Asthma and Allergic Disease Flashcards
According to GINA guidelines for adults and adolescents, what is the preferred initial therapy for infrequent asthma symptoms and no risk factors for exacerbations?
ICS-formoterol PRN
According to GINA guidelines for adults and adolescents, what is the preferred initial therapy for asthma symptoms or need for reliever 2x/mos or more?
Low dose ICS + SABA PRN
OR
ICS-formoterol PRN
According to GINA guidelines for adults and adolescents, what is the preferred initial therapy for troublesome asthma symptoms?
low dose ICS-LABA maintenance and reliever OR maintenance only low dose ICS-LABA OR Medium dose daily ICS
According to GINA guidelines for adults and adolescents, what is the preferred initial therapy for severe initial presentation or acute exacerbation?
Regular controller with high dose ICS or medium dose ICA-LABA
Consider course of oral steroids
According to GINA guidelines for children 6-11, what is the preferred initial therapy for infrequent symptoms less than 2x/mos?
as needed SABA
OR
ICS whenever SABA is taken
According to GINA guidelines for children 6-11, what is the preferred initial therapy for asthma symptoms or reliever use 2x/mos or more?
low dose ICS + SABA PRN
According to GINA guidelines for children 6-11, what is the preferred initial therapy for troublesome symptoms most days?
Low dose ICS-LABA + SABA PRN
OR
Medium dose ICS + SABA PRN
According to GINA guidelines for children 6-11, what is the preferred initial therapy for severe asthma symptoms?
Medium dose ICS-LABA
3 elements of severe asthma definition as per CTS statement
1) Asthma diagnosis confirmed by history and objective measures
2) Treatment needed = high dose ICS and second controller for previous year/oral steroids>50% in last year (asthma either uncontrolled despite these or needing the above for prevention of loss of control)
3) Environmental factors, comorbidities, adherence and inhaler technique addressed before labelling as severe asthma
Criteria for uncontrolled asthma
1) CTS asthma control criteria ACQ >1.5 or ACT or cACTn >20
2) Frequent (>2) exacerbation needing oral steroids
3) 1 or more severe exacerbation needing ICU or mechanical ventilation
4) FEV1 <80% with low ratio
CTS asthma control criteria (9)
1) Daytime sx < 4 days per week
2) Nighttime sx <1 night per week
3) Physical activity = normal
4) Exacerbations = mild, infrequent
5) Absence from work or school due to asthma: none
6) Need for SABA < 4 doses per week
7) PEF or FEV1 >90% of personal best
8) PEF diurnal variation <10-15%
9) Sputum eosinophils <2-3%
Uses for FeNO
1) Diagnose eosinophilic airway inflammation
2) Predict steroid responsiveness
3) Monitor treatment
4) Indicate non adherence to steroid therapy
3 isoforms for nitric oxidate synthetase (NOS)
1) Neuronal (nNOS)
2) Inducible (iNOS)
3) Endothelial (eNOS)
Upregulators for iNOS
TNF-alpha IL-1 beta IFN gamma IL-4 IL-13
FeNO levels in adults and children below which implies no eosinophilic airway inflammation and non responsiveness to steroids
Adults: <25 ppb
Children <20 ppb
What is considered a significant change in FeNO between visits?
Delta of 10% (values <50) and delta of 20% (>50)
What are the lower cutoffs for FeNO?
20 and 25 (>12yrs)
What are the upper cutoffs for FeNO?
35 and 50 (>12 yrs)
If an asthma patient as FeNO <20 and symptoms, how do you treat?
May not benefit from steroids and implies non-eosinophilic inflammation. Look for other cause
If an asthma patient as FeNO <20 and no symptoms, how do you treat?
can wean ICS and repeat FeNO after 4 weeks
If an asthma patient as FeNO <50 (or children >35) and symptoms, how do you treat?
check adherence and inhaler technique, assess for allergen exposure, may need to increased ICS
If an asthma patient as FeNO >50 and no symptoms, how do you treat?
no change in ICS, may relapse on weaning
If an asthma patient as FeNO 20-35 and no symptoms, how do you treat?
no changes in treatment
If an asthma patient as FeNO 20-35 and symptoms, how do you treat?
assess allergen exposure, check adherence, consider increasing ICS
Causes of normal FeNO in asthma (4)
1) Adequately treated with steroids - no sx
2) Technical faults - constant expiratory flow not maintained
3) Smoking can cause lower FeNO levels
4) Non eosinophilic asthma (steroid resistant)
Asthma, 3 cytokines targeted for treatment.
IL-4, IL-5, IL-13 (Th2 cell)
What has been demonstrated as indirect evidence of inflammation in asthmatics?
Elevated eNO
Lowered pH of lung condensate
Peripheral blood eosinophilia
General acceptance for asthma as an inflammatory dx due to:
- Evidence for steroid effectiveness
- Reversibility of BHR (bronchial hyper-reactivity) with prolonged allergen avoidance
Allergens assoc w/ Asthma
Mostly indoor-perennial or outdoor allergens with a long season
Dust mites = ++ important cause of sensitization
Perennial indoor allergens = associated with more severe asthma
Pollen allergies - generally assoc w/ less severe asthma
Molds may play a role - Alternaria and Aspergillus (ABPA) implicated
Factors implicating allergen deposition into lungs
Aerodynamic size affects both speed at which particles fall and deposition in the lungs
Particles <5um reach the alveoli needed to reach alveoli
Larger particles → bronchi; may cause allergy more effectively → carry more allergen
Mold spores (ie Aspergillus) = different than other particles - firm outer surface does not release protein rapidly, allergens often not expressed until spores germinate
Relationship with Asthma and IgE
Increased risk of acute asthma seen w/ both total serum IgE OR allergen specific IgE > 10 IU/ml
Interaction Btw Viral Infection & Allergic Responses in Children w Acute Asthma Episode
Viral illness = precipitant of asthma episodes
Children <3 yrs - essentially any virus can lead acute episode of asthma or bronchiolitis
(Major RF for wheeze in this population is small lung size at birth)
Children >3yo: Rhinovirus = main virus assoc with acute
episodes, AND the children are highly allergic (↑IgE)
Rhinovirus provoked wheezing stronger RF for subsequent wheezing by 6 years than RSV induced wheezing
Relationship between Rhinovirus and Asthma (mechanism)
Rhinovirus causes ↑ blood & nasal eosinophils, ↑ exhaled NO, ↓ exhaled pH
Response is more marked in asthmatic individuals with high IgE (>200IU/mL)
Unclear if asthma response 2° to viral infiltration of lungs OR events in nose trigger events in the lung e.g. cytokine/cell mediated effects
Studies suggest viral infections in atopic children initiate an atopy-dependent cascade that then amplifies and sustains airway inflammation –>exacerbation/loss of control
What can an Allergen challenge in an Allergic subject produce?
FEV1 ↓↓s w/n 15-min of allergy challenge Late responses include: - Eosinophil infiltration, - prolonged BHR -Mast cell release --> histamine, Platelet activating factor (PAF); IL-5
Mechanism of Treatment with Monoclonal Antibodies to IgE in Asthma
Monoclonal antibodies to the antigenic site on human IgE that binds to the receptor for IgE (FcεRI)
- only binds to free IgE that is not bound to mast cell or basophil → major benefit in some children
Changes in the lungs of children with asthma
Acellular infiltrate
Excess mucus production
Collagen deposition
Irritability of smooth muscle
The mechanism of this response involves a cascade of leukotrienes, prostaglandins, cytokines and chemokines → potential targets for therapy.
Key points regarding immunology and asthma (from Kendig chapter)
1) Treatment of asthma in children >3yrs focus = long-term anti-inflammatory Rx
2) Majority of those allergic = allergic to some allergen within their home (contributes to both sensitization AND asthma)
3) Viral infections = important in provoking wheezing exacerbation
4) Elevated IgE = strong assoc w/ asthma (These have been assoc w/ ↑specific AND total IgE.)
5) Targeted therapy (anti-inflammatories, allergen avoidance or immunotherapy, future tx directed at altering immune response)
Definition of Asthma
Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy
Characterized by variable, reversible obstruction of airflow, which may
improve spontaneously or after specific therapy
Characteristics of asthma in infancy
It most commonly presents in infancy with a viral RTI that causes lower airway inflammation with consequent wheezing and coughing known as bronchiolitis
Association of Rhinovirus and Asthma
Less commonly the cause of the initial episode may be even more likely associated with subsequent recurrent wheezing.
If a parent has asthma, chances of child having it
~25%
Pathology features of asthma
Increased thickness of reticular basement membrane and increased eosinophil density
1) Eosinophilia
2) Mucous plugs
3) Mucosal Edema
4) Mast cells
5) Thickened basement membrane (type 4 collagen deposition)
2 groups of early childhood asthma
1) non-atopic intermittent viral respiratory infection
2) chronic atopic asthma
Characteristics of non-atopic intermittent viral respiratory infection-induced asthma group
Predominates in infants and children.
Show no evidence of airway inflammation in children with a history of intermittent non-atopic asthma during their symptom-free periods.
Symptomatic preschool age non-atopic asthmatic children have predominantly noneosinophilic airway inflammation .
Characteristics of chronic atopic asthma group
More commonly in older children and adults.
Airway inflammation seems to persist in patients with atopic asthma, even when they are asymptomatic.
Eosinophilic airway inflammation characteristic of atopic children with asthma
Major cause of asthma exacerbations
Viral infections
Appear to be the major RF for the large increase in hospital admissions for asthma that occurs in the fall months.
The smaller airways in the young child are also more easily obstructed by inflammation associated with a viral respiratory infection, which is a likely contributing factor to increased hospitalization
Which group is more likely to have persistent symptoms over time?
Most preschool-age children with asthma remit or greatly improve by school age, those with evidence for atopy (i.e., the predisposition to make IgE antibody to major inhalants) are most likely to continue having a substantial frequency of asthmatic symptoms
Clinical presentation of asthma
Expiratory wheezing, and dyspnea.
Wheezing, is defined as musical, continuous sounds that originate from oscillations in narrowed airways.
Recurring lower respiratory symptoms consisting of cough, labored breathing, and expiratory wheezing are consistent with a diagnosis of asthma.
Clinical presentation of acute asthma exacerbation
Labored breathing with intercostal and suprasternal and substernal retractions may be present.
Physical findings:
- Polyphonic expiratory wheezing as a manifestation of diffusely narrowed small airways.
- Coarse crackles can be present from mucous in the larger airways.
- Hypoxemia from V/Q mismatching in early course of acute asthma with decreased PCO2 resulting from the increased hypoxic ventilatory drive.
- A rising PCO2 is an indication of impending respiratory failure.
CXR: atelectasis, peribronchial thickening
Diagnoses to consider when cough, wheeze or laboured breathing in the preschool age child is not consistent with asthma
Aspiration syndromes Bronchomalacia BPD PBB Compression of the airway from aberrant vessels CF FB in airway or esophagus PCD Pertussis Tracheal polyps Tracheomalacia VCD
Three distinct clinical patterns of asthma that can be seen in childhood
Intermittent (most common in preschool)
Chronic
Seasonal allergic.
Characteristics of Intermittent Asthma pattern
- Symptoms occur exclusively following viral RTI, these children are completely free from symptoms during the intercurrent periods.
- The major contributors to the high hospitalization rate in this age group
- an absence of specific IgE to major inhalant allergens is generally predictive of a viral respiratory infection– induced pattern
- Exam normal in between episodes
Characteristics of Chronic Asthma pattern
- Associated with persistent symptoms
- These children have daily or near daily symptoms of asthma, even between exacerbations.
- Have evidence for specific IgE to inhalant allergens.
2 components of asthma treatment
measures used to stop acute asthma symptoms, and maintenance medication to prevent attacks.
2 medications that are used for exacerbations
Bronchodilators and systemic corticosteroids are the major medications used for acute symptoms.
β2-adrenergic bronchodilator, provides rapid airway smooth muscle relaxation, which relief the bronchospastic component of the airway obstruction but have no effect on the progression of the process that results from inflammation.
Additional options for acute asthma exacerbation after SABA and steroids
Theophylline, magnesium and IV beta agonists
Systemic corticosteroids are potent anti-inflammatory agents for asthma and have long been recognized as effective for treating acute exacerbations.
Studies demonstrated that earlier aggressive systemic corticosteroids in children with an acute exacerbation decrease urgent medical care and hospitalization.
Issues with Theophylline
Narrow therapeutic index and is still less effective than a low-dose inhaled corticosteroid.
Maintenance medication with the most efficacy for asthma
Inhaled corticosteroids
- A minimal degree of hypothalamic-pituitary axis suppression and a small degree of transient growth suppression is detectable at modest doses, but neither clinically detectable adverse effects nor sustained effect on growth are apparent except at higher doses.
- Newer inhaled corticosteroid appears not to have dose-related systemic effects.
What is the most important modifiable factor that worsens asthma and increases hospitalizations?
Tobacco smoke
Also - House-dust mites have been identified as a major factor in increasing symptoms in known asthmatic.
Environmental strategies to decrease allergens
Placing dustproof casings on the mattress and pillow, the major source to dust mites, as is using a vacuum cleaner with a HEPA filter.
Reducing humidity in the home to below 60% has the potential to decrease indoor molds.
Patient Instruction Intervention Action Plan for Acute Symptoms of Asthma
Asthma symptoms
Symptoms likely to begin or increase with a viral respiratory infection
Increasing cough is often the first sign of asthma triggered by a viral respiratory infection
First = BD
If symptoms stop completely - repeat PRN
not completely = repeat BD
If not relieved or needing a third dose within 8 hours or more than 4 in 24 - go get seen
Causes of Wheezing in older children
Alpha 1 AT def Acute wheezing Viral Anatomic lesion/airway compression Asthma/EIB Bronchiectasis Cyst CF FB HP PCD Immunodeficiency Irritant inhalation Post infectious Recurrent/chronic wheezing Sarcoidosis Tumour Vascular ring VCD
Pathophysiology of Asthma
1) Airflow limitation due to obstruction (mucosal edema, bronchospasm, mucous plugging)
2) Obstruction creates increased resistance to airflow
- Leads to decreased ability to expel air = hyperinflation
3) Hyperinflation helps distend airways and maintain airway patency
4) Initially increased lung volumes compensate for obstruction (compensation is limited when tidal volume approaches volume of pulmonary dead space leads to hypoventilation)
5) Pulmonary circulation is affected by hyperinflation
6) Increased intra-alveolar pressure, decreased ventilation, decreased perfusion uneven ventilation perfusion within parts of the lung
7) Hyperventilation secondary to hypoxemic drive results reduced PaCO2
8) Metabolic acidosis = 2ndry to increased WOB, increased O2 consumption and excess SABA
Natural history of asthma
30-70% of children with episodic asthma have less severe or absent symptoms by late adolescence.
Disease severity in childhood usually determines disease severity in adolescence and adulthood
Mild/infrequent wheeze associated with viral infections was not likely to progress to severe disease
Factors associated with asthma symptom remission (according to the research)
1) Lack of allergen sensitivity
2) Less exposure to indoor allergens
3) Milder asthma
4) Older age
5) Less airway responsiveness (methacholine PC20)
6) Higher prebronchodilator FEV1.
Risk factors for death secondary to Asthma
- Labile asthma
- Respiratory infections
- Nocturnal asthma
- Hx of respiratory failure
- Marked variability in diurnal airflow obstruction
- Allergen exposure
- Psychosocial disturbance
- Poverty
- Hypoxic seizure in past
- Previous PICU admission
- Psychological factors
Typical triggers of Asthma
- Allergens (Majority of children with asthma have IgE mediated reactions)
- Irritants
- Weather change
- Infections
- Exercise
- Emotional factors
- GERD
- Allergic Rhinitis
- Nonallergic Hypersensitivity to drugs/chemicals
- Endocrine
- Nocturnal
Classification of Asthma
1) Intermittent Asthma
2) Mild persistent Asthma
3) Moderate Persistent Asthma
4) Severe Persistant Asthma
Other markers for Assessing Asthma control
Can use methacholine to assess degree of airway reactivity, and using this information to guide treatment has been shown to produce better PFTs and fewer exacerbations in one study (though received higher ICS)
▪ Generally not practical
Sputum eosinophilia can be used to adjust treatment fewer exacerbations/hospitalizations
▪ Generally not in younger patients, labour intensive, and uncomfortable
FeNO can be considered
▪ May not change despite treatment (30%)
▪ Can be helpful to rectify discordance between patient reported symptoms and airway inflammation
Mechanism of action of SABA
Bind to B adrenergic receptors throughout body (primarily on bronchial smooth muscle, epithelial cell, or mast cell)
o Convert ATP to AMP, and relax airway smooth muscle
Onset of action in few minutes, with peak action in 30 min, and duration for 4-6 hours
Side effects of SABA
Muscular tremor Tachycardia Irritability Hypokalemia Hypertension Tachyarrhythmia
Greater with systemic vs inhaled
May have reduced efficacy with repeated use
Postulated to be due to receptor desensitization (uncoupling receptor from G protein, inactivated receptors, or reduced receptor numbers
Mechanism of action of anticholinergics in asthma
Produce bronchodilation by antagonizing acetylcholine at receptor particularly on smooth muscle in large central airways
Ipratropium
o Onset: 20 min Peak effect at 60 min
o Poorly absorbed across mucous membranes, with little toxicity at usual doses
o Does NOT affect mucocilliary clearance
o Use: Children presenting to ED with asthma exacerbation Improves pulmonary
function and relieves symptoms
▪ Better response when combined with SABA
▪ Modest response Most helpful in severe obstruction
o Not effective in hospitalized children, especially if used in ED and still admitted
Tiotropium bromide
o Long acting, approved for COPD (not asthma)
o Duration exceeds 24 hours
o Dry powder inhaler
o In adults with poorly controlled asthma on ICS, improved control when tiotropium added to ICS (non inferior to addition of LABA)
What ideal criteria would ICS need to be effective in asthma?
o High affinity and potency at glucocorticoid receptor
o Prolonged lung retention
o High Serum binding to absorb systemically absorbed drug
o High volume of distribution
o Minimal/low oral bioavailability
o Rapid systemic inactivation (high first pass inactivation/ lung inactivation)
o Inhalation devices should provide maximal deposition in lungs, with little deposition in oropharynx or GI tract
Characteristics of Fluticasone
Potent and poorly absorbed topically active steroid
▪ Extensively metabolized in liver to inactive compounds
Highly lipophilic drug high affinity for lung glucocorticoid receptors (better than
beclomethasone)
▪ Slow rate of dissolution from receptor
▪ Negligible oral bioavailability
▪ Readily absorbed from respiratory mucosa and can enter systemic circulation (without hepatic metabolism)
More likely to produce sore throat and hoarseness
Reports of adrenal suppression
▪ Doses of > 400mcg/day in children < 12
Characteristics of Budesonide
Moderate potency
▪ Well documented efficacy and safety
Has a free C21 hydroxy group that allows formation of esters with Long chain fatty acids -> allows for inactive reservoir of drug within airway epithelium, that is slowly released
Characteristics of Beclomethasone
Less potent that fluticasone, and slightly less potent than budesonide
▪ Still effective in reducing symptoms and improving pulmonary function
o Readily absorbed from GI tract
o Metabolized into a more potent form (monopropionate)
▪ Less favourable topical to systemic potency ratio
o Available as a fine particle aerosol, with HFA propellant
▪ Allows for greater deposition into the lower/smaller airways and reduction of total dose
Characteristics of Mometasone
Potent, highly topically active steroid (often used for allergic rhinitis and dermatologic conditions)
▪ Poor systemic absorption
Similar to fluticasone, with higher receptor affinity and half life
Same safety profile as others
Characteristics of Ciclesonide
Prodrug, metabolized to active form in lung (airway epithelial cells)
▪ Membrane for conversion only found on lower airways
▪ Metabolite has 100x greater affinity for receptor
No oral bioavailability, tightly bound to plasma proteins
As effective as other ICS
Lower risk of candidiasis, no effect on growth, no adrenal suppression
Mechanism of Action of ICS
Passive diffusion across cell membrane into cytoplasm
Binds to glucocorticoid receptor
o Translocated to nucleus, and binds to glucocorticoid responsive elements on responsive genes
- Steroid receptor regulates transcription of target genes (direct and indirect, suppress or induce)
- Thought to also have non-genomic mechanism of action, that acts rapidly to cause vasoconstriction
- Major target is nuclear transcription factor (NFkB)
o Block signaling by binding to DNA and decreasing pro-inflammatory cytokines and chemokines
Most effective chronic treatment for asthma
- Reduce airway reactivity, reduce acute asthma symptoms and exacerbations, reduce late allergen response, decrease need for rescue bronchodilators
- Decrease collagen deposition in subepithelial basement membrane
- Withdrawl of ICS usually is accompanied by return of airway hyperresponsiveness and return of asthma symptoms
Side effects of ICS
Thrush, dysphonia
▪ Most common
▪ Dose related
▪ Reduced with spacer use and rinsing mouth with water afterwards
Adrenal Suppression
▪ Unlikely if receiving < 400mcg/day of Budesonide, or < 200mcg/day of Fluticasone
Growth
▪ Minimal effect, even with long term treatment
▪ Most effect occurs early, with catch up later
Side effects of Systemic Steroids
Weight gain HTN Osteoporosis Decrease linear growth Metabolic derangement Cataracts
Characteristics of Advair
Salmeterol (Advair = Fluticasone/salmeterol)
o Approved for children 4 years and older
o Partial agonist
o Slow onset of action (10-30 in)
o Long duration of action (due to side chain attachment)
o High selectivity for B2 receptor
o Highly lipophilic (> 10,000 times) when compared to albuterol
▪ Also higher recptor affinity than albuterol (3-4 times)
Characteristics of Symbicort
Formoterol (Symbicort = busesonide/fomoterol, Zenhale = mometasone/fometerol
o Approved for children 12 years and older
o Moderately lipophilic
o Full agonist
o Taken up by cell membrane to form dose dependent depot
▪ They diffuses out to interact with active site
o Rapid onset of action (~ 5 min)
o Duration of activity of ~ 12 hours
Concerns regarding single use of LABA
Chronic single agent use of LABA may decrease responsiveness to SABA
Single agent use of LABA (without ICS) results in deterioration of asthma control, and has been linked to death with monotherapy
LABA should never be used as monotherapy
Mechanism of Action of Leukotriene Antagonists
Lipid mediators produced by metabolism of arachidonic acid (AA)
o AA also produces Prostaglandins and thromboxane
- Leukotrienes (LT) mediate smooth muscle constriction, vascular permeability, mucous hyperseretion, edema formation, inflammatory cell recruitment
- LT produced by many airway cells (mast cell, eosinophil, basophil, macrophages, neutrophil)
Block receptor (Zafirukast, montelukast)
▪ Zafirlukast decreases day and night symptoms, reduced SABA, Given BID
▪ Montelukast is given daily
● Decreases urine LT, circulating eosinophils, FeNO.
● See improved FEV1, improved exercise symptoms
● See improvement quickly (some spirometry data after first dose)
● Less effect on Asthma as ICS
● Overall, when added to a ICS, tends to wok less effectively than when LABA added instead
Other option = block production
Side effects of Singulair
Headache, Abdo pain, vivid dreams, sleep disruption, behavioural changes
● Association with suicide report
● Reports of Churg strauss – Likely more so the removal of ICS than addition of LTRA
Characteristics about Methylxantines (Theophylline)
Restricted use currently (2nd or 3rd line)
o Poor acute bronchodilator
o Narrow therapeutic index, with significant adverse effects
o Replaced now by other anti-inflammatories
PDE inhibitor
o Smooth muscle relaxation, bronchodilation
o Central respiratory stimulant
o Increases diaphragmatic contractility (prevents fatigue)
- Low doses can be helpful for chronic management (serum level 5-10mg/mL)
o Theophiline + ICS may be able to spare some steroid (but less effective than ICS +LABA)
- Occasionally used in PICU
Side effects of Theophylline
Tremor GI irritation GI hemorrhage Agitation Convulsions Interaction with many other medications, (macrolides, fluoroquinolones elevate dose, carbamezipine lowers dose). Fever may increase serum concentrations
Characteristics of Cromolyn
Mild anti-inflammatory Can provide benefit for mild to moderate asthma ▪ Minimal effect for chronic asthma Less effective at EIB than SABA No longer available
Mechanism of Action of Omalizumab
Binds to serum IgE and prevents IgE from binding to mast cells and basophils
- Crosslinking of allergen and the subsequent inflammatory release = prevented
Effects of Omalizumab
1) Reduces sputum eosinophils, decreases Fc Receptor on basophils, mast cells, dendritic cells
2) Reduces early and late asthmatic responses after allergen challenge
3) Reduces ICS dose
4) Decreases exacerbations
5) Decreases rescue medication
6) Decreases symptoms
7) Improves QOL
Dosed q2-4 weeks
Dose determined by serum IgE and weight
Tends to be restricted to moderate to severe allergic asthma, with ongoing poor control
Observe for 16 weeks on treatment prior to determining if response occurred
Risks/drawbacks to Xolair
● Anaphylaxis
● Expensive
● Not everyone responds favourably (only 60% have positive response)
Role of Peak flow meters
Limited utility for regular home monitoring
Only modestly correlated with FEV1, as well as other spirometry measures
Greatest value when used to indicate severity of an exacerbation and response to treatment
- Use a person’s personal best as the target
- Effort dependent, so can be manipulated
- Only measures large central airways (not small airways)
Is upper airway disease a risk factor for asthma?
Yes
Relationship between allergic rhinitis and asthma
Patients w/ allergic rhinitis more likely to have increased bronchial hyperresponsiveness, even if no asthma diagnosed yet
Studies show that pts w/ sig nasal allergy (compared to those w/ no–mild symptoms of nasal disease) had more severe asthma + used more asthma inhalers
Common immunopathology of allergic rhinitis and asthma
Inflammatory cells in nasal and bronchial mucosa of pts with allergic rhinitis + asthma: eosinophils, mast cells, helper T cells (Th2)
Effects of rhinitis therapy on asthma
Treatment of rhinitis can result in improvements in asthma symptoms and bronchial hyper-responsiveness; suggests that nasal disease contributes to the pathophys of asthma. Treatment of rhinitis can reduce symptoms of mild asthma so need for asthma therapy can be reduced.
Unclear if these same findings happen in pts with more severe asthma.
Pathophysiologic connections between allergic rhinitis and asthma
- Systemic effects of nasal inflammation on lower airways
- Impaired mucosal function
- Nasal-bronchial reflex
- Mouth breathing caused by nasal obstruction
- Post nasal drip of inflammatory material
Work-up of allergic rhinitis in asthma patients
All pts w/ asthma should be evaluated to r/o concomitant allergic rhinitis
Question pts about: nasal congestion, sneezing, itching, discharge, postnasal drip
P/E: size and vascularity of nasal turbinates, type + presence of nasal secretions,
tonsillar size, color
Investigations: allergy skin tests or RAST to common airborne allergens
o NOT helpful: total serum IGE, nasal cytology, serum eosinophils
Treatment for allergic rhinitis
- Allergen avoidance strategies
- Pharmacotherapy (1st line = IN steroids)
Others: Oral antihistamine, Montelukast) - Allergen Immunotherapy
Clinical features of chronic sinusitis
Nasal congestion
Purulent anterior/posterior nasal drainage
Cough (poor response to typical asthma inhalers)
Headache common in teens + adults
Uncommon to have fever
Histopathology of chronic sinusitis
Infiltration of sinus tissue with eosinophils, hyperplasia of mucus-producing cells, stromal edema
Eosinophils invasion and deposition into tissues of paranasal sinuses → sinusitis and asthma
Eosinophil infiltration causes mucosal epithelial changes, predisposing to recurrent/chronic infxn
Characteristics of Allergic Fungal Sinusitis
Unusual type of chronic sinusitis in children caused by an allergic rxn to fungi
Features of nasal polyps, asthma, proptosis
AbN CT sinus finings, + skin test to fungi, high IgE, peripheral eosinophilia
+Fungal cultures
Effects of Sinus Therapy on Asthma
Long-term control of asthma symptoms may improve after surgical sinus procedures (but no long term or RCT studies)
Diagnostic: in all children with poorly controlled or steroid-requiring asthma, sinus radiograph suggested as 1st imaging study (although CT more sensitive) → If abN should receive medical therapy
Medical treatment of sinusitis
Antimicrobial: amox-clav x 21 days. Clarithro if allergic to amox. IF no response,
use b-lactamase resistant drug (ie. Cefuroxime).
Enhance secretion removal: saline irrigations, hot steam inhalations
Reduce nasal mucosal swelling:
▪ If severe, otrivin x 3 days
▪ If persists, continue with oral pseudoephedrine x 7-10d
▪ Use intranasal corticosteroid x 3-6 weeks
▪ If no response, use Pred 0.5mg/kg tapered over 5-7d
Definition of Hypersensitivity Pneumonitis
Immune mediated lung disease occurring in response to repeated inhalation of an antigen
Usually affects adults and older children and less commonly < 2 years
Pathogenesis of Hypersensitivity Pneumonitis
1) Initial event involves sensitization to an inhaled antigen in the distal airway (level and duration of exposure required is unknown)
2) Acute alveolitis develops with an increase in neutrophils (peaks at 48 hrs) → increase in the number of macrophages and lymphocytes
- Usually low CD4+/CD8+ T cell ratio
- Type IV cell-mediated delayed hypersensitivity responses
- Type III antigen-antibody complex → complement activation → neutrophils and macrophages → produce IL-1 and IL-8, TNF-alpha, MCP-1, MIP-1alpha, RANTES, CCL 18 → proliferation of lymphocytes and TH1 cells that produce IFN-gamma = granulomatous inflammation
- Also increase in BAL of NK cells (protective) and surfactant A (stimulates inflamm cytokine release)
Excessive accumulation of extracellular matrix components contributes to fibrotic process
Susceptibility factors: smoking, viral infections, endotoxin, genetic predisposition
Clinical Manifestations in the Acute stage of Hypersensitivity Pneumonitis
Fever, cough, dysnea 4-6 hours after exposure and may persist up to 18 hours
Usually recover in 2-5 days with episodes occurring after each subsequent exposure -Exam reveals crackling/rales in lower lung fields (wheezing uncommon)
Clinical Manifestations in the Sub-Acute stage of Hypersensitivity Pneumonitis
Intermittent low grade but continuous long term exposure (e.g. pet store employee)
Milder symptoms such as low grade fever, cough, chills, malaise, progressive dyspnea often with anorexia and weight loss
Usually reversible
Clinical Manifestations in the Chronic stage of Hypersensitivity Pneumonitis
Long term low grade exposure (e.g. parakeet owner or contaminated home humidifier)
Dyspnea, chronic cough, fatigue, anorexia, weight loss
Usually chronic irreversible disease
Bloodwork findings for Hypersensitivity Pneumonitis
Leukocytosis with neutrophilia in the acute phase
Increased ESR and CRP
- 50% have elevated rheumatoid factor + incr IgG, IgA, IGM
- IgG precipitating antibody seen on a double gel diffusion plate (only a marker of exposure and does not correlate with disease activity → 40-50% of asymptomatic exposed individuals will have antibody)
- Lymphocyte proliferation assays to the antigen are usually positive
Imaging findings of Hypersensitivity Pneumonitis
Acute HP: poorly defined, nodular infiltrates (can also see patchy ground glass opacities or diffuse infiltrates)
- May also have normal CXR after cessation of exposure and resolution of acute episode
- HRCT shows ground glass opacities usually in lower lung zones and sparing apices
Subacute HP: reticulonodular appearance with fine linear shadows and small nodules in mid-upper lung zones
- HRCT centrilobular nodules associated with larger areas of ground-glass opacity + air trapping and mosaic perfusion = headcheese sign (classic for subacute HP)
Chronic HP: diffuse reticulonodular infiltrates, volume loss, and coarse linear opacities more severe in mid-upper zones
-HRCT shows fibrotic changes including irregular linear opacities, honeycombing, and traction bronchiectasis
(DDX: sarcoidosis, IPF, collagen vascular disease)
- Can see centrilobular nodules when have ongoing antigen exposure
Note do NOT usually see: pleural effusion, pleural thickening, cavitation, calcification, atelectasis, or hilar adenopathy
PFT findings in Hypersensitivity Pneumonitis
Restriction with decreased lung volumes and decreased DLCO
Decrease in compliance (pressure volume curve shifted down and to right)
Decrease in PaO2 commonly seen in chronic HP but can be seen in acute/subacute
Desaturation with exertion or sleep
40% show nonspecific airway reactivity and 5-10% have asthma
BAL findings in Hypersensitivity Pneumonitis
Acute antigen exposure: neutrophilia then lymphocytic alveolitis ≥ 60%, low CD4+/CD8+ (vs. high ratio of > 3.5:1 in sarcoidosis)
Biopsy findings in Hypersensitivity Pneumonitis
Acute: interstitial mononuclear cell infiltrates + foamy macrophages/granulomata
Subacute classic triad: interstitial lymphocytic-histiocytic cell infiltrate, BO, scattered poorly formed non-necrotizing granulomata
Chronic: giant cells, granulomata, Schaumann bodies, usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) – like pattern
Treatment of Hypersensitivity Pneumonitis
Acute form: remove offending agent and if symptoms severe then use prednisone 60 mg daily (taper) -
Repeated acute or subacute form: decrease exposures and administer long term steroids EOD
Chronic: long term steroids but only if imaging and physiologic changes show a response
Follow-up with complete PFTs and CXR
Need to identify antigen to try to eradicate or remove patient from environment→ e.g. water should be changed frequently in humidifiers
Prognosis is good for acute/subacute stages if antigen detected and avoided but chronic HP not as good (esp if continued exposure)
Presence of fibrosis is the most important factor in prognosis (antigen class, symptom duration and PFTs are not sign of predictors for survival)
Common antigens for Hypersensitivity Pneumonitis
Avian (most common in children) Farmer's lung bagassosis Humidifier lung Air conditioner lung Lab worker's lung Pain refinisher's disease Drug-induced HP
Key cytokines critical for bone production of eosinophils
IL-3, IL-5, GM-CSF (produced by CD4+ T cells)
Eosinophils are Th2-driven granulocytes that have inflammatory and tissue distructive properties
Examples of drugs that can produce eosinophilic pneumonia
Drugs: sulfa, nitrofurantoin, penicillins, dilantin, carbamazepine, imipramine, aspirin, naproxen, bleomycin, MTX
Toxins: rubber workers exposed to aluminum silicate, grape workers exposed to sulfite, workers affected by scotchguard inhalation
Crack cocaine users can get a Loffler-like syndrome
Clinical presentation of drug-induced eosinophilic pneumonia
Symptoms start usually within 1 month of starting the drug and include cough, dyspnea and fever
Histologically there is pulmonary edema with lymphocytic and eosinophilic infiltrate with alveoli containing eosinophils and histiocytes (peripheral eosinophilia is common but always there)
CXR shows interstitial or alveolar infiltrates and often Kerley B lines
HRCT shows ground glass attenuation, consolidation, nodules and sometimes hilar adenopathy or pleural effusion
Treatment of drug induced eosinophilia
When stop offending drug, usually resolution of symptoms and eosinophilia with clearing of
CXR
Consider steroids when resolution is slow
Clinical presentation of Helminth-induced eosinophilia
1) Transpulmonary passage of helminth larvae (Loffler’s syndrome) most common = Ascaris
2) Hematogenous seeding
3) Pulmonary parenchyma invasion with helminths
4) Tropical pulmonary eosinophilia
Clinical presentation of fungal-induced eosinophilia (ABPA)
ABPA is a Th2 hypersensitivity lung disease caused by bronchial colonization with Aspergillus fumigatus that affects 1-2% of asthmatics and 7-9% of CF, relatively uncommon in kids
Diagnostic features: ▪ Asthma or CF ▪ Pulmonary infiltrates ▪ IgE > 1000 U/ml ▪ IgE anti-Aspergillus antibody ▪ IgG anti-Aspergillus antibody ▪ Peripheral blood and pulmonary eosinophilia ▪ Proximal bronchiectasis
Clinical symptoms: coughing, wheezing, anorexia, malaise, fever, expectorating brown plugs
DDx: viral or bacterial pneumonia, poorly controlled asthma, foreign body, CF, PCD, TB with eosinophilia, Hypersensitivity pneumonitis, Pulmonary neoplasm
Pathology of ABPA
Cylindrical bronchiectasis of the central airways, esp. the upper lobes (airways may be occluded by ‘mucoid impaction’ where filled with mucus and hyphae → can lead to atelectasis of segment → saccular bronchiectasis)
Clinical staging of ABPA
I) Acute stage
II) Remission
III) Exacerbation with recurrent of sx and 2 x incr in serum IgE
IV) Needs continuous steroids
V) Fibrotic stage (can lead to pulm HTN and cor pulmonale)
Classic CXR features of ABPA
Shadow in upper lobe with no change in volume
Tram line representing inflammation of airway walls
Toothpaste shadows or gloved-finger shadows from mucoid impaction
Lab investigations of ABPA
IgE antibodies to aspergillus Pos aspergillus preciptins Sputum positive for aspergillus Eosinophilia in blood or sputum Elevated IgE SPT to aspergillus (good neg predictive value)
Treatment for ABPA
steroids x 2-4 weeks then taper over 3-6 months, also some new RCTs in adults to suggest that itraconazole adjuvant decreases exacerbations requiring treatment with steroids, increases pulmonary function and exercise tolerance and decreases IgE levels
Diagnostic criteria for ABPA (classical)
1) Acute or subacute clinical deterioration not attributable to another etiology
2) Total IgE >1000 (unless receiving steroids)
3) Immediate cutaneous reactivity to Aspergillus while the patient is not being treated with antihistamines of in vitro presence of IgE antibody to Aspergillus
4) Precipitating antibodies or serum IgG antibody to Aspergillus
5) New or recent abnormalities on CXR or chest CT that have not cleared with antibiotics and standard physio
Minimal diagnostic criteria for ABPA
1) Acute or subacute clinical deterioration not attributable to another etiology
2) Total serum IgE concentration >500 (unless steroids)
If ABPA is suspected and the total IgE 200-500, repeat testing in 1-3 months
3) Immediate cutaneous reactivity to Aspergillus while he patient is not being treated with antihistamines or in vitro presence of IgE antibody to Aspergillus
4) One of the following:
- Precipitins. to Aspergillus or in vitro documentation of IgG antibody to Aspergillus
- New or recent abnormalities on CXR or chest CT that have not cleared with antibiotics and standard physio
Differences between acute and chronic eosinophilic pneumonia
Chronic mostly adults
Males more likely in acute, females in chronic
50% of chronic has asthma
Chronic = insidious onset
Acute mostly diffuse alveolar infiltrates, chronic = dense peripheral infiltrates
BAL acute = ≥45% eosinophils, chronic ≥25%
Chronic has blood eosinophilia with IgE elevated in most
Both = usually prompt response to steroids
Characteristics of Eosinophilic granuloma (formerly Histiocytosis X)
Benign form of LCH, affects mostly males
- Typically solitary lesion but can have multiple lesions that cause pain or asymptomatic with any bone involved → most common are ribs, calvarium and femur
- Lesions comprised of foamy vacuolated histocytes with variable numbers of eosinophilis, neutrophils, lymphocytes and plasma cells
- Pulmonary ILD occurs in 20% with CXR showing alveolar pattern early → 3-10 mm nodular shadows or reticulonodular pattern with predilection for apices → fibrosis and honeycombing
- Histopath: eosinophils present in lesion but not seen in BALF specimens
Characteristics of Churg-Strauss
Asthma, allergic rhinitis, sinusitis, eosinophilic vasculitis, granulomatous lesions
Nearly all patients have allergic rhinitis and pansinusitis + pulmonary symptoms
3 phases of Churg-Strauss
1) Development of asthma (tapering of steroids may unmask CSS)
2) Development of peripheral blood eosinophilia and eosinophilic tissue infiltrates
3) Eosinophilic vasculitis of extrapulmonary organs → skin, GI, heart, CNS
Histopathology of Churg-Strauss
Extensive eosinophil infiltration in interstitium, air spaces, and perivascularly with necrotizing and non-necrotizing granulomata involving blood vessels
Treatment of Churg-Strauss
Prolonged steroids
If untreated mortality 50% in first 3 months of onset of vasculitis vs. treated mean survival is 9 years
Pulmonary findings in Churg-Strauss
History of Asthma
Pulmonary:
- Patchy, transient infiltrates
- Eosinophilic infiltration of alveoli, interstitial, blood vessles
- Necrotizing and non-necrotizing granulomas
- Eosinophilic angiitis
Diagnostic criteria for Hypereosinophilic Syndrome
Absolute eosinophil count ≥ 1500 in peripheral blood for > 6 mos
Lack of evidence of parasitic, allergic or other recognized causes of eosinophilia
End-organ dysfunction due to eosinophilic infiltration
Characteristics of Hypereosinophilic Syndrome
More common in males and patients 20-50 yrs
- Presenting sx: fatigue, cough, dyspnea, myalgias, rash, retinal lesions
- Organ involvement: cardiac, cutaneous, neuro, pulmonary, spleen, liver, eye, GI (cardiac is major cause of mortality)
- Treatment: steroids are first line
Causes of Hypereosinophilic Syndrome
- Myeloproliferative variant
- Lymphocytic variant
- Familial
- Undefined
- Overlap
- Associated: CS, Mastocystosis, IBD, Sarcoid, HIV
