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Chronic respiratory disease, ics and risk of ntm2

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Chronic respiratory disease, ics and risk of ntm2 Chronic respiratory disease, ics and risk of ntm2 Presentation Transcript

  • Chronic Respiratory Disease,Inhaled Corticosteroids and Risk ofNon-tuberculous Mycobacteriosis (NTM)臨藥科技所 碩一 陳秋縈指導老師 張慧真主任Feb 6th, 2013
  •  Background Chronic respiratory disease and ICS therapy for COPD increase the risk ofpneumonia. Limited data on NTM. Objective Examine different type of chronic respiratory disease and ICS therapy as riskfactors for NTM pulmonary disease Study design Population-based case-control study Study population All adults in Denmark with microbiologically confirmed NTM pulmonarydisease between 1997 and 2008ICS: inhaled corticosteroidsNTM: Nontuberculous MycobacteriaChronic respiratory disease, inhaled corticosteroids and risk ofnon-tuberculous mycobacteriosis (NTM)Thorax. 2012 Jul 10.ORIGINAL ARTICAL2
  • Results Risk is increased in patient with chronic respiratory disease OR for NTM pulmonary diseaseAny chronic respiratory disease 16.5 (95% CI 12.2 to 22.2)− Bronchiectasis 187.5 (95% CI 24.8 to 1417.4)− Tuberculosis history 178.3 (95% CI 55.4 to 574.3)− COPD 15.7 (95% CI 11.4 to 21.5)− Pneumoconiosis 9.8 (95% CI 2.03 to 52.8)− Asthma 7.8 (95% CI 5.2 to 11.6) Among COPD patients, risk is associated with use, dose and type of ICS OR for NTM pulmonary disease regard to COPD and ICS use− Use: concurrent ICS vs. never received ICS 29.1 vs. 7.6− Dose: low-dose ICS vs. high-dose ICS 28.1 vs. 47.5− Type: OR was higher for fluticasone than for budesonide 31.0 vs. 19.8 Conclusion Chronic respiratory disease, particularly COPD treated with ICS therapy, is astrong risk factor for NTM pulmonary disease.3
  • Inhaled Corticosteroids (ICS) and risk ofpulmonary infection in COPD4
  • ICS Increase Risk of Pulmonary Infection in COPDPossible mechanism ICS Achieve locally high concentrations in the lung which may lead to localimmunosuppressive effects COPD Persistent inflammation causing airway and mucosal damage Compromising local immunity Impaired clearance of secretions Susceptible patient to high risk of colonization with pathogenic5
  •  Increased risk of pneumonia associated with3 Any inhaled corticosteroid (RR 1.57, 95% CI 1.41-1.75, NNH 33-60) Fluticasone (RR 1.67, 95% CI 1.47-1.89, NNH 28-53) For budesonide No significant association with increased risk of pneumonia2,3 Budesonide/Formoterol reported to have lower risk of pneumoniathan Fluticasone/Salmeterol in patients with COPD 1 Increased risk of pneumonia is not accompanied by acorresponding increase in mortality3,41. Int J Clin Pract 2011 Jul;65(7):7642. Lancet 2009 Aug 29;374(9691):7123. Curr Opin Pulm Med 2010 Mar;16(2):1184. Arch Intern Med 2009 Feb 9;169(3):219ICS Increased Risk of Pneumonia in COPDLiterature review6
  • Risk of Pneumonia Between Different Types of ICSPossible mechanism Potency and dosage Effect of delivery devices− Primary determinants of the dose delivered to the lungs− ex. Lung delivery of metered-dose inhaler (MDI): 20 % Pulmonary retention time Removed from the lungs before it substantially downregulateslocal immunity and allows proliferation of bacteriaProc Am Thorac Soc. 2004;1(4):356-63.Ann Pharmacother. 2009 Mar;43(3):519-27 7
  • Potency and Estimated Comparative Daily Dosages for ICSComparative daily dose (mcg)DrugRecepterbinding affinityLow Medium HighBeclomethasone MDI 0.4/13.5 80 -240 240 -480 >480Budesonide DPI 9.4 200 -600 600 -1200 >1200Ciclesonide MDI 0.12/12.0 80 -320 320 -640 >640Flunisolide MDI 1.8 320 320 -640 >640FluticasoneMDIDPI18 88 -264100 -300264 -440300 -500>440>500Mometasone DPI 23 220 440 >440Adapted from National Asthma Education and Prevention Program: Expert Panel Report III: Guidelines for the diagnosis and management ofasthma. Bethesda, MD. National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051)www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on December 6, 2012). Potency depends on their receptor-binding affinity Potency is the major determinants of the relative comparabledoses8
  • Risk of Pneumonia Between Different Types of ICSPossible mechanism Potency and dosage Effect of delivery devices− Primary determinants of the dose delivered to the lungs− ex. Lung delivery of metered-dose inhaler (MDI): 20 % Pulmonary retention time Removed from the lungs before it substantially downregulateslocal immunity and allows proliferation of bacteriaProc Am Thorac Soc. 2004;1(4):356-63.Ann Pharmacother. 2009 Mar;43(3):519-27 9
  • Comparison of Delivery DevicesDevice Advantages DisadvantagesMDISlow deep inhalation• Portable• Convenient• Nonbreath-activated• Patient coordination essential• High pharyngeal deposition• Difficult to deliver high dosesDPIRapid deep inhalation• Portable• Convenient• Breath-activated• Propellant not required• Difficult to deliver high doses• High pharyngeal deposition• Cannot use with endotracheal ortracheostomy tubesNebulizer• Patient coordination not required• High doses possible• Expensive• Contamination possible• Device preparation requiredMDI: Metered-dose inhaler DPI: Dry powder inhalerTerbuhalerAccuhalerEvohaler10
  • Risk of Pneumonia Between Different Types of ICSPossible mechanism Potency and dosage Effect of delivery devices− Primary determinants of the dose delivered to the lungs− ex. Lung delivery of metered-dose inhaler (MDI): 20 % Pulmonary retention time Removed from the lungs before it substantially downregulateslocal immunity and allows proliferation of bacteriaProc Am Thorac Soc. 2004;1(4):356-63.Ann Pharmacother. 2009 Mar;43(3):519-27 11
  • Pharmacodynamic/Pharmacokinetic Properties of ICSAnn Pharmacother. 2009 Mar;43(3):519-27.Proc Am Thorac Soc. 2004;1(4):356-63. Retention of ICS in the lung Lipophilicity, Lipid Conjugation Distribution into the lipophilic tissues of the lung and slow absorption intothe systemic circulationFluticasone is 6 to 8 times more lipophilic than budesonide.Budesonide is more rapidly cleared from airways than fluticasone.12
  • 本院吸入性類固醇品項Drug Device Dose per container Indication Dosage Cost /botBudesonide(Pulmicort Turbuhaler)200mcg/doseDPI 100 doses/btl AsthmaAdult: 200-400 mcg bidChild: 50-200 mcg bid366Budesonide(Duasma)200mcg/puffMDI 200 puffs/btlAsthma Adult: 200-400 mcg bidChild 6-12 yr: 100-200 mcg bid394Budesonide(Pulmicort Respule)1mg/2ml/ampNebulizer Once AsthmaAdult: 0.5-1 mg bidChild 6-12 yr: 0.25-0.5 mg bid67Fluticasone(Flixotide Accuhaler)250mcg/doseDPI 60dose/btlAsthmaAdult: 100-1000 mcg bid250mcg 不適用於兒童Children: 50-100 mcg bid545Salmeterol + Fluticasone(Seretide Evohaler)25/50mcg/dose25/250mcg/doseMDI 120dose/btlAsthmaCOPD Adult and child≧4 yr: 2puff bidAdult and child≧12 yr: 2puff bid8191433Salmeterol + Fluticasone(Seretide Accuhaler)50/250mcg/doseDPI 60 doses/btlAsthmaCOPDAdult and child≧ 4 yr: 1 puff bid 1060Formoterol + Budesonide(Symbicort Turbuhaler)4.5/160mcg/doseDPI 120dose/btlAsthmaCOPDAdults & children > 12 yrs, 1-2doses bid1257Beclomethasone + Formoterol(Foster)100/6mcg/doseMDI 120dose/btl AsthmaAdult≧18yr: 1-2 puff bid需冷藏,拆封後室溫保存可達5個月99213
  • NontuberculousMycobacteria (NTM) Introduction Epidemiology Diagnostic criteria Treatment14
  • Nontuberculous Mycobacteria (NTM) Mycobacteria other than M. Tuberculosis and M. Leprae More than 140 NTM species identified One third have been associated with disease in humans Environmental organisms found in water and soil Not contagious: no evidence of human-to-humantransmissionAm J Respir Crit Care Med. 2007;175:367–416.Uptodate 15
  • Classification of NTM Rapidly growing mycobacteria (RGM) M. abscessus, M. chelonae, M. fortuitum Slowly growing mycobacteria (SGM) Photochromogens− M. kansasii, M. Marinum, M. Simiae, M. asiaticum Scotochromogens− M. scrofulaceum, M. xenopi, M. szulgai, M. flavscens, M. gordonae Nonchromogens− M. avium complex (MAC), M. Malmoense, M. Ulcerans, M. Terrae complexUptodate16
  • Clinical Manifestation of NTM Disease Pulmonary disease (most common ) Especially in older persons M. avium complex (MAC), M. kansasii, M. abscessus Probably acquired by aerosol inhalation Superficial lymphadenitis Especially cervical lymphadenitis Children: MAC, M. scrofulaceum Skin and soft tissue infection Usually as a consequence of direct inoculation M. marinum, M. ulcerans, RGM spp Disseminated disease HIV infectionAm J Respir Crit Care Med. 2007;175:367–416.17
  • Predisposing factors to NTM lung infection Underlying lung disease and altered mucociliary clearance COPD, bronchiectasis, cystic fibrosis, pneumoconiosis, previous TB,esophageal motility disorders Immune deficiency HIV infection: reduced CD4 T-lymphocyte (usually <100/μL) Defects in IFN- γ, IL-12, TNF-α Immunosuppressive drugs Other underlying conditions Malignancy, alcohol abuseAm J Respir Crit Care Med. 2007;175:367–416.18
  •  Increased NTM isolation and decreased TB isolation From 32.3% to 49.8% (p<0.05) Increased disease incidence, predominately pulmonary NTMdisease All NTM disease: from 2.7 to 10.2 per 100,000 pt (p<0.0001) Pulmonary NTM disease: from 1.26 to 7.94 per 100,000 (p= 0.0194)Emerg Infect Dis. 2010 Feb;16(2):294-6.Epidemiologic Trends of NTM in Taiwan2000-2008TBNTMPrevalence of isolates Incidence of NTM diseasePulmonaryAllExtrapulmonary19
  • NTM species causing pulmonary infection in AsiaDistribution of NTM species varies by geographic regionEmerg Infect Dis. 2011 Mar;17(3):343-9.Taiwan1. MAC2. M. abscessus(RGM)20
  • Chang Gung Med J. 2009 Sep-Oct;32(5):499-508.Characteristics of Patients with NTM Pulmonary DiseasesSouthern vs. Northern TaiwanPredominantly male, elderly, pre-existing lung disease.21
  •  Rapid-growth species and MAC appear to be the major NTMspecies in TaiwanChang Gung Med J. 2009 Sep-Oct;32(5):499-508.Pathogens of NTM pulmonary diseaseSouthern vs. Northern Taiwan22
  • Symptoms of NTM lung disease Variable and not specific symptoms, similar to TB Cough (productive or dry) Hemoptysis Fever Night Sweats Weight loss and loss of appetite Loss of energy Others: shortness of breath, wheezing, and chest painAm J Respir Crit Care Med. 2007;175:367–416.23
  • Clinical Pulmonary symptoms Chest radiograph or chest HRCT scan Nodular or cavitary infiltrates, multifocal bronchiectasis Exclusion of other diagnoses Such as TB, malignancy, fungal diseaseMicrobiologic Recurrent positive culture results from sputum or bronchial wash Transbronchial or other lung biopsy with mycobacterialhistopathologic features Granulomatous inflammation or AFBATS: American Thoracic SocietyIDSA: Infectious Disease Society of AmericasAm J Respir Crit Care Med. 2007;175:367–416.ATS/IDSA Diagnostic Criteria for NTM lung diseaseClinical, radiological, and microbiological all required24
  • Management of NTM Infection Empiric therapy not recommended Treatment guided by the isolated species Species level indentification before proper treatment Combination antibiotics Susceptibility testing may not correlate to in vivo response inSlowly growing mycobacteria Except− MAC- macrolide− M. kansasii- rifampin Treatment duration Negative culture maintained 1 year on therapy Surgery management: localized infections and poor response todrug therapyAm J Respir Crit Care Med. 2007;175:367–416.Curr Opin Pulm Med. 2010 May;16(3):251-6.Expert Opin Pharmacother. 2012 May;13(7):967-86.Uptodate 25
  • Treatment of NTM pulmonary diseaseSpecies Preferred regimenSGMMACNodular or bronchiectatic: TIW regimenClarithromycin 1000mg/ Azithromycin 500-600mgRifampin 600mgEthambutol 25mg/kgFibrocavitary, severe nodular/bronchiectatic: daily regimenClarithromycin 500-1000mg/ Azithromycin 250mgRifampin 600mgEthambutol 15mg/kg±Amikin/Streptomycin for the first 2 monthsM. kansasiiRifampin 600 mg/dayIsoniazid 300 mg/dayEthambutol 15 mg/kg/dayRGMM. abscessusClarithromycin 500mg q12h/Azithromycin 200-500mg qd + Amikacin 7.5mg/kgbid + Cefoxitin 2g q4h/Imipenem 1g q6hM. fortuitumM. chelonaeTreatment depend on susceptibility testingAmikacin, tobramycin,imipenem, cefoxitin, levofloxacin, TMP/SMX,doxycycline, clarithromycin, azithromycinAm J Respir Crit Care Med. 2007;175:367–416.Curr Opin Pulm Med. 2010 May;16(3):251-6.Expert Opin Pharmacother. 2012 May;13(7):967-86.Uptodate 26
  • Summary Prevalence and incidence of NTM increases Patients with underlying diseases with chronicrespiratory disease or immune deficiency are prone todevelop NTM infections Clinicians in taiwan should consider NTM as a possiblecause of TB-like disease in these population27
  • Thank you for your attention