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    Figure 1. Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000.
    In Panel A, data concerning infectious diseases are derived from reports of the Centers for Disease Control and Prevention, except for the data on hepatitis A, which are derived from Joussemet et al.12 In Panel B, data on immune disorders are derived from Swarbrick et al.,10 Dubois et al.,13 Tuomilehto et al.,14 and Pugliatti et al.15
  • Slide 4
    Allergic rhinitis and asthma frequently coexist. Most patients with asthma have allergic rhinitis (up to 80%).15-18 Among participants from two French centers in the European Community Respiratory Health Survey (ECRHS), 79% (77/98) of patients with asthma had concurrent rhinitis, and 20% (77/378) with allergic rhinitis had concurrent asthma. Asthma was defined as one or more asthma attacks in the preceding 12 months or positive response to metachloline challenge. Patients were considered to have allergic rhinitis if they responded positively to one or two questions regarding rhinitis symptoms.18
    Epidemiologic studies support the suggestion that allergic rhinitis should be suspected as a comorbid condition in most patients with asthma.
  • IgE is a key component of asthma in most asthma patients, as shown by Burrows and colleagues who investigated the relationship between IgE levels and the risk of developing asthma in adults. As the graph shows, the higher the total serum IgE concentration, the higher were the odds of having asthma.
    Burrows et al studied the association of self-reported asthma and serum IgE levels in 2657 subjects in a general population. They found that, regardless of the subjects’ allergy status or age group, the prevalence of asthma was closely related to the serum IgE level (P<0.0001).
    The figure in this slide shows the odds ratio of having asthma at seven levels of total IgE concentrations after correction for age, sex, smoking habits, and skin-test index in a logistic analysis. The solid green line represents the risk of asthma. Vertical lines are 95% confidence intervals around the regression for each odds ratio corresponding to a given log IgE level. The log odds ratio of having asthma increases linearly with the serum IgE level.
    Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989;320:271-277.
  • The high levels of TH2-type cytokines that are found at sites of allergic inflammation are consistent with a TH2-cell-based aetiology of atopic disease. Furthermore, studies in mouse models of asthma have shown that allergic airway inflammation is dependent on CD4+ T cells and, more specifically, is seen when T-cell receptor-transgenic TH2, but not TH1, cells are adoptively transferred to mice. Finally, the absolute requirement for TH2 cells in directing allergic airway inflammation has been shown by the use of interleukin-4 (IL-4)-deficient mice. In these studies, defective priming of TH2 cells in the absence of IL-4 resulted in a failure to generate allergic inflammatory responses after subsequent airway challenge. Of note, if IL-4 was blocked only during inhaled antigen challenge, airway inflammatory responses were intact, indicating that once TH2-cell priming has occurred, IL-4 is no longer necessary for airway inflammation. This has also been confirmed by studies in which effective TH2-cell sensitization was achieved despite the absence of IL-4. Specifically, we have shown that IL-4-independent TH2-cell responses with high levels of IL-5 and IL-13 production can be generated in IL-4-deficient mice by epicutaneous exposure to soluble protein. In this system, mice showed no deficit in airway eosinophilia or mucus secretion following inhaled antigen challenge. So, the main role of IL-4 in allergic airway inflammation is during the initial priming of TH2-effector cells, whereas IL-5 and IL-13 have been shown, in numerous studies in both mice and humans, to be more directly responsible for the characteristic eosinophil infiltrates and mucus hypersecretion.
  • As mentioned before, the same high level of exposure to PAMPs that contributes to the generation of adaptive immune responses to microbial pathogens also seems to initiate a pathway for the development of regulatory T cells52, 53. For example, Zuany-Amorim et al.60 have shown that pre-treatment of mice with a killed-mycobacteria suspension results in the development of a CD4+ regulatory T-cell population that is capable of suppressing subsequent airway inflammatory responses. Similarly, McGuirk et al.52 have shown that regulatory T-cell clones can be generated from lungs of mice following acute infection with the microbial pathogen Bordetella pertussis. Furthermore, in this study, the pathogen-derived molecule filamentous haemagglutinin was shown to induce the production of IL-10 by DCs, which promotes the induction of naive T-cell differentiation along a regulatory T-cell pathway. So, it might be that high levels of PAMP exposure, which occur during natural encounters with microbial pathogens, leads to the development of DCs with a particular regulatory T-cell-inducing phenotype61.
    The second scenario for the generation of regulatory T cells, however, does not seem to involve activated DCs. Instead, it has been proposed that DCs fail to mature after encounter with non-microbial (non-PAMP-containing) antigens, which results in a state of tolerance. Given that natural encounter with allergens, as occurs in the respiratory tract, should not involve PAMP-induced innate immune signals, it would be predicted that no response is made to these antigens. In fact, tolerance induced following inhalation of soluble protein antigen has been described in animal models55, 62. Specifically, exposure of mice to inhaled ovalbumin (OVA), in the absence of co-stimulatory signals induced by adjuvant or the innate immune system, leads to a state of unresponsiveness to further antigen challenge. This unresponsive state has been shown to involve regulatory T cells and IL-10, and to be dependent on interactions with inducible T-cell co-stimulator (ICOS)56, 63. These results are consistent with the two-signal model of immune activation, which provides a means of protection from unwanted responses to non-pathogenic foreign antigens. The two proposed pathways for the natural generation of regulatory T cells that have been described are outlined in Fig. 3.
  • IgE binds to high- and low-affinity receptors (FcRI or FcRII) on effector cells. The inflammatory cascade is initiated when IgE bound to effector cells is cross-linked by allergen. This results in the degranulation of effector cells and the release of a comprehensive array of mediators that are linked to the pathophysiology of asthma.
  • This slide shows autopsy specimens from the small airways of a patient with chronic severe asthma, a patient with acute fatal asthma, and a normal individual. In the healthy individual, the epithelium is not highly folded and the lumen remains open. In contrast, the airway wall of the patient with acute fatal asthma shows marked thickening and is completely occluded by the highly folded epithelium and mucous plug.
    Interestingly, the airway of the patient with chronic severe asthma is less acutely constricted, but the airway wall is still much thicker than normal, and the airway is partially obstructed by a cellular plug.
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  • Omalizumab is a humanized monoclonal antibody for the treatment of allergy-related asthma that selectively binds to human IgE regardless of specificity.
    Omalizumab works by forming complexes with circulating IgE which inhibits the binding of IgE to the high-affinity IgE receptor (FcRI) on the surface of mast cells and basophils. Binding of Omalizumab to IgE forms small, biologically inert complexes.
    To avoid the clinical problems associated with murine antibodies, humanization of the murine anti-IgE was performed. Humanized anti-IgE was developed by grafting the variable sequence of a mouse antibody (binds to the Fc3 binding domain of IgE) onto the constant IgG1 kappa human framework. Omalizumab consists of > 95% IgG1 kappa human framework and < 5% mouse sequence, which is hidden from the immune system when Omalizumab binds to IgE.
    (Refer to full prescribing information for questions about the immunogenicity of Omalizumab.)
  • This slide illustrates Omalizumab binding to an IgE molecule, which also takes place at the constant region of the IgE molecule. Note that IgE binds either to the FcRI receptor on the mast Cell OR to Omalizumab, but it cannot bind to both at the same time.
    Omalizumab inhibits the binding of Ig E to the high-affinity IgE receptor FcRI on the surface of mast cells and basophils. Reduction in surface-bound IgE on FcRI-bearing cells limits the degree of release of mediators of the allergic response. Treatment with Omalizumab also reduces the number of FcRI receptors on basophils in atopic patients.
    (In theory, Omalizumab should also eliminate binding of IgE to low-affinity receptors.)
  • Asthma

    1. 1. ASTHMAASTHMA Andrej Petrov M.D.Andrej Petrov M.D. Assistant Professor of MedicineAssistant Professor of Medicine Division of Pulmonary, Allergy and Critical CareDivision of Pulmonary, Allergy and Critical Care MedicineMedicine University of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicine
    2. 2. LECTURE OUTLINELECTURE OUTLINE  EpidemiologyEpidemiology  Immunology and pathogenesisImmunology and pathogenesis  Clinical presentationClinical presentation  DiagnosisDiagnosis  TherapyTherapy
    3. 3. DEFINITIONDEFINITION  Chronic inflammatory disorder of the airwaysChronic inflammatory disorder of the airways  Widespread but variable airflow obstruction that isWidespread but variable airflow obstruction that is often reversible either spontaneously or withoften reversible either spontaneously or with treatmenttreatment  Bronchial hyperresponsiveness to a variety ofBronchial hyperresponsiveness to a variety of stimulistimuli
    4. 4. Asthma Facts in the United StatesAsthma Facts in the United States  Annual number of hospitalizations: 478,000Annual number of hospitalizations: 478,000  Annual number of deaths from asthma: 4,657Annual number of deaths from asthma: 4,657  Annual number of work days lost: 14.5 millionAnnual number of work days lost: 14.5 million  Annual number of school days lost: 14 millionAnnual number of school days lost: 14 million  Estimated direct and indirect medical costs: $16Estimated direct and indirect medical costs: $16 billionbillion Morb Mortal Wkly Rep. 2002 March 29; 51:1-13.
    5. 5. Adult Asthma FactsAdult Asthma Facts  14.5 million workdays lost due to asthma, a 2.314.5 million workdays lost due to asthma, a 2.3 fold increase from the early 80s to the mid 90sfold increase from the early 80s to the mid 90s  Adults accounted for over 1.3 million ED visitsAdults accounted for over 1.3 million ED visits and 288,000 hospitalizations due to asthmaand 288,000 hospitalizations due to asthma  One third of asthma related deaths occur inOne third of asthma related deaths occur in patients 35-44 years oldpatients 35-44 years old  Over 50% of asthma related deaths occur inOver 50% of asthma related deaths occur in patients 65 years and olderpatients 65 years and older Morb Mortal Wkly Rep. 2002 March 29; 51:1-13.
    6. 6. Bach, J.-F. N Engl J Med 2002;347:911-920 Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000
    7. 7. Most Patients with Asthma Have Allergic Rhinitis • Approximately 80% of asthmatics have allergic rhinitis Adapted from The Workshop Expert Panel. Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334; Sibbald B, Rink E Thorax 1991;46:895-901; Leynaert B et al Am J Respir Crit Care Med 2000;162:1391-1396. Asthma alone Allergic rhinitis alone Allergic rhinitis + asthma
    8. 8. IgE and Asthma in Adults Asthma Serum IgE (IU/mL) Oddsratio N = 2657 0.32 1 3.2 10 32 100 320 1000 3200 11 2.52.5 55 1010 2020 4040 Burrows B, et al. New Engl J Med. 1989;320:271-277.
    10. 10. Distribution of Dendritic Cells in the LungsDistribution of Dendritic Cells in the Lungs
    12. 12. Pathways for the natural generation of regulatoryPathways for the natural generation of regulatory T-cell populationsT-cell populations
    13. 13. IgE-dependent Release of Inflammatory Mediators IgE Allergens FcεRI Over Minutes Lipid mediators: Prostaglandins Leukotrienes Wheezing Bronchoconstriction Over Hours Cytokine production: Specifically IL-4, IL-13 Mucus production Eosinophil recruitment Immediate Release Granule contents: Histamine, TNF-α, Proteases, Heparin Sneezing Nasal congestion Itchy, runny nose Watery eyes
    14. 14. Airway Inflammation in AsthmaAirway Inflammation in Asthma
    15. 15. Acute Fatal Asthma Impact of Inflammation on Small AirwaysImpact of Inflammation on Small Airways Normal Chronic Severe Asthma
    16. 16. Airway RemodelingAirway Remodeling Peter Jefferey, AJRCCM 2001
    23. 23. TISSUE DAMAG E
    25. 25. SYMPTOMSSYMPTOMS  Recurrent episodes of:Recurrent episodes of: • Shortness of breathShortness of breath • WheezingWheezing • Chest tightnessChest tightness • Cough, particularly at night and early in theCough, particularly at night and early in the morningmorning
    26. 26. Before 10 Minutes After Allergen Challenge BronchoconstrictionBronchoconstriction
    27. 27. Mechanisms of AirwayMechanisms of Airway ObstructionObstruction Smooth Muscle Contraction Mucus Hypersecretion Loss of Elastic Recoil ? Peribronchial Fibrosis Airway Wall Edema Vascular dilatation
    28. 28. A Scheme of Immune and Inflammatory Events Associated with the Pathophysiology of Asthma, with Emphasis on Early-versus Late-Phase, Asthmatic Responses. JACI 2003; 111, 1
    29. 29. PATTERN OF SYMPTOMSPATTERN OF SYMPTOMS  Perennial, seasonal or bothPerennial, seasonal or both  Continual, episodic or bothContinual, episodic or both  Diurnal variations, especially nocturnal andDiurnal variations, especially nocturnal and on awakening early in the morningon awakening early in the morning
    30. 30. PRECIPITATING AND/ORPRECIPITATING AND/OR AGGRAVATING FACTORSAGGRAVATING FACTORS  Viral respiratory infectionsViral respiratory infections  Environmental allergensEnvironmental allergens  ExerciseExercise  Occupational chemicals or allergensOccupational chemicals or allergens  IrritantsIrritants  Changes in weatherChanges in weather  Endocrine factorsEndocrine factors  GERDGERD  SinusitisSinusitis
    31. 31. PHYSICAL EXAMPHYSICAL EXAM  Normal physical examNormal physical exam  Expiratory wheezing with normal orExpiratory wheezing with normal or decreased air movementdecreased air movement  Accessory respiratory muscle useAccessory respiratory muscle use  Ominous sign- no wheezing with decreasedOminous sign- no wheezing with decreased air movementair movement
    33. 33. Spirometry: A Simple, Basic MeasurementSpirometry: A Simple, Basic Measurement  Essential to initial evaluationEssential to initial evaluation  Helps assess severity of airflow obstructionHelps assess severity of airflow obstruction  Aids in differential diagnosisAids in differential diagnosis • Obstructive versus restrictive airwayObstructive versus restrictive airway diseasedisease • Reversibility of airflow obstructionReversibility of airflow obstruction  Confirms periodic home PEFRConfirms periodic home PEFR measurements in selected patientsmeasurements in selected patients
    34. 34. Spirometry in asthmaSpirometry in asthma  Decreased FEV1/FVC ratioDecreased FEV1/FVC ratio  Improvement in FEV1>12% withImprovement in FEV1>12% with bronchodilator or therapybronchodilator or therapy  Normal DLCONormal DLCO  Increased residual volumeIncreased residual volume  Normal spirometryNormal spirometry
    35. 35. FlowFlow (l/s)(l/s) Volume (l)Volume (l) -2-2 00 -4-4 11 33 22 44 55 21 3 4 5 -6-6 Pre-albuterol Post-albuterol Predicted Spirometry: Flow-Volume Loops inSpirometry: Flow-Volume Loops in AsthmaAsthma
    36. 36. Reasons for Performing BronchoprovocationReasons for Performing Bronchoprovocation Challenges in Clinical PracticeChallenges in Clinical Practice  Clarify a clinical diagnosis of asthma when aClarify a clinical diagnosis of asthma when a reasonable degree of doubt existsreasonable degree of doubt exists  To determine the presence of bronchialTo determine the presence of bronchial hyperresponsiveness in patients with chronichyperresponsiveness in patients with chronic coughcough  To quantify the severity of the airwayTo quantify the severity of the airway hyperresponsivenesshyperresponsiveness
    37. 37. Caveats on BronchoprovocationCaveats on Bronchoprovocation A positive methacholine or histamineA positive methacholine or histamine challenge is not equivalent to a diagnosischallenge is not equivalent to a diagnosis of asthmaof asthma A negative histamine or methacholineA negative histamine or methacholine challenge probably excludes currentchallenge probably excludes current asthmaasthma Non-asthmatics can have positiveNon-asthmatics can have positive methacholine or histamine challengesmethacholine or histamine challenges
    39. 39. INHALANT ALLERGENSINHALANT ALLERGENS Animal allergensAnimal allergens House-dust mitesHouse-dust mites Cockroach allergensCockroach allergens Indoor fungi (molds)Indoor fungi (molds) Outdoor allergensOutdoor allergens
    40. 40. ALLERGEN SKIN TESTSALLERGEN SKIN TESTS Eugene Braunwald, Atlas of Internal Medicine, 2nd edition
    41. 41. EVALUATIONEVALUATION  CBC with differential ( eosinophilia oftenCBC with differential ( eosinophilia often seen in asthma, ABPA and CS vasculitis)seen in asthma, ABPA and CS vasculitis)  Total igETotal igE  Optional specific IgE to allergensOptional specific IgE to allergens  CXRCXR  CT of the chestCT of the chest  ABG in status asthmaticusABG in status asthmaticus
    43. 43. Classification of Asthma - EPR IIClassification of Asthma - EPR II Intermittent AsthmaIntermittent Asthma  MILDMILD Persistent AsthmaPersistent Asthma  MILDMILD sx frequency < 1/daysx frequency < 1/day FEV1>60%FEV1>60%  MODERATEMODERATE sx frequency 1/daysx frequency 1/day FEV1=40-60%FEV1=40-60%  SEVERESEVERE sx frequency > 1/daysx frequency > 1/day FEV1<40%FEV1<40% sx frequency less than 2 times / week sx frequency 2 times / week or more
    44. 44. Goals of Therapy: Asthma ControlGoals of Therapy: Asthma Control ■■ Minimal or no chronic symptoms day or nightMinimal or no chronic symptoms day or night ■■ Minimal or no exacerbationsMinimal or no exacerbations ■■ No limitations on activities; no school/work missedNo limitations on activities; no school/work missed ■■ Maintain (near) normal pulmonary functionMaintain (near) normal pulmonary function ■■ Minimal use of short-acting inhaled beta2-agonistMinimal use of short-acting inhaled beta2-agonist ■■ Minimal or no adverse effects from medicationsMinimal or no adverse effects from medications
    45. 45. Symptom Relievers for AsthmaSymptom Relievers for Asthma Intermittent AsthmaIntermittent Asthma  MILDMILD PRNPRN ββ-agonist QID-agonist QID Persistent AsthmaPersistent Asthma  MILDMILD PRNPRN ββ-agonist QID-agonist QID  MODMOD PRNPRN ββ-agonist QID-agonist QID  SEVERESEVERE PRNPRN ββ-agonist QID-agonist QID
    46. 46. Controllers for AsthmaControllers for Asthma Intermittent AsthmaIntermittent Asthma  MILDMILD NoneNone Persistent AsthmaPersistent Asthma  MILDMILD Low dose ICS or LTLow dose ICS or LT blockerblocker  MODERATEMODERATE Mod dose ICSMod dose ICS + LA Bronchodilator+ LA Bronchodilator + LT Blocker+ LT Blocker  SEVERESEVERE High dose ICSHigh dose ICS + LA Bronchodilator+ LA Bronchodilator + LT Blocker+ LT Blocker OCSOCS
    47. 47. Omalizumab Characteristics • Humanized mAb against IgE • Binds circulating IgE regardless of specificity • Forms small, biologically inert Omalizumab:IgE complexes • Does not activate complement Adapted with permission from Boushey H. J Allergy Clin Immunol. 2001;108:S77-S83. Murine CDRs* (< 5% of molecule) IgG1 kappa Human framework (> 95% of molecule) *CDR = complementarity-determining region
    48. 48. Omalizumab Blocks IgE Binding to Mast Cells Mast cell IgE molecule FcεRI receptor Omalizumab Omalizumab
    50. 50.  "I used to think that I could"I used to think that I could outrun my asthma. I'd justoutrun my asthma. I'd just take my quick-relief medicinetake my quick-relief medicine when I had trouble breathing,when I had trouble breathing, and everything was cool.and everything was cool.  "My asthma finally tackled me"My asthma finally tackled me during a big game, and I hadduring a big game, and I had to be carried off the field. Andto be carried off the field. And that's when it hit me:that's when it hit me:  I should be playing offense,I should be playing offense, not defensenot defense  So now I follow my doctor'sSo now I follow my doctor's advice and a daily treatmentadvice and a daily treatment plan that helps preventplan that helps prevent symptoms from occurring insymptoms from occurring in the first place.the first place.  "Whether you're running for"Whether you're running for the end zone, or heading forthe end zone, or heading for other goals, don't let asthmaother goals, don't let asthma get in the way."get in the way."
    51. 51.  Thank you!!Thank you!!  ComprehensiveComprehensive Lung Center,Lung Center, UPMCUPMC  Tel: 412-648-Tel: 412-648- 61616161