RESPIRATORY ISSUES
From Contemporary and Future Pediatrics, presented January 26-31, 2005, by the University of Miami School of
Medicine, Department of Pediatrics and Department of Dermatology and Cutaneous Surgery
| UPDATE ON CYSTIC FIBROSIS— David Geller, MD, Assistant Clinical Professor of Pediatrics, Florida State University
College of Medicine, Pediatric Pulmonologist, and Director of the Cystic Fibrosis Center, Orlando, Florida
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| Overview: clinical symptoms of cystic fibrosis (CF)—malnutrition and/or malabsorption; recurrent respiratory tract infections
(eg, chronic sinusitis); male infertility; diagnosis—usually made by sweat chloride testing; genotyping; gene
sequencing; standard therapy—good nutrition; oral pancreatic enzymes to facilitate digestion; high-calorie diet; preservation
of lung function (airway clearance techniques and antibiotics as needed for infection)
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| Classic presentation: chronic sinusitis; severe recurrent bronchial infections; 3% to 5% of patients develop severe cirrhosis;
pancreatic insufficiency; 15% to 20% of patients have meconium ileus at birth; high sweat chloride values; obstructive
azoospermia from congenital bilateral absence of vas deferens (CBAVD); nonclassic—radiographic evidence of
chronic sinusitis (only 10% to 20% of patients symptomatic); airway disease milder and occurs later; may have adequate
pancreatic function for first several years
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| Prognostic factors: median predicted survival early-to-mid 30s; genetic—sex; pancreatic status; gene modifiers; most
common CF gene delta-F508; environmental—socioeconomic status; exposure to cigarette smoke; access to health care;
Pseudomonas infection; nutrition
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| Role of nutrition: stunted growth can occur in first year after birth; malnutrition associated with more severe lung disease;
treatment—high-protein and high-fat diets; fat soluble vitamins (A, D, E, and K); in patients with pancreatic insufficiency,
pancreatic enzymes; consider appetite stimulants
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| Pathophysiology: cystic fibrosis transmembrane conductance regulator (CFTR) essentially chloride pump (helps get chloride
out of cell); mutations occur along protein molecule (some cause protein to be made incompletely; some mutations
in regulatory portion of gene [gating mechanism for letting chloride in and out]); goal to have sufficient periciliary fluid
to move mucus properly; if regulatory portion of molecule not working well, gate will not open and close properly (no
water out); CFTR protein—in apical portion of cell membrane; sodium and water must pass through to hydrate mucus
layer on ciliary layer; periciliary fluid level allows cilia to move thin layer of mucus out of lungs; in CF, periciliary fluid
becomes dehydrated, and cilia do not work properly; less cough and mucociliary clearance; result thick mucus in lungs;
when chloride cannot get out of cell, sodium enters to balance sodium and chloride concentrations; water accompanies
sodium, which dehydrates salt layer; cascade effect—defective protein leads to decreased chloride secretion and increased
reabsorption of sodium and water, leading to bronchial obstruction by thick sticky mucus; poor movement leads
to infection; sticky mucus attractive to microorganisms; neutrophils release contents (including DNA; makes mucus
stickier); elastase destroys lung tissue and ability of antibodies to fight microbes (result, tissue damage and bronchiectasis)
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| Treatment targets: abnormal gene—gene replacement therapy (investigational); abnormal protein—protein rescue
(protein correction); getting proteins to surface apical membrane or to function better; alternative pathways—activation
of alternative chloride channels to humidify mucus (or to prevent sodium and water from being resorbed); controlling infection
and inflammation—antibiotics; anti-infective and anti-inflammatory medication (eg, high-dose ibuprofen); steroids
studied (problem of side effects); when all else fails, lung transplantation; chest physiotherapy—still best way to
prevent damage
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| Dornase alfa (Pulmozyme): breaks up long DNA molecule from neutrophils; makes mucus less sticky; study—in first
week or two, improvement in forced expiratory volume (FEV1 ) as high as 12% to 14%; few mild cases in study; early intervention
(study)—at end of 2 yr, 3% improvement in lung function
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| Pathogens: ≈40% of CF patients <1 yr of age colonized with Staphylococcus aureus; overall, by 1 yr of age, about one
third of patients have Pseudomonas aeruginosa in lungs (colonies in lung form biofilms that protect against antibiotics);
by adolescence, ≈80% of patients have Pseudomonas
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Pseudomonas Infection
| Symptoms: increased cough and sputum (sometimes, fever); appetite and weight loss; coughing up blood
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| Treatment overview: acute—treat 10 days to several months, depending on severity; intravenous (IV) antibiotics (usually,
combination that includes aminoglycoside and semisynthetic penicillin or cephalosporin); long-term—inhaled antibiotics;
daily pulmonary toilet to eliminate organisms and to suppress inflammatory response
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| Tobramycin: aminoglycosides inactivated by sputum (need high levels to kill organism); study by Mendelman—drug concentrations
in sputum 25-fold greater than minimum inhibitory concentration (MIC) needed to eliminate Pseudomonas
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 | Inhaled tobramycin (TOBI): delivers drug directly to source of problem (minimizes amount in systemic circulation);
study by Ramsey—group that received TOBI ≈12% better than group that received placebo; study by Moss—in first
6 mo, patients 13 to 17 yr of age 23% better than placebo; at end of 2 yr, FEV1 still 14% above baseline; group that did
not receive therapy initially did not catch up; each dose takes 20 min to administer; 30 to 40 mg of tobramycin needed
to eliminate P aeruginosa in lung of CF patient
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| Dry powder inhaler: spray-dried tobramycin with surfactant and perfluorocarbon; easily inhaled; avoids upper airway
deposition; simple device
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| Azithromycin for chronic P aeruginosa infection (study): patients with panbronchiolitis tend to have Pseudomonas in
airways; children <6 yr of age with FEV1 ≥30% of predicted; 250 mg or 500 mg azithromycin (Zithromax) 3 times/wk;
findings—improvement in FEV1 ; reduction in exacerbation rate and hospitalizations; weight gain
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More Management Tips
| Aztreonam for inhalation: eFlow is new aerosol device that cuts treatment time to 2 or 3 min; vibrating mesh technology
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| Hypertonic saline (study): 4 mL of nebulized hypertonic saline twice daily vs regular saline; nebulized formulation about
as effective as Pulmozyme (≈5% improvement in lung function after 1 yr); regular saline group also improved; possible
alternative to more expensive medications
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| More therapeutic approaches
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| Gene therapy: mechanisms used to target nucleus (adenovirus and adeno-associated virus; liposomes; DNA nanoparticles);
goal to avoid host immune response
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| Protein correction: goal to get protein to cell surface or to make it function better; gentamcin and congeners—used for
stop codon genes; exposure to gentamicin causes continued production of protein; sildenafil—corrects Ä-F508 CFTR
in nasal epithelial cells; off-label use; not clinically tested
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| Altered ion transport: stimulating alternative chloride channels or preventing sodium from being reabsorbed into cell; in
clinical development
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| Preventing tissue destruction caused by infection and inflammation: Pseudomonas vaccine (study)—30 patients received
vaccine yearly for 10 yr; no decline in lung function (unlike placebo); marked delay in colonization
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| Newborn screening (stool trypsinogen): study from Centers for Disease Control and Prevention [CDC] and CF Foundation);
benefits of early diagnosis and treatment—better overall nutrition and pulmonary function; less colonization
with P aeruginosa and fewer hospitalizations; problem of false positives; children diagnosed at 10 mo to 1 yr of age already
have growth stunting
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| NEW APPROACHES TO THE CARE OF CHILDREN WITH ASTHMA —Wayne J. Morgan, MD, Professor, Pediatrics
and Physiology, University of Arizona Health Sciences Center, Tucson; Chief, Pediatric Pulmonary Section, Arizona Respiratory
Center, and Director, Tucson Cystic Fibrosis Center
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Assessing Asthma Severity
| Study by Fuhlbrigge: Asthma Control Test (ACT) questionnaire able to assess asthma severity about as well as subspecialist
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Predicting Response to Specific Therapies
| Adult asthma clinical research network (ACRN): adverse effects of β-agonist medication (particularly albuterol) occur
more often in patients homozygous for arginine at amino acid 16 of β2 -adrenergic receptor
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| Single nucleotide polymorphism (SNP) study: 2 groups (homozygous for arginine or glycine) given regular albuterol or
placebo; ipratropium (Atrovent) used as needed; morning peak expiratory flow rate (PEFR) decreased when asthma less
controlled; those who received albuterol improved during treatment and continued to improve; glycine group—regular albuterol
use (which should be prn medicine) improved status off controller medications; arginine group—placebo group
off albuterol improved; group on albuterol did not improve, and worsened when albuterol stopped; in patients prescribed
albuterol, ≈16% homozygous for arginine, and may have difficult time if using albuterol regularly
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| Characterizing response to leukotriene receptor antagonist and inhaled corticosteroid (CLIC) study: leukotriene
receptor antagonist (montelukast [Singulair]) compared to inhaled corticosteroid (ICS; fluticasone [Flovent]); more responders
to fluticasone than Singulair
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| FEV1 response >5%: in predicting response, sicker patients had greater odds ratio of responding to fluticasone; no measures
predictive of response in montelukast; low lung function predicted 3.5 times greater likelihood of responding; almost
all biomarkers for inflammation (particularly exhaled nitric oxide [eNO]) predicted greater response
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| Conclusions: biomarkers of inflammation and lung dysfunction (FEV1 ) predict better response to fluticasone; for patient
with mild asthma, minimal inflammation, and allergic rhinitis, consider Singulair (in more severe disease, fluticasone)
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Role of eNO
| Introduction: NO produced by many cells in lung, but particularly by respiratory epithelium; increases in presence of inflammation
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| Exhaled NO and biomarkers of atopy (study by Strunk): IgE correlation of 0.48 or 0.5; nice correlation between absolute
number of eosinophils in blood and eNO
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| Childhood Asthma Management Program (CAMP) study (subanalysis by Covar): issue whether airway remodeling preventable
by using budesonide (compared to nedocromil or placebo); findings—no remodeling in placebo group; inhaled steroids
improved outcomes but did not cause remodeling; at end of study, lower eNOs (normal <20 parts per billion [ppb]) in
group that received budesonide (inhaled steroid; placebo and nedocromil comparable); once budesonide discontinued, washout
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New Medications to Modify Inflammatory Cascade
| Introduction: TH 1 lymphocytes fight infection (particularly viruses; TH 2 lymphocytes more for allergy inciting parasites); in
asthma, both acting, but asthmatics particularly characterized by having more TH 2 type disease; interleukin (IL)-12 or interferon
(INF)-γ hygiene hypothesis suggests immunomodulation possible in utero and early ex utero; ongoing study looking
at early sublingual immunization to prevent development of asthma; eosinophils key to airway inflammation; however, in recent
study, asthma unchanged despite elimination of eosinophils in airway using IL-5 blocker; montelukast affects single
component in cascade (immune system pathways redundant)
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| Omalizumab: humanized monoclonal anti-IgE; basophils release cytokines when stimulated by multivalent allergen; attaches
to IgE so that it cannot bind with basophils; reduces frequency of exacerbations and need for steroid medication;
currently used in most severe nonresponsive patients
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| New steroids on horizon: loteprednol—safe and effective in allergic rhinitis; inactive metabolites do not affect hypothalamic-pituitary-adrenal
(HPA) axis (side effect of adrenal suppression less likely); ciclesonide—inhaled steroid; prodrug
activated in airway epithelium by esterases of lungs; may be highly efficacious because of lung deposition and binding affinity
to glucocorticoid receptor (GCR); oral bioavailability negligible
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Preventing Persistent Asthma in Toddlers with Recurrent Wheeze
| Patients at risk: children who wheeze persistently in infancy and at 6 yr of age have 20 times greater risk for asthma; effective
interventions must begin early in childhood
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| Prevention of Early Asthma in Kids (PEAK) study design: high-risk, recurrent wheezers 2 to 4 yr of age given low-dose
fluticasone for 2 yr; at end of secondary prevention treatment, drug discontinued and patients observed for 1 yr to see
whether asthma returns; study ongoing
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Allergen Immunotherapy (AIT) in Pediatric Asthma
| Cochrane Database of Systematic Reviews: 75 trials (concealment of allocation only in 15); in those, AIT associated with
reduction in asthma symptoms, medication, and bronchial hyperreactivity; no consistent effect on lung function; in 1 trial,
benefit possibly comparable to inhaled steroids
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| Conclusions and caveats: not known whether effect of ATT same in patients receiving corticosteroids as in those who are not;
limit prophylaxis to specific extracts of unavoidable, clinically relevant allergen; consider AIT in monoallergic asthmatic who
cannot avoid exposure or in children who fail conventional asthma care
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Doubling ICS Dose with Early Exacerbation
| Study by Harrison: 390 participants ≥16 yr of age; over 12 mo, 53% had deterioration and exacerbation; primary outcome
number of participants who needed oral prednisolone (number no different whether or not ICS doubled); no difference in
mean peak flow or symptoms
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| Managing early and/or mild exacerbations (speaker’s approach): 80% of exacerbations viral induced; administer β-agonist
every 3 to 4 hr for 24 hr; if asthma worsens or persists >24 hr, 1 mg/kg prednisolone for 4 to 5 days; at present, literature
does not support doubling dose of ICS
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Educational Objectives
| The goal of this program is to educate the listener about selected respiratory diseases. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Describe the clinical diagnosis of cystic fibrosis in children.
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| 2. Describe the pathophysiology of cystic fibrosis.
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| 3. Choose appropriate therapy for cystic fibrosis.
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| 4. Describe new medications for managing asthma in children.
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| 5. Describe new devices for delivering asthma medication.
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Discussed on This Program
Albuterol (salbutamol sulphate in United Kingdom) (several formulations and trade names)
Azithromycin [Zithromax]
Aztreonam [Azactam]
Beractant (natural lung surfactant) [Survanta] 9/27/05
Budesonide (several formulations and trade names) Dornase alfa (recombinant human deoxyribonuclease; DNase)
[Pulmozyme]
Ciclesonide ( investigational) [Alvesco]
Fluticasone propionate (several formulations and trade names)
Gentamicin sulfate (several formulations and trade names)
Ibuprofen (several formulations and trade names)
Ipratropium bromide [Atrovent]
Loteprednol etabonate [Alrex, Lotemax]
Montelukast sodium [Singulair]
Nedocromil sodium [Alocril, Tilade]
Omalizumab [Xolair]
Prednisolone (several formulations and trade names)
Sildenafil citrate [Viagra]
Tobramycin sulfate (several formulations and trade names)
Suggested Reading
Abramson MJ et al: Allergen immunotherapy for asthma. Cochran.Database Syst Rev 4:CD001186, 2003; Bacharier LB
et al: Hospitalization for asthma: atopic, pulmonary function and psychological correlates among participants in Childhood
Asthma Management Program. Pediatrics 112:e85, 2003; Covar RA et al: Relations between exhaled nitric oxide and measures
of disease activity among children with mild-to-moderate asthma. J Pediatr 142:469, 2003; Demko CA et al: Gender
differences in cystic fibrosis: Pseudomonas aeruginosa infection. J Clin Epidemiol 48:1041, 1995; Fuhlbrigge AL:
Asthma severity and asthma control: symtoms, pulmonary function, and inflammatory markers. Curr Opin Pulm Med 10:1,
2004; Geller DE et al: Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an
improved drug delivery system. Chest 123:28, 2003; Geller DE et al: Pharmakokinetics and bioavailability of aerosolized tobramycin
in cystic fibrosis. Chest 122:219, 2002; Gruchalla RS et al: Inner City Asthma Study: relationships among sensitivity,
allergen exposure, and asthma morbidity. J Allergy Clin Immunol 115:478, 2005; Guilbert TW et al: Atopic
characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol
114:1282, 2004; Guilbert TW et al: The Prevention of Early Asthma in Kids study: design, rationale and methods for
the Childhood Asthma Research and Education network. Control Clin Trials 25:286, 2004; Harrison TW et al: Doubling
the dose of inhaled corticosteroid to prevent asthma exacerbations: randomized controlled trial. Lancet 363:271, 2004; Israel
E et al: Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomized, placebo-controlled cross-
over trial. Lancet 364:1505, 2004; Mendelman PM et al: Aminoglycoside penetration, inactivation, and efficacy in cystic fibrosis
sputum. Am Rev Respir Dis 132:761, 1985; Milla CE et al: Trends in pulmonary function in patients with cystic fibrosis
correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 162:891, 2000; Moss RB et al:
Long-term benefits of inhaled tobramycin in adolescent patients with cystic fibrosis. Chest 121:55, 2002; Quan JM et al: A
two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities.
J Pediatr 139:813, 2001; Rabin HR et al: Pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol 37:400,
2004; Ramsey BW et al: Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled
Tobramycin Study Group. N Engl J Med 340:23, 1999; Saiman L et al: Azithromycin in patients with cystic fibrosis
chronically infected with Pseuodomonas aeruginosa: a randomized controlled trial. JAMA 290:1749, 2003; Schechter MS
et al: The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States. Am J Respir Crit
Care Med 163:1331, 2001; Strunk RC et al: Relationship of exhaled nitric oxide to clinical and inflammatory markers of
persistent asthma in children. J Allergy Clin Immunol 112:883, 2003; Szefler SJ et al: Characterization of within-subject responses
to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 115:233, 2005; Taussig LM et al: Tucson
Children’s Respiratory Study: 1980 to present. J Allergy Clin Immunol 111:661, 2003;
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. Dr. Geller has participated
in the Speakers’ Bureaus for AstraZeneca, Chiron, Genentech, and GlaxoSmithKline; he has been a consultant for PARI
and Chiron and has received research grants from AstraZeneca, Chiron, Genentech, Aventis, PARI, Trudell Medical, Boehringer
Ingelheim, Corus Pharamceuticals, and Peninisula. Dr. Morgan has been a consultant to Genentech.
Drs. Geller and Morgan were recorded at Contemporary and Future Pediatrics, presented January 26-31, 2005, in Bal
Harbour, Florida, by the University of Miami School of Medicine, Department of Pediatrics and Department of Dermatology
and Cutaneous Surgery. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the
production of this program.
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