Childhood Bronchial Asthma

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Host Factor

Twins study: Effect of genetic factors is about 35% to 70%
No gene or genes involved in the heritability of atopy or asthma has been identified with certainty.
Results suggest involvement of multiple genes and chromosomal regions likely to harbor asthma susceptibility genes.

Environmental Factors

Allergens:

Outdoor: Pollen (tree, grass, and flower), molds (Aspergillus fumigatus and others)
Indoor: Mites (Dermatophagoides pteronyssinus, D. farina), Animals (cats, dogs, birds), cockroaches

Viral respiratory infections:

Mainly RSV
Others include: Rhinovirus, Parainfluenza virus

Airway Hyperresponsiveness

Asthma-related inflammatory cells act in tandem to initiate, orchestrate, and sustain airway hyperresponsiveness (AHR) via the release of several inflammatory mediators.
BAL & biopsy studies suggest the following asthma-related inflammatory cells & mediators play important roles (3 granulocytes & several non-granulocytes):

Mast cells (granulocyte) - Histamine
Eosinophils (earliest asthma-related granulocyte!) - Major Basic Protein (MBP) and Monocyte Chemoattractant Protein (MCP)
Neutrophils (uncertain role)
Alveolar macrophages (from blood monocytes) & T-lymphocytes:
- Cytokines/growth factors: IL-3, IL-4, IL-5, IL-1, IL-6, TNF-alpha, GM-CSF, PDGF, and TGF-beta
- Products of arachidonic acid pathways: Prostaglandins, thromboxanes, leukotrienes
- Platelet-activating factor (PAF)
Airway epithelial cells: Endothelins, pro-inflammatory cytokines/chemokines, growth factors like PDGF, GM-CSF, Nitric Oxide, and locally generated non-adrenergic non-cholinergic (NANC) nervous system neuropeptides

Endothelins: Potent vaso- & bronchoconstrictor peptides along with growth factors like GM-CSF, may play a role in fixed airway narrowing via stimulation of smooth muscle proliferation & fibrosis.
Nitric oxide: A bronchodilator of the NANC nervous system, generated in airway epithelial cells with nitric oxide synthase (NOS, inducible by cytokines); reduces mucosal edema via intraluminal exudation of plasma and sustains inflammation via amplification of Th-2 lymphocyte-mediated response.
NANC neuropeptides:
- Substance P: Causes microvascular leakage, mucosal edema, and mucus hypersecretion.
- Neurokinin A

Arachidonic Acid as a Source of Airway Prostaglandins, Thromboxanes & Leukotrienes

Prostaglandins & thromboxanes: Products of the cyclooxygenase subpathway, while leukotrienes are generated by the lipo-oxygenase enzyme pathway.
PGD-2: Capable of producing sustained bronchoconstrictor effects via amplification of the inflammatory process; its importance in asthma pathology remains undefined.
PGF-2alpha (prostanoid): Potentiates the effects of histamine on airway caliber and is a potent bronchoconstrictor.
Prostacyclin: A vasodilator that contributes to mucosal inflammation/edema & hence bronchoconstriction in humans.
PGE-2: A bronchoprotective agent with bronchodilatory properties.
Pathogenesis: Likely regulated by the bronchoconstrictive:bronchodilatory prostanoid ratio.
Thromboxane A-2: A bronchoconstrictive mediator with a significant role in the late asthmatic response. OKY-046 has anti-thromboxane effects and may be effective in the late response.
LTC4, LTD4 & LTE4: Sulfidopeptides (collectively formerly known as SRSA) with bronchoconstrictive properties via effects on microvascular permeability & mucociliary functions.
Anti-5-lipooxygenase & anti-LTCs (e.g., Zileuton, Zafirlukast, Montelukast): These agents are broncho- & nasoprotective against cold air and nasal allergen challenges, respectively.

Pathogenesis – Target Cells’ Effects of Inflammatory Mediators

Airway smooth muscle contraction – Not an increase in response to spasmogens but attributable to:
- Diminished responsiveness of beta-adrenoceptors (surgical & post-mortem studies)
- Possibly due to uncoupling – reference to tachyphylaxis in chronic beta-2 agonist usage.
- Growth factor-related hypertrophy and hyperplasia
Airway epithelial shedding – Appears as “creola bodies” in BAL and is predominantly mediated by eosinophil MBP, oxygen-derived free radicals, and several inflammatory cellular proteases.
- Effects: Loss of mucosal epithelial barrier function, neural endopeptidases (to degrade mediators), exposure of airway sensory nerves, and enhancement of local reflexes due to loss of epithelial-derived relaxant factor (EDRF).
Subepithelial fibrosis – Effect of growth factor cytokines like PDGF and TGF-beta derived from macrophages and/or epithelial cells.
- Effects: Subepithelial deposits of collagen (type III & V) and myofibroblasts; increased size of basement membrane (this is a consistent finding in fatal asthma).
Vascular response (Vasodilatation, Microvascular leakage & Plasma extravasation)
- Increased blood flow is important in exercise-induced asthma (EIA) & removal of mediators.
- Consequences of microvascular leakage & plasma extravasation caused by mediator release include increased airway secretions, decreased mucociliary clearance, generation of new mediators from plasma precursors like kinins, and mucosal edema.
Mucus hypersecretion
- Possibly a consequence of increased secretory response to mediators associated with neural element stimulation.
- Viscid mucus plugs from this hypersecretion are a frequent cause of fatal asthma.

Pathogenesis

Chronic eosinophilic inflammation
CD4+ Th2 lymphocytes
Interleukins
IgE antibodies (Allergen-specific)
Mast cells (and other effector cells)
Sensitization: Years of continued exposure to allergens in early life with asymptomatic inflammation (inducers).
Early response: Allergen re-exposure or trigger agents like smoke, exercise, cold air, etc., with consequent mediator release (inciters).
Late response: Allergen re-exposure or trigger with consequent prolonged and intense bronchoconstriction due to mediator-associated amplification of the inflammation via further granulocyte activation (mast cells, eosinophils, neutrophils); viral infections are particularly effective in enhancing the late response.

Pathogenesis: Inducers vs. Inciters

Inducers (Precipitating) – Continued allergen exposure (for years) in early life causes sensitization with the generation of allergen-specific IgE, asymptomatic inflammation, and bronchial hyperresponsiveness (BHR).
- Factors/agents: Viruses, HDM, Fel-D1, Per-A1, pollen, fungi
Inciters (Triggers) – Re-exposure to allergens, viral or intracellular pathogen (Mycoplasma or Chlamydial) infections, or non-specific environmental agents/irritants like smoke (cigarette or culinary), ozone, physical stimuli like exercise or cold air, endogenous variables like emotional stress, and diurnal variation in beta-2 or nebulized mediators (of weak solutions of histamine or methacholine).

The 2 Asthma phenotypes & the “hygiene hypothesis”

Aetiology of asthma is complex, and multiple environmental and genetic determinants are implicated.

Predisposing and protective factors

The Allergic Cascade

Sensitization

CD4+ Th2 cells and B cells interact and produce allergen-specific IgE.
Interactions between CD4 T Cells and B Cells are important in IgE synthesis.
IgE antibodies synthesized bind to high-affinity IgE receptors on the surface of mast cells in tissue or peripheral-blood basophils, and low-affinity IgE receptors on the surface of lymphocytes, eosinophils, platelets, and macrophages.
This process is known as sensitization.

Early Phase Response

When a sensitized individual comes in contact with the same allergen again, there is molecular bridging of the receptors.
This occurs when the allergen interacts with receptor-bound IgE molecules, causing activation of the cell and the release of preformed and newly generated mediators including histamine, prostaglandins, leukotrienes, and cytokines, among others.
Once present in various tissues, mediators may produce various physiological effects, depending on the target organ.
The early response involves mucosal edema and bronchospasm, producing airway obstruction.

Late Phase Response

If no intervention occurs, there is an influx of inflammatory cells, mainly eosinophils and neutrophils.
This further worsens airway narrowing and consequently increases airflow obstruction.

Normal vs asthmatic bronchiole

The airway obstruction is due to:

The swelling of the airway mucosa due to inflammation
Mucosal edema
Mucus plugs in the airways
Bronchospasm of the muscles around the airways

Specimen of bronchial mucosa from a subject without asthma (Panel A) and a patient with mild asthma (Panel B) (Hematoxylin and Eosin, x40).

In the subject without asthma, the epithelium is intact; there is no thickening of the sub-basement membrane, and there is no cellular infiltrate.
In contrast, in the patient with mild asthma, there is evidence of goblet-cell hyperplasia in the epithelial-cell lining. The sub-basement membrane is thickened, with collagen deposition in the submucosal area, and there is a cellular infiltrate.

Airway Remodeling in Asthma

Remodeling entails thickening of the airway walls, with increases in submucosal tissue, the adventitia, and smooth muscle.
Preventing the progressive loss of lung function in childhood may require recognition and treatment of the disease during the first five years of life.

Pathophysiology of asthma

Mechanisms of Virus-Induced Asthma

Production of virus-specific IgE antibody
Enhanced leucocyte inflammatory function
Enhancement of factors involved in late phase response to allergen challenge
Altered autonomic nervous system:
- Beta-adrenergic blockade
- Cholinergic stimulation
Damage to airway epithelium:
- Neutral endopeptidase deficiency
- Loss of endogenous bronchodilator receptors
- Expression of adhesion molecules (e.g., ICAMs, VCAMs)

General

Diagnosis is clinical, but it is not an “all-or-none” diagnosis due to a wide spectrum of disease severity.
No radiographic, blood, or histopathologic parameter is diagnostic, but some objective pulmonary function tests (PFTs) may be suggestive.
Clinical Clues which are by no means exclusive to asthma include:

Key Symptoms -

Cough
Wheeze (polyphonic)
Dyspnoea or shortness of breath
Chest tightness

When two or more of these are present, their peculiarities that suggest asthma as the likely morbidity include:

Variability
Intermittent nature
Nocturnal and seasonal preponderance

Cough-type (or cough-variant) asthma occurs when cough is the predominant symptom without a wheeze.

Corroborative Symptoms and Risk Factors

Personal or family history of atopic diatheses (eczema, allergic rhinitis, vernal conjunctivitis)
Symptom flares following recognized trigger factors like:

Viral respiratory infections
Dusty chores
Physical exertion
Tobacco smoke
Exposure to animal danders or feathers
Rarely, to aspirin, NSAIDs, or beta-blockers

Physical Signs

In between episodes when the child is symptomatic, corroborative physical signs may be absent.
In those with chronic asthma, residual signs of hyperinflation may be seen.
During acute exacerbations, respiratory distress associated with bilateral, widespread polyphonic expiratory wheeze/rhonchi.
Objective changes (suggestive of lower airway obstruction) in PFTs are best considered under investigative findings.

Objective Tests of Lung Function

Essentially aimed at demonstrating variability of airflow:

% Variability of PEFR and/or FEV1 (Max. PEFR - Min. PEFR / Max. PEFR x 100 = % variability):

> 20% is suggestive but poorly specific.

15% change (or 10%) in FEV1 after a test, or 20% change in PEFR before and after “measured” exercise like 6 minutes of free running to raise pulse rate to > 160/min; PEFR at 10-minute intervals for subsequent 30 minutes.
15% rise in FEV1 or 20% PEFR after inhaled β₂ agonist via nebulizer or MDI.
15% rise in FEV1 or 20% PEFR after 2 weeks of systemic steroid therapy (oral prednisolone, 1-2 mg/kg).
Histamine or Metacholine challenge, then measure FEV1 or PEFR.
Others:

FEV1/FVC
FEF 25-75%
Specific spirometric pattern
Chest X-ray (CXR)

Lung Function tests are notoriously difficult/not possible in children < 5 years, hence the need for other indices, and if still in doubt, wait until the child is older.

Characteristic Patterns of Obstructive & Restrictive Disease as Measured by Spirometry

Parameter (Normal range % predicted)	Minimum Significant Change after Bronchodilator	Obstruction	Restriction
FVC	> 80% +10%	N or low	Low
FEV1	> 80% +10%	Low	N or low
FEV1/FVC	> 80%	Low	High
FEF25-75	> 70% +25%	Low	Normal, high, or low

Indications for Pulmonary Function Tests (PFTs) in Children

Recurrent wheezing
Chronic cough, especially nocturnal
Unexplained dyspnoea
Exercise-induced breathlessness and/or cough
Coughing & wheezing associated with cold air exposure or weather changes
Slowly resolving or recurrent bronchitis or bronchiolitis
Follow-up care and assessment
Recurrent pneumonia
Pre-surgery investigation of lobectomy for chronic suppurative lung disease

In general, extrapolations from cohort or controlled studies and expert opinions indicate that the diagnosis of childhood asthma (including those in whom Pulmonary Function Testing (PFT) is not possible) is based on:

Identifying any of the key symptoms and giving careful consideration to alternative diagnoses (see table below).
Repeating assessment after a treatment trial and questioning the diagnosis if treatment is ineffective.

Diagnosis of asthma in children

Uncommon Features of Asthma
	Clinical Clues	Possible Diagnoses
Perinatal & Family Hx	Symptoms present from birth or perinatal lung problem Family Hx of unusual chest disease Severe Upper Respiratory Tract Disease	Developmental anomaly, ciliary dyskinesia, chronic lung disease, CF Developmental anomaly, neuromuscular disorder, CF Host defence defect
Symptoms & Signs	Excessive vomiting or Possetting Dysphagia Abnormal voice or cry Focal chest signs Inspiratory stridor as well as wheeze Failure to thrive	Reflux/GERD, Aspiration syndromes Swallowing problems +/- aspiration Laryngeal problems TB, Bronchiectasis, developmental disorder, Post-viral syndrome Central airway or laryngeal disorder Host defence, GERD, CF
Investigations	Focal or Persistent radiological signs	TB, Bronchiectasis, FB aspiration, Developmental disorder, Post-infective disorder, recurrent aspiration

History Taking in a Child with Bronchial Asthma

When taking a history of a child with bronchial asthma, it's important to ask questions that will help you understand the severity, triggers, and management of the condition. Here’s a guide on the important questions to ask:

1. Symptom History

Onset: When did the symptoms first start? Was there a particular event or trigger?
Nature of Symptoms: What are the primary symptoms (e.g., wheezing, coughing, shortness of breath, chest tightness)?
Frequency: How often do these symptoms occur? Are they daily, weekly, or less frequent?
Timing: Are the symptoms worse at night, early morning, or during certain seasons?
Duration: How long do the symptoms last when they occur?
Severity: How severe are the symptoms? Do they interfere with daily activities or sleep?
Associated Symptoms: Is there any sputum production? If so, what is its color and consistency?

2. Trigger Factors

Environmental: Are there known triggers like dust, pollen, cold air, smoke, or strong odors?
Allergies: Is there a history of allergies? Any known triggers such as animals, food, or medications?
Infections: Have viral infections been associated with the onset of symptoms?
Exercise: Does physical activity trigger symptoms? What type of exercise?
Weather Changes: Are symptoms worse with changes in weather, particularly with cold air or humidity?
Emotional Stress: Do emotional stressors appear to exacerbate symptoms?

3. Past Medical History

Previous Diagnoses: Has the child been previously diagnosed with asthma or any other respiratory conditions?
Hospitalizations: Has the child ever been hospitalized for asthma? How many times, and what were the circumstances?
Medication Use: What medications have been prescribed in the past? Were they effective? Any side effects?
Allergies: Does the child have a history of eczema, allergic rhinitis, or other atopic conditions?
Growth and Development: Has asthma affected the child’s growth or physical development?

4. Family History

Asthma and Allergies: Is there a family history of asthma, allergies, or other respiratory conditions?
Genetic Predispositions: Any known genetic conditions related to asthma or respiratory health?

5. Social and Environmental History

Living Conditions: Where does the child live? Are there any environmental factors at home (e.g., mold, pets, smoke)?
School Environment: Are there known triggers at school, such as dust or exposure to infections?
Exposure to Smoke: Is the child exposed to cigarette smoke? Either at home or elsewhere?
Socioeconomic Factors: Are there any socioeconomic factors that might impact the management of the child’s asthma?

6. Impact on Daily Life

School Attendance: Has asthma affected the child’s school attendance or performance?
Physical Activity: Does asthma limit the child’s ability to engage in physical activities?
Quality of Life: How does asthma affect the child’s overall quality of life, including sleep and social interactions?

7. Current Management

Medications: What medications is the child currently using? Include dosages, frequency, and method of administration.
Compliance: Is the child compliant with their medication regimen? Are there any barriers to compliance?
Use of Rescue Medications: How often is the rescue inhaler used? Does it effectively relieve symptoms?
Asthma Action Plan: Does the child have an asthma action plan? Are they and their caregivers familiar with it?

8. Review of Systems

Respiratory: Ask about any chronic cough, recurrent chest infections, or other respiratory symptoms.
Cardiovascular: Check for any associated chest pain or palpitations.
Gastrointestinal: Any history of acid reflux, which can exacerbate asthma symptoms.
Neurological/Psychological: Assess for any anxiety or stress-related symptoms that could impact asthma control.

Clinical Examination of a Child with Bronchial Asthma

1. General Appearance

Distress Level: Look for signs of respiratory distress such as anxiety, restlessness, or difficulty speaking in full sentences.
Posture: Note if the child is in a tripod position (leaning forward with hands on knees), which is often seen in severe respiratory distress.
Cyanosis: Check for cyanosis (bluish discoloration of the lips or nail beds), indicating hypoxia.

2. Respiratory Rate and Effort

Tachypnea: Measure the respiratory rate. An increased rate (tachypnea) may indicate distress.
Use of Accessory Muscles: Observe for the use of accessory muscles of respiration (neck and intercostal muscles), which can signify increased work of breathing.
Nasal Flaring and Grunting: In younger children, nasal flaring and grunting are signs of severe respiratory effort.
Wheezing: Listen for wheezing, which is a high-pitched sound typically heard during expiration. Wheezing may also be present during inspiration in more severe cases.

3. Chest Examination

Inspection:
- Chest Shape: Look for any signs of hyperinflation (barrel chest), which can occur in chronic or severe asthma.
- Symmetry: Assess for symmetrical chest movement during breathing.
Palpation:
- Tenderness: Check for any tenderness or deformities.
- Tactile Fremitus: This can be reduced in areas of hyperinflation.
Percussion:
- Hyperresonance: Percuss the chest to check for hyperresonance, which may indicate air trapping.
Auscultation:
- Breath Sounds: Assess the breath sounds. Reduced breath sounds may indicate severe obstruction or air trapping.
- Wheezes: Identify the presence, timing (inspiratory vs. expiratory), and location of wheezes.
- Prolonged Expiration: A prolonged expiratory phase is typical in asthma.
- Rhonchi: Coarse, low-pitched wheezing (rhonchi) may indicate mucus in the larger airways.
- Silent Chest: A very concerning sign, a "silent chest" occurs when wheezing stops due to severe obstruction, indicating a life-threatening situation.

4. Cardiovascular Examination

Heart Rate: Assess for tachycardia, which can be a sign of hypoxia or a side effect of bronchodilators.
Pulsus Paradoxus: Measure the blood pressure for pulsus paradoxus, where there is a greater than normal drop in systolic pressure during inspiration. This can indicate severe asthma.
Peripheral Perfusion: Check capillary refill time and peripheral pulses to assess perfusion.

5. ENT Examination

Nasal Polyps: Inspect the nasal passages for polyps, which can be associated with allergic conditions.
Nasal Mucosa: Look for signs of allergic rhinitis, such as swollen, pale, or bluish nasal mucosa.
Oropharynx: Assess for throat erythema or postnasal drip, which may indicate allergic rhinitis or sinusitis.

6. Skin Examination

Eczema: Look for signs of atopic dermatitis (eczema), which is commonly associated with asthma.
Allergic Shiners: Check for dark circles under the eyes, which can be a sign of chronic allergic conditions.
Dermatographism: Gently scratch the skin to see if it becomes raised and red, which is another sign of atopy.

7. Abdominal Examination

Diaphragmatic Excursion: Assess for any signs of abdominal distension, which can limit diaphragmatic movement and worsen respiratory symptoms.
Hepatomegaly: In severe asthma, air trapping can push the diaphragm downward, leading to a palpable liver edge.

8. Neurological and Mental Status

Alertness: Evaluate the child’s level of alertness and orientation. Drowsiness or confusion may indicate severe hypoxia.
Speech: Check for the ability to speak in full sentences. Difficulty speaking in complete sentences can be a sign of severe respiratory distress.

Bronchiolitis
Pulmonary Tuberculosis
Aspiration of Foreign Body (FB)
Hyperventilation Syndrome
Vocal Cord Dysfunction Syndrome
Habit Cough
Bronchiectasis
Ciliary Dyskinesia
Alpha-1 Antitrypsin Deficiency
Cystic Fibrosis in Caucasians
Hysteria (especially in adolescent girls with prior wheezy illnesses)

Co-morbidities:

Allergic rhinoconjunctivitis
Atopic eczema
Vernal conjunctivitis
Food allergy
Drug hypersensitivity
*Menses & Pregnancy
*Gastroesophageal Reflux Disease (GERD)
*Chronic (bacterial) sinusitis
*Allergic Bronchopulmonary Aspergillosis (ABPA)

*Can worsen disease severity/frequency

Complications

Respiratory

Air-leak syndromes
Atelectasis
Respiratory failure
Ventilation-perfusion mismatch
Mucoid impaction of the bronchi
Right middle lobe syndrome

Non-respiratory

Growth aberrations vis-à-vis effects of corticosteroids; possible prepubertal deceleration with delayed onset of puberty
Sleep disorders
Sudden symmetric limb paralysis (Hopkins syndrome)
Acid-base aberrations
Note: Like in bronchiolitis, heart failure is rare, but cor pulmonale may occur.

Chest Radiograph

Usually indicated in a child with the first episode of wheeze, cough, and/or chest tightness to exclude alternative diagnoses, such as foreign body (FB).
Normal or exaggerated bronchovascular markings may be observed between episodes of acute attacks.
Increased anteroposterior (AP) diameter, flattened diaphragmatic domes, horizontal ribs, and relative microcardia may suggest hyperinflation during an acute attack.
Associated radiologic signs of right middle lobe (RML) syndrome due to mucus plug obstruction may be evident, but co-existing pneumonia is an unusual feature of acute asthma.

Skin Prick Test

Drops of allergen solution are placed on the skin.
The point of a disposable needle, held almost parallel to the skin, is used to introduce the solution into the superficial epidermis.
A new needle is used for each allergen solution.
The reaction is read in 20 minutes.
The diameter of the urticaria (not erythema!) is measured; a value greater than 2 mm is considered a positive reaction.

Traditional
- Intrinsic or cryptogenic
- Extrinsic
Based on phenotype
- Transient Early Wheezers (TEW)
- Atopic
- Non-atopic
Based on severity
- Mild intermittent
- Mild persistent (Chronic)
- Moderate persistent (Chronic)
- Severe persistent (Chronic)

Traditional Classification Based on Triggering/Precipitating Factors

Intrinsic – Non-atopic, asthmatics react to internal, nonallergenic factors
Extrinsic – Patients sensitive to external allergens

Intrinsic vs Extrinsic Triggers
Intrinsic	Extrinsic
Acute Respiratory infections (esp. < 6 yrs)	Smoke
Emotional Stress	Pollen
Exercise & Fatigue	Animal Dander
Endocrine Changes	House dust mites (D. pteronyssinus and D. farinae)
Weather – extreme – cold/hot	Cockroaches'
Humidity Variations	House Dust Or Mold
Anxiety	Kapok Or Feather Pillows
Coughing Or Laughing	Food Additives Containing Sulfites
Genetic Factors	Other Sensitizing substances; e.g. Fried oil, insecticide, perfume
Drugs; e.g. aspirin, β-blockers

Classification of Asthma Severity
Severity	Symptoms Per Day	Symptoms Per Night	PEF or FEV1	PEF Variability
Intermittent	< 1 time a week	≤ 2 times a month	≥ 80%	< 20%
Mild Persistent	> 1 time a week but < 1 time a day	> 2 times a month	≥ 80%	20 – 30%
Moderate Persistent	Daily	Attacks affect activity	60% - 80%	> 30%
Severe Persistent	Continuous	Frequent	≤ 60%	> 30%

Goals

Achieving and maintaining symptom control & preventing exacerbations by attaining normal or near-normal lung functions.
Optimize lifestyles by maintaining normal activity levels including exercise & ensuring no loss of school days.
Avoiding adverse effects of anti-asthma medications by opting for treatments with the lowest side-effect profiles.

GINA 6-Part Management Programme

Co-management or Guided Self Management, i.e., Parent/patient education regarding partnership in asthma.
Assessing & Monitoring Severity with objective measures of lung function.
Avoiding &/or Controlling Trigger Factors, i.e., Environmental manipulation.
Establishing Medication Plans for Chronic Management, i.e., Day-to-day management guidelines.
Establishing Plans for Managing Acute Exacerbations.
Providing Regular Follow-up Care.

Co-management or Guided Self Management

Accomplished via:

Effective & open communication & encouragement for achieving patient/parent motivation, skill, & confidence.
Making the child/parent an effective first line of accomplishing management strategies for controlling asthma-related symptoms.
Giving clear guidelines on when medical/hospital intervention is required, i.e., a written action plan.

Remember the 4 (or 5) Rs of Co-management:

Reaching an agreement on goals like sports’ participation, avoiding frequent exacerbations/night-time symptoms, school absence, & side effects of anti-asthma medications.
Rehearsal.
Repetition.
Reward/reinforcement.
Providing written guidelines & action plan for easy reference.

Four (4) Elements of an Effective Co-management Programme

Ensuring patient/parents’ proper understanding of the condition.
Monitoring symptoms via the use of home-usable devices, especially PF meter, symptom diary & drug use/compliance.
Providing a pre-arranged action plan for day-to-day care and acute exacerbations.
Provision of written guidelines.
Above all, interaction between the family and the physician constitutes the most important prerequisite for addressing complex psychosocial factors like poor self-esteem, denial, and poor medication compliance, which are likely to impede effective control.

British Guideline on Self Management (2007)

“Patients with asthma should have an agreed written action plan & their own peak flow meter with regular checks of inhaler technique & compliance. They should know when to increase their medications and when to seek medical assistance. Use of asthma action plans has been shown to decrease hospitalizations and deaths due to asthma.”

Objective Measures of Assessing & Monitoring Severity via Measuring Lung Function

Accomplished via:

Appropriate/effective home use of peak flow meters; every patient should own a PEF meter.
Effective use of a symptom diary as a guide to the need and type of medications required using the action plan guidelines.
Intermittent measurement of PFTs using spirometry & documenting hard copies of flow volume curves.

Avoiding &/or Controlling Trigger Factors

Accomplished via:

Control or elimination of biotic or abiotic potential or proven allergens/provocateurs via HDM avoidance measures, removal of household pets & avoiding exposure to cigarette smoke.
Pharmacologic control of allergen exposure-related airway inflammation via the use of safe (usually inhaled) anti-inflammatory agents.
Immunotherapy or desensitization.

Does Reducing Asthma Triggers Always Work?

The control of allergens has not been demonstrated to work as monotherapy. A recent study showed that house dust mite allergen avoidance and dietary fatty acid modification in the first few years of life do not prevent asthma, eczema, or atopy in children with a family history of asthma (Guy et al, Allergy, 2006).

Conventional wisdom and indeed the recommendations from many asthma experts still endorse allergen avoidance measures in early life.

Early Interventions Don't Prevent Asthma in High-Risk Children

House dust mite allergen (HDM) avoidance and dietary fatty acid modification in the first few years of life do not prevent asthma, eczema, or atopy in children with a family history of asthma, new research shows.

Sensitization to HDM and consumption of diets with a low omega-3 to -6 fatty acid ratio have been linked to asthma. Guy et al studied 616 children who were randomized to receive HDM avoidance, a diet with an increased omega-3 to -6 fatty acid ratio, both interventions, or no intervention during the first 5 years of life. Of these children, 516 were available for evaluation at 5 years.

The HDM avoidance measure involved the use of allergen-impermeable linens and regular washing with an anti-HDM detergent. With the diet intervention, parents were encouraged to prepare their child's meals using canola-based oils and tuna oil capsules to achieve a high omega-3 to -6 fatty acid ratio.

Although HDM avoidance measure reduced bedding allergen levels by 61%, it had no effect on the occurrence of asthma, wheeze, or atopy. In fact, eczema was actually more common in the HDM avoidance group than in controls: 26% vs. 19%.

Similarly, while the diet intervention did succeed in increasing the omega-3 to -6 fatty acid ratio, it did not prevent asthma, wheezing, eczema, or atopy.

Despite the null findings of the present study, previous reports support the view that, under certain circumstances, asthma can be prevented. However, the most effective, practical forms of early life environmental modification and the circumstances under which it will be appropriate to implement them remain to be established.

Newer Therapy of Chronic Asthma

Omalizumab
Sublingual Immunotherapy

Omalizumab

Omalizumab is a recombinant DNA-derived humanized IgG monoclonal antibody that selectively binds to human immunoglobulin E (IgE). It inhibits the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, limiting the release of allergic mediators.

Omalizumab is approved for use in children 6 years and older with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.

Sublingual Immunotherapy

Sublingual immunotherapy is a newer, more convenient option than injectable immunotherapy.

Medication Plans for Chronic Management

Accomplished via:

Valid classification of the disease severity using clinical & PFT parameters as appropriate (refer to classification criteria into 4 clinical categories).
Appending the appropriate medications for the level of severity and subsequently stepping up or down the medications depending on the frequency & severity of symptoms, and objective measures of PFTs/PEFR values, i.e., stepwise approach.
Note the current emphasis on the need for an early introduction of effective inhaled anti-inflammatory medications for long-term control, and the related need for demonstrating & ascertaining proficiency in the use of inhaler devices, as well as the use of rescue treatment with systemic steroids for acute attacks.

Classification for Long-Term Management

Intermittent
Mild persistent
Moderate persistent
Severe persistent

Summary of stepwise management in children less than 5

Summary of stepwise management in children 5-12

Pharmacological management

Immunotherapy

Immunotherapy can be used as an adjunct to standard drug therapy in allergic asthmatic children.
Sublingual (allergy drops) and injectable (allergy shots) therapies have been shown to reduce the presence of asthma and the overall use of asthma medication.

Management of Acute Exacerbations

Establishing Plans for

Acute attacks are markers of failure of chronic/day-to-day management (by physician and family/patient), or massive exposure to potential trigger(s).
Note the emphasis on the use of inhaled bronchodilators for acute exacerbations as opposed to systemic steroids (parenteral or oral), which are more valuable for managing chronic inflammation rather than acute flares.

Summary of acute asthmatic response

Levels of severity of acute exacerbation of asthma

Clinical features for assessment of severity

Management of asthma in children in A and E

Drugs Available for Treatment of Asthma

1. Relievers (usually blue)

β2 agonists: salbutamol, albuterol, terbutaline
Adrenaline
Theophyllines
Anticholinergics
Ephedrine-containing drugs (e.g., franol, tedral) are of little relevance in modern practice

2. Preventers (usually beige or brown)

Sodium cromoglycate
Ketotifen
Nedocromil sodium
Corticosteroids (CCS)

Inhaled corticosteroids (ICS): budesonide, beclomethasone, fluticasone
Therapeutic importance more evident in the past 2 or more decades due to the greater availability of these considerably safer inhaled preparations
Probably the most effective preventer of frequent exacerbations
Systemic steroids: prednisolone (short-term rescue treatment for acute exacerbations, 5-7 days); hydrocortisone (useful in the management of severe acute asthma)
In 1980, Clark remarked:
‘In general, CCS are used when other measures have failed to control asthma’
‘There remains some doubt about the role of CCS in the management of acute severe asthma.’
Clark TJH, 1980

3. Controllers (possibly purple)

Long-acting beta-2 agonists: salmeterol, formoterol, bambuterol
Useful for long-term control as add-on agents for frequent nocturnal symptoms

Classification of Drugs Used in the Treatment of Asthma
PREVENTERS (Anti-inflammatory action to prevent asthma attacks)	CONTROLLERS (Sustained bronchodilator action but weak or unproven anti-inflammatory action)	RELIEVERS (Quick relief of symptoms and for use in acute attacks as PRN dosage only)
Inhaled corticosteroids Beclomethasone Budesonide Fluticasone Flunisolide Triamcinolone Oral corticosteroids Prednisone Prednisolone Methylprednisolone Disease modifiers - Leukotriene antagonists Montelukast Zafirlukast	Long-acting β2 agonists Salmeterol Formoterol Sustained release theophylline tablets	Short-acting β2 agonists Salbutamol Terbutaline Fenoterol Anti-cholinergics Short-acting theophyllines

Comparative Effects of Anti-asthma Medications
Medications	Bronchodilator	Bronchoprotection: Response to Allergen Exp.	Histamine	Resolution
Bronchodilators: β–adrenergic	+++	I	+++< col/td>	-
Theophylline	++	I, L	+	+
Anticholinergic	+	-	ND	ND
Non-bronchodilator medications: Cromolyn Na	_	I, L, AR	_	++
Nedocromil Na	_	I, L, AR	_	+++
Glucocorticoids	I, L, AR	L, AR	+++	+++

Note:

I = Immediate response
L = Late response
AR = Airway hyperresponsiveness
ND = Not determined

ARI, Pathogens & Asthma

ARI induces Bronchial Hyperresponsiveness (BHR) in early life.
Relationship between snuffles (cold) and acute wheezy illnesses has been recognized for ages, as evident in Milne’s famous quote:
“They asked if the sneezles come after the wheezeles or if the first sneezles came first.”
Freeman & Todd (1962) suggested that asthmatics are predisposed to relative IgA deficiency, which may be associated with atopy.
Numerous studies (see table) have shown that it is viral, as against bacterial infection, that induces BHR and subsequently triggers flares of asthma.
In a study of about 56 acute asthmatic attacks, Gbadero, Johnson & Aderele (1996, Thorax) identified a viral agent in about 50% of those who had viral studies; RSV, PIVs, and Flu A were the commonest IDs.

Any Changes in Asthma Mx or Are We Going Round in Cycles?

In the last 25 years:

Definition of asthma has changed.
Prevalence of asthma has doubled.
Better understanding of the pathogenesis and pathophysiology of asthma, especially the central role of chronic airway inflammation.
Drug management has improved with the availability of safer anti-inflammatory agents and much better drug delivery devices.
Globally applicable guidelines are now available for the management of asthma with regular reviews.

Novel Theories on Asthma

Gastro-oesophageal reflux disease: Lowered intra-oesophageal pH initiates a fall in FEV1.
United airways disease: Hypothesis implies unity of the upper and lower airways in asthma.
Hygiene hypothesis: States that reduced exposure to allergens in early life is implicated in the growing propensity for allergy sensitization.

Pathophysiology of Asthma – The Immune System

The 3 main components are antibodies, inflammatory cells, and inflammatory mediators.
The basis for the immunological response can be found in utero.
There are B & T lymphocytes. B lymphocytes are responsible for the production of immunoglobulins, especially IgE. T helper (Th) lymphocytes include Th1 & Th2.
Th2 is responsible for the production of cytokines, especially IL-4, which stimulates B cells to produce IgE.
IgE is fundamental to the allergic immune response.
Th1 secretes IFNγ, which is toxic. Its effect is countered by IL-4 & IL-5 produced by Th2.
It seems that the natural state of the fetus is skewed towards the production of Th2 cells.

The Unique Paradoxes of Asthma:

Reversible, yet potentially fatal.
Presentation is episodic, yet it is a chronic (inflammatory) disorder.
There are newer & more specific pharmacologic agents available, yet most deaths are due to under-treatment!

Practice Questions

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Contributors

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