume loop deformation and direct visualization of the vocal cords.

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• Flow–volume loops may show inspiratory loop truncation representing variable extrathoracic airflow obstruction, which may result in reduced maximal inspiratory flow at 50% vital capacity/maximal expiratory flow at 50% vital capacity ratio due to predominant inspiratory flow limitation.• An abnormally high forced inspiratory flow at 25% vital capacity/forced inspiratory flow at 75% vital capacity ratio would indicate an initial normal flow followed by rapid flow decline, reflecting paradoxical vocal cord movement during inspiration.

Vocal Cord Dysfunction and Severe Asthma Ayres AJRCCM 2012;184:3• The gold standard for VCD diagnosis is laryngoscopic demonstration of paradoxical vocal cord movement during spontaneous or induced symptoms, but normal laryngeal function when the patient is asymptomatic does not exclude VCD.• Specific maneuvers such as repeating low- and high-pitched sounds, forceful inspiration and expiration, and exposure to substances known by the individual patient to induce symptoms can be helpful in inducing an attack during laryngoscopy.• Classically in VCD, the vocal cords adduct anteriorly leaving an open posterior glottic chink, the adduction occurring either during inspiration or throughout the respiratory cycle.

Abnormal Vocal Cord Function in Difficult-to-Treat Asthma Low AJRCCM 2012;184:50 % pts with difficult-to-treat asthma 60 –A novel imaging technique, 50 – dynamic 320-slice computerized tomography (CT), 40 – 50% to examine laryngeal behavior 30 – in healthy individuals and individuals with asthma. 20 –Vocal cord movement 10 – was imaged 0 Vocal cord excessive narrowing

Abnormal Vocal Cord Function in Difficult-to-Treat Asthma Low AJRCCM 2012;184:50 % pts with difficult-to-treat asthma 60 –A novel imaging technique, 50 – dynamic 320-slice 19% Severe in computerized tomography (CT), of patients 40 – 50% to examine laryngeal behavior (abnormal >50% in healthy individuals and 30 – of inspiration or individuals with asthma. 20 – expiration time).Vocal cord movement 10 – was imaged 0 Vocal cord excessive narrowing

Abnormal Vocal Cord Function in Difficult-to-Treat Asthma Low AJRCCM 2012;184:50 % pts with difficult-to-treat asthma 60 – novel imaging technique,A Imaging revealed that 50 – dynamic 320-slice laryngeal dysfunction computerized tomography (CT), characterized the 40 – 50% to examine laryngeal behavior movement abnormality 30 – in healthy individuals and rather than individuals with asthma. 20 – isolated vocal cordVocal cord movement dysfunction. 10 – was imaged 0 Vocal cord excessive narrowing

Abnormal Vocal Cord Function in Difficult-to-Treat Asthma Low AJRCCM 2012;184:50Abnormal laryngeal function demonstrated in a patient with asthma with severe intermittent narrowing of the upper airway. Images obtained initially. Images during a symptomatic period.

Abnormal Vocal Cord Function in Difficult-to-Treat Asthma Low AJRCCM 2012;184:50Abnormal laryngeal function demonstrated in a patient with asthma with severe intermittent narrowing of the upper airway. Note the extent of overall laryngeal narrowing, rather than isolated vocal cord closure. Images obtained initially. Images during a symptomatic period.

Broncodisplasia polmonare

High-Dose Docosahexaenoic Acid Supplementation ofPreterm Infants: Respiratory and Allergy Outcomes Manley Pediatrics 2011;128:e71•Docosahexaenoic acid (DHA) is an n-3 long-chainpolyunsaturated fatty acid (LCPUFA), which along with theother n-3 LCPUFA, eicosapentaenoic acid, is provided in thediet by fish and fish oils.•These LCPUFA are known to modulate inflammation and arealso postulated to modulate the neonatal immune response.•For example, supplementation with n-3 LCPUFA duringpregnancy is known to be associated with decreasedmessenger RNA levels of TH2-related molecules in the fetusand decreased maternal inflammatory cytokines.

High-Dose Docosahexaenoic Acid Supplementation of Preterm Infants: Respiratory and Allergy Outcomes Manley Pediatrics 2011;128:e71 657 preterm infants 33 RR of BDP in boys weeks‘ gestation who consumed expressed breast 1.0 – milk from mothers taking 0.9 – either tuna oil 0.8 – 0.7 – (high-DHA diet) or soy oil (standard-DHA) capsules. 0.6 – 0.5 – 0.67 0.4 – Incidence of 0.3 – p=0.03 bronchopulmonary dysplasia 0.2 – 0.1 – (BPD) and parental reporting 0 of atopic conditions over the DHA diet first 18 months of life.

High-Dose Docosahexaenoic Acid Supplementation of Preterm Infants: Respiratory and Allergy Outcomes Manley Pediatrics 2011;128:e71 657 preterm infants 33 RR of BDP in all infants with weeks‘ gestation who a birth weight of 1250 g consumed expressed breast 1.0 – milk from mothers taking 0.9 – either tuna oil 0.8 – 0.75 0.7 – (high-DHA diet) or soy oil 0.6 – (standard-DHA) capsules. 0.5 – 0.4 – p=0.04 Incidence of 0.3 – bronchopulmonary dysplasia 0.2 – 0.1 – (BPD) and parental reporting 0 of atopic conditions over the DHA diet first 18 months of life.

Hyperoxia arrests alveolar development through suppression of histone deacetylases in neonatal rats Zhu Pediatr Pulmonol 2012;47:2641) Bronchopulmonary dysplasia (BPD) mainly occurs in preterm infants. It is histopathologically characterized by fewer and larger alveoli and less secondary septa, suggesting an arrested or disordered lung development.2) Histone deacetylase (HDAC) plays an important role by regulating gene transcription.

Hyperoxia arrests alveolar development through suppression of histone deacetylases in neonatal rats Zhu Pediatr Pulmonol 2012;47:264 Rats subjected to hyperoxia (85% O2) Arrest of alveolarization, and an elevated expressionSuppression of the HDAC1/HDAC2 of the cytokine-induced expression and activity, and the neutrophil chemoattractant- overall HDAC activity 1 (CINC-1) in the lungs of newborn rats.

Hyperoxia arrests alveolar development through suppression of histone deacetylases in neonatal rats Zhu Pediatr Pulmonol 2012;47:264 Rats subjected to hyperoxia (85% O2) Preservation of HDAC activity by theophylline significantly improved alveolar development Arrest of alveolarization, and attenuated and an elevated expression CINC-1 release.Suppression of the HDAC1/HDAC2 of the cytokine-induced expression and activity, and the neutrophil chemoattractant- overall HDAC activity 1 (CINC-1) in the lungs of newborn rats.

Hyperoxia arrests alveolar development throughsuppression of histone deacetylases in neonatal rats Zhu Pediatr Pulmonol 2012;47:264 Hyperoxia arrested alveolar development Control Hyperoxia

Role of pulmonary infection in the development of chronic lung disease of prematurity Beeton ERJ 2011;37:1424 OR for development of chronic lung disease (CLD) of  192 newborn infants 4 – prematurity. (61 term and 131 pre- 3.6 term) of <34 weeks 3 – gestation.  16S ribosomal RNA 2 – (rRNA) genes by PCR of DNA isolated from gastric and lung fluid 1 – 1.6 3.2 samples. 00 Presence of 16S Ureaplasma spp. rRNA genes

Role of pulmonary infection in the development of chronic lung disease of prematurity Beeton ERJ 2011;37:1424 OR for development of chronic lung disease (CLD) of 5.1 5 – prematurity. 4 – 3 – 3.8 2.4 3.2 2 – 1 – 00 1.7 Presence of 16S Ureaplasma Presence of 16S Ureaplasma rRNA genes spp. rRNA genes spp. First 3 days After Identification of

Role of pulmonary and late microbial presence in neonatal chronic Both early infection in the development of lung disease of prematurity lung fluid samples was significantly associated with the development ofBeeton ERJ 2011;37:1424 CLD suggesting that both ante- and post-natal OR for role in the development infection play a development of chronicof CLD. lung disease (CLD) of 5.1 5 – prematurity. 4 – 3 – 3.8 2.4 3.2 2 – 1 – 00 1.7 Presence of 16S Ureaplasma Presence of 16S Ureaplasma rRNA genes spp. rRNA genes spp. First 3 days After Identification of

Clarithromycin in Preventing Bronchopulmonary Dysplasiain Ureaplasma urealyticum–Positive Preterm Infants Ozdemir Pediatrics 2011;128:e1496 Nasopharyngeal swabs % infants with positive culture for for U. urealyticum. U.urealyticum developing BDP 224 infants with a 40 – p<0.001 birth weight between 750 and 1250 g in the first 3 postnatal days. 30 – 36.4% Infants with a positive 20 – culture randomly assigned to receive either intravenous clarithromycin or 10 – 2.3% placebo. 0 Clarithromycin Placebo

Clarithromycin in Preventing Bronchopulmonary Dysplasiain Ureaplasma urealyticum–Positive Preterm Infants Ozdemir Pediatrics 2011;128:e1496 Nasopharyngeal swabs % infants with positive culture for Multivariate logistic for U. urealyticum. U.urealyticum developing BDP regression analysis 224 infants with a p<0.001 40 – birth confirmed the weight between 36.4% independent 750 and 1250 g in the first 3 postnataleffect 30 – preventive days. of clarithromycin for Infants with a positive culture development of 20 – the randomly assigned to BPD receive (OR: 27.2, p=0.007 ). 10 – either intravenous clarithromycin or 2.3% placebo. 0 Clarithromycin Placebo

Clarithromycin in Preventing Bronchopulmonary Dysplasiain Ureaplasma urealyticum–Positive Preterm Infants Ozdemir Pediatrics 2011;128:e1496 Nasopharyngeal swabs % infants with positive culture for for U. urealyticum. Clarithromycin U.urealyticum developing BDP treatment prevents 224 infants with a 40 – p<0.001 development of BPD birth weight between 750 and 1250 g infants in preterm in the first 3 postnatal days. who are born at 30 – 36.4% 750 to 1250 g Infants with a positive culture colonized with 20 – and randomly assignedurealyticum. U. to receive either intravenous clarithromycin or 10 – 2.3% placebo. 0 Clarithromycin Placebo

Clarithromycin in Preventing Bronchopulmonary Dysplasiain Ureaplasma urealyticum–Positive Preterm Infants Ozdemir Pediatrics 2011;128:e1496 Nasopharyngeal swabs for U. urealyticum. % infants with positive culture for U.urealyticum 224 infants with a 40 – birth weight between 750 and 1250 g in the 33% first 3 postnatal days. 30 – Infants with a positive 20 – culture randomly assigned to receive either intravenous 10 – clarithromycin or placebo. 0

Clarithromycin in Preventing Bronchopulmonary Dysplasiain Ureaplasma urealyticum–Positive Preterm Infants Ozdemir Pediatrics 2011;128:e1496 Nasopharyngeal swabs % infants developing BDP for U. urealyticum. 224 infants with a 40 – birth weight between 750 and 1250 g in the first 3 postnatal days. 30 – 36.4% Infants with a positive 20 – culture randomly 15.3% assigned to receive 10 – either intravenous clarithromycin or 0 placebo. (+) (-) U.urealyticum

Perinatal Risk Factors for Bronchopulmonary Dysplasiain Extremely Low Gestational Age Infants: A PregnancyDisorder–Based Approach. Durrmeyer, J Pediatr 2012;160:578 % newborn developing BPD. 396 infants from 349 40 – pregnancies. 30 – Perinatal characteristics: 29% p<0.01 1) preterm labor; 20 – 2) pregnancy-associated vascular disorders such as 10 – 11% preeclampsia or fetal growth restriction. 00 vascular disease preterm labor group group

Perinatal Risk Factors for Bronchopulmonary Dysplasiain Extremely Low Gestational Age Infants: A PregnancyDisorder–Based Approach. Durrmeyer, J Pediatr 2012;160:578 Independent risk factors % newborn developing BPD. of BPD were 396 infants from 349 age a low gestational 40 – pregnancies. preterm in the 30 – Perinatallabor group characteristics: and severe growth 29% p<0.01 1) preterm labor; 20 – restriction in the 2) pregnancy-associated vascular disease group.as vascular disorders such 10 – 11% preeclampsia or fetal growth restriction. 00 vascular disease preterm labor group group

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights BeTranslated Into Therapies? Wright Pediatrics 2011;128:111The transcription factor NF-кB regulates the cellular response to inflammatory and oxidantstress, as well as stretch. Normally, NF-кB remains sequestered in the cytoplasm bound tomembers of a family of inhibitory proteins

Targeting Inflammation to Prevent Bronchopulmonary Dysplasia: Can New Insights BeTranslated Into Therapies? Wright Pediatrics 2011;128:111Efficacy of Selected Treatments for the Prevention of BPD

Lung function abnormalities in infants developingbronchopulmonary dysplasia May Arch dis Child 2011;96:1014 74 infants with a median gestational age of 30 weeks and birth weight of 1200 g. 35 had no BPD, 12 developed Infants developing BPD, mild BPD and 23 developed moderate/severe BPD, had moderate/severe BPD. lower mean FRC (p=0.009) and Lung function by functional lower mean compliance residual capacity (FRC) by (p=0.005) throughout the helium gas dilution on days 28-day period than those 3, 5, 7, 14, 21 and 28. who did not develop BPD.

Lung function abnormalities in infants developingbronchopulmonary dysplasia May Arch dis Child 2011;96:1014 Mean for 28-day period of 74 infants with a median FRC (ml/kg) 25 - gestational age of 30 weeks p=0.009 and birth weight of 1200 g. 20 – 35 had no BPD, 12 developed 20.8 mild BPD and 23 developed 15 – 17.1 moderate/severe BPD. 15.1 10 – Lung function by functional residual capacity (FRC) by 05 – helium gas dilution on days 00 3, 5, 7, 14, 21 and 28. No BPD Mild BDP Moderate /severe BDP

Lung function abnormalities in infants developingbronchopulmonary dysplasia May Arch dis Child 2011;96:1014 74 infants with a median gestational age of 30 weeks Mean for 28-day period of and birth weight of 1200 g. Compliance (ml/cm H2O/kg) 35 had no BPD, 12 developed 1.5 – p=0.005 mild BPD and 23 developed moderate/severe BPD. 1.0 – 1.30 Lung function by functional 0.93 0.88 residual capacity (FRC) by 0.5 – helium gas dilution on days 0 0 3, 5, 7, 14, 21 and 28. No BPD Mild BDP Moderate /severe BDP

Lung function abnormalities in infants developingbronchopulmonary dysplasia May Arch dis Child 2011;96:1014 Infants with 74 infants with a median gestational age of 30 weeks more severe Mean for 28-day period of and birth weight of 1200 g. Compliance (ml/cm H2O/kg) initial lung 35 had no BPD, 12 developed disease were 1.5 – p=0.005 mild BPD and 23 developed more likely 1.30 moderate/severe BPD. 1.0 – to develop Lung function by functional 0.93 0.88 moderate/severe 0.5 – residual capacity (FRC) by BPD. helium gas dilution on days 0 0 3, 5, 7, 14, 21 and 28. No BPD Mild BDP Moderate /severe BDP

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 1) Hypocarbia and/or hypercarbia are implicated as a causative factor in periventricular leukomalacia, intra-ventricular hemorrhage, and chronic lung disease. 2) Extreme fluctuations in partial pressure of arterial carbon dioxide (PaCO2) and higher max PaCO2 are associated with worse neurodevelopmental outcomes. Prevention of extreme hypocarbia and/or hypercarbia in preterm infants is essential.

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 3) Though arterial blood gas analysis is the gold standard of monitoring partial pressure of arterial oxygen (PaO2) and PaCO2, it leads to blood loss and iatrogenic anaemia, may cause procedural pain, and each sample is only a snapshot view of the sampling moment. 4) End-tidal carbon dioxide (ETCO2) measurement is a continuous and non-invasive indirect measurement of blood carbon dioxide tensions with fast response time to changes in blood CO2. 5) The principal determinants of ETCO2 are alveolar ventilation, pulmonary perfusion (cardiac output), and CO2 production.

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 Scatterplot (with identity line) of end-tidal CO2 and PaCO2 relationship r=0.69 p<0.0001 Simultaneous end-tidal and arterial CO2 pairs. 143 ventilated low birth weight infants (VLBWI).

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 Scatterplot (with identity line) of end-tidal CO2 and PaCO2 relationship r=0.69 p<0.0001 Simultaneous end-tidal There was a significant and arterial CO2 pairs. correlation 143(r = 0.69; P < 0.0001) ventilated low birth between ETCO2 and weight infants (VLBWI). PaCO2 values.

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 Bland-Altman plot of the difference between the end-tidal and arterial CO2 versus the average of the two simultaneous readings r=0.16 p=0.06 Simultaneous end-tidal and arterial CO2 pairs. 143 ventilated low birth weight infants (VLBWI).

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 Bland-Altman plot of the difference between the end-tidal and arterial CO2 versus the average of the two simultaneous readings r=0.16 p=0.06 But the ETCO2 value Simultaneous end-tidal andwas lower than the arterial CO2 pairs. corresponding PaCO2 143value in 94% pairs, ventilated low birth weight infants (VLBWI). with a mean bias of 13.5 ± 8.4 mmHg

End-tidal carbon dioxide monitoring in very low birthweight infants: Correlation and agreement with arterial carbon dioxide. Trevisanuto Pediatr Pulmonol 2012;47:367 Bland-Altman plot of the difference between the end-tidal and arterial CO2 versus the average of the two simultaneous readings ETCO2 should not Simultaneous end-tidal r=0.16 p=0.06 replace PaCO2 and arterial CO2 pairs. measurements in 143ventilated VLBWI, ventilated low birth weight may have a role but infants (VLBWI). to detect trends of PaCO2.

Nasal Intermittent Positive-Pressure Ventilation vs Nasal Continuous Positive Airway Pressure for Preterm Infants With Respiratory Distress Syndrome Meneses APAM 2012;166:372 RR of invasive ventilation infants (n=360) with respiratory distress 1.0 – syndrome 0.9 – 0.8 – nasal intermittent 0.7 – positive-pressure ventilation (NIPPV) vs 0.6 – 0.5 – 0.60 0.4 – nasal continuous positive 0.3 – airway pressure (NCPAP). 0.2 – 0.1 – 0 NIPPV vs NCPAP

Nasal Intermittent Positive-Pressure Ventilation vs Nasal Continuous Positive Airway Pressure for Preterm Infants With Respiratory Distress Syndrome Meneses APAM 2012;166:372 Nasal intermittent RR of invasive ventilation infants (n=360) with positive-pressure respiratory distress 1.0 – ventilation (NIPPV) syndrome 0.9 – nasal decreases the 0.8 – intermittent 0.7 – need for invasive positive-pressure ventilation within ventilation (NIPPV) vs 0.6 – 0.5 – 0.60 0.4 – nasal continuous positive the first 72 hours 0.3 – airway pressure (NCPAP). of life compared 0.2 – with NCPAP. 0.1 – 0 NIPPV vs NCPAP

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis Lee AJRCCM 2012;184:1390RationaleGastroesophageal reflux (GER) is highly prevalent in patientswith idiopathic pulmonary fibrosis (IPF). Chronic microaspirationsecondary to GER may play a role in the pathogenesis andnatural history of IPF.ObjectivesTo investigate the relationship between GER-related variablesand survival time in patients with IPF.

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis Lee AJRCCM 2012;184:1390 % patients with 50 –204 patients 40 – 45% 47% with idiopathic pulmonary 30 – 34% fibrosis (IPF). 20 – 10 – 5% 00 Reported History Reported use Nissen symptoms GERD of GERD fundoplication of GERD disease medication

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis Lee AJRCCM 2012;184:1390 % patients with 50 – Use of GER medications204 patients 40 – 45% 47% was an with idiopathic pulmonary independent 30 – 34% fibrosis (IPF). predictor 20 – of longersurvival time. 10 – 5% 00 Reported History Reported use Nissen symptoms GERD of GERD fundoplication of GERD disease medication

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis Lee AJRCCM 2012;184:1390 Survival time estimates based on presence or absence of GER symptoms. GER medication use Nissen fundoplication

Bilateral Spontaneous Pneumothoraces in a Healthy Young Adult Saenz AJRCCM 2012;184:1A 28-year-old male presented with sudden-onset of shortness of breath whilesitting in front of his computer. Chest X-ray revealed bilateral pneumothoraces(Fig.1). Left-sided thoracostomy was performed emergently, followed bycomplete resolution of the right-sided pneumothorax, and partial resolution onthe left (Fig.2). Figure 1 Figure 2

Bilateral Spontaneous Pneumothoraces in a Healthy Young Adult Saenz AJRCCM 2012;184:1To avoid bilateral recurrence, he underwent video-assistedthoracoscopic surgery with pleurodesis on the left side.The two pleural spaces are separated by the parietal pleura ofboth lungs and adipose tissue.In rare instances, there is a communication between the twopleural spaces, called ―buffalo chest,‖ in reference to NorthAmerican buffalos, which have a single pleural sac.It can be associated with cases of lung metastases, histiocytosis X,lymphangioleiomyomatosis, and chronic obstructive pulmonarydisease; or iatrogenic after thoracic surgery.Less frequently it is congenital, as in the case of our patient.

Clinical features of paediatric pulmonary hypertension: a registry study. Berger, Lancet 2012;379:537Background:• Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children.• The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension.

Clinical features of paediatric pulmonary hypertension: a registry study. Berger, Lancet 2012;379:537 % of patients with pulmonary hypertension and 100 – 90 – 80 – 88% 362 patients aged ≤18 yrs 70 – at diagnosis with pulmonary 60 – hypertension (mean pulmonary 50 – artery pressure ≥25 mm Hg). 40 – 31 centres in 19 countries. 30 – 20 – 12% 10 – 0 Pulmonary arterial Respiratory disease hypertension (PAH) or Hypoxaemia

Clinical features of paediatric pulmonary hypertension: a registry study. Berger, Lancet 2012;379:537 In patients with pulmonary arterial hypertension (PAH) 362 patients aged ≤18 yrs 60 – at diagnosis with pulmonary 50 – 57% hypertension (mean pulmonary 40 – artery pressure ≥25 mm Hg). 30 – 43% 31 centres in 19 countries. 20 – 10 – 0 Idiopathic [IPAH] Associated with or Familial [FPAH] other disorders

Clinical features of paediatric pulmonary hypertension: a registry study. Berger, Lancet 2012;379:537 In patients with pulmonary arterial hypertension (PAH) 362 patients aged ≤18 yrs 60 – 85% of cases at diagnosis with pulmonary 50 – 57% were associated pulmonary hypertension (mean with 40 – congenital heart artery pressure ≥25 mm Hg). 30 – 43% disease. 31 centres in 19 countries. 20 – 10 – 0 Idiopathic [IPAH] Associated with or Familial [FPAH] other disorders

Clinical features of paediatric pulmonary hypertension: a registry study. Berger, Lancet 2012;379:537 % Clinical symptoms at diagnosis 100 362 patients aged ≤18 yrs 80 at diagnosis with pulmonary hypertension (mean pulmonary 60 65% artery pressure ≥25 mm Hg). 40 41% 31 centres in 19 countries. 20 20% 18% 0 13%

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child Navarini CHEST 2011;140:1086Case Report: A hypotrophic 15-month-old Tunisian female child was referred to the emergency department with a first episode of apnea and cyanosis, resembling seizures or blue spells. At rest, she required 3 L/min oxygen to maintain a SaO2 > 92%; when stressed she desaturated down to 50%. She was tachydyspneic and had a palpable left parasternal lift and an accentuated pulmonary component of S2 (accentuation of the pulmonic component of the second heart sound).

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child Navarini CHEST 2011;140:1086 Chest radiograph. ECG showed right axis deviation and repolarization disturbances. Transthoracic Doppler echocardiography revealed severe pulmonary hypertension with an estimated pulmonary artery systolic pressure of 60-70 mm Hg.

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child Navarini CHEST 2011;140:1086 Chest radiograph. Normal-sized heart ECG showed right axis deviation and with ill-defined repolarization disturbances. diffuse increased lung density Transthoracic Doppler echocardiography revealed with resultant severe pulmonary hypertension poorly defined with an estimated pulmonary pulmonary vasculature. artery systolic pressure of 60-70 mm Hg.

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child Navarini CHEST 2011;140:1086 Chest radiograph. Right sided heart catheterization ECG showed right axis confirmed the diagnosis deviation and of pulmonary arterial repolarization disturbances. hypertension (PAH) (mean pulmonary artery Transthoracic Doppler pressure, 25 mmHg and echocardiography revealed elevated pulmonary severe pulmonary hypertension vascular resistance with an estimated pulmonary of 3 Wood units) with artery systolic pressure good vasoreactivity to of 60-70 mm oxygen. 100% Hg.

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry Brown CHEST 2011;140:19 Pulmonary arterial hypertension (PAH) is an uncommon disorder characterized by: • abnormal increases in pulmonary artery pressure (PAP); • normal pulmonary capillary wedge pressure (PCWP); • increased pulmonary vascular resistance (PVR). PAH results in right ventricular pressure/volume overload leading to right ventricular failure and death.

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry Brown CHEST 2011;140:19 % pts experiencing symptoms for >2 yrs before Common presenting symptoms of PAH was recognized Pulmonary arterial hypertension are dyspnea on exertion, edema, 30 – fatigue and chest pain. 2967 US adult patients with PAH, 20 – March 2006 - September 2007. 21.1% Patients were considered to have delayed disease recognition 10 – if > 2 yrs elapsed between symptom onset and the patient receiving a PAH diagnosis. 0

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry Brown CHEST 2011;140:19 % pts experiencing symptoms for >2 yrs before Common presenting symptoms of PAH was recognized Pulmonary arterial hypertension are dyspnea5on exertion, edema, 30 – 1 in patients fatigue and chest pain. diagnosed with PAH 2967 US adultsymptoms PAH, reported patients with 20 – March 2006 > September 2007. for - 2 yrs before their disease 21.1% Patients were considered to have was recognized. delayed disease recognition 10 – if > 2 yrs elapsed between symptom onset and the patient receiving a PAH diagnosis. 0

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry Brown CHEST 2011;140:19 OR for delayed diagnosis Common presenting symptoms of Pulmonary arterial hypertension 5 – are dyspnea on exertion, edema, 4 – fatigue and chest pain. 3 – 3.07 2967 US adult patients with PAH, March 2006 - September 2007. 2 – 1.93 1.72 Patients were considered to have 1 – delayed disease recognition if > 2 yrs elapsed between 0 Symptoms Obstructive Sleep symptom onset and the patient at age airways apnea <36 yrs disease receiving a PAH diagnosis.

Delay in Recognition of Pulmonary Arterial Hypertension: Factors Identified From the REVEAL Registry Brown CHEST 2011;140:19 OR for delayed diagnosis Common presenting symptoms of Pulmonary arterial hypertension Younger individuals 5 – are dyspnea on exertion, edema, and patients with 4 – fatigue and chest pain. histories of common 3.07 3 – respiratory disorders 2967 US adult patients with PAH, were most likely March 2006 - September 2007. 2 – to experience 1.93 1.72 Patients were considered to have 1 – delayed PAH delayed disease recognition recognition. if > 2 yrs elapsed between 0 Symptoms Obstructive Sleep symptom onset and the patient at age airways apnea <36 yrs disease receiving a PAH diagnosis.

Current approach to the diagnosis of acute nonmassive pulmonary embolism Moores CHEST 2011;140:5091) Pulmonary embolism (PE) is a common and potentially lethal disease.2) The presenting symptoms vary widely, ranging from the asymptomatic patient to those with obstructive shock and circulatory collapse.3) Patients presenting with systemic hypotension are categorized as having massive acute PE.4) Patients presenting with nonmassive PE, that is, those patients with normal systolic BP, either with (submassive) or without evidence of right ventricular dysfunction.

Current approach to the diagnosis of acute nonmassive pulmonary embolism Moores CHEST 2011;140:509Pretest probability and clinical decision rulesOptimal interpretation of many diagnostic tests is assisted byhaving an estimate of pretest probability (PTP) of disease. The signsand symptoms of PE are well known, but all lack sufficient sensitivityand specificity to be used in isolation. A recent analysis of >1700consecutive patients with suspected PE confirmed that no riskfactor, clinical sign, or symptom can rule in or out the diagnosisof PE. However, when used in combination, these factors canhelp us determine the overall likelihood of PE being present.

Current approach to the diagnosis of acute nonmassive pulmonary embolism Moores CHEST 2011;140:509D-dimer testingD-dimer is a degradation product of cross-linked fibrin, and thus itis elevated in acute thrombotic disorders. The strength of the testlies in its very high sensitivity (and, thus, high negative predictiveand negative LR values) that allows for the exclusion of venoustrombo-embolism in patients with lower pretest probabilities ofdisease.

Current approach to the diagnosis of acute nonmassive pulmonary embolism Moores CHEST 2011;140:509Diagnostic imagingCompression ultrasonography (CUS)CUS of the lower extremities is an inexpensive, noninvasive means ofdiagnosing venous trombo-embolism. Sensitivity and specificity ofCUS for deep venous trombosis in symptomatic patients is quitegood, with estimates of 89% to 96% and 94% to 99%, respectively.V/Q scanningV/Q scanning was the imaging modality of choice for diagnosis of PEfor decades, but it has largely been supplanted by CT pulmonaryangiography (CTPA) in recent years.

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury Budinger AJRCCM 2012;183:1043RationaleAcute lung injury and the acute respiratory distress syndromeare characterized by increased lung oxidant stress andapoptotic cell death.The contribution of epithelial cell apoptosis tothe development of lung injury is unknown.ObjectivesTo determine whether oxidant-mediated activation of theintrinsic or extrinsic apoptotic pathway contributes to thedevelopment of acute lung injury.

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury Budinger AJRCCM 2012;183:1043Oxidants generated in response to hyperoxia might activatethe intrinsic cell death pathway to induce mitochondrial outermembrane permeabilization.Activation of this pathway requiresoligomerization of the proapoptoticBcl-2 family members BAX or BAKon the outer mitochondrial membrane,allowing the release of cytochrome cand other proapoptotic proteinsfrom the mitochondrialintermembrane space into the cytosol. Cell apoptosis

Epithelial Cell Death Is an Important Contributor to Oxidant-mediated Acute Lung Injury Budinger AJRCCM 2012;183:1043 Hyperoxia O2 Overexpression of SOD2 prevents hyperoxia-induced BAX activation and cell death in primary alveolar epithelial cells and prolongs the survival of mice.mouse model ofoxidant-induced lung injury By contrast, Cyclophilin D–deficient mice were not protected from hyperoxia, indicating that opening of the mitochondrial permeability transition pore is dispensable for hyperoxia-induced lung injury.

Early Corticosteroids in Severe Influenza A/H1N1Pneumonia and Acute Respiratory Distress Syndrome Brun-Buisson AJRCCM 2012;183:1200RationaleDespite their controversial role, corticosteroids are oftenadministered to patients with adult respiratory distresssyndrome (ARDS) secondary to viral pneumonia.ObjectivesTo analyze the impact of corticosteroid therapy on outcomesof patients having ARDS associated with influenza A/H1N1Pneumonia.

Early Corticosteroids in Severe Influenza A/H1N1Pneumonia and Acute Respiratory Distress Syndrome Brun-Buisson AJRCCM 2012;183:1200 % patients received corticosteroids 208 critically 40 – ill patients with influenza 39.9% 30 – A/H1N1v 2009 83/208 infection, 20 – selected if fulfilling 10 – criteria for ARDS. 0

Early Corticosteroids in Severe Influenza A/H1N1Pneumonia and Acute Respiratory Distress Syndrome Brun-Buisson AJRCCM 2012;183:1200 HR for death 208 critically 2.5 – ill patients with influenza 2.0 – 2.4 A/H1N1v 2009 p=0.004 1.5 – infection, selected if 1.0 – fulfilling 0.5 - criteria for ARDS. 0.0 received corticosteroids

Early Corticosteroids in Severe Influenza A/H1N1Pneumonia and Acute Respiratory Distress Syndrome Brun-Buisson AJRCCM 2012;183:1200 Early corticosteroids therapy HR for death 208 critically (≤3 d of mechanical ventilation) 2.5 – ill patients more strongly appeared with influenza associated with mortality 2.0 – 2.4 A/H1N1v 2009 than late administration. p=0.004 1.5 – infection, Patients receiving selected if steroids had more 1.0 – fulfilling acquired pneumonia and 0.5 - criteria for a longer duration a trend to ARDS. of ventilation. 0.0 received corticosteroids

Early Corticosteroids in Severe Influenza A/H1N1Pneumonia and Acute Respiratory Distress Syndrome Brun-Buisson AJRCCM 2012;183:1200 Conclusions Our study provides no evidence of a beneficial effect of corticosteroids in patients with ARDS secondary to influenza pneumonia, but suggests that very early corticosteroid therapy may be harmful.

Corticosteroid Treatment in Critically Ill Patients with Pandemic Influenza A/H1N1 2009 Infection Analytic Strategy Using Propensity Scores Kim AJRCCM 2012;183:1207 % subjects receiving 245 adult patients with corticosteroids 50 – confirmed pandemic H1N1 admitted to the 40 – intensive care unit. With and without 30 – 44% corticosteroid 20 – 107/245 treatment 10 – retrospectively compared. 00

Corticosteroid Treatment in Critically Ill Patients with Pandemic Influenza A/H1N1 2009 Infection Analytic Strategy Using Propensity Scores Kim AJRCCM 2012;183:1207 Mortality 60 – 245 adult patients with confirmed pandemic 50 – 58% H1N1 admitted to the 40 – intensive care unit. P<0.001 30 – With and without corticosteroid 20 – 27% treatment 10 – retrospectively compared. 0 Given Not given steroids steroids

Corticosteroid Treatment in Critically Ill Patients with Pandemic Influenza A/H1N1 2009 Infection Analytic Strategy Using Propensity Scores Kim AJRCCM 2012;183:1207 Mortality The steroid group 60 – 245 more patients with was adult likely to have confirmed pandemic 58% superinfection, 50 – H1N1 admitted to the such as secondary 40 – intensive care unit. or bacterial pneumonia P<0.001 invasive fungal infection, With and without 30 – and had more prolonged corticosteroid 20 – 27% intensive care unit stays treatment than the retrospectively 10 – no-steroid group. compared. 0 Given Not given steroids steroids

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What 2012 pulmonology

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