3 - 03.02.2024 Obstructive lung disease Asthma, pneumonia, chronic bronchitis, emphysema.pdf

pulmonology

1. Obstructive lung disease: Asthma, pneumonia,
chronic bronchitis, emphysema
Tatia Chubinidze

2. What is COPD?
Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by
persistent respiratory symptoms and airflow limitation that is not fully reversible.
COPD includes emphysema, an anatomically defined condition characterized by destruction of the
lung alveoli with air space enlargement; Chronic bronchitis, a clinically defined condition with chronic
cough and phlegm; and small airway disease, a condition in which small bronchioles are narrowed
and reduced in number.
The classic definition of COPD requires the presence of chronic airflow obstruction, determined by
spirometry, that usually occurs in the setting of noxious environmental exposures most commonly
cigarette smoking.
Emphysema, chronic bronchitis, and small airway disease are present in varying degrees in different
COPD patients.

3. Asthma is a syndrome characterized by airflow obstruction that varies
markedly, both spontaneously and with treatment.
Asthma is a heterogeneous disease with several phenotypes recognized.

4. PREVALENCE
Asthma is one of the most common chronic diseases globally worldwide.
The prevalence of asthma has risen in affluent countries over the last 30 years but now
appears to have stabilized, with ~10–12% of adults and 15% of children affected by the
disease.

5. Asthma can present at any age, with a peak age of 3 years.
In childhood, twice as many males as females are asthmatic, but by
adulthood the sex ratio has equalized.
Deaths from asthma are relatively uncommon, and in many affluent countries
have been steadily declining over the last decade. A rise in asthma mortality
seen in several countries during the 1960s was associated with increased use
of short-acting inhaled β2 -adrenergic agonists.
Major risk factors for asthma deaths are poorly controlled disease with
frequent use of bronchodilator inhalers, lack of or poor compliance with ICS
therapy, and previous admissions to hospital with near-fatal asthma.

6. RISK FACTORS AND TRIGGERS
Asthma is a heterogeneous disease with interplay between genetic and environmental
factors. Several risk factors that predispose to asthma have been identified.

7. Atopy
Atopy is the major risk factor for asthma, and non-atopic individuals have a very low risk of
developing asthma.
Patients with asthma commonly suffer from other atopic diseases, particularly allergic rhinitis,
which may be found in >80% of asthmatic patients, and atopic dermatitis (eczema). The
allergens that lead to sensitization are usually proteins that have protease activity, and the
most common allergens are derived from house dust mites, cat and dog fur, cockroaches (in
inner cities), grass and tree pollens, and rodents (in laboratory workers).
Atopy is due to the genetically determined production of specific IgE antibody, with many
patients showing a family history of allergic diseases.

8. Genetic Predisposition
The familial association of asthma and a high degree of concordance for asthma in
identical twins indicate a genetic predisposition to the disease; however, whether or not
the genes predisposing to asthma are similar or in addition to those predisposing to atopy is
not yet clear.
The most consistent findings have been associations with polymorphisms of genes on
chromosome 5q, including the T helper 2 (Th2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13,
which are associated with atopy.

9. Epigenetic Mechanisms
There is increasing evidence that epigenetic mechanisms may be important, particularly
in the early development of asthma.

10. Infections Although viral infections (especially Rhinovirus) are common as triggers of asthma
exacerbations, it is uncertain whether they play a role in etiology. There is some association
between respiratory syncytial virus infection in infancy and the development of asthma.
Infection is very common in children.
Atypical bacteria, such as Mycoplasma andChlamydophila have been implicated in the
mechanism of severe asthma.
Living in damp houses with exposure to mold spores is now recognized to be a risk factor, and
removal of these factors may improve asthma.
Intestinal parasite infection, such as hookworm, may also be associated with a reduced risk
of asthma.
The mechanism whereby these viruses causeexacerbations is poorly understood, but there is
an increase in airway inflammation with increasednumbers of eosinophils and neutrophils.

11. Diet
The role of dietary factors is controversial. Observational studies have shown that diets low
in antioxidants such as vitamin C and vitamin A, magnesium, selenium, and omega-3
polyunsaturatedfats (fish oil) or high in sodium and omega-6 polyunsaturates are
associated with an increased risk of asthma. Vitamin D deficiency may also predispose to
the development of asthma.
Obesity is also an independent risk factor for asthma, particularly in women, but the
mechanisms are not yet clear.
Some foods such as shellfish and nuts may induce anaphylactic
reactions that may include wheezing.

12. Air Pollution
Air pollutants such as sulfurdioxide, ozone, and diesel particulates may trigger asthma
symptoms.
There is increasing evidence that exposure to road traffic pollution is associated with
increased asthma symptoms, with the main culprits being diesel particulates and nitrogen
dioxide.
Indoor air pollution is also important with exposure to nitrogen oxides from cooking stoves and
exposure to passive cigarette smoke.

13. Allergens
Inhaled allergens are common triggers of asthma symptoms and have also been implicated in
allergic sensitization.
The increase in house dust mites in centrally heated poorly ventilated homes with fitted carpets has
been implicated in the increasing prevalence of asthma in affluent countries.
Domestic pets, particularly cats, have also been associated with allergic sensitization.
Other allergens, including grass pollen, ragweed, tree pollen, and fungal spores are seasonal.
Inhaled allergens activate mast cells with bound IgE directly leading to the immediate release of
bronchoconstrictor mediators, resulting in the early response that is reversed by bronchodilator.

14. Occupational Exposure
Occupational asthma is relatively common and may affect up to 10% of young adults.
Individuals may also be exposed to allergens in the workplace such as small animal allergens in
laboratory workers and fungal amylase in wheat flour in bakers.
Cleaners commonly develop occupational asthma owing to exposure to aerosols of cleaning
liquids.
Occupational asthma may be suspected when symptoms improve during weekends and holidays.

15. Obesity
Asthma occurs more frequently in obese people (BMI >30 kg/m2) and is often more difficult to control.
Although mechanical factors may contribute, it may also be linked to the pro-inflammatory
adipokines and reduced anti-inflammatory adipokines that are released from fat cells.

16. Other Factors
Several other factors have been implicated in the etiology of asthma, including lower
maternal age, duration of breastfeeding, prematurity and low birthweightand inactivity.
There is also an association with acetaminophen (paracetamol) consumption in childhood,
which may be linked to increased oxidative stress.
Betaadrenergic blockers commonly acutely worsen asthma, and their use may be fatal. The
mechanisms are not clear but are likely mediated through increased cholinergic
bronchoconstriction.

17. EXERCISE
Exercise is a common trigger of asthma, particularly in children.
The mechanism is linked to hyperventilation, which results in increased osmolality in airway
liningfluid and triggers mast cell mediator release, resulting in bronchoconstriction.

18. PHYSICAL FACTORS
Cold air and hyperventilation may trigger asthma through the same mechanisms as exercise.
Laughter may also be a trigger.
Many patients report worsening of asthma in hot weather and when the weather changes.
Some asthmatics become worse when exposed to strong smells or perfumes, but the mechanism of
this response is uncertain.

19. HORMONES
Some women show premenstrual worsening of asthma, which can occasionally be very severe.
The mechanisms are not completely understood, but are related to a fall in progesterone and
in severe cases may be improved by treatment with high doses of progesterone or gonadotropin-
releasing factors.
Thyrotoxicosis and hypothyroidism can both worsen asthma, although the mechanisms are uncertain.
STRESS
Many asthmatics report worsening of symptoms with stress.
Psychological factors can induce bronchoconstriction through cholinergic
reflex pathways.

20. PATHOPHYSIOLOGY
Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways.
One of the main aims of treatment is to reduce this inflammation.
The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of
mucosal mast cells. There are also structural changes in the airways. A characteristic finding is
thickening of the basement membrane due to subepithelial collagen deposition.
The epithelium is often shed or friable, with reduced attachments to the airway wall and increased
numbers of epithelial cells in the lumen. The airway wall itself may be thickened and edematous,
particularly in fatal asthma.
Another common finding in fatal asthma is occlusionof the airway lumen by a mucous plug, which is
comprised of mucous glycoproteins secreted from goblet cells and plasma proteins from leaky bronchial
vessels.
The pathology of asthma is remarkably uniform in different phenotypes of asthma, including atopic
(extrinsic), non-atopic (intrinsic), occupational, aspirin-sensitive and pediatric asthma.

21. Airway Inflammation
There is inflammation in the respiratory mucosa from the trachea to terminal bronchioles, but with a
predominance in the bronchi (cartilaginous airways), but it is still uncertain how inflammatory cells
interact and how inflammation translates into the symptoms of asthma.
The pattern of inflammation in asthma is characteristic of allergic diseases, with similar inflammatory
cells seen in the nasal mucosa in rhinitis.
Although the common pattern of inflammation in asthma is characterized by eosinophil infiltration,
some patients with severe asthma show a neutrophilic pattern of inflammation that is less sensitive to
corticosteroids.

22. MAST CELLS
Mast cells are important in initiating the acute bronchoconstrictor responses to allergens.
Mast cells are activated by allergens through an IgE-dependent mechanism.

23. MACROPHAGES AND DENDRITIC CELLS
Macrophages, which are derived from blood monocytes, may traffic into the airways in asthma and
may be activated by allergens via low-affinity IgE receptors (Fcε RII).
Macrophages have the capacity to initiate a type of inflammatory response via the release of a
certain pattern of cytokines, but these cells also release anti-inflammatory mediators (e.g., IL-10)and,
thus, their roles in asthma are uncertain.
Dendritic cells are specialized macrophage-like cells in the airway epithelium, which are the major
antigen-presenting cells. Dendritic cells take up allergens, process them to peptides, and migrate to
local lymph nodes where they present the allergenic peptides to uncommitted T lymphocytes to
program the production of allergen-specific T cells.
The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic patients
instructs dendritic cells to release chemokines that attract Th2 cells into the airways.

24. EOSINOPHILS
Eosinophil infiltration is a characteristic feature of asthmatic airways.
Eosinophil recruitment involves adhesion of eosinophils to vascular endothelial cells in the airway
circulation due to interaction between adhesion molecules, migration into the submucosa under the
direction of chemokines, and their subsequent activation and prolonged survival.
NEUTROPHILS
Increased numbers of activated neutrophils are found in sputum and airways of some patients with
severe asthma and during.
LYMPHOCYTES
T lymphocytes play a very important role in coordinating the inflammatory response in asthma through
the release of specific patterns of cytokines, resulting in the recruitment and survival of eosinophils and
in the maintenance of a mast cell population in the airways.

25. Inflammatory Mediators
FIGURE 281-5 T lymphocytes in asthma. Allergen interacts with
dendritic cells and releases thymus stimulated lymphopoietin (TSLP)
which stimulate activated dendritic cells to release the chemokines
CCL17 and CCL22, which attract T helper 2 (TH2) lymphocytes.
Allergens and viral infection may release interleukins (IL)-25 and -33
which recruit and activate type 2 innate lymphoid cells (ILC2). Both
TH2 and ILC2 cells release IL-5 and epithelial cells CCL11 (eotaxin),
which together lead to recruitment of eosinophils into the airways.

26. CLINICAL FEATURES AND DIAGNOSIS
The characteristic symptoms of asthma are wheezing, dyspnea, and coughing, which are variable,
both spontaneously and with therapy.
Symptoms may be worse at night and patients typically awake in the early morning hours.
Prodromal symptoms may precede an attack, with itching under the chin, discomfort between the
scapulae, or inexplicable fear (impending doom).
Typical physical signs are inspiratory.
Some patients, particularly children, may present with a predominant nonproductive cough (“cough-
variant asthma”).

27. DIAGNOSIS
The diagnosis of asthma is usually apparent from the symptoms, but must be confirmed by objective
measurements of lung function.
Lung Function Tests Simple spirometry
confirms airflow limitation with a reduced
FEV1 , FEV1 /FVC ratio, and PEF (Fig. 281-
6). Reversibility is demonstrated by a
>12% and 200-mL increase in FEV1 15 min
after an inhaled short-acting β2 -agonist
(SABA; such as inhaled albuterol 400 μg)
or in some patients by a 2–4 week trial of
oral corticosteroids (OCS) (prednisone or
prednisolone 30–40 mg daily).

28. Hematologic Tests Blood tests are not usually helpful.
Total serum IgE and specific IgE to inhaled allergens may be measured in some patients.
Imaging Chest roentgenographyis usually normal but in more severe patients may show
hyperinflated lungs. In exacerbations, there may be evidence of a pneumothorax.
Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in patients with
bronchopulmonary aspergillosis.
High-resolution CT may show areas of bronchiectasis in patients with severe asthma and there
may be thickening of the bronchial walls, but these changes are not diagnostic of asthma.
Skin Tests
Skin prick tests to common inhalant allergens (house dust mite, cat fur, grass pollen) are
positive in allergic asthma and negative in intrinsic asthma, but are not helpful in diagnosis.

29. Differential Diagnosis
It is usually not difficult to differentiate asthma from other conditions that cause wheezing and
dyspnea.
Upper airway obstruction by a tumor or laryngeal edema can mimic severe asthma.
The diagnosis is confirmed by a flow-volume loop that shows a reduction in inspiratory as well as
expiratory flow, and bronchoscopy to demonstrate the site of upper airway narrowing.
Left ventricular failure may mimic the wheezing of asthma but basilar crackles are present in contrast
to asthma.
Eosinophilic pneumonias and systemic vasculitis, including ChurgStrauss syndrome
(eosinophilic granulomatosis with polyangiitis) and polyarteritis nodosa, may be
associated with wheezing.

30. TREATMENT
The main drugs for asthma can be divided into bronchodilatators.
Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma.
This gives rapid relief of symptoms but has little or no effect on the underlying inflammatory process.
β2 -Agonists activate β2 -adrenergic receptors, which are widely expressed in the airways.
β2 -Agonists are usually given by inhalation to reduce side effects.
SABA, such as albuterol andterbutaline, have a duration of action of 3–6 h.

31. Side Effects
Adverse effects are not usually a problem with β2 - agonists when given by inhalation.
The most common side effects are muscle tremor and palpitations, which are seen more commonly
in elderly patients. There is a small fall in plasma potassium due to increased uptake by skeletal
muscle cells, but this effect does not usually cause any clinical problem.
Tolerance
Tolerance is a potential problem with any agonist given chronically.

32. Anticholinergics
Muscarinic receptor antagonists, such as ipratropium bromide, prevent cholinergic nerveinduced
bronchoconstriction and mucus secretion.
They are less effective than β2 -agonists in asthma therapy as they inhibit only the cholinergic
reflex component of bronchoconstriction, whereas β2 -agonists prevent all bronchoconstrictor
mechanisms.

33. Inhaled Corticosteroids
ICS are by far the most effective controllers for asthma, and their early use has revolutionized asthma
therapy.
Mode of Action ICS are the most effective anti-inflammatory agents used in asthma therapy, reducing
inflammatory cell numbers and their activation in the airways.
ICS reduce eosinophils in the airways and sputum, and numbers of activated T lymphocytes and
surface mast cells in the airway mucosa.
Systemic Corticosteroids
Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of
acute severe asthma.

34. Cromones
Cromolyn sodium and nedocromil sodium are asthma controller drugs that appear to inhibit
mast cell and sensory nerve activation and are, therefore, effective in blocking trigger-induced
asthma.
Steroid-Sparing Therapies
Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin have all been used as
steroid-sparing therapies, but none of these treatments has any long-term benefit and each is
associated with a relatively high risk of side effects.
Anti-IgE
Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound
IgE and, thus, inhibits IgE-mediated reactions.
This treatment has been shown to reduce the number of exacerbations in patients with severe
asthma and may improve asthma control.

35. Immunotherapy
Specific immunotherapy using injected extracts of pollens or house dust mites has not been very
effective in controlling asthma and may cause anaphylaxis.
Side effects may be reduced by sublingual dosing.
It is not recommended in most asthma treatment guidelines because of lack of evidence of clinical
efficacy and potential anaphylaxis.

36. MANAGEMENT OF CHRONIC ASTHMA

37. Acute Severe Asthma-A high concentration of oxygen should be given by face mask to achieve
oxygen saturation of >90%. The mainstay of treatment are high doses of SABA given either by nebulizer
or via a MDI with a spacer. In severely ill patients with impending respiratory failure, IV β2 -agonists may
be given. A nebulized anticholinergic may be added if there is not a satisfactory response to β2 -
agonists alone, as there are additive effects. In patients who are refractory to inhaled therapies, a slow
infusion of aminophylline may be effective, but it is important to monitor blood levels, especially if
patients have already been treated with oral theophylline. Magnesium sulfate given intravenously or
by nebulizer is effective when added to inhaled β2 -agonists, and is relatively well tolerated but is not
routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure,
when the PCO2 is normal or rises. For patients with respiratory failure, it is necessary to intubate and
institute ventilation. These patients may benefit from a general anesthetic, such as halothane, if they
have not responded to conventional bronchodilators. Sedatives should never be given as they may
depress ventilation. Antibiotics should not be used routinely unless there are signs of pneumonia.

38. Chronic Obstructive Pulmonary Disease- Emphysema
COPD includes emphysema, an anatomically defined condition characterized
by destruction of the lung alveoli with air space enlargement.

39. The dominant current paradigm for the pathogenesis of emphysema comprises a series of four
interrelated events:
✓Chronic exposure to cigarette smoke in genetically susceptible individuals triggers inflammatory and
immune cell recruitment within large and small airways and in the terminal air spaces of the lung.
✓Inflammatory cells release proteinases that damage the extracellular matrix supporting airways,
vasculature, and gas exchange surfaces of the lung.
✓Structural cell death occurs through oxidant-induced damage, cellular senescence, and proteolytic
loss of cellular-matrix attachments leading to extensive loss of smaller airways, vascular pruning, and
alveolar destruction.
✓Disordered repair of elastin and other extracellular matrix components contributes to air space
enlargement and emphysema.

40. Emphysema is classified into distinct pathologic types, which include centrilobular, panlobular, and
paraseptal.
Centrilobular emphysema, the type most frequently associated with cigarette smoking is
characterized by enlarged air spaces found (initially) in association with respiratory bronchioles.
Centrilobular emphysema is usually most prominent in the upper lobes and superior segments of lower
lobes and is often quite focal.
Panlobular emphysema refers to abnormally large air spaces evenly distributed within and across
acinar units. Panlobular emphysema is commonly observed in patients with α1 AT deficiency, which
has a predilection for the lower lobes.
Paraseptal emphysema occurs in 10–15% of cases and is distributed along the pleural margins with
relative sparing of the lung core or central regions. It is commonly associated with significant airway
inflammation and with centrilobular emphysema.

42. CT scan demonstrating emphysema. High-resolution CT
scan of the thorax at the level of the tracheal carina in a
patient with emphysema. The left lung is seen on the right.
There are multiple areas of confluent parenchymal loss
(bullae) that appear as black areas with no parenchymal
markings. There are additional small areas of parenchymal
loss consistent with emphysema. The right upper lobe
bronchus is seen entering the lung; its walls are thickened,
thereby suggesting chronic inflammation.
Chest radiograph showing substantial
subcutaneous emphysema and
pneumomediastinum in a patient with a
severe asthma attack.

44. CLINICAL PRESENTATION
The three most common symptoms in COPD are cough, sputum production, and exertional dyspnea.
Many patients have such symptoms for months or years before seeking medical attention.
In the early stages of COPD, patients usually have an entirely normal physical examination.
Current smokers may have signs of active smoking, including an odor of smoke or nicotine
staining of fingernails. In patients with more severe disease, the physical examination of the
lungs is notable for a prolonged expiratory phase and may include expiratory wheezing.
Patients with severe airflow obstruction may also exhibit use of accessory muscles of
respiration, sitting in the characteristic “tripod” position to facilitate the actions of the
sternocleidomastoid, scalene, and intercostal muscles.
Patients may develop cyanosis, visible in the lips and nail beds.

45. Patients with chronic bronchitis are more likely to be heavy and cyanotic (“blue bloaters”), current
evidence demonstrates that most patients have elements of both chronic bronchitis and
emphysema and that the physical examination does not reliably differentiate the two entities.
Advanced disease may be accompanied by cachexia, with significant weight loss, bitemporal
wasting, and diffuse loss of subcutaneous adipose tissue.
Signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since the advent of
supplemental oxygen therapy.

46. LABORATORY FINDINGS
The hallmark of COPD is airflow obstruction (discussed above).
Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1 /FVC.
The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the
GOLD spirometric severity classification.

47. Radiographic studies may assist in the classification of the type of COPD.
Obvious bullae, paucity of parenchymal markings, or hyperlucency on chest x-ray suggests the
presence of emphysema.
Increased lung volumes and flattening of the diaphragm suggest hyperinflation but do not provide
information about chronicity of the changes.
Chest computed tomography (CT) scan is the current definitive test for establishing the presence or
absence of emphysema, the pattern of emphysema, and the presence of significant disease
involving medium and large airways.
It also enables the discovery of coexisting interstitial lung disease and bronchiectasis, which are
common complications in COPD.
Smokers with COPD are at high risk for development of lung cancer, which can be identified on a
chest CT scan.

48. TREATMENT
Chronic Obstructive Pulmonary Disease STABLE PHASE COPD The two main goals of therapy are to
provide symptomatic relief (reduce respiratory symptoms, improve exercise tolerance, improve
health status) and reduce future risk (prevent disease progression, prevent and treat
exacerbations, and reduce mortality).

49. Chronic obstructive pulmonary disease
Book: Lee Goldman, MD and Andrew I. Schafer, MD -
Goldman-Cecil Medicine Pg: 535 - 544
ASTHMA
Book: Lee Goldman, MD and Andrew I. Schafer, MD -
Goldman-Cecil Medicine Pg: 527 - 534
ASTHMA
Book: Harrison’s Principles of Internal Medicine, Twentieth
Edition (Vol.1 & Vol.2) Pg: 1957 - 1970
Chronic obstructive pulmonary disease
Book: Harrison’s Principles of Internal Medicine, Twentieth
Edition (Vol.1 & Vol.2) Pg: 1990 - 1997

50. Thank you!