Upload
tobias-baker
View
221
Download
3
Tags:
Embed Size (px)
Citation preview
EXHALED NITRIC OXIDE IN ASTHMA
DR. MUKHTAR A. ADEIZA
DEPARTMENT OF MEDICINE
Ahmadu Bello University Teaching Hospital,Zaria
Thoracic club meeting, 17th march 2011
OUTLINE• Introduction
• History
• Synthesis of NO
• Functions of NO
• Measurement of NO
• Uses in Asthma
• Other uses
• Conclusion
Introduction• Asthma is a chronic inflammatory disease of the
airways that involves a complex interaction of recurrent episodes of reversible airflow obstruction, bronchial hyperresponsiveness and an underlying inflammation.
• Clinical manifestations include:– Episodic wheezing– Coughing– Shortness of breath– Chest tightness
Introduction
• In the United States, asthma affects more than 22 million people and is one of the most common chronic diseases of childhood, affecting more than 6 million children. (NHLBI, 2007)
• In the United Kingdom, 20% of school age children are affected.
• West Africa, 5.7%• Nigeria, 5.4%
Introduction
• Decisions regarding asthma management are currently based on symptoms and conventional lung function tests.
• Exhaled nitric oxide (FeNO) measured in a breath test has recently emerged as a potentially useful tool in the assessment and management of patients with asthma.
6
MucushypersecretionHyperplasia
Eosinophil
Mast cell
Allergen
Th2 cell
VasodilatationNew vessels
Plasma leak Oedema
Neutrophil
Mucus plug
Macrophage/dendritic cell
BronchoconstrictionHypertrophy / hyperplasia
Cholinergic reflex
Epithelial shedding
Subepithelialfibrosis
Sensory nerve activation
Nerve activation
Modern view of asthma
Barnes PJ
Th2 cytokine pattern
Nitric Oxide (NO)
• NO is a biomarker of eosinophilic airway inflamation.
• Produced by the action of proinflammatory cytokines on inducible nitric oxide synthase both in vivo and in vitro.
Structure of NO
Properties of NO
• Small highly reactive molecule (“radical molecule”)
• Made up of one atom each of N and O
• Uncharged with an unpaired electron
• Can diffuse freely across membranes
• T1/2 is 2-30 seconds
• Decays into nitrate after spontaneously transmitting signal
History
• 1987, EDRF shown to posesss biological and chemical properties similar to NO.
• 1992, NO was named “Molecule of the Year” by the journal Science.
• 1998, Furchgott, Ignarro and Murad were awarded the Nobel Prize for Medicine for their work on this molecule.
History
• 1990s, numerous authors reported that fractional exhaled nitric oxide concentration (FeNO) was:– Higher in asthmatic patients than in healthy
controls.
– levels decreased in asthmatic patients treated with inhaled corticosteroids.
– Closely linked to eosinophilic airway inflammation.
Synthesis of NO• Mammals synthesize NO by way of the NO
synthase enzyme (NOS)
• NOS converts the amino acid L-arginine into L-citrulline and NO.
• The 3 known isoforms of the NOS are classified according to their:
– activity,– Location– molecular cloning
• Two are constitutive & the third is inducible.
Synthesis of NO
L-Arginine
↓
↓←← iNOS
↓
Nitric Oxide + L-Citrulline
Regulation of NO production
NOS isoformsiNOS eNOS nNOS
SOURCE Macrophages, Bronchial epithelial cells, hepatocytes
Blood vessels, platelets
Nerve cells, skeletal muscles
EXPRESSION Inducible Constitutive Constitutive
CALCIUM Ca ²+ independent Ca ²+ dependent Ca ²+ dependent
CONCENTRATION Nanomolar Picomolar Picomolar
INHIBITION BY CORTICISTEROIDS
Yes No No
MOA of NO on smooth muscles
• NO is an endogenous and diffusible simple free radical that stimulates the enzyme guanylate cyclase.
• Increased generation of cyclic guanosine monophosphate (cGMP).
• Relaxation of smooth muscles results in bronchodilation and vasodilatation.
Functions of NO
• Weak bronchodilator effect.• Vasodilatation.• Neurotransmitter.• Increased host resistance (deaminates
DNA).• Upregulates TH2 & Downregulates TH1.
• Intensify edema, plasma exudation and cause denudation and desquamation of the epithelial lining.
Factors affecting FeNO levels• Age
• Sex
• Anthropometry and race
• Smoking and diet
• Medications
• Circadian rhythm & seasonal variation
• Others– FeNO decreases after spirometry, sputum
induction, bronchoprovocation and within 30mins of exercise.
Measurement of FeNO
• PREPATATION– Do not eat, drink, or do strenuous exercise for
1 hour before the test is scheduled.– Do not perform spirometry or peak flow for 1
hour before the test is scheduled.– Continue to take all your medicine as you
usually do, unless you have been told to withhold medications for other testing you will be doing.
Procedure
• Differ depending on the patients condition:
ONLINE: In patients who are able to cooperate, exhale directly.
OFFLINE: In patients who are unable to cooperate, exhale into a reservoir.
• Single-breath online measurement (SBOL) is the technique of choice in adults and children able to cooperate.
Experimental setup used to measure FeNO
Measurement of FeNO
• NO can be measured precisely using chemiluminescence.
• NO and ozone react in a cooled chamber to form NO2 .
• This photochemical reaction emits infrared light that can be detected by a photomultiplier tube with a linear response.
Procedure
• Inhales NO-free air (NO <5 ppb) for 2 to 3 seconds through a mouthpiece.
• Exhale completely at a constant flow rate of 50ml/s for 10seconds (ATS, 20005).
• Values are then captured and recorded in real time.
• A variability of no more than 10% over 3 measurements or no more than 5% over 2 measurements is recommended.
Equipment
• NIOX analyzerStandard stationary chemoluminiscence analyzer
• NIOX-MINOBased on electrochemical analysis
portable hand held device
Comparison of NIOX & NIOX-MINONIOX NIOX-MINO
Dimension,(hwd, cm) 50 × 30 × 40 24 × 13 × 10
Weight of the analyzer, kg
40 0.8
Accuracy :Measurements <50 ppb Measurements >50 ppb
±2.5%±5%
±5%±10%
Range of measurements, ppb
0-200 5-300
Lower detection limit, ppb
1.5 5
Reference range
• The establishment of reference values for a population is difficult because of the numerous confounding factors as discussed above.
• The average normal level of eNO in different studies ranges from 20 to 30 parts per billion.
Refernce range
• Olin et al, defined a value of 24.0 to 54.0 ppb depending on age and height.
• Abba et al, 7.66 to 46.6 ppb among nonsmoking, nonatopic adult male Saudi subjects.
Clinical application
• The availability of cheap, portable and reliable equipment for the measurement of FeNO has led to widespread use of FeNO as a noninvasive diagnostic and management tool particularly in bronchial asthma.
Diagnosis of asthma
• Malberg et al. observed that high FENO values ( ≥3SD) correlated with clinical asthma (p<0.0001)
• More than 90% specificity for the diagnosis of asthma in both adults and children.
• Excellent correlation with esinophilic airway inflammation as represented by blood, sputum, and mucosal esinophilia.
Diagnosis of asthma
• Higher diagnostic sensitivity (88%) when compared to various LFTs like induced sputum (86%) and forced spirometry (47%).
• Atopy limits the clinical utility of the test in children.
Monitoring of asthma
• Monitor antiinflammatory treatment with ICS.
• Identify patients who will respond to ICS (FeNO >47ppb).
• When tailoring ICS dose in asthma, mean daily dose if ICS was lower in the FeNO group compared to symptoms/spirometry.
Diseases & factors that affect FeNOINCREASED DECREASED VARIABLE
Asthma Cystic fibrosis COPD
Exposure to pulmonary allergens
Primary ciliary dyskinesia Bronchiectasis
Pollution Pulmonary hypertension Fibrosing alveolitis
Apnea Pneumonia Sarcoidosis
Bronchodilators (transient) Gastroesophageal reflux Systemic sclerosis
Viral respiratory infection Laryngeal tracheomalacia
Pulmonary tuberculosis Sputum induction
Allergic rhinoconjunctivitis. Nasal polyposis
Bronchoconstriction
Diseases & factors that affect FeNO
INCREASED DECREASED VARIABLE
Posttransplant bronchiolitis Forced spirometry (transient)
Chronic inflammatory intestinal disease
HIV infection
Hepatopulmonary syndrome Smoking
Liver cirrhosis Alcohol
Caffeine
Menstruation
Nebulizer therapy with distilled water
Conclusion
• FeNO measurements are quick and easy to perform and may be readily incorporated into
routine pulmonary function test procedures.
• This advance offers the possibility that a diagnosis of asthma may be performed more easily and confirmed with much greater confidence than has been possible to date.
Conclusion
• The possibility of easily taking measurements of FeNO in an office setting even by relatively young children, and the availability of a portable device, opens a significant perspective for the routine use of FeNO evaluation in daily practice.
The future
• Development of local reference values
• Integration of FeNO use into medical practice in both primary care and specialist settings in Nigeria.
THANK YOU