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Asthma Update

Asthma Update. Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi, USA JLArnold@umc.edu. Disclosures . AAFA No other disclosures or industry affiliations. Objectives .

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Asthma Update

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  1. Asthma Update Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi, USA JLArnold@umc.edu

  2. Disclosures AAFA No other disclosures or industry affiliations

  3. Objectives At the conclusion of this presentation, participants should: 1. Be familiar with recent studies on the use of anticholinergic medications in asthma 2. Be able to discuss the relationship between ICS and growth in children 3. Be able to interpret current data on acetaminophen and asthma

  4. All asthmatics are not created equally • Where we’ve been: • Homogenous asthma manifested by bronchospastic obstruction…mucus, inflammation • Owl’s blood in wine, tobacco, coffee/tea, Indian hemp, ether or opium; then systemic steroids, theophylline and SABA… then ICS with and without LABA • Control based on lung function and symptomatology

  5. All asthmatics are not created equally Where we’re going: • Asthma is heterogeneous- • Differences in pathology, symptomatology, response to therapy and prognosis (Lotvall, JACI 2011) • 70-95% w/ mild to moderate ds- managed with ICS and beta 2 • 5-35% fail standard tx: severe disease or “refractory” asthma (Morjariaet al, COACI 2011) • Mixed inflammatory: • Cells (neutrophils, eosinophils and basophils) • Cytokines (interleukin [IL]-4, and chemokines) • B-cells and activated T-cells [Th1, Th2, Th17] (Durrani &Busse ,Chest, 2011)

  6. All asthmatics are not created equally • Influence of co-morbidities • Obesity, CRS, GERD- • Atopy not as big an influence as we thought (Turato AJRCCM 2008) • Routine ICS fail to alter remodeling (Guilbert NEJM 2006, Murray Lancet 2006) • Definition of control? - dual domains: • QOL, symptoms and exacerbations • Preservation (or loss ) of lung function , exacerbations and medication risk/SE (Durrani, 2011)

  7. Asthma Heterogeneity and Phenotyping • Asthmatics w/ 1° neutrophilic inflammation are: • More steroid resistant than eosinophilic asthmatics. • More likely to have severe asthma with more acute exacerbations (Wenzel, 2006; Gibson, 2009). • Asthmatics who smoke are more likely to have asthma resistant to low dose ICS (Tomlinson et al., 2005; Lazarus et al., 2007).

  8. First Things First • Current step up tx from a low dose ICS: • Either double the glucocorticoid dose • or add a LABA (or leukotriene inhibitor) • ICS have a “relatively flat dose–response curve”; controversial • LABAs are controversial (B16-Arg/Arg) • Taking a new look at an old drug: anticholinergics Smith, L. Anticholinergicsfor Patients with Asthma? New Engl J Med Oct., 2010; 363:1764-1765

  9. Tiotropium bromide step-up therapy for adults with uncontrolled asthma Peters, SP. et al. 2010, N. Engl. J. Med. 363, 1715-1726 • 200 poorly controlled asthmatics • 3 arms: tiotropium + ICS salmeterol + ICS doubled the ICS per NAEPP • As effective as adding salmeterol and more effective than doubling the ICS

  10. Tiotropium versus Salmeterolfor the Prevention of Exacerbations of COPD Vogelmeier, C., et al., N Engl J Med. March 2011; 364:1093-1103 • 1-year, randomized, D-B, D-D, parallel-group • Compared # of moderate or severe exacerbations in ptswith moderate-to-very-severe COPD & hxof exacerbations in the preceding 12 months • 7, 376 patients randomly assigned • Tiotropium (n=3707) or Salmeterol (n= 3669) • Tiotropium more effective than Salmeterol: • Increased time to first exacerbation (187 days vs 145) • Reduced annual # of exacerbations (0.09 vs 0.13) • Incidence of adverse events similar (64 deaths/1.7% vs 78/2.1%)

  11. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial Kerstiens, H. et al., JACI, Aug 2011; 128 (2): 308-314 • R, D-B, P-C crossover study; 107 pt., 54% F, mean 55 y/0 • 1º endpoint peak FEV1 • 3 arms: tx for eight weeks each • Original meds (@ least ICS + LABA) + tiotropium 5 mcg + tiotropium 10 mcg + placebo • Both doses of tiotropium once daily “significantly improves lung function”…”in pt. w/ inadequately controlled severe, persistent asthma.”

  12. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma Bateman ED, et al. JACI 2011 Aug; 128 (2): 315-322 • 16 week, D-B,D-D, P-C trial in 388 (B16-Arg/Arg) asthmatics not controlled on ICS alone; 18-67 yr • After 4 week run in w/ BID salmeterol MDI, • Randomized 1:1:1 & compared salmeterol + ICS (n=134) tiotropium + ICS (n=128) placebo + ICS (n= 125)

  13. Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma Measured weekly AM PEF: 1º endpoint PEF Tiotropium -3.9 ± 4.87 L/min Salmeterol - 3.2 ± 4.64 L/min Placebo -24.6 ± 4.84 L/min Tiotropium and salmeterol were roughly equivocal Both were significantly more effective than placebo

  14. Future for triple inhalers? Barnes, Peter J. w/ NHLBI Expert Review article (Expert Rev. Respir. Med 5 (3), 297-300 (2011) @ www.expert-reviews.com First triple inhaler containing formoterol, tiotropium and ciclesonide (Triohale, Cipla) marketed in India Too soon to tell, but data might support using tiotropium as add on therapy in certain phenotypes/severe asthmatic poor responders

  15. Steroid use in growth of children • 2000 N Engl J Med; Agertoft and Pederson • 211 children over 10 years- 142 w budesonide 18 control pt w/asthma never ICS 51 siblings w/o asthma • Children w/asthma treated w/ long term budesonide reached nl adult height • 2011 JACI; Guilbertet al. • Are certain subgroups of children @ higher risk from ICS? • Children 2 and 3 years old w/ recurrent wheezing (high risk for asthma) • Two arms: fluticasone x 2 years vs placebo • Followed for 2 years after ICS d/c’d • Overall, no diff. in linear growth b/w ICS or not • Children < 15 kg did have significantly less linear growth than placebo or children > 15 kg

  16. Acetaminophen and Atopy: Causality or Commonality? Shaheen, S. et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorhpisms and childhood asthma. JACI, Dec. 2010; 126(6): 1141-1148. British Avon Longitudinal Study of Parents and Children (ALSPAC) 14000 children from utero to 8th year Mother reported acetaminophen exposure in utero and early childhood, hx of early wheezing, allergy and asthma s/s, environmental exposures and family lifestyles. PFT, blood or skin tests for allergies and genetic testing of mother and child b/w ages 7 and 8 yrs. Longitudinal association w/ childhood asthma was limited to children who had wheezed in infancy- Suggests casual relationship

  17. Paracetamol, non-steroidal anti-inflammatory drugs, and risk of asthma in adult survivors of childhood cancer • Marquis, A. et. al, JACI Jan. 2011; 127(1): 270-272 • 1293 young adults “cured from CA” from Swiss Childhood Cancer Registry • < 16 at time of dx; > 16 @ time of survey;@ least 5 yrs post diagnosis • PMH of asthma, frequency and type of analgesics: • Paracetamol alone • Nonaspirin NSAIDs alone • ASA alone • Or different combinations of these three • Found a positive association b/w non-ASA NSAIDs and asthma = paracetamol and asthma; if this is causal, not limited to acetaminophen. • Most likely explanation is confounding by indication- more studies needed

  18. Respiratory tract infections and not paracetamol medication during infancy are associated with asthma development in childhood Schnabel, E. and Heinrich, J.; JACI Nov. 2010; 126(5): 1071-1073. 3097 healthy full term infants under Influences of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood (LISA) Birth – 6 years; monthly diaries of febrile illnesses, type & medication use Measured IgE to common inhalants at 2 and 6 years age by CAP-RAST < 5% of these children were tx with anything other than acetaminophen Children with asthma had > fever than non-asthmatics No correlation b/w allergic sensitization and acetaminophen Suggests increased incidence of URI and febrile illnesses in asthmatic children more likely source of association.

  19. Upcoming therapies under investigation

  20. Upcoming therapies under investigation

  21. Case study 30 year old male born early @ 2#; early wheezer; frequent URI with normal immune system work up- lost to FU age 5-15 yrs. Formally diagnosed with asthma as teenager 3 hospitalizations over the last 5 years; 1 ICU (6 months ago)- no intubations Maximum ICS with LABA combination, leukotriene inhibitor and PPI; pharmacy records indicate appropriate med. refill rates Skin test mildly positive to DM but not impressive Co-morbidities include GERD, obesity and nasal polyposis Labs: normal CBC with exception of mildly elevated peripheral blood eosinophils, normal CMP but moderately elevated IgE

  22. He asks you if there is any hope for him to live a normal life, stay out of the hospital and play sports with his newborn sons one day… You tell him: 1. Only if you take your medications! Your lack of asthma control indicates you’re non-compliant 2. Only if you lose weight! Your obesity makes it impossible to adequately treat you. 3. Hang in there! There is a lot of research currently underway that is specifically targeted towards difficult to control asthmatics and it looks promising. We’re gaining more understanding of which therapies are better suited for you and making progress. Lets schedule a visit with your doctor to sit down and discuss options.

  23. Resources Apter, A. Advances in adult asthma diagnosis and treatment and HEDQ 2010. J Allergy Clin Immunol, 2011 , Jan; 127(1): 116-122. Bateman ED, Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011 Aug;128(2):315-22. Barnes PJ. Triple inhalers for obstructive airways disease: will they be useful? Expert Rev Respir Med. 2011 Jun;5(3):297-300. No abstract available. PMID: 21702649 Corren, J., et al.Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge. J Allergy Clin Immunol. 2011, Feb;127(2):398-405. (www.ncbi.nlm.nih.gov/pubmed/21281870) Cox, Linda S., How Safe are the Biologicals in Treating Asthma and Rhinitis? Allergy, Asthma & Clinical Immunology 2009, 5:4 (doi:10.1186/1710-1492-5-4)

  24. Resources Durrani, S., Busse, W. ; Biological Therapy for Asthma. Chestnet.org. PCCSU Article | 03.15.11; volume 25 online. Garcia-Marcos, L., et al. Early exposure to acetaminophen and allergic disorders. Curr Opin Allergy Clinic Immunolo. June, 2011; 11(3): 162-173. Gonem S, et al. Evidence for phenotype-driven treatment in asthmatic patients.. Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):381-5. Review. PMID: 21670666 Guilbert, T., et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. JACI 2011, Nov; 128(5): 956-963. Kerstjens HA, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011 Aug;128(2):308-14. Epub 2011 Jun 2.

  25. Resources Marquis, A., et al. Paracetamol, nonsteroidal anti-inflammatory drugs and the risk of asthma in adult survivors of childhood cancer. J Allergy Clin Immunol 2011 Jan; 127 (1): 270-272. Maneechotesuwan K, et al. Bronchodilator effect of Ipraterol on methacholine-induced bronchoconstriction in asthmatic patients. J Med Assoc Thai. 2011 Feb;94 Suppl 1:S66-71. Morjaria, J, et al.Stratified Medicine in Selecting Biologics for the Treatment of Severe Asthma. CurrOpin Allergy CliniImmunolo. 2011; 11(1): 58-63. (www.medscape.com/viewarticle/735050) Shaheen, S., et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol. 2010 Dec; 126(6): 1141-1148. (http://www.jacionline.org/article/S0091-6749(10)01408-9/fulltext) Schnabel, E. Heinric, J. Respiratory tract infections and not paracetamol medications during during infancy are associated with asthma development in childhood. JACI. 2010 Nov; 126 (5) 1071-1073.

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