ASTHMA

- Syndrome characterized by airflow obstruction that varies markedly, both spontaneously and
with treatment
- Narrowing of airways is usually reversible, but in some patients with chronic asthma there may
be an element of irreversible airflow obstruction.
- Heterogeneous disease with interplay between genetic and environment factors.

PREVALENCE

- Most common chronic diseases globally

- Currently affects 300million people worldwide with 250,000 deaths annually
- 10-12% adults; 15% children affected by disease
- rising prevalence: increased urbanization,
atopy and other allergic diseases- reasons for increase are likely to be systemic
rather than confined to the lungs.
- Most px with asthma in affluent countries are atopic with allergic sensitization to the house dust
mite Dermatophagoides pteronyssinus and other environment allergens such as animal fur and
pollen
- Present in any age; peak ageof 3 years
- Childhood: Males 2x as female
- Adult: equalized

RISK FACTORS AND TRIGGERS

 ATOPY
- Major risk factor for asthma, and non-atopic individuals have a very low risk of developing
asthma.
- Other atopic diseases: allergic rhinitis- >80%
Atopic dermatitis (eczema)
- Found 40-50% of the population
- Environmental and genetic factor: predispose the development of asthma in atopic individuals.
- Allergens: lead to sensitization are usually proteins that have protease activity and most
common allergens derived from house dust mites, cat and dog fur, cockroaches, grass and
pollens, rodents
- Genetically determined production of a specific IgE antibody
 GENETIC PREDISPOSITION
- Familial association of asthma and high degree of concordance for asthma in identical twins
- Polygenic
-most consistent findings have been associations with polymorphisms of genes chr, 5q,
including the T-helper 2 (TH2) cells interleukin IL-4, IL5, IL9, IL-13 which is associated with atopy.
- Novel genes- assc. w/ asthma ADAM-33, DPP-10 AND ORMDL3, positional cloning.
 EPIGENETIC MECHANISMS
- DNA methylation and Histone modification patterns may influenced by diet, cigarette smoke
exposure and air pollution and may affect the genes involved in the pathogenesis of asthma.
 INFECTIONS
- Viral infections (rhinovirus) are common triggers of asthma exacerbations
- Respiratory syncytial virus infection-very common in children
- Mycoplasma and Chlamydophila- severe asthma
- HYGIENE HYPOTHESIS- proposes that lack of infections in early childhood preserves the TH2 cell
bias at birth whereas exposure to infections and endotoxin results in a shift toward predominant
protective TH1 immune response.
- Intestinal parasite such as hookworm- reduced risk of asthma
 DIET-controversial
- Low vit. C, A, magnesium, selenium, and omega-3 polyunsaturated fats (fish oil) or high Na and
omega B-6 polyunsaturated and vit. D deficiency – increased risk of asthma
- Obesity-independent risk factor for asthma
 AIR POLLUTION
- Sulfur dioxide, ozone and diesel particulates, nitrogen dioxide and cigarette smoke-trigger
asthma
 ALLERGENS
- Inhaled allergens-are common triggers of asthma symptoms and implicated in allergic
sensitization
- Allergic sensitization-domestic pets (cats), house dust mites
- Note: early exposure to cats in the home may be protective through inductive tolerance
 OCCUPATIONAL EXPOSURE
- Relatively common affect 10% of young adults.
- -suspected when symptoms improve during weekends and holidays.
 OBESITY
-occurs more frequently in obese people (BMI:>30mg/m2)and often more difficult to control.
 OTHER FACTORS
- Lower maternal age, duration of breast feeding, prematurity, low birthweight, inactivity and
acetaminophen (paracetamol).
 INTRINSIC ASTHMA
- 10%-negative skin test to inhalant allergens and normal serum conc. IgE.
- Px with non-atopic or intrinsic asthma usually show later onset of dse (adult onset asthma)
commonly have concomitant nasal polyp, and may be aspirin-sensitive.
- More severe, persistent asthma.
- Staphylococcal enterotoxins-serve as superantigen
- Type 2 innate lymphoid cells (ILC2)- drive the eosinophilic inflammation in this non-allergic pxs.
 ASTHMA TRIGGERS- several stimuli trigger airway narrowing, wheezing, and dyspnea in
asthmatic pxs
 Allergens- most common that can trigger asthma Dermatophagoides specie
 Virus infections
 Pharmacologic agents
 Exercise
 Physical factors
 Food and diet
 Air pollution
 Occupational factors
 Hormones
  Gastroesophageal reflux
 Stress

PATHOPHYSIOLOGY

- Associated with specific chronic inflammation of the mucosa of the lower airways.
- Airway Mucosa- is infiltrated with activated eosinophils and T lymphocytes and there is
activation of mucosal mast cells
- A characteristic finding is thickening of the basement membrane due to subepithelial collagen
deposition also found in pxs with eosinophilic bronchitis presenting as cough who do not have
asthma, therefore marker of eosinophilic inflammation in the airway as eosinophils release
fibrogenic mediators
- Airway wall itself may be thickened and edematous, occlusion of the airway lumen by a mucous
plug which is compromised of mucous glycoproteins secreted from goblet cells and plasma
proteins from leaky bronchial vessel – fatal asthma
- Vasodilation and increased numbers of blood vessels (angiogenesis)
- Bronchoscopy- narrowed , erythematous, and edematous
- Pathologic changes- found in all airway but do not extend to the lung parenchyma
- Peripheral airway inflammation- found in severe asthma

 AIRWAY INFLAMMATION
- There is an inflammation in the respiratory mucosa from the trachea to terminal bronchioles
- Predominant in the bronchi(cartilaginous airways)
- Specific pattern- assc. With airway hyperresponsiveness (AHR)
- Physiologic abnormality of asthma- correlated airflow obstruction
- Pattern of inflammation of asthma- characteristic of allergic diseases with similar inflammatory
cells seen in the nasal mucosa in rhinitis.
- Common pattern of inflammation-characterized by eosinophilic infiltration
 MAST CELLS
- Are important initiating the acute bronchoconstrictor responses to allergens and several other
indirectly acting stimuli, such as exercise and hyperventilation (via osmolality changes) as well as
fog.
- Activated by allergen through an IgE-dependent mechanism and binding of specific IgE to mast
cells renders them more sensitive to activation by physical stimuli such as osmolality
- Humanized anti-IgE antibodies- which inhibit IgE mediated effects reduce asthma symptoms and
reduced exacerbation.
- Mast cells release- histamine, prostaglandin D2, cysteinyl-leukotrienes, cytokines, chemokines,
growth factors and neutrophins.
 MACROPHAGES AND DENDRITIC CELLS
- MACROPHAGES- derived from blood monocytes, may traffic into the airways in asthma and may
activated by allergens via low-affinity IgE receptors (FcRII).
- DENTRIRIC CELLS- are specialized macrophage-like cells in the airway epithelium, which are the
major antigen-presenting cells.
- IMMATURE DENDRITIC CELLS- in the respiratory tract promote TH2 cell differentiation and
require cytokines such as AL-12 and TNF-a, to promote the normally preponderant TH1.
 EOSINOPHILS
- Characteristic feature of asthmatic airmays
- Linked to the development of AHR through the release of basic proteins and oxygen derived free
radicals.
 NEUTROPHILS
- Roles are resistant to the anti-inflammatory effects of corticosteroids and currently unknown.
 LYMPHOCYTES
- T-LYMPHOCYTES- play a very important role in coordinating the inflammatory response in
asthma through the release of specific patterns of cytokines, resulting recruitment and survival
of eosinophils and in the maintenance of the mast cell population in the airways.
- TH2-skewed to express naïve immune system and the immune system of asthmatics.
- TH1- predominant in normal airways
- Regulatory T- cells (Treg)- play an important role in determining the expression of other T cells,
and there is evidence for reduction in a certain subset of tregs (CD4+, CD25+) that express the
transcription factor FOXP3 in asthma that is assc. With increased TH2 cells.
 STRUCTURAL CELLS
 -epithelial cells, fibroblasts and airway smooth-muscle cells- important sources of inflammatory
mediators such as cytokines and lipid mediators, in asthma.
 INFLAMMATORY MEDIATORS

 Cytokines
 Chemokines
 Oxidative stress
 Nitric oxide
 Transcription factors

 EFFECTS OF INFLAMMATION
 Airway epithelium
 Fibrosis
 Airway smooth muscle
 Vascular responses
 Mucus hypersecrection
 Neural regulation
 AIRWAY REMODELING
-characteristically found in the asthma and these lead to irreversible narrowing of the airway.
-characteristics structure changes- increased airway smooth muscle, fibrosis, angiogenesis and
mucus hyperplasia
 PHYSIOLOGY
-results in a reduction in forced expiratory volume in 1 sec. (FEV1), FEV1/FVC ration , and peak
expiratory flow (PEF) as well as an increase in airway resistance.
 AIRWAY HYPERRESPONSIVENESS (AHR)
-characteristic physiologic abnormality of asthma and describes the excessive
bronchoconstrictor response to multiple inhaled triggers that would have no effect in normal
airways
 CLINICAL FEATURES AND DIAGNOSIS
SYMPTOMS- may be worst at night and pxs typically awake in the early morning hours.
o wheezing
o dyspnea
o coughing

-pxs may report difficulty in filling their lungs with air.

-increased mucus production, with typically tenacious mucus that is difficult to expectorate

-increased ventilation and use of accessory muscle of ventilation

PRODROMAL SYMPTOMS
o itching under the chin
o discomfort between the scapula
o inexplicable fair (impending doom)

PHYSICAL SIGNS
o inspiratory
o greater extent expiratory
o rhonchi throughout the chest
o hyperinflation

-children- predominant nonproductive cough (cough-variant asthma)

DIAGNOSIS

 LUNG FUNCTION TEST

- SIMPLE SPIROMETRY: confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and PEF
 AIRWAY RESPONSIVENESS
- Increased AHR in normally measured by methacholine or histamine challenge with calculation of
the provocative concentration that reduces FEV1 by 20% (PC20).
 HEMATOLOGIC TESTS- not usually hepful
 IMAGING
-CHEST ROENTGENOGRAPHY- usually normal but in more severe patients may show
hyperinflated lungs.
 SKIN TESTS
- SKIN PRICK TEST- to common inhalant allergens (dust mite, cat fur, grass pollen) are positive in
allergic rxn and negative in intrinsic asthma.
 EXHALED NO
- FRACTIONAL EXHALED NO- is now being used as a noninvasive test to measure eosinophilic
airway inflammation.
DIFFERENTIAL DIAGNOSIS
o UPPER AIRWAY OBSTRUCTION- by a tumor or laryngeal edema can mimic severe asthma, but
patients typically present with stridor localized to large airway.

-Diagnosis confirmed:

FLOW VOLUME LOOP- that shows reduction in inspiratory as well as expiratory flow

BRONCOSCOPY- to demonstrate the site of upper airway narrowing

o ENDOBROCHIAL OBSTRUCTION W/ A FOREIGH BODY- persistent wheezing in a specific area of
the chest
o LEFT VENTRICULAR FAILURE- may mimic the wheezing the asthma but basilar crankles are
present in contrast to asthma
o EOSINOPHILIC PNEUMONIAS AND SYSTEMIC VASCULITIS- INCLUDING CHURG-STRAUSS
SYNDROME (eosinophilic granulomatosis with polyangiitis) and polyarteritis nodosa- associated
with wheezing
o COPD- less variably, never completely remit and show less(no) reversibility to bronchodilators.

TREATMENT

 BRONCHODILATOR THERAPIES-act primary airway smooth muscle to reverse the

bronchoconstriction of asthma.
1. B2-AGONIST-activated B2-adrenergic receptors which are widely expressed in the airway.
 MOA: to relax airway smooth muscle cells of all the airways where they act as
functional antagonists, reversing and preventing contraction of airway smooth
muscle cells by all known bronchoconstrictors.
 CLINICAL USE: given inhalation to reduce side effect
-SABA (albuterol and terbutaline) –duration 3-6h, rapid onset bronchodilation
needed to relief saymptoms
-LABA(salmeterol andformoterol)- duration 12h given 2x daily by inhalation, should
not be given in the absence of ICS therapy as they do not control the underlying
inflammation.
 SIDE EFFECTS: muscle tremor and palpitation(common elderly)
 TOLERANCE: potential tolerance if given chronically
 SAFETY: used LABA with ICS
 2. ANTICHOLINERGICS
-MUSCURINIC RECEPTOR ANTAGONISTS (ipratropium bromide)-prevent cholinergic nerve-
induced bronchoconstriction and mucus secretion.
-less effective than B2-agonist.
 SE: dry mouth (elderly), urinary retention and glaucoma
3. THEOPHYLLINE
-widely prescribed as an oral bronchodilator several years ago, especially as it was
inexpensive.
-brochodilator effect- is due to inhibition of phosphodiesterase in airway smooth muscle
cells which increased CAMP but doses required for bronchodilation commonly cause SE that
are mediated mainly by phosphodiesterase inhibition.
 CLINICAL USE: used as additional bronchodilator in pxs with severe asthma when
plasma conc. 10-20mg/L are required although this conc. Assc. with SE.
 SE: nausea, vomiting, headache-due to phosphodiesterase inhibition
Diuresis and palpitation
High conc- cardiac arrhythmias, epileptic seizure and death-due adenosine A1-RA

 CONTROLLER THERAPIES
1. INHALED CORTICOSTEROIDS- most effective controllers for asthma, use has revolutionized
asthma theray
 MOA: most effective anti-inflammatory agents used in asthma theray, reducing
inflammatory cell numbers and their activation in the airway.
 CU: most effective controllers in the management of asthmaand beneficial in
treating asthma of any severity and age
 SE: hoarseness (dysphonia) and oral candidiasis
Long term used- Children: impaired growth; Adult: osteoporosis
2. SYSTEMIC CORTICOSTEROIDS-used intravenously (hydrocortisone or methylprednisolone)
for the treatment of acute severe asthma, effective and easier to used.
3. ANTILEUKOTRIENES-CYSTEINYL-LEUKOTRIENES: are potent brochoconstrictors; they cause
microvascular leakage and increase eosinophilic inflammation through the activation of cys-
LT1- receptors
4. CROMONES- CROMOLYN Na AND NEDOCROMIL Na: are asthma controller drugsthat appear
to inhibit mast cell and sensory nerve activation and are therefore, effective in blocking
trigger-induced asthma such as EIA and allergen- and sulfur dioxide induced synptoms.
5. STEROID SPARING THERAPIES-immunomodulatory treatments, used to reduce the
requirement for OCS in pxs w/ severe asthma, serious SE in therapy.
 6. ANTI-IgE- OMALIZUMAB: blocking abs that neutralizes circulating IgE w/o binding to cell
bound IgE and inhibit IgE-mediated rxns.
7. ANTI-IL5- abs that block IL-5 (mepolizumab,reslizumab) or its receptor(benralizumab)
markedly reduced blood and tissue eosinophils and reduce exacerbation.
8. IMMUNOTHERAPY-effective in controlling asthma and may caused anaphylaxis
9. ALTERNATIVE THERAPIES
-HYPNOSIS, ACUPUNCTURE, CHIROPLAXIS, BREATHING CONTROL, YOGA AND
SPELEOTHERAPY

10. BROCHIAL THERMOPLASTY-is brochoscopic treatment using thermal enery to ablate airway
smooth muscle in accessible bronchi.

MANAGEMENT OF CHRONIC ASTHMA

 STEPWISE THERAPY
ACUTE SEVERE ASTHMA

 CLINICAL FEATURES
o Increased chest tightness
o Wheezing
o Dyspnea
o Poorly relieved by their usual reliever inhaler
o Breathless
o Cyanotic

-EXAMINATION:
o Increased ventilation
o Hyperinflation
o Tachycardia
o Pulsus paradoxus

ABG: hypoxemia, PCO2 low due to hyperventilation

 TREATMENT
-high conc. Of oxygen should be given by the face to achieve oxygen saturation of >90%
-mainstay : high doses of SABA
-severely ill pxs- given IV B2-agonist
-infusion of aminophylline-effective but need to monitor blood level

REFRACTORY ASTHMA

MECHANISMS: most common reason for poor control of asthma is poor adherence of
medication, particularly ICS.

TREATMENT: it is important to check adherence and the correct use of inhalers and to identify
and eliminate any underlying triggers.

-low dose of theophylline, maintenance treatment of OCS

CORTICOSTEROID-RESISTANT ASTHMA

- Poor response to corticosteroid therapy and various molecular abnormalities that impair anti-
inflammatory action of corticosteroid.

BRITTLE ASTHMA- chaotic variations in lung function despite taking appropriate theray
o Type 1 BA-continuous infusion of B2-agonist
o Type 2BA- generally normal or near-normal lung function but precipitous, unpredictable falls
in ling function that may result death.

ASPIRIN SENSITIVE ASTHMA- 1-5% of asthmatics become worse with aspirin and other COX inhibitors,
although commonly seen in severe cases, pxs require admission.

ASTHMA IN THE ELDERLY- start any age, include elderly.

PREGNANCY-1/3 of asthmatic pxs who are pregnant improve during the course of pregnancy

-1/3 deteriorate

-1/3 unchanged

CIGARETTE SMOKING-20% asthmatic smoke adversely affect asthma, faster decline in lung function.

BROCHOPULMONARY ASPERGILLOSIS- uncommon and result from allergic pulmonary rxns.

ASTHMA-COPD OVERLAP