ASTHMA
Dr. Ssemakula Isa
FACILITATOR: Prof. BRUCE J KIRENGA
Session Outline
• Definition of Asthma
• Epidemiology of Asthma
• Pathophysiology
• Predisposing factors, Triggers
• Clinical presentation
• Diagnosis
• Management
Definition
• Asthma is defined by Global initiative of Asthma (GINA) as a
heterogenous disease usually characterized by chronic airway
inflammation and accompanied by a history of recurrent or persistent
respiratory symptoms such as a wheeze, shortness of breath, chest
tightness and cough that vary over time and in intensity, together
with variable airflow obstruction.
• Airway narrowing is usually reversible but may be irreversible.
Epidemiology
• Global prevalence is increasing.
• Affects over 300M people globally.
• About 250,000 deaths annually.
• High Income Countries:10-12 % adults, 15% children.
• Low and Middle Income countries: Rising prevalence associated with
increased urbanization
• This is in sync with rising prevalence of atopy and other allergic
diseases. Reason for increase likely systemic rather than lung
Epidemiology - continued
• Presents at any age, peak age 3 years
• Childhood, M:F =2:1; Adulthood M:F =1:1
• Longitudinal studies that have followed up asthmatics up to 40 years
suggest that most asthmatics are asymptomatic during adolescence,
but asthma returns in some, during adult life.
• Asthma imposes a substantial burden on patients, families and the
community. It causes respiratory symptoms, limitations of activit, flare
ups and may be fatal
Burden of Asthma in Uganda
• Prevalence and factors associated with asthma among adolescents and adults
in Uganda: a general population based survey by Bruce J. Kirenga, Corina de
Jong et al 2019
RESULTS
• The prevalence of asthma was 11.0% (males 10.3%, females 11.4%, urban
13.0% and rural 8.9%.
• Significantly is associated with smoking, biomass smoke exposure,
urbanization, allergic diseases and postive family historty
Risk factors
• Atopy – major risk factor. Patients suffer from other atopic diseases
such as Allergic Rhinitis (>80%), Atopic dermatitis(Eczema)
Not all atopic patients have Asthma.
• Genetic predisposition – different genes contribute (polygenic),
severity is also genetically predetermined.
Genetic polymorphisms may also determine response to asthma
therapy
• Epigenetic mechanisms-DNA methylation and histone modification
may be influenced by diet, cigarette smoke exposure, air pollution
Risk factors contd
• Air pollution –Airpollutants such as Sulphur dioxide, ozone; Road traffic
pollutants such as diesel particulates, Nitrogen dioxide
Indoor air pollution – exposure to nitrogen dioxide from cooking stoves,
exposure to passive cigarette smoke.Maternal smoking is also a risk factor
• Infections – RSV, Atypical bacteris –Mycoplasma, Chlamydophila
Living in damp houses with exposure to mold spores. Children born on farms
exposed to endotoxin compared to diary farms- less allergic sensitisation.
Hookworms – less risk
• Allergens –Inhaled allergens such as house dust mites. Domestic pets e.g
cats associated with allergic sensitization. Early exposure may be protective
Risk factors
• Diet. Still controversial. Diets low in antioxidants such as Vitamin C,
Vitamin A, Selenium, Mg.
• Obesity – More common in obese esp women. Linked to
proinflammatory adipokines and reduced anti-inflammatory
adipokines released from fat cells
• Occupational exposure; may affect up to 10% of young adults. More
than 300 sensitizing agents have been identified. Animal lab workers,
cleaners, chemical industries- exposure to toluene diisocyanate.
Symptoms improve during holidays and weekends.]
Asthma Triggers
They trigger airway narrowing, wheezing and dyspnoea
• Allergens –dermatophagoides species,
Perennial; environmental exposures, cats and other domestic pets,
cockroaches
Seasonal: grass pollen, fungal spores, tree pollen
• Virus infections – Rhinovirus, Respiratory Syncytial Virus, coronavirus
• Drugs –B blockers, including the selective B, B2blockers, or topical
application. Aspirin in some. ACEIs – less kinin breakdown
• Exercise – in Children. Hyperventilation – increased osmolality in
airway lining fluid –mast cell mediator release. Exercise induced
Asthma begins after exercise has ended.
• Physical factors – Cold air and hyperventilation. Laughter may be a
trigger. Strong smells or perfumes. Hot weather and changes in
weather.
• Air pollution; Increased ambient levels of sulphurdioxide, ozone,
diesel particulates, nitrogen dioixide
• Occupational factors; Patients have symptoms at work and relief away
from work.
• Food and diet. Little evidence. Some food preservatives-
metabisulfite; Tartrazine, yellow food coloring agent.
• Hormones –characterized by premenstrual worsening of asthma.
Related to fall in progesterone. Thyrotoxicosis and hypothyroidism can
worsen asthma.
• Stress- it may worsen asthma in some; psychological factors can
induce bronchoconstriction through cholinergic reflex pathways.
• NSAIDS -- samters syndrome (asthma, ASA senstivity , polyps)
ASTHMA DEVELOPMENT PATHWAY
pathophysiology
Pathophysiology
Air way hyperresponsivenes
Inflamation (pathogenesis)
Pathophysiology
• Airway inflammation and airway hyperresponsiveness:
From the trachea to terminal bronchioles, mostly bronchi.
Chronic inflammation with acute inflammatory episodes superimposed
Cells:
Mast cells – initiate the acute bronchoconstrictor response to allergens
through an IgE dependent mechanism
Mast cells release several bronchoconstrictor mediators such as
histamine, prostaglandin D2, cyteinyl leukotrienes, cytokines,
chemokines and neutrophils
• Macrophages and dendritic cells
Macrophages may be activated by allergens via low affinity IgE
receptors. Dendritic cells are antigen presenting cells.
• Eosinophils
Eosinophilic infiltration is a hallmark of asthmatic airways. Linked to
development of of AHR through the release of basic proteins and
oxygen derived free radicals. Release growth factors involved in airway
remodeling and in exacerbations.
• Neutrophils. Increased in sputum and airways of some patients with
severe asthma.
• T lymphocytes
Play a cardinal role. Release cytokines resulting in recruitment and
survival of eosinophils and maintenance of mast cell population in the
airways.
• Structural cells such as epithelial cells, fibroblasts, airway smooth
muscle cells are sources of inflammatory mediators such as cytokines
and lipid mediators
Pathological features
• Specific chronic inflammation of mucosa of the lower airways
• airway mucosa is infiltrated with activated eosinophils and T
lymphocytes, and activation of mucosal mast cells.
• Thickening of the basement membrane due to subepithelial collagen
deposition
• Airway may be thickened and edematous
• Occlusion of airway by mucous plug
• Airway narrowed, erythematous and edematous
• Inflammatory mediators: Mast cell mediators such as histamine,
prostaglandin D2, cysteinyl-leukotrienes,
• Cytokines eg TH2 cytokines IL4, IL5, IL9, IL13, proinflammatory
cytokines such as TNF-alpha, IL 1beta.
• Chemokines Eotaxin(CCL11), CCL17 and CCL22
Effects
• Airway epithelium – epithelial damage/epithelial shedding contributing to
Airway Hyperresponsiveness.
• Fibrosis – Basement membrane is thickened due to subepithelial fibrosis
• Airway smooth muscle – There is hypertrophy and hyperplasia of airway
smooth muscle. PDGF
• Vascular response – increased airway mucosal blood flow due to increase
in number of blood vessels. VEGF
• Mucus hypersecretion –increased mucus secretion- resulting from
hyperplasia of submucosal glands and increased number of goblet cells
• Neural regulation –defects in autonomic neural control may
contribute to airway hyperresponsiveness. Cholinergic pathways
through release of Acetylcholine acting on muscarinic receptors cause
bronchoconstriction.
• Airway remodeling – the changes in the structure of the airway may
lead to irreversible narrowing of the airway. They include increased
airway smooth muscle,fibrosis, angiogenesis, and mucus hyperplasia
Reversible airflow limitation
• Limitation of airflow is due mainly to bronchoconstriction from mast
cell mediators. Other contributors –airway edema, vascular
congestion,luminal occlusion with exudate
• Results in a reduction in forced expiratory volume in 1 second(FEV1),
FEV1/FVC ratio, and peak expiratory flow,as well as an increase in
airway resistance
• There is air trapping and increased residual volume
• In more severe cases, there is reduced ventilation and increased
pulmonary blood flow resulting in ventilation-perfusion mismatch
Is it asthma? Clinical Features
History
• Wheezing, dyspnea, chest tightness and coughing
Symptoms may worsen at night. Prodromal symptoms may precede an attack
–itching under the chin, inexplicable fear
Probe for possible triggers – exercise, laughter,allergens, cold air.
Examination
Often normal
Most frequent finding; wheezing on auscultation, especially on forced
expiration
Investigations
Spirometry to assess variable expiratory airflow limitation
a) Reduced FEV1, FEV1/FVC ratio, and PEF. FEV1/FVC ratio -Less than 0.7
in adults, 0.85 in children
b) Post-bronchodilator spirometry, >12% and 200ml increase in FEV1;
• 15 min after SABA. This is called ‘bronchodilator reversibility’
• 2-4 week trial of oral corticosteroids (prednisolone 30-40 mg daily).
c) Average daily diurnal PEF variability greater than 10%
• If lung function is normal, repeat reversibility testing when
symptomatic.
• Plethysmography shows increased airway resistance
Differential diagnosis
• COPD
• Left ventricular failure
• Upper airway obstruction by a tumor or laryngeal edema
• Vocal cord dysfunction
Proposed diagnostic approach
• Possible asthma= symptoms alone, response to medications, supportive
evidence such as allergy family history etc.
• Probable asthma= symptoms, supportive evidence plus significant
reversibility (FEV1 of 200 ml or greater and 12% improvement from
baseline after inhalation of short acting beta2-agonists) and no airflow
limitation (FEV1/FVC ratio<0.70 or LLN)
• Definite asthma=evidence of expiratory airflow limitation (FEV1 of 200 ml
or greater and 12% improvement from baseline after inhalation of short
acting beta2-agonists) plus airflow limitation (FEV1/FVC ratio<0.70 or LLN)
The diagnosis cannot be confirmed in 25-35% of patients with Asthma
How much asthma
What to initiate and how much?
Goals of treatment
• Minimal chronic symptoms, including nocturnal
• Minimal exacerbations
• No emergency visits
• Minimal use of a required beta2 agonist
• No limitation on activities,including exercises
Bronchodilator therapies
• Beta2 agonists –
relax smooth muscle and inhibits mast cells
SABA –albuterol, terbutaline. Duration of action: 3-6 hours
LABA –salmeterol, formoterol . Duration of action: over 12hours
Other LABAs –indicaterol, olodaterol, vilanterol given once a day
• Anticholinergics –
• muscarinic receptor antagonists prevent cholinergic nerve induced
bronchoconstriction and mucus secretion
LAMA – Tiotropium bromide, Glycopyrronium bromide
Controller therapies
• Inhaled corticosteroids (ICS)
Reduce eosinophils, numbers of activated T lymphocytes, surface mast
cells
• Antileukotrienes – Montelukast, Zafirlukast
Useful as add on therapy
Low, medium, high dose ICS
UPDATED!
Inhaled corticosteroid Total daily dose (mcg)
Low Medium High
Beclometasone dipropionate (CFC) 200–500 >500–1000 >1000
Beclometasone dipropionate (HFA) 100–200 >200–400 >400
Budesonide (DPI) 200–400 >400–800 >800
Ciclesonide (HFA) 80–160 >160–320 >320
Fluticasone furoate (DPI) 100 n.a. 200
Fluticasone propionate (DPI or HFA) 100–250 >250–500 >500
Mometasone furoate 110–220 >220–440 >440
GINA 2016, Box 3-6 (1/2)
Triamcinolone acetonide 400–1000 >1000–2000 >2000
Other options
• Systemic corticosteroids
IV hydrocortisone, methylprednisolone used in treatment of acute
severe asthma
Note: Oral corticosteroids(OCS) are as effective as IV-CS.
• Cromones –cromolyn sodium, nedocromil sodium
• Anti-IgE –omalizumab
• Non pharmacologic therapies
Routine assessment of an
Asthmatic
• Asthma control
• Assess symptom control over the last 4 weeks
• Identify any modifiable risk factors for poor outcomes
• Measure lung function before starting any treatment, 3-6 months later, and
then periodically.
• Are there any comorbidities?
Rhinitis, GERD, obesity, obstructive sleep apnea, anxiety
• Assess asthma control.
• Poor symptom control is a burden to patients and risk factor for flare ups
Risk factors for Exacerbations
• Uncontrolled asthma symptoms
• Medications: ICS not prescribed, poor adherence, incorrect inhaler
technique
• Cormorbidities eg obesity, GERD, chronic rhinosinusitis, anxiety,
depression,pregnancy, confirmed food allergy
• Exposures: smoking, allergen exposure if sensitized, air pollution
• Setting: major socioeconomic problems
• Lung function: Low FEV1, esp if less than 60% predicted
Monitoring
• How often should asthma be reviewed?
• 1-3 months after treatment started, then every 3-12 months
• During pregnancy, every 4-6 weeks
• After an exacerbation, within 1 week
• Stepping up asthma treatment
• Sustained step-up, for at least 2-3 months if asthma poorly controlled
• Important: first check for common causes (symptoms not due to asthma, incorrect inhaler
technique, poor adherence)
• Short-term step-up, for 1-2 weeks, e.g. with viral infection or allergen
• May be initiated by patient with written asthma action plan
• Day-to-day adjustment
• For patients prescribed low-dose ICS/formoterol maintenance and reliever regimen*
• Stepping down asthma treatment
• Consider step-down
GINA 2016
after good control maintained for 3 months
• Find each patient’s minimum effective dose, that controls both symptoms and
exacerbations
References
• Harrison’s textbook of Medicine 20th Edition
• GINA Pocket Guide for Asthma Management and Prevention 2022
• Kirenga Bruce ‘Difficult to treat Asthma’ APU conference proceedings
2019
• Prevalence and factors associated with asthma among adolescents
and adults in Uganda: a general population based survey by Bruce J.
Kirenga, Corina de Jong et al 2019
