Pathophysiology

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710

K e y t e r m s acute bronchitis, 736 acute respiratory distress syndrome,

730 adenocarcinoma, 739 aspiration, 754 atelectasis, 752 bronchiolitis, 737 chronic bronchitis, 721 chronic obstructive pulmonary

disease (COPD), 711 cor pulmonale, 748 croup, 743 cyanosis, 756 cystic fibrosis, 723 dyspnoea, 755 emphysema, 723 empyema, 753 eupnoea, 756 haemoptysis, 756 hypercapnia, 752 hyperventilation, 756 hypoventilation, 755 hypoxaemia, 750 influenza, 736 large cell carcinoma, 739 obstructive sleep apnoea, 742 pertussis, 738 pleural effusion, 753 pneumoconiosis, 732 pneumonia, 733 pneumothorax, 752 pulmonary embolism, 747 pulmonary oedema, 749 small cell carcinoma, 740 squamous cell carcinoma, 739 status asthmaticus, 717 sudden infant death syndrome

(SIDS), 746 TNM classification, 741 tubercles, 734 tuberculosis, 734Introduction, 711

Disorders of the pulmonary system, 711 Obstructive airway diseases, 711 Restrictive airway diseases, 729 Infections of the pulmonary system, 732 Pneumonia, 733 Tuberculosis, 734 Acute bronchitis, 736 Influenza, 736 Lung cancer, 738 Types of lung cancer, 738

Obstructive sleep apnoea, 742 Alterations of pulmonary blood flow and

pressure, 746 Pulmonary embolism, 747 Cor pulmonale, 748 Clinical manifestations of pulmonary

alterations, 749 Conditions caused by pulmonary alterations,

749 Signs and symptoms of pulmonary alterations,

755

C h a p t e r o u t l i n e

Alterations of pulmonary function across the life span Vanessa Marie McDonald, Steven Maltby and Darrin Penola

C H A P T E R

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CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 711

conditions. In this way, you can learn about the pathophysiology of the pulmonary conditions and so understand how these alterations manifest in individuals.

Disorders of the pulmonary system Obstructive airway diseases Obstructive airway diseases are characterised by airflow obstruction or limitation that causes more difficulty during expiration. More force — that is, the use of the accessory muscles of expiration — is required to expire a given volume of air or emptying of the lungs is slowed, or both. In adults and children, the major obstructive airway disease is asthma, with chronic obstructive pulmonary disease (COPD) also highly prevalent in the adult population. Airflow obstruction is usually variable in asthma, whereas in COPD it is less reversible. The unifying symptom of obstructive airway diseases is dyspnoea (difficulty breathing or breathlessness). Manifestations of obstructive airway diseases include an increased work of breathing, ventilation/perfusion mismatching, a decreased forced expiratory volume in one second (FEV1) and decreased FEV1/forced vital capacity (FVC) ratio.

Obstructive airway diseases are prevalent in the Australian and New Zealand populations leading to a high disease burden. In the following section we examine the pathophysiology of asthma in both children and adults, to provide a more thorough understanding of the disease.

Asthma There are large variations in the incidence and prevalence of asthma according to geographical regions. Worldwide it is estimated that over 300 million people have asthma and there is likely to be a marked increase in this number over the next two decades as modern lifestyles and urbanisation occur in developing countries.3 Rates of asthma are higher in Westernised societies than developing countries and indeed the prevalence of asthma in Australia and New Zealand is high by international standards.3–5

In Australia, more than two million people have asthma (10.2% of the population), with slightly higher rates in children compared to adults.6 In childhood more males than females have asthma; however, this trend reverses in adulthood, with more females than males having asthma.5

Unfortunately, as with so many chronic diseases, the Indigenous populations in both Australia and New Zealand have higher rates of asthma compared to the non-Indigenous populations: in New Zealand the prevalence of asthma in Māori and Pacific Islander adults is greater than in the non-Indigenous population4,5 and in Australia asthma is the second most common illness, affecting greater than 60% of the Indigenous population compared to non-Indigenous.5

While mortality rates from asthma decreased through to the end of the 20th century, rates remained stable between 2004–2013 in Australia, at around 1.5 deaths per 100 000

Introduction At some stage everyone experiences an alteration to the pulmonary system. This may range from a minor respiratory illness through to chronic lung diseases and cancers. The common cold, a mild upper respiratory tract infection arising from several different viruses, is one of the most familiar pulmonary infections and most people experience one or two infections each year. Often more serious is the impact of influenza, commonly referred to as the ‘flu’, with an estimated 5–20% of the Australian and New Zealand populations infected each year and up to half a million deaths worldwide.1

Pulmonary diseases and disorders can severely limit an individual’s ability to perform activities of daily living and result in frequent hospitalisations. Moreover, alterations to the pulmonary system contribute significantly to mortality rates in Australia and New Zealand. The lungs, with their large surface area, are constantly exposed to the external environment. Therefore, lung disease is greatly influenced by conditions of the environment, occupation and personal and social habits. For instance, individuals who smoke are known to be at a greater risk of lung conditions compared to non-smokers. Symptoms of lung disease are common and associated not only with primary lung disorders but also with diseases of other organ systems.

Alterations of respiratory function in children are influenced by physiological maturation as a function of age, genetics and environmental conditions. A variety of upper and lower airway infections can cause respiratory problems or play a role in the pathogenesis of more chronic pulmonary diseases. Infants, especially premature infants, may present special problems because of the immaturity of their lung, airway and chest wall structures, as well as the immaturity of pulmonary homeostasis (e.g. a lack of surfactant production) and immunological immaturity. Immunisation and attentive healthcare can greatly reduce the incidence and severity of pulmonary disorders in children. The lungs continue to mature up until about 20 years of age for females and 25 years for males. Thereafter ageing is associated with a progressive decline in lung function resulting in both airflow limitation and reduced exercise capacity. The morphological and immunological changes that occur during ageing can lead to increased air trapping and a reduction in chest wall compliance causing an increased work of breathing for older individuals.2

Pulmonary disease is often classified using different categories and may be described as acute or chronic, obstructive or restrictive, or infectious or non-infectious. Because skillful and knowledgeable clinical practice plays a major role in the management of pulmonary conditions, healthcare professionals who have a clear understanding of the pathophysiology of common pulmonary disorders can provide more optimal management of affected individuals with the goal of improving outcomes.

This chapter examines the more common alterations to the pulmonary system and then provides detailed information about the signs and symptoms that arise from these

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The airflow limitation resulting from these physiological changes is episodic and usually reversible. The clinical pattern of asthma is variable, and the immunological processes underlying asthma pathophysiology also vary between individuals. Classically, asthma is associated with a predominance of CD4+ T lymphocyte cells and the release of type 2 helper T cell (TH2)-associated mediators such as IL-4, IL-5 and IL-13 and airway eosinophilia. Alternatively, non-TH2 asthma includes a predominance of TH1 (and associated IFNγ), and TH17 (with associated IL-17 cytokine production) and neutrophilic airway inflammation.15 Assessment of the inflammatory cells from sputum can identify individuals with differing patterns of airway inflammation, which is becoming increasingly important for the integration of targeted therapies (such as anti-IgE), which are only effective in subsets of patients.16 Remodelling of the airway structures also occurs in the long term.

In asthma, the airways respond in an abnormal, exaggerated way to inflammatory mediators, such as an allergen or irritants or triggers like pollution, exercise, cold air or respiratory infection (bacterial or viral). Allergic responses can be initiated by a type I hypersensitivity reaction (see Chapter 15). Exposure to allergens or irritants results in a cascade of events, beginning with mast cell degranulation and the release of multiple inflammatory mediators (see Fig. 25.1). Some of the most important mediators that are released during an acute allergic asthmatic episode are histamine, interleukins, prostaglandins, leukotrienes and nitric oxide. The vasoactive effects of these cytokines include vasodilation and increased capillary permeability. This causes an increase in blood flow to the area, and inflammatory cells and chemicals move through the cells into the interstitial tissue. Alternatively, triggers such as bacterial or viral infection or exposure to pollutants can activate lung macrophages and resident innate immune cells. Activation results in local release of pro-inflammatory cytokines and tissue inflammation. In both cases, chemotactic factors (chemicals that attract inflammatory cells to the site of inflammation) are produced, which result in bronchial infiltration by eosinophils, neutrophils, and lymphocytes (different types of white blood cells). These activated immune cells, particularly eosinophils, release a variety of chemicals that contribute to inflammation and tissue damage. The resulting inflammatory process produces bronchial smooth muscle spasm, vascular congestion, oedema formation, production of thick mucus, impaired mucociliary function, thickening of airway walls and increased bronchial hyperresponsiveness (see Fig. 25.2). In addition, there is alteration to the normal autonomic control of bronchial smooth muscle because the production of neuropeptides (small protein-like substances that are released by neurons to communicate with other neurons) leads to acetylcholine-mediated bronchospasm. These changes, combined with epithelial cell damage caused by immune cell infiltration, produce airway hyperresponsiveness and obstruction and, if untreated, can lead to long-term airway damage that is irreversible.

population.7 Furthermore, Australian asthma mortality rates remain high by international standards,8 and while asthma deaths continue to occur in all age groups, the risk of dying from asthma increases with age.9 In 2015 there were 421 deaths in Australia due to asthma, representing 0.3% of all deaths that year.9 Rates of hospitalisation are fairly low, with approximately 38 000 hospitalisations in 2011–12 or 0.4% of all hospitalisations in Australia,10 with less than 5% of adults and children with asthma being hospitalised for episodes of acute asthma. Nonetheless, the economic costs are high, as the direct costs associated with asthma are estimated at $1.2 billion, total economic costs (including disability and premature mortality) at $3.3 billion and total burden of disease costs of $23.7 billion.11

Asthma is likely to result from a complex interaction of genetic and environmental components. It can be defined as:

… a heterogeneous disease [meaning that it varies considerably for different people], usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation.12

Asthma is a familial disorder, and many genes have been identified that may play a role in the susceptibility and pathogenesis of asthma, including those that influence the production of interleukins IL-4, IL-5 and IL-13, immunoglobin E (IgE), eosinophils, mast cells, β(beta)- adrenergic receptors (for the stress response using adrenaline) and airway hyperresponsiveness (the ability of the airways to constrict more easily and to a greater degree in response to a bronchoconstrictor or stimulus).

Risk factors for asthma, in addition to family history, include allergen exposure, living in urban areas, exposure to air pollution and cigarette smoke, recurrent respiratory viral infections and other allergic diseases, such as allergic rhinitis.13 There is considerable evidence that exposure to high levels of certain allergens during childhood increases the risk for asthma. Furthermore, decreased exposure to certain infectious organisms appears to create an immunological imbalance that favours the development of allergy and asthma. This complex relationship has been called the hygiene hypothesis, in which it is thought that living with low levels of infectious organisms can make the immune system particularly prone to the development of allergy.14 People living in urban environments have been shown to have a higher disposition to asthma compared to those who reside in rural areas. The likely exposure to air pollution combined with decreased exercise also play a role in the increasing prevalence of asthma.13

PAT H O P HYS I O LO G Y The principal characteristics of asthma are airway inflammation, airway hyperresponsiveness and mucus hypersecretion resulting in airflow obstruction, leading to symptoms of dyspnoea, cough, chest tightness and wheeze.12

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For acute allergen-induced asthma, the paradigm of the early asthmatic response remains useful (see Fig. 25.3A). This begins immediately after exposure and lasts up to 2 hours. The allergen binds to preformed immunoglobin E (IgE) on the surface of mucosal mast cells, and cross-linking of these IgE molecules triggers degranulation of the mast cells, releasing mediators such as histamine, leukotrienes, prostaglandin D2, platelet-activating factor and certain cytokines. These mediators cause airway smooth muscle constriction (bronchospasm), increased vascular permeability (mucosal oedema) and mucus secretion.

The late asthmatic response starts 4–8 hours after the initial exposure and may persist for up to 24 hours (see Fig. 25.3B). The response is characterised by inflammatory

Examination of postmortem lung specimens of individuals who have died from asthma reveals abnormalities consistent with both acute and chronic changes in the airways. These include extensive mucus plugging, mucosal oedema and denudation of bronchial and bronchiolar epithelium (loss of epithelium). Eosinophilia (an increased amount of eosinophils) is present in the submucosa in some cases, and a multicellular inflammatory infiltrate accumulates in the airways. Thickening of the basement membrane, airway smooth muscle hypertrophy and mucous gland hypertrophy are often noted, sometimes even in pathology specimens from people with mild asthma, providing evidence that there may be long-term airway structural changes associated with asthma.

C O

N C

E P

T M A

initiator mediators dysfunctional process

Colour code

Bronchial hyperresponsiveness Airway obstruction

Allergen or irritant exposure

promotes

releasesrelease release

act to

which

increases

results in

leads to

produces

over time

causes

cause

Mast cell degranulation

Chemotactic mediators Chemical mediator

Stimulate nerve terminal endings

Release of neurotransmitters

Cellular in�ltration (neutrophils, lymphocytes, eosinophils)

Autonomic dysregulation

Immune activation (IL-4, IgE production)

Vasoactive mediators

Vasodilation Increased capillary permeability

Bronchospasm Vascular congestion

Mucus secretion Impaired mucociliary function Thickening of airway walls

Increased contractile response of bronchial smooth muscle

Release of neuropeptides

Epithelial desquamation (removal of epithelial lining) and �brosis (excessive connective tissue)

FIGURE 25.1

The pathophysiology of asthma. A concept map outlining the effects of exposure to an allergen or irritant, which causes an inflammatory cascade leading to acute and chronic airway dysfunction.

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severe, the number of alveoli being adequately ventilated and perfused decreases. Air trapping continues to worsen and the work of breathing increases further, leading to hypoventilation (decreased tidal volume), carbon dioxide retention and respiratory acidosis (from the reduction in carbon dioxide removal). Respiratory acidosis signals respiratory failure (Fig. 25.4 summarises these steps).

C L I N I C A L MA N I F E S TAT I O N S When asthma is well controlled individuals should experience few if any symptoms and pulmonary function tests will usually be within normal limits. However, individuals with asthma are at risk of acute exacerbations, usually as a result of exposure to triggers that cause an airway inflammatory response and acute bronchoconstriction. These may include exposure to allergens, infections, occupational exposures, tobacco smoke or from treatment non-adherence. Further, 5–10% of individuals with asthma have severe disease which requires high-dose therapy to control, or remains uncontrolled despite treatment.17 Exacerbations are defined as ‘events that require urgent action on the part of the patient and physician to prevent a serious outcome, such as hospitalization or death from asthma’.18 During an exacerbation, the individual may experience bronchoconstriction, expiratory wheezing, dyspnoea, cough, prolonged expiration, tachycardia and tachypnoea (increased ventilatory rate). Severe episodes involve the accessory muscles of ventilation and wheezing is heard during both inspiration and expiration. Pulsus paradoxus (an exaggerated decrease in systolic blood pressure during inspiration) may be noted. Lung function measured by spirometry is reduced. Because the severity of blood gas alterations is difficult to evaluate by clinical

cell recruitment (neutrophils, eosinophils, basophils, lymphocytes) that was triggered earlier by chemotactic factors and endothelial adhesion molecules (molecules that attach to the endothelial). Another wave of mediator release occurs, again causing bronchospasm, oedema and mucus secretion. Epithelial damage and impaired mucociliary function (the sweeping ability of the cilia lining the airways) may be seen following immune cell activation within the lungs, including production of toxic mediators by eosinophils, neutrophils and activated macrophages. This local injury stimulates local nerve endings, which may aggravate bronchoconstriction and mucus secretion through autonomic pathways.

In chronic asthma, some of these mechanisms may be operational on an ongoing basis. There are increased numbers of inflammatory cells, which may lead to long-term changes such as goblet cell hyperplasia (abnormally increased number of mucus-secreting cells) and airway wall remodelling (subepithelial fibrosis, smooth muscle hypertrophy).

Airway obstruction increases resistance to airflow and decreases flow rates, primarily expiratory flow. For instance, a 10% reduction in airway calibre leads to a 2% increase in resistance. Impaired exhalation causes air trapping and hyperinflation distal to obstructions and increases the work of breathing. Intrapleural and alveolar gas pressures rise and cause decreased perfusion of the alveoli. These changes lead to uneven ventilation–perfusion relationships causing hypoxaemia (a reduction in oxygen levels in the blood). Hyperventilation is triggered by lung receptors responding to the hyperinflation and causes a decrease in carbon dioxide levels in the blood (PaCO2) and increased pH (which results in respiratory alkalosis). As the obstruction becomes more

Pulmonary artery Cartilage Submucosal

gland

Basement membrane

Epithelium

Goblet cell

Alveoli

Respiratory bronchioles

Bronchioles

Mast cell

Parasympathetic nerve

Smooth muscle

Smooth muscle constriction

Mucus plug

Hyperinflation of alveoli

Mucus accumulation

Degranulation of mast cell

A B

FIGURE 25.2

Changes in airways due to asthma. A Normal lung with clear airways. B Thick mucus, mucosal oedema and smooth muscle spasm causing obstruction of small airways occurs in asthma, breathing becomes laboured and expiration is difficult due to the airway restrictions.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 715

altered by regional hypoxic vasoconstriction, as well as the effect of increased intraalveolar pressure (caused by hyperinflation) to decrease perfusion of the alveolar capillaries. Typically, the ventilatory rate (commonly referred to as the respiratory rate in clinical environments) is elevated to compensate for hypoxaemia, with reduced minute ventilation because of increased airway resistance and lung hyperinflation. Thus, the carbon dioxide level is low (30–35 mmHg compared to the normal level of 35–45 mmHg) or can be normal. Retention of carbon dioxide is a late finding and reflects inadequate alveolar ventilation and increased functional dead space as little air

signs alone, arterial blood gas levels should be measured if oxygen saturation falls below 90%. The usual findings are hypoxaemia with an associated respiratory alkalosis. The severity of acute asthmatic episodes is outlined in Table 25.1.

The typical arterial blood gas abnormalities seen in acute asthma are hypoxaemia, hypocapnia (low blood carbon dioxide levels) and respiratory alkalosis (a pH level above 7.45). As bronchial obstruction is non-uniform, ventilation becomes uneven, causing ventilation–perfusion mismatch and further hypoxaemia. The degree of hypoxaemia is usually mild; however, arterial saturations of less than 90% indicate severe airway obstruction. Pulmonary circulation may be

Mast cell

Antigen

Dendritic cell

Goblet cell

Mast cell

Antigen entry to airway

Mast cell degranulation and release of mediators

Mediator e�ects

Airway smooth muscle constriction

Vascular leak of �uid

Mucus secretion

Smooth muscle

Eosinophil Neutrophil

Vascular cell adhesion moleculeTH2 cell

FIGURE 25.3

Asthmatic responses at a cellular level. A Early asthmatic response. 1 Inhaled antigen enters the airway and binds to IgE on mast cells. 2 Mast cells degranulate and release mediators such as histamine, prostaglandin D2 and platelet-activating factor, which promotes inflammation. 3 These chemicals open junctions between cells, allowing the allergen to penetrate below the epithelial surface, which induces active bronchospasm, oedema and mucus secretion. At the same time, as shown on the left, antigen may be received by dendritic cells and later present to T helper (TH) lymphocytes in the airway mucosa (see B). B Late asthmatic response. There are areas of epithelial damage caused at least in part by toxicity of eosinophil. Local T lymphocytes produce IL-4 and IL-13, which promote switching of B cells to favour IgE production, and IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor, which encourage eosinophil differentiation and survival.

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TABLE 25.1 Assessment of acute asthma episodes in adults

FINDINGS MILD MODERATE SEVERE AND LIFE THREATENING

Physical exhaustion No No Yes

Paradoxical chest wall movement may be present

Talks in Sentences Phrases Words

Pulse rate < 100/min 100–120/min More than 120/min Pulsus paradoxus Not palpable May be palpable Palpable

Central cyanosis Absent May be present Likely to be present

Wheeze intensity Variable Moderate to loud Often quiet

PEF More than 75% predicted (or best if known)

50–75% predicted (or best if known)

Less than 50% predicted (or best if known) or less than 100 L/min

FEV1 More than 75% predicted 50–75% predicted Less than 50% predicted or less than 1 L

Oximetry on presentation Less than 90%

Cyanosis may be present

Arterial blood gases Not necessary Necessary if initial response poor

Necessary

Other investigations Not required May be required Check for hypokalaemia

Chest x-ray to exclude other pathology (i.e. infection, pneumothorax)

FEV1 = forced expiratory volume in first second; PEF = peak expiratory flow

C O

N C

E P

T M

A P Oedema, mucus, muscle spasm

causes

causes causes

causes

leads to

leads to results in

results in

Resistance to airflow

Impaired expiration

Air trapping

Alveolar hyperinflation

Uneven ventilation/perfusion

Decreased alveolar ventilation

Decreased pulmonary blood flow

Impaired gas exchange

Hypoxaemia Hypercapnia

Respiratory failure

FIGURE 25.4

Asthma airway obstruction cascade. The oedema, mucus and mucus spasm cause resistance to airflow, such that air remains trapped in the lungs. As a result, there are impairments in gas exchange that can lead to respiratory failure.

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determines how much and how quickly air can be expired from the lungs. The key variables measured during spirometry are forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and peak expiratory flow (PEF) (see Table 25.2). Spirometry may be used to diagnose airway obstruction, assess its severity and prognosis and to demonstrate any reversible effect. An example of airway obstruction compared to normal spirometry is provided in Fig. 25.5, including the response to treatment using bronchodilators.

In children less than 5 years of age spirometry is not recommended. In such cases, a history from the parents is crucial. Between episodes, the diagnosis of asthma is

is being moved. Alterations of pH homeostasis usually start with respiratory alkalosis (pH greater than 7.45) caused by hyperventilation, which literally ‘blows off ’ carbon dioxide. With severe airway obstruction, the end result of the pathophysiological processes may be respiratory failure, with acute carbon dioxide retention and respiratory acidosis (pH less than 7.35).

When bronchospasm worsens during a severe asthmatic episode the individual may progress to a condition known as status asthmaticus. This is defined as a severe asthmatic episode that does not respond to pharmacological control. Acute airway inflammation causes bronchospasm to worsen. Mucus plugging, oedema and cellular infiltration lead to further airway narrowing. Partial obstruction leads to segmental hyperinflation, which may become extreme and compromise effective tidal volume. Expiratory flow rates such as FEV1 and peak flow are also markedly reduced. If status asthmaticus continues, hypoxaemia worsens, expiratory flows and volumes decrease further, and effective ventilation decreases. Metabolic acidosis may accompany status asthmaticus as the carbon dioxide level in the blood begins to rise. Asthma becomes a life-threatening condition at this point, often with impending respiratory or cardiac arrest if treatment does not reverse this process quickly. A silent chest (no audible air movement) and a carbon dioxide level over 70 mmHg are ominous signs of impending death.

E VA LUAT I O N A N D T R E AT M E N T The diagnosis and monitoring of asthma is undertaken using spirometry. Spirometry measures lung function and

TABLE 25.2 Common spirometric indices

SPIROMETRIC INDICES

FEV1 — Forced expiratory volume in one second: the volume of air expired in the first second of the blow volume exhaled

FVC — Forced vital capacity: the total volume of air that can be forcibly exhaled in one breath

FEV1/FVC ratio — The fraction of air exhaled in the first second relative to the total

VC — Vital capacity: a volume of a full breath exhaled in the patient’s own time and not forced. Often slightly greater than the FVC, particularly in COPD

PEF — The maximum rate of air flow out of the lungs during forced expiration

Fl ow

( L/

Volume (L)

Normal Obstructive–reversible Obstructive–non-reversible 10

0 1 2 3 4 5

Fl ow

( L/

Volume (L)

0 1 2 3 4 5

Fl ow

( L/

Volume (L)

0 1 2 3 4 5

A B C

FIGURE 25.5

Flow volume curves. A Normal. B Obstructive, responsive to bronchodilator treatment. C Obstructive, non-responsive to bronchodilator treatment. The defining characteristic in obstructive lung disease is a reduction in FEV1 with a normal forced vital capacity (FVC). In B & C, the FVC in both cases was identical yet FEV1was reduced. The FEV1/ FVC ratio was therefore below the normal 0.7 in healthy individuals. Note the improvement in B after bronchodilator treatment. These expiratory flow volume curves show pre- and post-bronchodilator spirometry. The pre-bronchodilator effort is represented by the blue curve and the post-bronchodilator effort by the red curve.

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supported by other clinical signs and symptoms, which may include but are not limited to a history of allergies and recurrent episodes of breathlessness or exercise intolerance. For ongoing asthma management, written asthma action plans, self-monitoring through peak expiratory flow monitoring or symptom diaries, self-management education including disease knowledge and skills (inhaler technique, adherence) and regular review are essential and lead to improved health outcomes. A written asthma action plan (Fig. 25.6) is a set of written instructions that helps people with asthma detect early signs and symptoms of an exacerbation and provides instructions about how to manage these exacerbations. The plan should include instructions for maintenance therapy, early exacerbation management and crisis management.5

The goals of long-term asthma management are to achieve and maintain asthma control, to maintain lung function and activity, and to prevent morbidity and mortality from asthma. A stepwise approach is recommended, involving education, avoidance of triggers and pharmacotherapy stepped up and down according to asthma control. The cornerstone of effective asthma management involves pharmacotherapies including, but not limited to, inhaled corticosteroids and bronchodilator therapy.5 Medications are often referred to according to their mechanistic role: • Reliever medications: these provide acute relief of

symptoms by allowing rapid bronchodilation. They relax bronchial smooth muscle and are administered on an as-needed basis. Examples include salbutamol or terbutaline (short-acting β2[beta]-agonist) and ipratropium bromide (anti-muscarinic antagonist).

• Symptom controllers: these provide long-acting bronchodilation (up to 12 hours) and are administered twice daily to decrease the symptoms of asthma. These medications should not be taken to provide rapid relief of symptomatic asthma. Examples include salmeterol and eformoterol, both long-acting β2-agonist drugs.

• Preventer medications: these preventative medications treat inflammation and help achieve overall asthma control. When the appropriate level has been achieved, they provide substantial benefits to individuals with asthma. Examples include inhaled corticosteroids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone propionate, fluticasone furoate), leukotriene- receptor antagonists (montelukast) and cromones (cromoglycate and nedocromil).5

There are also combination medications that contain a symptom controller and preventer medication, enabling the individual to administer medication in a single inhaler. Examples include fluticasone and salmeterol (Seretide), budesonide and eformoterol (Symbicort), fluticasone furoate and vilanterol (Breo) and fluticasone propionate and formoterol (Flutiform).

More recently, the use of monoclonal antibody therapies have been introduced for people with severe asthma. Anti-immunoglobulin therapy has shown promise in some

people with asthma. Omalizumab is an anti-immunoglobulin E (IgE) antibody that binds to free IgE and is effective in combination with other medications in severe persistent allergic asthma.16 Those who are symptomatic, despite being managed on high doses of inhaled and oral corticosteroids or long-acting β2-agonists, and who have failed to respond to other asthma therapies are most suitable.16 Mepolizumab is another newer medication, which is an antibody (IgG1, kappa), that targets human IL-5. IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation and survival of eosinophils. In some people with severe asthma it has been shown to significantly reduce acute exacerbations. Those most likely to respond to mepolizumab are adults and adolescents with severe asthma, who experience persistent asthma exacerbations despite optimal inhaled therapy, and with evidence of high eosinophil levels from blood counts or sputum.19

There are a growing number of options for management of chronic asthma depending on the duration of the condition and the severity of the symptoms, as well as individual adherence issues. Guidelines have been outlined and widely distributed by the National Asthma Council Australia (www.nationalasthma.org.au) and the New Zealand Guidelines Group (www.nzgg.org.nz). The most important element of regular asthma management is the reduction of inflammation.

Acute asthma episodes can be life threatening and therapy should be directed at maintaining a patent (open) airway and providing rapid bronchodilation and effective ventilation to maintain adequate gas exchange (see Table 25.1 for details of the severity of asthmatic episodes). Administration of oxygen and rapid-acting bronchodilators such as salbutamol (β2-agonist — that is, one that will interact with a group of adrenergic receptors in the lungs; see Chapter 6) are typically used for management of acute asthma, as well as systemic steroids for moderate to severe attacks to decrease inflammatory responses in the lungs.

R E S E A R C H I N F C U S Asthma genes Genomic screening of populations suggests that there is no single ‘asthma gene’ but rather numerous genes that may be associated with asthma. It may ultimately be possible to associate certain gene variants with specific clinical patterns of asthma and with responsiveness to specific asthma treatments. For example, one variant (or polymorphism) is the gene for the β2-adrenergic receptor, which has been shown to be associated with a poor or even adverse response to salbutamol in one study. If findings such as these can be corroborated and expanded in larger studies, ultimately it may be possible to develop individual profiles to optimise asthma therapy.

http://www.nationalasthma.org.au/

http://www.nzgg.org.nz/

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 719

FIGURE 25.6

Example of an asthma action plan template. This template plans out the preventer and reliever medications for the patient to use between varying symptoms (from well to worse).

720 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

F O C U S O N L E A R N I N G

1 Discuss the mechanisms that cause obstruction in asthma.

2 Describe the differences in airflow with respect to FEV1 and FVC during asthma.

3 Discuss the clinical manifestations of asthma in childhood.

4 Explain the full progression of blood gas abnormalities in a severe asthma episode.

5 Discuss therapy options for individuals with asthma.

P A

E D

IA T

R IC

Paediatrics and asthma Asthma affects approximately 10% of children aged 0–14 years in Australia and New Zealand and although the childhood prevalence of asthma in this region is decreasing it is still among the highest in the world.5 Unlike asthma prevalence in adults where the rates of asthma are higher among Indigenous populations compared with non-Indigenous populations, asthma rates among these two populations of children are similar.4,5 However, the incidence of severe asthma episodes and the rate of hospitalisations are greater in Indigenous populations compared with non-Indigenous populations.4,5

While the pathophysiology of asthma in children is similar to that of adults, several pertinent points need to be highlighted. Asthma is clinically different in children due to the pattern of asthma, natural history and anatomical features.20 For instance, wheezing in childhood can be both associated and not associated with asthma. The classification of asthma is based on the clinical patterns, rather than objective evaluation using spirometry. There are currently many theories regarding the mechanisms of the disease in childhood. There is not one single gene responsible for the manifestation of asthma. The wide spectrum of clinical disease probably reflects a complex interaction between genetic susceptibility and environmental factors, including early exposure to allergens and infections, particularly viral respiratory infections (see ‘Research in Focus: Asthma genes’). Although the genetic expression of asthma is difficult to identify, many discrete clinical presentations have been demonstrated.21 There are at least three different manifestations for childhood asthma. These are: 1 Transient wheezing limited to the first 3–5 years of

life. This is associated with decreased lung function, maternal smoking during pregnancy and exposure to other siblings or children at day-care centres. There is no association with a family history of asthma.

2 Non-atopic wheezing associated with lower respiratory tract illness before 3 years of age.

3 IgE-mediated wheezing associated with classic asthma; an early risk factor for persistent asthma.

Atopy (an allergic reaction when IgE increases due to environmental allergens — associated with a strong family

history of allergies) is strongly associated with classical asthma that persists into adulthood. However, wheezing illnesses in childhood usually resolved by about 6 years of age, especially when the wheezing is intermittent.5,12,20 The classification of childhood asthma is divided into three levels: infrequent intermittent, frequent intermittent and persistent (see Fig. 25.7). Broadly speaking, these classifications include the following: 1 Infrequent intermittent asthma: isolated episodes

usually triggered by an upper respiratory tract infection with episodes more than 6 weeks apart.

2 Frequent intermittent asthma: episodes less than 6 weeks apart but similar to infrequent intermittent asthma.

3 Persistent asthma (mild, moderate, severe): these children have symptoms of asthma at least weekly and experience night waking. They have the greatest number of hospitalisations and usually have asthma through to adulthood.

In a typical asthmatic episode, the major complaints are cough, wheeze and shortness of breath. There may or may not have been signs of a preceding upper respiratory infection, such as rhinorrhoea (discharge of nasal mucus,

75% Infrequent intermittent asthma (75%)

Frequent intermittent asthma (20%)

Persistent asthma (5%)

20%

FIGURE 25.7

Classification of childhood asthma and their distribution. Infrequent, intermittent asthma is the most common type of childhood asthma.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 721

with systemic consequences including systemic inflammation and complex chronic comorbidities.28 This results in significant and progressive functional impairment with reduced exercise capacity and increased exacerbations.29 (Fig. 25.8).

COPD is diagnosed using spirometry, with a FEV1/FVC ratio of less 70% following administration of a bronchodilator.30 The ratio should be greater than 70% in individuals without airway obstruction lung pathophysiology:

FEV FVC

or more in healthy airways1 100 70× = %

This is combined with a thorough history including history of smoking (or exposure to other noxious inhalational agents).

The disease is primarily caused by cigarette smoke (of any cigarette type) and both active and passive smoking have been implicated. This is the most important cause of COPD, and smokers demonstrate a steady decline in pulmonary function (see Fig. 25.9). The risk of developing COPD with continued long-term smoking, irrespective of cigarette type, is high. Other risks include inhaled noxious particles such as occupational exposure and air pollution. In the following sections we take a closer look at the two main conditions that result in COPD.

CHRONIC BRONCHITIS Chronic bronchitis is defined as hypersecretion of mucus and chronic productive cough for at least 3 months of the year (usually the winter months) for at least 2 consecutive years.26 It is almost always caused by cigarette smoking and by exposure to inhaled noxious particles. It differs from episodes of acute bronchitis, which are usually caused by infection and are reversible, whereas chronic bronchitis is an irreversible condition of progressive decline.

PAT H O P HYS I O LO G Y Inspired irritants result in airway inflammation with infiltration of neutrophils, macrophages and lymphocytes into the bronchial wall. Continual bronchial inflammation causes bronchial oedema and increases the size and

Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a progressive chronic disease characterised by irreversible obstruction of the airways. It is Australia’s fourth leading cause of death and third leading cause of disability.22 Moderate to severe COPD affects 7.5% of Australians over 40 years with prevalence rising rapidly with age; 29% of Australians over 75 years have COPD.23 Worldwide, COPD is the third leading cause of death.24 An economic report estimated the cost of COPD in Australia as $8 billion.25 This consisted of lost productivity ($6.8 billion), health system expenditure ($0.9 billion), patient expenses ($0.3 billion), and additional COPD-related welfare payments ($0.9 billion). People with COPD experience multiple clinical management problems related to airway, comorbidity, risk factors and self-management domains, and these problems have a major impact on health status.

COPD is a preventable, chronic disease that is characterised by persistent respiratory symptoms and airflow limitation, which is due to airway or alveolar abnormalities, that are usually caused by significant exposure to noxious particles or gases, with the most common cause being cigarette smoking.26 The airflow limitation in COPD is largely irreversible. COPD can be characterised pathophysiologically by emphysema, chronic bronchitis (and bronchiolitis), or commonly the coexistence of both emphysema and chronic bronchitis. The airflow limitation is caused by damage to the small airways, as a result of two main diseases: chronic bronchitis, which consists of airway inflammation and remodelling, and emphysema, which consists of destruction of alveolar tissue, and a decrease in elastic recoil.26

COPD is associated with a range of immunological processes. In COPD neutrophils, macrophages and CD8+ T-lymphocytes play a major role in the airway inflammation and lung damage. Proinflammatory cytokines such as IL-6, IL-8, IL-1β and tumour necrosis factor alpha (TNF-α) are also released in the COPD airway. Eosinophilic airway inflammation occurs in approximately 30% of individuals with the disease.27

While COPD is primarily a pulmonary condition, it is now also recognised as a multi-system disease associated

often termed ‘runny’ nose) or low-grade fever. In children, about 70–80% of acute wheezing episodes are associated with viral respiratory infections. In infants and toddlers under 2 years old, the most common of these is respiratory syncytial virus. In older children and adults, the major viral trigger is rhinovirus (commonly referred to as the ‘common cold’ virus). On physical examination, there is an expiratory wheeze that is often described as high-pitched and musical, and exhalation is unusually longer than inhalation. Breath

sounds may become faint when air movement is poor. The child may speak in short sentences or not at all because of dyspnoea (difficulty breathing). Ventilatory rate and heart rate are elevated to compensate for the low oxygen levels and increased work of breathing. Nasal flaring and use of accessory muscles with retractions in the substernal, subcostal, intercostal, suprasternal or sternocleidomastoid muscle areas are evident. The child may appear anxious or be diaphoretic (excessive sweating), which are often important signs of respiratory compromise.

722 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

number of mucous glands and goblet cells in the airway epithelium. Thick, tenacious mucus is produced and cannot be cleared because of impaired ciliary function. The defence mechanisms of the pulmonary system are compromised, increasing susceptibility to pulmonary infection and injury. Frequent infectious exacerbations are complicated by bronchospasm with dyspnoea and a productive cough. The pathophysiology of chronic bronchitis is shown in Fig. 25.10.

Initially this process affects only the larger bronchi, but eventually all airways are involved. As the airways become increasingly narrowed, airway obstruction results (see Figs 25.11 and 25.12). The airways collapse early in expiration, trapping gas in the distal portions of the lung. Eventually ventilation–perfusion mismatching (see Chapter 24) and hypoxaemia occurs. Extensive air trapping puts the respiratory muscles at a mechanical disadvantage, resulting in hypoventilation and hypercapnia.

Cigarette smoke

Spill-over

SYSTEMIC INFLAMMATION Cytokines, IL-1�, IL-6, IL-18, TNF� Acute phase proteins: CRP

Peripheral lung inflammation

Biomass fuel

Normal ageing

Physical activity

Skeletal muscle weakness Cachexia

Cardiovascular – Coronary artery disease – Chronic heart failure – Hypertension

Metabolic diseases – Diabetes – Metabolic syndrome – Obesity

Bone disease Osteoporosis Osteopenia

Depression

Hypoxia

FIGURE 25.8

COPD, systemic inflammation and comorbidities. Chronic inhalation of smoke leads to COPD and lung inflammation, which can lead to systemic inflammation. COPD also leads to a reduction in physical activity, which worsens systemic inflammation. The consequences of this chronic systemic inflammation can include cardiovascular, metabolic, and bone disorders, as well as depression.

R E S E A R C H I N F C U S Coexisting asthma and COPD Asthma and COPD are most often considered distinct conditions with different diagnostic and management approaches. However, in practice, patients frequently exhibit features of more than one disease particularly in an older population. This is referred to as asthma-COPD overlap and refers to the coexistence of asthma, emphysema or chronic bronchitis; it is prevalent in over 50% of people over the age of 50 years, and people who have features of both diseases experience more frequent and severe exacerbations, increased symptom burden and worse health status. Traditionally people with features of both diseases have been excluded from clinical trials, and as a result the evidence base for management of asthma-COPD overlap is limited. This area is currently a focus of research.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 723

workload of breathing, so that late in the course of disease, many individuals will develop hypoventilation and hypercapnia.

C L I N I C A L MA N I F E S TAT I O N S O F CO P D Table 25.3 lists the common clinical manifestations of COPD including chronic bronchitis.

Acute exacerbations of COPD are a common feature which put the patient at immediate risk of distress, hospitalisation and even death. Acute exacerbations represent a significant contribution to the healthcare costs associated with these conditions.31

Acute exacerbations of COPD are not only a concern during the immediate time of that exacerbation; after recovery they can also have a negative effect on disease trajectory. In COPD the frequency of exacerbations is associated with an accelerated decline in lung function, accelerated decrease in health status and decreased survival (Fig. 25.14). Furthermore, recent evidence indicates that exacerbations cluster together in time and that after one exacerbation patients are at a heightened risk of a second.32 This is important given the detrimental effect recurrent exacerbations have on outcomes for people with COPD.

E VA LUAT I O N A N D MA N AG E M E N T O F CO P D Under-diagnosis of COPD is common; rates of under-diagnosis have been reported as high as 78%.33 Disease-specific guidelines propose diagnostic criteria to assist clinicians in the diagnosis of COPD. In clinical practice, COPD is usually diagnosed based on a history of smoking, or exposure to other noxious agents and a FEV1/ FVC% (otherwise known as forced expiratory ratio (FER)) of less than 70%.30 The Australian and New Zealand guidelines for treatment are based on the spirometry severity grading scale.30 Other useful assessments in the evaluation include pulmonary function tests to measure lung volumes and gas diffusion, chest x-rays, blood gas analysis and physical examination.

The goals of COPD management are to reduce the risk of exacerbation and minimise symptoms.30 This approach recommends short-acting bronchodilators and reduction of risk by stopping smoking, and by ensuring influenza vaccinations across all COPD severity grades. Addition- ally, pharmacotherapy including inhaled glucocorticos- teroids and long-term oxygen therapy is recommended as severity, symptoms and exacerbation frequency increase. Pulmonary rehabilitation is recommended for COPD individuals who are symptomatic regardless of severity.30,34

CYSTIC FIBROSIS Cystic fibrosis is the most common autosomal recessive inherited disease affecting Caucasians and results from defective epithelial chloride ion transport. The chromosomal mutation results in the abnormal expression of the protein, cystic fibrosis transmembrane conductance regulator, which is a chloride channel (it allows the diffusion of chloride

EMPHYSEMA Emphysema is abnormal permanent enlargement of gas-exchange airways accompanied by destruction of alveolar walls. Obstruction results from changes in lung tissues, rather than mucus production and inflammation as in chronic bronchitis. The major mechanism of airflow limitation is loss of elastic recoil (see Fig. 25.11). The major cause of emphysema is cigarette smoking, although air pollution and childhood respiratory infections are contributing factors.

PAT H O P HYS I O LO G Y Emphysema begins with destruction of alveolar septa, which eliminates portions of the pulmonary capillary bed and increases the volume of air in the alveoli (see Fig. 25.13). It is postulated that inhaled oxidants in tobacco smoke and air pollution stimulate inflammation, which over time causes alveolar destruction and loss of the normal elastic recoil of the bronchi (see Fig. 25.10). Alveolar destruction produces large air spaces within the lung tissue and air spaces adjacent to pleurae. These areas are not effective in gas exchange. The loss of alveolar tissue means a loss of the respiratory membrane where gases cross between air and the blood, resulting in a significant ventilation– perfusion mismatching and hypoxaemia. Expiration becomes difficult because loss of elastic recoil reduces the volume of air that can be expired passively and air is trapped in the lungs. Air trapping causes an increase in expansion of the chest, which puts the muscles of ventilation at a mechanical disadvantage. This results in increased

Smoked regularly and susceptible to the effects

100

Age (years) 25 50 75

(% o

f v al

ue a

t a ge

2 5 y

ea rs

)

Onset of symptoms

Death

Severe disability

Stopped smoking at age 65 years

Never smoked or not susceptible to smoke

Stopped smoking at age 45 years

FIGURE 25.9

Time course of smoking and the changes with smoking cessation at 45 and 65 years of age. Notice that for the smoker who quit at age 45, the serious progression of COPD is much slower than that for the smoker who quit at age 65. In both cases, the disease progression is slower than for those who continue smoking.

724 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe C

O N

C E

P T

M A

P Tobacco smokeAir pollution

Inflammation of the airway epithelium

Systemic effects (muscle weakness, weight loss)

Breakdown in lung elastic tissue

causes

leads to

results in results in

can result in

evidenced by

Continuous bronchial irritation and inflammation

Chronic bronchitis (bronchial oedema, hypersecretion of

mucus, bacterial colonisation of airways)

Emphysema (destruction of alveolar septa and

loss of elastic recoil of bronchial walls)

Infiltration of inflammatory cells and release of cytokines (neutrophils, macrophages, lymphocytes, leukotrienes,

interleukins)

Airway obstruction Air trapping

Loss of surface area for gas exchange Frequent exacerbations

(infections, bronchospasm)

Dyspnoea Cough

Hypoxaemia Hypercapnia

Cor pulmonale

FIGURE 25.10

The pathophysiology of COPD. Chronic inhalation of smoke leads to inflammation of the lungs. This inflammation manifests as bronchial inflammation and mucus production, leading to chronic bronchitis, and also manifests as break down of alveolar tissue, leading to emphysema. Together, chronic bronchitis and emphysema lead to significant impairments in breathing, leading to symptoms that may be severe for the patient.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 725

respiratory failure and death.36 The typical features of cystic fibrosis lung disease are mucus plugging, chronic inflammation and chronic infection. The mucus plugging seen in cystic fibrosis probably results from both increased production of mucus and altered chemical properties of the mucus. Mucus-secreting airway cells (goblet cells and submucosal glands) are increased in number and size. Cystic fibrosis mucus is dehydrated and viscous because of defective chloride secretion and excess sodium absorption — as a result, the mucus secretions are thick and sticky. This decreases the fluid volume on the airway surface, impairing the mobility of the cilia and thereby allowing mucus to adhere to the airway epithelium, along with bacteria and injurious byproducts from neutrophils.

Chronic inflammation is believed to contribute to long-term lung damage and there is evidence that this

out of the cell) present on the surface of many types of epithelial cells including the airways, bile ducts, pancreas, sweat ducts and vas deferens.

In Australia, approximately 1 in 3630 people are born with cystic fibrosis, and about 1 in 25 are carriers who are not affected by the mutation.35 Cystic fibrosis has long been considered a disease of childhood; however, over time there have been significant improvements in the management and treatment options for people with cystic fibrosis, such that in the last four decades the survival has improved dramatically. Improved treatments and increased survival have consequently led to a significant increase in the number of adult patients with cystic fibrosis, such that cystic fibrosis can no longer be considered a paediatric disease alone. The number of cystic fibrosis patients over the age of 18 has increased significantly and the most recently published data from the Australian cystic fibrosis data register report that approximately half of patients are adults.35

PAT H O P HYS I O LO G Y Although cystic fibrosis affects many organs (endocrine, gastrointestinal, renal and reproductive systems) the most important effects are on the lungs and in 90% of cases, chronic pulmonary infections eventually lead to

Muscle

Air movement during INSPIRATION

Air movement during EXPIRATION

Mucus plug

Bronchial walls collapse

Alveolar walls

FIGURE 25.11

Mechanisms of air trapping in chronic obstructive pulmonary disease. During inspiration, the force of airflow is sufficient to overcome the mucus. However, during expiration, the airways partially collapse, and the mucus becomes sufficient to plug the airway to a much greater extent, causing difficulty exhaling.

Pulmonary artery Cartilage Submucosal

gland

Basement membrane

Epithelium

Goblet cell

Alveoli

Mucus accumulation

Mucus plug

Hyperinflation of alveoli

Respiratory bronchioles

Bronchioles

Mast cell

Parasympathetic nerve

Smooth muscle

Enlarged submucosal gland

Inflammation of epithelium

FIGURE 25.12

Airway obstruction resulting from chronic bronchitis. A Normal lungs with clear airways. B Inflammation and airway thickening of mucous membrane with accumulation of mucus and pus leading to obstruction and characterised by a cough.

726 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

the age of 30 years.37 Combined with chronic bacterial infection, these lead to microabscess formation, bronchiectasis, patchy consolidation and pneumonia, peribronchial fibrosis and cyst formation (see Fig. 25.15). There is a progressive decrease in the amount of available and functional lung tissue. The pathophysiology for these changes are outlined in Fig. 25.16. Over time, pulmonary

process begins in infancy. Abnormal cytokine profiles promote a proinflammatory state.

Individuals with cystic fibrosis have a propensity for chronic bronchial infection. It is likely that local factors in the cystic fibrosis airway microenvironment favour bacterial colonisation, because there is no systemic immune defect. Staphylococcus aureus and Pseudomonas aeruginosa are common, and Pseudomonas aeruginosa ultimately colonises airways in approximately 70% of adults between the ages of 18 and 29 and 82.3% of adults with cystic fibrosis over

A B

FIGURE 25.13

The effects of emphysema on the gas exchange units. A Normal lung with many small alveoli. B Lung tissue affected by emphysema. Notice that the alveoli have merged into larger air spaces, reducing the surface area for gas exchange.

TABLE 25.3 Clinical manifestations of COPD

VARIABLES BRONCHITIS EMPHYSEMA

Age (years) 40–45 50–75

Infections Common Occasional

Dyspnoea Mild, late in course

Severe, early in course

Productive cough Classical sign Late in course with infection

Wheezing Intermittent Common

History of smoking Common Common

Prolonged expiration

Always present Always present

Cyanosis Common Uncommon

Chronic hypoventilation

Common Late in course

Chest x-ray findings

Prominent vessels Hyperinflation

General appearance

‘Blue bloater’ ‘Pink puffer’

Barrel chest Occasionally Classic

Exacerbation Q

ua lit

y of

li fe

Death Time

Progressive decline in lung function

Decline in quality of life with exacerbations

FIGURE 25.14

Effect of exacerbations on lung function and quality of life in COPD. In the individual with COPD, there is a progressive decline in lung function. However, exacerbations can cause the decline to progress quicker, leading to a quicker decline in the quality of life.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 727

(meconium blocking the bowel) at birth, which is indicative of cystic fibrosis. Approximately 80% of individuals with CF have pancreatic insufficiency leading to malabsorption, symptoms include frequent, loose and oily stools and, if not treated, either meconium ileus in infants or distal intestinal obstructive syndrome in adults develops. More subtle presentations include chronic sinusitis, nasal polyps and rectal prolapse. Complications of cystic fibrosis may include liver disease and cystic fibrosis related diabetes, each of which occurs in approximately one-quarter of adults.

E VA LUAT I O N A N D T R E AT M E N T In Australia and New Zealand, newborn infants are screened for cystic fibrosis. The blood test measures pancreatic enzyme levels and, if the levels are abnormal, genetic testing for the cystic fibrosis mutation is undertaken. However, the testing is not definitive: there are numerous cystic fibrosis-associated mutations and up to 5% of all tests will not be conclusive. Therefore, the definitive diagnosis is confirmed from a sweat test, which determines the level

vascular remodelling occurs because of localised hypoxia and arteriolar vasoconstriction, and pulmonary hypertension and cor pulmonale (right ventricular enlargement) may develop in the late stages of disease.

C L I N I C A L MA N I F E S TAT I O N S The most common presentations are respiratory or gastrointestinal. Respiratory symptoms include persistent cough or dyspnoea and recurrent or severe pulmonary infection. Lung function decreases in individuals with cystic fibrosis with increasing age. For instance, at 18 years, FEV1 is approximately 80% of predicted volumes.37 Physical signs that develop over time include barrel chest and digital clubbing. Over time, more serious pulmonary conditions may arise, such as haemoptysis and pneumothorax (see ‘Clinical manifestations of pulmonary alterations’). Classic gastrointestinal presentations include meconium ileus

R E S E A R C H I N F C U S Nutrition and COPD Malnutrition is a major concern for individuals with COPD because they have increased energy expenditure, decreased energy intake and impaired oxygenation. The disproportionate muscle wasting is similar to that which occurs with other chronic diseases, such as cancer, heart failure and AIDS. Systemic inflammatory mediators may impair appetite and contribute to hypermetabolism. There are several detrimental effects of malnutrition: (1) adversely affects exercise tolerance by limiting skeletal and respiratory muscle strength and aerobic capacity; (2) limits surfactant production; (3) reduces cell-mediated immune responses; (4) reduces production of proteins (protein synthesis); and (5) increases morbidity and mortality. The goal of medical nutrition therapy is to maintain an acceptable and stable weight for the individual. This can be accomplished by including foods of high energy density, snacking frequently, choosing soft foods, having an adequate intake of fluids and providing assistance with shopping and meal preparation. Increasing omega-3 fatty acids and antioxidant intake may modulate the effects of systemic inflammation. Protein intake should be maintained at 1.0–1.5 g/kg of body weight, and a daily vitamin C supplement should be added to the diet if the individual is still smoking.

On the other hand, obesity is observed at high rates of prevalence in COPD, and the prevalence is increasing. The rates of obesity in COPD have been reported at rates with an even higher prevalence than that seen in the general population. Obesity is usually associated with increased risk of all cause mortality in the general population, and is linked to metabolic syndrome. Discordantly, obesity in COPD is associated with improved survival and reduced lung function decline. The focus of current research is to define the best approach to the management of obesity in COPD populations.

FIGURE 25.15

The pathology of the lung in cystic fibrosis. Key features are widespread mucus impaction of airways and bronchiectasis (especially from upper lobe [U]), with haemorrhagic pneumonia in the lower lobe (L). Small cysts (C) are present at the apex of the lung.

728 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

of sweat chloride concentration (indicative when in excess of 60 mmol/L).

Treatment is primarily focused on pulmonary health and nutrition. Common pulmonary therapies include techniques to promote mucus clearance, such as chest physical therapy and positive pressure devices, bronchodilators, aerosolised DNase which liquefies mucus, and inhaled mucolytics such as hypertonic saline and mannitol. Inhaled maintenance antibiotics can be used to suppress Pseudomonas aeruginosa when it is present and this has a beneficial clinical impact. Oral antibiotics are used fairly liberally for minor pulmonary exacerbations. Intravenous antibiotics are used to treat more severe exacerbations of pulmonary infection. Lung transplantation is an option for selected individuals with end-stage lung disease from cystic fibrosis. Complications are usually related to infection or rejection and survival at 5 years posttransplant is approximately 67%.38

Approximately 80% of individuals with cystic fibrosis have pancreatic insufficiency and therefore need to take

pancreatic enzymes (for digestion of nutrients) before meals and snacks for their entire lifetime. Fat-soluble vitamins must be supplemented. Energy needs are high, especially with advancing lung disease and high-kilojoule supplements or even gastrostomy feeding may be warranted. Nutritional care for individuals with cystic fibrosis has become increasingly aggressive because of the documented link to better long-term outcomes.

Fortunately, there have been major improvements in cystic fibrosis outcomes over the last few decades. These improvements are related to advances in treatment but of equal importance relate to the specialist multidisciplinary centres for children and adults with cystic fibrosis. Specialist centre care has been shown to be associated with improved clinical outcomes for children and adults; those treated in these centres have better nutritional status, chest x-ray scores and pulmonary function compared to other cystic fibrosis patients, and this approach is recommended as an essential component of management.

C O

N C

E P

T M

A P Chromosome 7CFTR defect

Defective chloride secretion

Cilia movement

Mucus plugs and impaired mucus clearance

Pulmonary defence mechanisms

Chronic bacterial infection

Chronic in�ammation

Cyst formation

Bronchiectasis

Dehydrated mucus

Viscous mucus

causes

leads toimpairs

affects results in

results in (over time)

leads to

contributes to contributes tocontributes to

FIGURE 25.16

The pathogenesis of bronchiectasis and cyst formation in cystic fibrosis. The altered chloride secretion leads to dehydrated, thick mucus, which cannot be moved easily by the impaired cilia. As a result, mucus accumulates and impairs normal pulmonary defence mechanisms, leading to infections and inflammation. CFTR = cystic fibrosis transmembrane regulator.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 729

R E S E A R C H I N F C U S New treatments for cystic fibrosis There have been recent advances in cystic fibrosis with the development of new therapies that target specific defects of the CFTR (cystic fibrosis transmembrane conductance regulator) function. The first CFTR modulator approved for use in cystic fibrosis is Ivacaftor. Ivacaftor targets the underlying protein defect in patients with the G551D mutation, and has been show to significantly improve lung function, exacerbations rates, weight and quality of life in adults. Lumacaftor/Ivacaftor combination is another targeted therapy that leads to improved lung function, exacerbations and nutrition in a subset of patients with cystic fibrosis. These treatments represent a new era of precision medicine in cystic fibrosis and emerging therapies are currently being developed and trialled.

FIGURE 25.17

Bronchiectasis on a chest x-ray. Note the dilated bronchi close to the midline (see arrows).

Bronchiectasis is a debilitating illness in which individuals suffer significant respiratory morbidity and poor health-related quality of life. Exacerbations occur at rates of 1.5–6.5 per patient per year and are associated with an increased risk of admission and readmission to hospital, and high healthcare costs.39 Data estimating rates of hospital admissions, average length of stay and the economic burden of the disease give an indication as to the impact of this condition. The average annual age-adjusted rate of hospitalisations is 16.5 per 100 000 population,40 and an average annual increase of hospitalisation rates of 2.4% among men and 3.0% among women was identified between 1993 and 2006. These data highlight the need to optimise management of the disease. It is increasingly recognised that bronchiectasis may coexist with other common respiratory diseases such as COPD and asthma and that many of the clinical consequences may overlap. Literature reports up to 57% of people with COPD have coexisting bronchiectasis41 and 24.8% of people with severe persistent asthma have been shown to have coexisting bronchiectasis when examined with high resolution CT scan, despite being previously undiagnosed.42

Bronchiectasis is associated with multiple comorbidities that may alter the disease presentation, be a systemic consequence of the same pathophysiological process or act as confounding factors in the diagnosis and treatment of the disease.

The symptoms of bronchiectasis may date back to a childhood illness or infection. The disease is commonly associated with recurrent lower respiratory tract infections and expectoration of large amounts of purulent sputum and haemoptysis are common. Pulmonary function studies show decreased vital capacity and expiratory flow rates. Bronchiectasis is often associated with bronchitis and atelectasis. Treatment of bronchiectasis involves avoidance and management of chest infections, antibiotics, airway clearance techniques, mucolytic agents and pulmonary rehabilitation in individuals who experience dyspnoea as part of their activities of daily living.

BRONCHIECTASIS Bronchiectasis is an abnormal permanent dilation and distortion of the bronchi and bronchioles, resulting from chronic inflammation of the airways, and leading to progressive destruction of the bronchial walls and lung tissue. Bronchiectasis has a distinctive appearance on x-rays (see Fig. 25.17) and chest computerised tomography (CT) scans.

The prevalence of bronchiectasis among adults in Australia and New Zealand is largely uncertain due to lack of population studies and it is likely that any existing bronchiectasis prevalence rates are underestimated due to lack of diagnosis or misdiagnosis of the disease.

F O C U S O N L E A R N I N G

1 Differentiate between the different components of COPD.

2 Discuss the anatomical and pathophysiological changes in chronic bronchitis.

3 Describe the changes in oxygenation and ventilation in individuals with emphysema.

4 Describe the pathogenesis of impaired mucus clearance and lung changes in cystic fibrosis.

Restrictive airway diseases Restrictive airway diseases are not as prevalent as obstructive airway diseases in the Australian and New Zealand populations. They are fundamentally different from obstructive diseases, but many of the clinical manifestations

730 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

are similar. Therefore, it is essential that you can differentiate between these two groups of disorders, such that clinical management can be directed appropriately.

Restrictive lung diseases are characterised by decreased compliance (stretchiness) of the lung tissue, resulting in an increased work of breathing. Individuals with lung restriction complain of dyspnoea and have an increased ventilatory rate and decreased tidal volume — that is, they breathe fast but with smaller breath size. Pulmonary function testing reveals a decrease in FVC often accompanied with a reduction in FEV1. Therefore, the ratio of FEV1/FVC can be normal but usually increased — that is, about 80% of the forced expired air is expelled from the lungs in the first second — yet the overall amount of air forcibly exhaled is less than normal (see Fig. 25.18). Restrictive lung diseases commonly affect the alveolar–capillary membrane and cause decreased diffusion of oxygen from the alveoli into the blood, resulting in hypoxaemia. Some of the most common restrictive lung diseases in adults are acute respiratory distress syndrome, inhalational disorders, idiopathic pulmonary fibrosis and interstitial lung disease.

Acute respiratory distress syndrome Acute respiratory distress syndrome is a dramatic life-threatening condition characterised by acute lung inflammation and diffuse alveolar capillary injury. It can affect all age groups. Individuals who progress to acute

Fl ow

( L/

Volume (L)

FIGURE 25.18

Flow volume loop — restrictive lung disease. These expiratory flow volume curves show pre- and post- bronchodilator spirometry. The pre-bronchodilator effort is represented by the blue curve and the post-bronchodilator effort by the red curve. Note that there is a reduction in both FEV1 and FVC. Therefore, when calculated, the FEV1/FVC ratio is not different from that in healthy individuals; however, there is restriction throughout the entire expiratory phase.

respiratory distress syndrome typically are critically ill and require intensive care treatment. The mortality rate is high; however, advances in therapy have decreased mortality in people younger than 60 years. The most common predisposing factors are sepsis and multiple trauma; however, there are many other causes, including pneumonia, burns, aspiration, cardiopulmonary bypass surgery, pancreatitis, blood transfusions, drug overdose, high concentrations of supplemental oxygen and disseminated intravascular coagulation.

PAT H O P HYS I O LO G Y The hallmark of acute respiratory distress syndrome is lung inflammation. There is activation of the inflammatory response (see Fig. 25.19), including complement, cytokines, arachidonic acid metabolites and platelet-activating factor.

All disorders causing acute respiratory distress syndrome cause massive pulmonary inflammation that injures the alveolar–capillary membrane and which produces severe pulmonary oedema and hypoxaemia. The damage can occur directly, as with the aspiration of highly acidic gastric contents or the inhalation of toxic gases, or indirectly from chemical mediators released in response to systemic disorders such as sepsis. Injury to the pulmonary capillary endothelium stimulates platelet aggregation (platelets sticking together) and intravascular thrombus formation. Endothelial damage also initiates the complement cascade, stimulating neutrophil and macrophage activity and the inflammatory response.

Once activated, macrophages produce toxic mediators such as tumour necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) (see Chapter 12). The role of neutrophils is central to the development of acute respiratory distress syndrome. Activated neutrophils release a battery of inflammatory mediators, including proteolytic enzymes (enzymes that break down proteins), toxic oxygen products, arachidonic acid metabolites (prostaglandins, thromboxanes, leukotrienes) and platelet-activating factor. These mediators extensively damage the alveolar–capillary membrane and greatly increase capillary membrane permeability. This allows fluids, proteins and various blood cells to leak from the capillary bed into the pulmonary interstitium and alveoli. The resulting pulmonary oedema severely reduces lung compliance and impairs alveolar ventilation. Mediators released by neutrophils and macrophages also cause pulmonary vasoconstriction, which leads to worsening of ventilation–perfusion mismatching and hypoxaemia. This vicious cycle continues and is difficult to halt.

The initial lung injury also damages the alveolar epithelium. This cell injury increases alveolar capillary permeability, increases susceptibility to bacterial infection and pneumonia, and decreases surfactant production. Alveoli and respiratory bronchioles fill with fluid or collapse. The lungs become less compliant, ventilation of alveoli decreases and pulmonary blood flow is shunted right to left. The work of breathing increases. The end result is acute respiratory failure.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 731 C

O N

C E

P T M

A P

Neutrophil aggregation and release of mediators

Alveolar-capillary membrane permeability

Clinical lung injury

Alveolar epithelial damage

Type II pneumocyte damage

Endothelial damage

Platelet aggregation

results in

starts

causes

precipitates

increases

allows

results in

contributes to contributes to

leads to

can cause

causes

affects

also

initiates

causescontributes

causes

Release of neutrophil chemotactic factors

Complement activation

Bacterial endotoxin release

Macrophage mobilisation

Release of cytokines (TNF, IL-1)

Vasoconstriction

Decreased �ow to selected areas

Ventilation perfusion mismatching

Exudation of �uid, protein, RBCs into

interstitium

Pulmonary oedema and haemorrhage with

severe impairment of alveolar ventilation

Acute respiratory failure

Decreased surfactant production

Bacterial infection

Atelectasis and impaired lung compliance

Pneumonia

Hypoxaemia

FIGURE 25.19

The proposed mechanism for the pathophysiological changes associated with acute respiratory distress syndrome. Damage to the alveoli leads to increased susceptibility to pneumonia and atelectasis. Damage to endothelial cells leads to activation of platelets and complement, which triggers a series of events that can result in pulmonary oedema and hypoxaemia. IL-1 = interleukin-1; RBCs = red blood cells; TNF = tumour necrosis factor.

732 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

disease, the individual’s history of exposure is important in determining the diagnosis. Pneumoconiosis often occurs after years of exposure to the offending dust, with progressive fibrosis of lung tissue. Asbestosis, silicosis and coal worker’s pneumoconiosis are among the three most important dust-related diseases from occupational exposure in Australia, and recent local and international data suggest that there is a resurgence of coal worker’s pneumoconiosis.43 Asbestosis has the highest mortality of these three; though the risk of environmental exposure has been recognised for decades, it is to be hoped that with the controls now in place, exposure to asbestos will be limited in the future. However, there is also some concern remaining regarding exposure to asbestos, due to individuals undertaking their own home renovations, as the untrained renovator may disturb asbestos from numerous products that were used previously in home construction.

Deposition of dusts from silica, asbestos and coal leads to chronic inflammation. In addition, scarring of the alveolar–capillary membrane leads to a build-up of connective tissue in the lung (termed pulmonary fibrosis). These dust deposits are permanent and lead to progressive pulmonary deterioration. Clinical manifestations with advancement of disease include cough, chronic sputum production, dyspnoea, decreased lung volumes and hypoxaemia. Diagnosis is confirmed by chest x-ray and CT scans. Treatment (such as pain control) is usually palliative (to reduce symptoms of the disease) and focuses on preventing further exposure, particularly in the workplace.

The chemical mediators responsible for the alveolar capillary damage of acute respiratory distress syndrome often cause widespread inflammation, endothelial damage and capillary permeability throughout the body, resulting in the systemic inflammatory response syndrome, which then leads to multiple organ dysfunction syndrome. In fact, death may not be caused by respiratory failure alone but by multiple organ dysfunction syndrome associated with acute respiratory distress syndrome. (Multiple organ dysfunction syndrome is discussed in Chapter 23.)

C L I N I C A L MA N I F E S TAT I O N S Acute respiratory distress syndrome develops acutely after the initial insult, usually within 24 hours, though occasionally it is delayed up to a few days. The classic signs and symptoms of acute respiratory distress syndrome are marked dyspnoea, rapid shallow breathing, inspiratory crackles, respiratory alkalosis, decreased lung compliance, hypoxaemia unresponsive to oxygen therapy (called refractory hypoxaemia) and diffuse alveolar infiltrates seen on chest x-rays, without evidence of cardiac disease.

E VA LUAT I O N A N D T R E AT M E N T Diagnosis is based on physical examination, analysis of blood gases and radiological examination. Treatment for acute respiratory distress syndrome remains supportive in nature and the goals are to maintain adequate tissue oxygenation, minimise acute lung injury and avoid further pulmonary complications. Most individuals with acute respiratory distress syndrome require mechanical ventilation and often relatively high levels of positive end-expiratory pressure to promote alveolar ventilation and stabilisation and redistribution of alveolar oedema fluid into the interstitium.

Inhalation disorders EXPOSURE TO TOXIC GASES Inhalation of gaseous irritants can cause significant respiratory dysfunction. Gases that are toxic to the pulmonary system include smoke, ammonia, hydrogen chloride, sulfur dioxide, chlorine and nitrogen dioxide. Inhalation of a toxic gas results in severe inflammation of the airways, alveolar and capillary damage and pulmonary oedema. Initial symptoms include burning of the eyes, nose and throat; coughing, chest tightness and dyspnoea. Hypoxaemia is common. Treatment includes supplemental oxygen, mechanical ventilation and support of the cardiovascular system due to hypotension. Most individuals respond quickly to therapy. Some, however, may improve initially then deteriorate as a result of bronchiectasis (persistent dilation of the bronchioles) or bronchiolitis (inflammation of the bronchioles).

PNEUMOCONIOSIS Pneumoconiosis represents any change in the lung caused by inhalation of inorganic dust particles, usually in the workplace. As in all cases of environmentally acquired lung

F O C U S O N L E A R N I N G

1 Describe the pathophysiology of acute respiratory distress syndrome.

2 Discuss the clinical manifestations of acute respiratory distress syndrome and how they progress differently from other lung diseases.

3 Differentiate between inhalational gas and particle exposure.

Infections of the pulmonary system Infections of the pulmonary system are some of the most common infections in humans. Symptoms of respiratory infection include increased sputum, cough, sore throat and fever; mild infections do not usually require medical intervention. Most of these infections — the common cold, pharyngitis (sore throat) and laryngitis — involve only the upper airways (i.e. the top part of the conducting airways). Although the lungs have direct contact with the atmosphere, they usually remain sterile as the upper airways filter and clear the inspired air of contaminants and thus more serious infections are prevented. Infections of the lower respiratory

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 733

virus and parainfluenza virus are common aetiological microorganisms. Legionella species is also an important cause of community-acquired pneumonia. Pseudomonas aeruginosa, other gram-negative microorganisms and Staphylococcus aureus are the most common aetiological agents in hospital-acquired pneumonia. Immunocompromised individuals (e.g. people with HIV or individuals who have undergone organ transplantation) are especially susceptible to Pneumocystis jiroveci, mycobacterial infections and fungal infections, such as aspergillus, of the respiratory tract. These infections can be difficult to treat and have a high mortality rate.

PAT H O P HYS I O LO G Y Aspiration of oropharyngeal secretions is the most common route of lower respiratory tract infection; thus, the nasopharynx and oropharynx constitute the first line of defence for most infectious agents. Another route of infection is through the inhalation of microorganisms that have been released into the air when an infected individual coughs, sneezes or talks, or from aerosolised water such as that from contaminated respiratory therapy equipment. This route of infection is most important in viral and mycobacterial pneumonias and in Legionella outbreaks. Pneumonia can also occur when bacteria are spread to the lungs in the blood from bacteraemia (bacteria within the blood) that can result from infection elsewhere in the body or from intravenous drug abuse.

In healthy individuals, pathogens that reach the lungs are expelled or held in check by mechanisms of defence (see Chapters 12 and 13). If a microorganism gets past the upper airway defence mechanisms, such as the cough reflex and mucociliary escalator, the next line of defence is the alveolar macrophage (see Chapter 24 for details on pulmonary system defence mechanisms). This phagocyte is capable of removing most infectious agents without setting off significant inflammatory or immune responses. However, if the microorganism is virulent (small numbers can be pathogenic) or present in large enough numbers, it can overwhelm the alveolar macrophages. This results in a full-scale activation of the body’s defence mechanisms, including the release of multiple inflammatory mediators,

tract occur most often in individuals whose normal defence mechanisms are impaired and often provide more serious alterations to the pulmonary system, which can also have profound systemic effects, such as changes in cellular metabolism, affecting homeostasis. Of all the pulmonary infections in adults, pneumonia is the most serious and a leading cause of death in both males and females in Australia and New Zealand, especially in people older than 65 years of age.44 We now examine the pathophysiology of this serious infection.

Pneumonia Pneumonia is infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa or parasites. Risk factors for pneumonia include advanced age, individuals who are immunocompromised, underlying lung disease, alcoholism, altered consciousness, smoking, malnutrition and immobilisation. The causative microorganism influences how the individual presents clinically, how the pneumonia should be treated and the prognosis. Community-acquired pneumonia tends to be caused by different microorganisms compared to healthcare-acquired infections (healthcare- acquired infections are discussed in Chapter 14). In addition, the characteristics of the individual are important in determining which microorganism is likely to infect them; for example, immunocompromised individuals tend to be susceptible to opportunistic infections (pathogens that cause infections but not in healthy individuals) that normally are uncommon in adults. In general, infections acquired within healthcare facilities and those affecting immunocompromised individuals have a higher mortality rate than community- acquired pneumonia. Some of the most common causal microorganisms are listed in Table 25.4.

The most common community-acquired pneumonias are caused by bacteria, particularly those caused by Streptococcus pneumoniae (also known as the pneumococcus), which has a relatively high mortality rate in the elderly. Mycoplasma pneumoniae is a common cause of pneumonia in young people living in close contact, such as in dormitories. Influenza is the most common viral community-acquired pneumonia in adults and children; respiratory syncytial

TABLE 25.4 Common microorganisms of pneumonia

COMMUNITY-ACQUIRED PNEUMONIA HEALTHCARE-ACQUIRED PNEUMONIA IMMUNOCOMPROMISED INDIVIDUALS

Streptococcus pneumoniae Pseudomonas aeruginosa Pneumocystis jiroveci (Pneumocystis pneumonia)

Mycoplasma pneumoniae Staphylococcus aureus Mycobacterium tuberculosis

Haemophilus influenzae Klebsiella pneumoniae Atypical mycobacteria

Oral anaerobic bacteria Escherichia coli Fungi

Influenza virus Respiratory viruses

Legionella pneumophilae Protozoa

Chlamydia pneumoniae Parasites

Moraxella catarrhalis

734 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

further diagnostic studies may include bronchoscopy (in which a scope with a camera is introduced into the lungs to visualise the airways) or lung biopsy. Positive identification of viruses can be difficult. Blood cultures often help to identify the virus if systemic disease is present.

Antibiotics are used to treat bacterial pneumonia; however, resistant strains of pneumococcus are on the rise. Antibiotics are chosen based on the likely causative microorganism according to the clinical presentation and history. Viral pneumonia is usually treated with supportive therapy alone; however, antiviral medication may be needed in severe cases. Infections with opportunistic microorganisms may be polymicrobial (many species of microorganism) and require multiple drugs, including antifungals. Adequate hydration and good pulmonary hygiene (e.g. deep breathing, coughing, chest physiotherapy) are important aspects of treatment for all types of pneumonia.

Tuberculosis Tuberculosis, commonly abbreviated to TB, is an infection caused by Mycobacterium tuberculosis, a bacterium that usually affects the lungs but may invade other body systems. Worldwide, tuberculosis is the leading cause of death from a curable infectious disease and was responsible for an estimated 1.8 million deaths in 2015.45 There are new cases of tuberculosis each year in Australia and New Zealand although the rates are very low compared with other developed countries. In 2012 there were 1317 cases of TB reported in Australia; these data represent a rate of 5.8 cases for every 100 000 people. Alarmingly the incidence rates of TB among the Indigenous population was five times that of the non-Indigenous Australian-born population in 2012 and 2013.45

PAT H O P HYS I O LO G Y Tuberculosis (TB) is transmitted from person to person in airborne droplets. Microorganisms lodge in the lung periphery, usually in the upper lobe. Once the bacteria are inspired into the lung, they multiply and cause lung inflammation. Some bacteria migrate through the lymphatics and become lodged in the lymph nodes, where they encounter lymphocytes that initiate the immune response. The infection can either be active or latent.

Inflammation in the lung causes activation of alveolar macrophages and neutrophils. These cells engulf the bacteria and begin the process by which the body’s defence mechanisms isolate and prevent their spread. The neutrophils and macrophages seal off the colonies of bacteria, forming granulomatous lesions called tubercles. Infected tissues within the tubercles die, forming cheese-like material that is necrotic (see Fig. 25.21).46 Scar tissue then grows around the tubercles, completing isolation of the bacteria. The immune response is complete after about 10 days, preventing further spread of the bacteria.

Once immunity develops, tuberculosis may remain dormant for life.46 If the immune system is impaired or if live bacteria escape into the bronchi, active disease occurs

cellular infiltration and immune activation. These inflammatory mediators and immune complexes can damage bronchial mucous membranes and alveolar–capillary membranes, causing the alveoli and terminal bronchioles to fill with infectious debris and exudate (fluid moving into a site of inflammation). In addition, some microorganisms release toxins from their cell walls that can cause further lung damage. The accumulation of exudate in the alveoli leads to dyspnoea, ventilation–perfusion mismatching and hypoxaemia.

There are many viruses that can cause pneumonia, including influenza virus, respiratory syncytial virus, adenoviruses and parainfluenza virus. Viral pneumonia is the primary cause of pneumonia in children and older adults. Although viral pneumonia can be severe, it is usually mild and self-limiting. However, it can set the stage for a secondary bacterial infection by providing an ideal environment for bacterial growth and by damaging ciliated epithelial cells, which normally prevent pathogens from reaching the lower airways. Viral pneumonia can be a primary infection or a complication of another viral illness, such as chickenpox or measles (spread from the blood). The virus not only destroys the ciliated epithelial cells but also invades the goblet cells and bronchial mucous glands. Sloughing of destroyed bronchial epithelium occurs throughout the respiratory tract, preventing mucociliary clearance. Bronchial walls become oedematous and infiltrated with leucocytes. In severe cases, the alveoli are involved, with decreased compliance and increased work of breathing.

C L I N I C A L MA N I F E S TAT I O N S Many cases of pneumonia are preceded by an upper respiratory infection, which is often viral. Individuals then develop fever, chills, productive or dry cough, malaise, pleural pain and sometimes dyspnoea and haemoptysis (blood in the sputum). Physical examination may reveal signs of pulmonary consolidation, such as dullness to percussion (creation of vibrations, typically by tapping the chest) and inspiratory crackles. Individuals may also demonstrate symptoms and signs of underlying systemic disease or sepsis.

E VA LUAT I O N A N D T R E AT M E N T Diagnosis is made on the basis of the physical examination, white blood cell count, chest x-ray, stains and cultures of respiratory secretions, and blood cultures. The white blood cell count is usually elevated, although it may be low if the individual is debilitated or immunocompromised. Chest x-rays show infiltrates that may involve a single lobe of the lung or may be more diffuse (see Fig. 25.20). Once the diagnosis of pneumonia has been made, the pathogen is identified by means of sputum characteristics (gram stain; see Chapter 14 for details) and cultures or, if sputum is absent, blood cultures. Because many pathogens exist in the normal oropharyngeal flora, the specimen may be contaminated with pathogens from oral secretions. If sputum studies fail to identify the pathogen, the individual is immunocompromised or the individual’s condition worsens,

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 735

recommendations of the Australian National Tuberculosis Advisory Committee are that tuberculin skin testing be used as the standard test for latent tuberculosis infection, with targeted use of interferon gamma release assays (Quantiferon Gold) when high specificity is desired.47 When an individual becomes infected with the pathogenic bacteria, Mycobacterium tuberculosis, the bacterial antigen is recognised by the immune system and T cells are sensitised. The T cells then release the cytokine, interferon gamma, which stimulates macrophages to phagocytose bacteria (see Chapter 13 for more details on immune responses).

Treatment consists of antibiotic therapy to control active or latent tuberculosis infection and prevent transmission. Today, with the increased numbers of immunosuppressed individuals and drug-resistant bacteria, treatment is never single drug therapy as resistance appears rapidly; the recommended treatment includes a combination of drugs to which the organism is susceptible, including isoniazid, rifampin, pyrazinamide and ethambutol. Combination therapy is usually continued for 6 months.

and may spread through the blood and lymphatics to other organs.

C L I N I C A L MA N I F E S TAT I O N S In people with active infection the most common clinical features of tuberculosis include chronic cough, sputum production, loss of appetite, weight loss, fever, night sweats, chest pain and haemoptysis. Individuals with latent infection are usually asymptomatic; however, they remain at risk of reactivation of tuberculosis in their lifetime.

E VA LUAT I O N A N D T R E AT M E N T Tuberculosis is usually diagnosed by a positive tuberculin skin test, sputum culture and chest x-rays. However, due to the high rate of false positives with the tuberculin skin test (meaning that the test reveals a positive tuberculosis result when the disease is not present), newer diagnostic tests have been developed. One such test, the interferon gamma release assay, measures interferon gamma that has been released from T cells of the immune system. The

Bronchopneumonia

Lobar pneumonia

FIGURE 25.20

Bacterial pneumonia seen in gross lung, chest x-ray and illustration. A Lobar pneumonia occurs when bacterial infection occurs in a portion of the lobe or the entire lobe. B Bronchopneumonia with patchy consolidation throughout the lung.

736 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

of the airways is usually caused by viruses, whereas the chronic airway inflammation is mainly caused by smoking. Acute bronchitis is likely to lead to a full recovery once the inflammation is resolved, whereas chronic bronchitis is irreversible. Many clinical manifestations of acute bronchitis are similar to those of pneumonia (fever, cough, chills and malaise — a general feeling of being unwell), but chest x-rays show no infiltrates. Individuals with viral bronchitis present with a non-productive cough that often occurs in paroxysms (sudden fits of coughing) and is aggravated by cold, dry or dusty air. In some cases, purulent sputum is produced. Chest pain often develops from the effort of coughing. Treatment consists of rest, aspirin, humidity and a cough suppressant, such as codeine.51

Bacterial bronchitis is rare in previously healthy adults except after viral infection but is common in patients with COPD. Although individuals with bronchitis do not have signs of pulmonary consolidation on physical examination (e.g. crackles), many will require chest x-ray evaluation to exclude the diagnosis of pneumonia. Bacterial bronchitis is treated with rest, antipyretics (fever-reducing drugs) and antibiotics.

Influenza Influenza is a common respiratory viral infection that affects millions of people worldwide.1 The influenza virus can infect all age groups. There are a number of groups that are at a higher risk of influenza including the elderly; adults and children (aged 6 months and over) with chronic disorders of the pulmonary or circulatory systems, and nursing home and long-term-care residents. The virus can rapidly spread worldwide and has a seasonal variation that affects Australia and New Zealand predominately from June to September.44,52

PAT H O P HYS I O LO G Y There are three main strains of influenza virus: type A, type B and type C. All three can cause influenza in humans, but type A is the most prevalent and is responsible for the yearly influenza known as ‘seasonal flu’. Type A has many different subtypes, which are classified using the letters ‘H’ and ‘N’, denoting two different surface proteins. For example, the most common virus causing infection in humans is type A (H1N1), which itself has many different subtypes. However, the virus can change — called antigenic drift, which means that mutations occur in the virus antigen such that the body’s antibodies cannot recognise the virus and hence it represents a new primary immune response. This is the primary reason why ‘new’ types of flu circulate each year. Antigenic drift has led to major pandemics that have resulted in massive mortality worldwide. Alarmingly, type A affects not only humans, but also horses, pigs, birds and aquatic birds. Avian and swine type A influenza have infected humans, and human-to-human transmission has occurred, leading to pandemics.

The influenza virus enters the upper airways from airborne secretions of an infected individual. If the virus is

In the past, individuals with active tuberculosis were isolated from the community. Today, individuals remain at home or, rarely, in hospital, until sputum cultures show that the active disease has been eliminated. Directly observed therapy short courses (DOTS) has been integral in the control of tuberculosis worldwide.48 DOTS involves five elements: political commitment; microscopy services; drug supplies; surveillance and monitoring systems and use of highly efficacious regimens; and direct observation of treatment.49 Building on this the World Health Organization has developed the END TB Strategy which aims to end the global tuberculosis epidemic.50

Acute bronchitis Acute bronchitis is an acute infection or inflammation of the airways or bronchi and is usually self-limiting. In the vast majority of cases, it is caused by viruses.51 It differs from chronic bronchitis of COPD, in that acute inflammation

FIGURE 25.21

Tuberculosis in the lung. The grey-white areas represent the lesions formed from the bacteria.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 737

not immobilised by the inflammatory and immune systems, it invades the respiratory tract lining and proliferates. The triggered inflammatory mediators cause mucosal hyperaemia (redness to the mucosal lining), upper airway oedema and excess mucous secretion. The incubation period (until the appearance of symptoms) is up to 72 hours.

C L I N I C A L MA N I F E S TAT I O N S The classic signs and symptoms of cough and fever are usually indicative of influenza infection. They are often accompanied by generalised myalgia (muscle pain), headache and sore throat. The onset of the illness is abrupt and usually lasts between 3 and 5 days. Influenza infections can invade the lower respiratory tract and cause pneumonia, especially in children, the elderly and immunocompromised individuals (see Fig. 25.22).

E VA LUAT I O N A N D T R E AT M E N T Diagnosis of influenza is often difficult because of the rapid onset and relatively short duration. In addition, it is often hard to obtain isolation of the virus in specimens. The most effective treatment is prevention. Handwashing combined with pulmonary hygiene lowers the risk of acquiring the virus. In Australia and New Zealand, influenza vaccines are available for those at higher risk of attaining the virus, such as healthcare workers, those with chronic illnesses, infants and the elderly.

FIGURE 25.22

Chest x-ray changes in a patient with influenza pneumonia. The primary chest x-ray changes include small multifocal, patchy consolidations throughout both lungs, predominantly in the bases.

P A

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R IC

Paediatrics and pulmonary infections Respiratory infections are common in children and are a frequent cause of hospitalisations. Clinical presentation, the age of the child and the season of the year can often provide clues to the type of microorganism, even when the agent cannot be proven.

Bronchiolitis Bronchiolitis is a rather common, viral-induced lower respiratory tract infection that occurs almost exclusively in infants and young toddlers. It has a seasonal, yearly incidence (May–October) and is the leading cause of hospitalisations for infants during the winter season. The most common associated pathogen is respiratory syncytial virus, which accounts for 50–80% of hospitalisations,53 but it may also be associated with human rhinovirus, adenoviruses, influenza, parainfluenza and mycoplasma. Healthy infants usually make a full recovery from respiratory syncytial virus bronchiolitis, but infants who were born premature with a birth weight of less than 2500 grams have a much higher risk for a more severe or even fatal course.

PATHOPHYSIOLOGY Viral infection causes necrosis of the bronchial epithelium and destruction of ciliated epithelial cells. There is infiltration with lymphocytes around the bronchioles and a cell-mediated hypersensitivity to viral antigens with release of lymphokines causing inflammation, as well as activation of eosinophils, neutrophils and monocytes. The submucosa becomes oedematous and cellular debris and fibrin form plugs within the bronchioles. Oedema of the bronchiolar wall, accumulation of mucus and cellular debris and, perhaps, bronchospasm narrow many peripheral airways. Other airways become partially or completely occluded. Atelectasis (collapse of lung tissue) occurs in some areas of the lungs and hyperinflation in others. There is air trapping and functional residual capacity is greatly increased. Compliance is decreased because the lungs are already highly inflated and because airway resistance within the lungs is uneven and increased. The decrease in compliance and the increase in airway resistance result in a substantial

Continued

738 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

Australia, lung cancer incidence and mortality in females is projected to rise, while the rates for males are in decline.

The most common cause of lung cancer is cigarette smoking, being linked to approximately 70% of cases in females and 90% in men. It has been shown that the number of cigarettes that people smoke and the number of years they smoke are directly related to the risk of developing lung cancer. There is an increased risk of developing lung cancer with advancing age, with a three times greater risk in people aged 65 years and older compared with their younger counterparts. This is evidenced by the fact that only 1% of lung cancers occur in people less than 40 years of age.56 In addition, second-hand (passive or environmental) smoke exposure is also a risk for lung cancer, so an individual exposed to the smoke from someone else’s cigarettes also has this increased risk. Smokers with obstructive airway disease (low FEV1) are at even greater risk. Genetic predisposition to developing lung cancer also plays a role in the pathophysiology. Other risk factors include occupational exposure to certain workplace toxins, radiation, air pollution and tuberculosis.

Types of lung cancer Primary lung cancers arise from the bronchi within the lungs and are therefore called bronchogenic carcinomas. Although there are many types of lung cancer, lung cancer is divided into two major categories: non-small cell carcinoma (75–85% of all lung cancers) and small cell carcinoma (15–25% of all lung cancers). The category non-small cell carcinoma can be subdivided into three

Lung cancer Lung cancer arises from the epithelium of the respiratory tract. Therefore, the term lung cancer excludes other pulmonary tumours such as sarcomas, lymphomas, blastomas, haematomas and mesotheliomas.

In 2010 more than 8000 people died from lung cancer in Australia.56 Of all the cancers, lung cancer is the leading cause of death in Australia.56 Since 2006 the number of lung cancer-related deaths has exceeded breast cancer, and while there has been a decline in mortality from most cancers between 1991 and 2010 the mortality rate from lung cancer in the female population has continued to rise.56 The incidence and mortality rates of lung cancer in the Indigenous population are approximately double those of the non-Indigenous population. Concomitantly, smoking rates in the Indigenous population are also greater.56

In New Zealand, lung cancer is the most common cause of cancer death for both males and females.57 Similarly in

increase in the work of breathing. Serious alterations in gas exchange occur because of airway obstruction and patchy atelectasis. Hypoxaemia develops because of ventilation–perfusion mismatch and hypercapnia may occur in severe cases. It has been suggested that children with acquired bronchiolitis may later develop asthma, but the relationship between these two respiratory disorders is unclear.

CLINICAL MANIFESTATIONS Symptoms usually begin with significant rhinorrhoea (runny nose) followed by a tight cough over the next few days, along with systemic signs of poor feeding, lethargy and fever. Infants typically have tachypnoea (increased ventilatory rate), variable degrees of respiratory distress and abnormal auscultatory findings of the chest. Wheezing is most common.

EVALUATION AND TREATMENT Diagnosis of bronchiolitis is made by a review of the signs and symptoms (e.g. rhinitis, cough, wheezing, chest retractions, tachypnoea) and chest x-ray findings.

Treatment is determined by the severity of the disease and the age of the child. Most cases are mild and usually require no specific treatment. Preventive treatment using pulmonary and hand hygiene combined with decreased exposure to people in the susceptible months decreases the risk of infection. Respiratory syncytial virus antibody is recommended for high-risk infants under 2 years old.54

Pertussis Pertussis is caused by the bacterium Bordetella pertussis. The symptoms are thick secretions, a chronic cough and spasm following coughing fits, which give a characteristic ‘whoop’ sound — hence the commonly used name ‘whooping cough’. The infection has an incubation period of 7–10 days and is highly contagious, but vaccination can prevent the infection. However, despite the availability of a vaccine, Australia and New Zealand experience periodic outbreaks of pertussis, with 11 863 cases reported in Australia in 2014.55 Pertussis is particularly lethal in newborns and infants who are too young to have received two or more doses of the vaccine (see Chapter 14 for immunisation schedules).

F O C U S O N L E A R N I N G

1 Differentiate between different pneumonias.

2 Discuss the effects of tuberculosis on pulmonary structures.

3 Discuss why influenza virus is virulent and can lead to pandemics.

4 Describe the typical presentation of respiratory syncytial virus bronchiolitis.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 739

non-productive cough or haemoptysis (which is the coughing up of blood in the sputum; see ‘Clinical manifestations of pulmonary alterations’ below). Pneumonia and atelectasis are often associated with squamous cell carcinoma. Chest pain is a late symptom associated with large tumours. These tumours can remain fairly well localised and tend not to metastasise until late in the course of the disease. The preferred treatment is surgical resection, although once metastasis (spread away from the original site) has taken place, total surgical resection is more difficult and survival rates decrease dramatically.58 Radiation therapy and chemotherapy improve outcomes in many individuals.

Adenocarcinoma (meaning that the tumour arises from the glands) constitutes 35–40% of all bronchogenic carcinomas (see Fig. 25.24). The increase in incidence of adenocarcinoma has been ascribed to the increasing occurrence of lung cancer in females, environmental and occupational carcinogens, and changes in the histological criteria for diagnosis. These tumours, which are usually smaller than 4 cm, more commonly arise in the peripheral regions of the lung tissue. They may be asymptomatic and discovered by routine chest x-ray in the early stages or the individual may present with pleuritic chest pain and shortness of breath from pleural involvement by the tumour. Surgical resection is possible in a high proportion of cases, but because metastasis occurs early, the 5-year survival rate is low.

Large cell carcinomas constitute 10–15% of bronchogenic carcinomas (see Fig. 25.25). This cell type has lost all evidence of differentiation and therefore is sometimes referred to as undifferentiated large cell anaplastic cancer (literally meaning that the cells revert back to an immature form). Because large cell carcinomas show none of the histological findings of squamous cell carcinoma or

common types of lung cancer: squamous cell carcinoma, adenocarcinoma and large cell carcinoma. Characteristics of these tumours, including the clinical manifestations, are listed in Table 25.5. Many cancers that arise in other organs of the body metastasise to the lungs; however, these are not considered as lung cancers and are categorised by their primary site of origin.

Non-small cell carcinoma Squamous cell carcinoma accounts for about 30% of bronchogenic carcinomas. These tumours are typically located near the hilum and project into the bronchi (see Fig. 25.23). Because of the location in the central bronchi, obstructive manifestations are nonspecific and include

TABLE 25.5 Characteristics of lung cancers

TUMOUR TYPE GROWTH RATE METASTASIS DIAGNOSIS CLINICAL MANIFESTATIONS

Non-small cell carcinoma Squamous cell carcinoma

Slow Late; mostly to hilar lymph nodes

Biopsy, sputum analysis, bronchoscopy, electron microscopy

Cough, haemoptysis, sputum production, airway obstruction, hypercalcaemia

Adenocarcinoma Moderate Early; to lymph nodes, pleura, bone, adrenal glands and brain

Radiography, fibreoptic bronchoscopy, electron microscopy

Pleural effusion

Large cell carcinoma

Rapid Early and widespread Sputum analysis, bronchoscopy, electron microscopy (by exclusion of other cell types)

Chest wall pain, pleural effusion, cough, sputum production, haemoptysis, airway obstruction resulting in pneumonia

Small cell carcinoma Very rapid Very early; to

mediastinum, lymph nodes, brain, bone marrow

Radiography, sputum analysis, bronchoscopy, electron microscopy

Cough, chest pain, dyspnoea, haemoptysis, localised wheezing, airway obstruction, signs and symptoms of excessive hormone secretion

FIGURE 25.23

Squamous cell carcinoma. A Normal carina and bronchi of left upper lobe. B Carina of left lower lobe with swollen mucosa (thin dark line showing extent of swelling), white lesion (squamous cell cancer, bottom arrow) and haemorrhage on upper surface (top arrow).

740 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

FIGURE 25.25

Large cell carcinoma. A Gross lung with a large white-grey mass on lower right margin. B Chest x-ray of a large cell carcinoma in the right lower lobe (red arrow).

FIGURE 25.24

Adenocarcinoma. This gross lung lobe has a large white mass (carcinoma). The cancers are predominately on the peripheral aspects of the lung, not in the large airways.

adenocarcinoma, they are diagnosed by a process of exclusion. The cells are large and contain darkly stained nuclei. These tumours commonly arise centrally and can grow to distort the trachea and cause widening of the carina, which can result in breathing difficulties. Once metastasis has occurred, surgical therapy is limited to palliative procedures — meaning that care is for comfort only, as the individual cannot be cured.

Small cell carcinoma Small cell carcinomas constitute 15–20% of bronchogenic carcinomas. Most of these tumours are central in origin (see Fig. 25.26). This cell type has the strongest correlation with cigarette smoking. Because these tumours show a rapid rate of growth and tend to metastasise early and widely, small cell carcinomas have the worst prognosis. Survival time for untreated small cell carcinoma is usually only 1–3 months. Approximately only 14% of treated individuals are alive 2 years after diagnosis.

Small cell carcinoma is most often associated with ectopic hormone production, meaning that hormones are produced in tissues, in this case cancerous lung tissue, away from the usual glands. Neuroendocrine cells containing neurosecretory granules exist throughout the tracheobronchial tree and may be associated with small cell carcinoma. Ectopic hormone production is important to the clinician because resulting signs and symptoms may be the first manifestation

of the underlying cancer. Small cell carcinomas most commonly produce antidiuretic hormone from associated neuroendocrine cells and develop the syndrome of inappropriate antidiuretic hormone secretion. Individuals with lung cancer secrete large quantities of steroids, leading to the development of an atypical Cushing’s syndrome (see Chapter 11).

Signs and symptoms related to this condition include muscular weakness, facial oedema, hypokalaemia, alkalosis, hyperglycaemia, hypertension and increased pigmentation. Treatment of small cell carcinoma is usually palliative. More than 85% of tumours will have metastasised by the time of diagnosis. Chemotherapy and radiation can significantly prolong life and relieve symptoms, but relapse is inevitable in most individuals.59

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 741

cell type, and the evaluation of lymph nodes and other organ systems is used to determine the stage of the cancer. The histological cell type and the stage of the disease are the major factors that influence the choice of therapy. The current accepted system for the staging of non-small cell carcinoma is the TNM classification. This system is a code in which T denotes the extent of the primary tumour, N indicates the lymph node involvement and M describes the extent of metastasis. Small cell carcinoma is so rapidly progressive that its staging system consists of only two stages: limited and extensive disease.

The only proven way of reducing the risk for lung cancer is the cessation of smoking. To date, trials evaluating the use of various early screening modalities such as chest x-ray and CT scanning have not resulted in a decrease in lung cancer mortality.61 The management of lung cancer has been outlined here under each cell type, but it is generally chosen on the basis of tumour stage and patient functional status. Current modalities include combinations of surgical resection, chemotherapy and radiation; however, new genetic and immunological therapies are being explored (see ‘Research in Focus: Genetic and immunological therapies for lung cancer’).

PAT H O P HYS I O LO G Y Tobacco smoke contains more than 30 carcinogens and is responsible for causing 80–90% of lung cancers. These carcinogens result in multiple genetic abnormalities in bronchial cells including deletions of chromosomes, activation of oncogenes and inactivation of tumour suppressor genes. The most common genetic abnormality associated with lung cancer is loss of the tumour suppressor gene p53; mutations in this gene have been found in 50–60% of non-small cell carcinomas and 90% of small cell carcinomas.60 Once lung cancer is initiated by these carcinogen-induced mutations, further tumour development is promoted by growth factors. Further cellular toxicity is enhanced through smoke-induced toxic free radical production.

The bronchial mucosa suffers multiple carcinogenic ‘hits’ due to repetitive exposure to cigarette smoke and eventually epithelial cell changes begin to be visible on biopsy. These changes progress from metaplasia (changing from one cell type to another cell type) to carcinoma in situ and finally to invasive carcinoma. Further tumour progression includes invasion of surrounding tissues and finally metastasis to distant sites including the brain, bone marrow and liver.

C L I N I C A L MA N I F E S TAT I O N S There are many different signs and symptoms in individuals with lung cancer. It is somewhat dependent on the location of the cancer in the pulmonary system as to what clinical manifestations will arise. Table 25.5 summarises the characteristic clinical manifestations according to tumour type. By the time there are manifestations severe enough for the individual to notice them, the disease is usually advanced.

E VA LUAT I O N A N D T R E AT M E N T Diagnostic tests for the evaluation of lung cancer include chest x-ray, sputum cytology, chest-computed tomography, fibreoptic bronchoscopy and biopsy. Biopsy determines the

FIGURE 25.26

Small cell carcinoma. The cancer can be seen as the white growths.

R E S E A R C H I N F C U S Genetic and immunological therapies for lung cancer Although new chemotherapeutic agents have slightly improved outcomes in the management of lung cancer, overall survival rates remain poor and the toxicities of these regimens limit their use. New understandings of the genetic and immunological features of lung cancer cells have led to new treatments. Gene therapy is emerging as a way of restoring normal tumour suppressor gene function and increasing tumour responsiveness to chemotherapy and radiation therapy. Immunological therapies include antibodies to growth factor receptors and anti-angiogenesis drugs (those that prevent the growth of new blood vessels from the tumour). The effectiveness of these strategies is still being evaluated, but new knowledge is leading to new opportunities for treatment.

F O C U S O N L E A R N I N G

1 Describe the incidence and mortality of lung cancer and the differences between the sexes.

2 Discuss the pathological differences between non-small cell carcinoma and small cell carcinoma.

742 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

PAT H O P HYS I O LO G Y Anatomical and structural factors in the upper airway play a crucial role in the development of obstructive sleep apnoea. The tonsils, adenoids, tongue and soft tissue that surround the pharynx become enlarged, reducing the lumen (airway size). This is more pronounced in obese individuals who have a large neck circumference. Collectively, these factors predispose the individual to upper airway collapse during sleep.69 In children, the most pathophysiological reason for obstructive sleep apnoea is due to adenotonsillar hypertrophy; however, rates of childhood obesity are also likely to contribute to the rates of childhood sleep apnoea.

When obstructive sleep apnoea is present, the pharyngeal tissue completely obstructs the airway, preventing ventilation. This causes a cycle of obstructive breathing during sleep when the airway repeatedly collapses, and this periodic breathing eventually produces arousal, which interrupts the sleep cycle, reducing total sleep time and producing sleep deprivation.69 The often sustained and repeated apnoeic periods result in hypoxaemia (inadequate oxygen levels in the blood), which, it has been proposed, influences neural control of the upper airway. Hypoxaemia is more pronounced during periods of rapid eye movement (REM) sleep. The reason for this is unknown, but it may explain the tiredness and insomnia reported by individuals with obstructive sleep apnoea.

Sleep apnoea produces low oxygen saturation (see Fig. 25.27) and eventually leads to polycythaemia (a blood

Obstructive sleep apnoea Obstructive sleep apnoea generally results from upper airway obstruction recurring during sleep, with excessive snoring and multiple apnoeic episodes (periods were there is no breathing) that last at least 10 seconds but can last up to 60 seconds or more. Approximately 9–25% of the middle-aged population in Australia have obstructive sleep apnoea,62 and the prevalence in older people is likely to be higher as sleep complaints and disorders are more common in the elderley.63 In New Zealand, the prevalence of obstructive sleep apnoea has been estimated at 4.1% for males and 0.7% for females.64 Within Indigenous populations, the prevalence is higher for both males and females. Childhood obstructive sleep apnoea is also quite common, with an estimated prevalence of 1–10%.65 In children, unlike in adults, obstructive sleep apnoea occurs equally among girls and boys.

There is an increased risk of death from cardiovascular disease associated with obstructive sleep apnoea.66 The exact reason for this is unknown; however, the repeated episodes of hypoxia related to apnoea during sleep are likely to impact on the cardiovascular system. It has also been shown that obstructive sleep apnoea is an independent risk factor for increased mortality from any cause.67 Other deleterious consequences of obstructive sleep apnoea include unrefreshing sleep, excessive daytime sleepiness and neurocognitive impairment.68

100

Sp O

2 ( %

)

100

Sp O

2 ( %

)

11:00 pm 1 am 3 am 4 am 5 am 6 am2 am Time (clock)

12 Midnight

FIGURE 25.27

Oxygen saturation levels during sleep apnoea. Oxygen saturation (SpO2) levels during sleep in A a healthy individual, and B an individual with severe obstructive sleep apnoea. In the healthy individual, oxygen saturation remains close to 100%. With the individual with sleep apnoea, the large reductions in oxygen saturation during sleep are due to the repeated apnoea episodes.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 743

and alcohol consumption.69 The most accurate diagnosis of obstructive sleep apnoea is an overnight polysomnogram, also known as a sleep study.70 This test records brain activity (electroencephalogram), eye movement, muscle activity (electromyogram), heart rate, air flow and oxygen haemoglobin (SpO2) levels during sleep and collectively allows classification of the amount and duration of apnoeic periods, thereby permitting diagnosis of obstructive sleep apnoea.

Treatments include nasal continuous positive airway pressure (CPAP) and dental devices, upper airway and jaw surgery in selected individuals, and management of obesity.70 In children, if obstructive sleep apnoea is documented or strongly suspected clinically, tonsillectomy and adenoidectomy are the treatments of choice. For severely affected children who do not respond to surgery or who have different problems, such as obesity, that cannot be remedied rapidly, CPAP, similar to adult management, may be required.

disorder causing excessive red cell production), pulmonary hypertension, right-sided heart failure, liver congestion, cyanosis and peripheral oedema. Systemic hypertension may result from repeated episodes of apnoea and hypoxaemia.

C L I N I C A L MA N I F E S TAT I O N S Due to obstruction of the upper airway, snoring is the most common manifestation. There may be periods of increased ventilatory effort without an audible airflow. During the apnoeic periods, breathing can cease for 10 seconds up to 1 minute and these episodes can occur repeatedly throughout sleep.70 Therefore, sleep is often restless, and there is daytime tiredness and sleepiness. This chronic tiredness impacts on daytime cognitive and neurobehavioural performance. For instance, obstructive sleep apnoea has been associated with an increased mortality from traffic accidents.69 Cardiac arrhythmias during sleep apnoea are common, such as sinus pauses (temporary cessation of sinus node activity) and premature ventricular contractions.71 In children, bedwetting and chronic mouth breathing are associated with obstructive sleep apnoea.

E VA LUAT I O N A N D T R E AT M E N T There usually is a history of snoring and laboured breathing during sleep, which may be continuous or intermittent in individuals with obstructive sleep apnoea. Associated risk factors include advancing age, obesity, gender (males are more affected than females), genetic predisposition, smoking

F O C U S O N L E A R N I N G

1 Describe the signs and symptoms suggestive of obstructive sleep apnoea in children and adults.

2 Discuss the effect of sleep apnoea on daytime activities.

P A

E D

IA T

R IC

Paediatrics and pulmonary disorders There are some important childhood pulmonary disorders that need to be explored. In this section we examine some of the major childhood disorders, starting with croup. Croup Classic croup is an acute inflammation of the upper airways and almost always occurs in children between 3 months and 5 years of age.72 In 85% of cases, croup is caused by a virus, most commonly parainfluenza and in other instances by influenza A or respiratory syncytial virus, however bacteria and atypical agents have also been identified.72 The incidence of croup is higher in males and is most common during the winter months. PATHOPHYSIOLOGY Airway obstruction occurs in the subglottic region of the trachea, just below the vocal cords. Contributory factors include mucosal oedema and secretions related to the viral infection. Anatomically, the subglottic region is slightly narrower than the rest of the trachea and in children the subglottic mucous membrane is more loosely attached and more vascular than in adults. These factors make the airway susceptible to compromise in children.

If there is significant narrowing of the airway in this area, work of breathing will increase and the excessive negative pressure generated may even cause the airway structures higher up to collapse with inspiration (see Fig. 25.28). The turbulent flow across this obstruction will cause stridor (an abnormal, harsh, high-pitched sound caused by turbulent flow in a partially obstructed upper airway) on inspiration and sometimes also on expiration (see Fig. 25.29). Croup tends to affect younger children more prominently because they have smaller airways that are therefore compromised more easily (see Fig. 25.30). CLINICAL MANIFESTATIONS Typically, the child experiences rhinorrhoea, sore throat and low-grade fever for a few days, then develops a seal- like barking cough. Most cases resolve spontaneously within 24–48 hours and do not warrant hospitalisation. However, the presence of inspiratory stridor or respiratory distress suggests a more severe situation. EVALUATION AND TREATMENT The degree of symptoms determines the level of treatment. Treatment may include injected, oral or nebulised

Continued

744 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

glucocorticoids to reduce the inflammation. The presence of stridor at rest, moderate or severe retractions of the chest or agitation suggests more severe disease and requires hospitalisation for observation and treatment. Severe obstruction requires emergency care to protect the airway. Respiratory distress syndrome of the newborn The name respiratory distress syndrome of the newborn refers to a lung disorder that remains a significant cause of neonatal morbidity and mortality.73 It occurs almost exclusively in premature infants. Respiratory distress syndrome occurs in 60% of infants born at less than 28 weeks gestation, in 30% of those born at 28–34 weeks and in fewer than 5% of those born after 34 weeks. The incidence and death rates have declined significantly since the introduction of antenatal steroid therapy and postnatal surfactant therapy.74 Risk factors include premature birth, caesarean delivery without labour, gender (male), diabetic mother and perinatal asphyxia.

PATHOPHYSIOLOGY Respiratory distress syndrome is caused by surfactant deficiency and also a deficiency in alveolar surface area for gas exchange. Surfactant is the material that lines the

Epiglottis

False cords True cords Subglottic

tissue Trachea

A B

FIGURE 25.30

The larynx and subglottic trachea. A Normal. B Narrowing and obstruction from oedema caused by croup.

Snoring zone

Inspiratory stridor zone

Voice quality zone

Cough quality zone Expiratory

stridor zone

FIGURE 25.29

Respiratory sounds and their anatomical location. Alterations in respiratory sounds inform about the airways in those respective anatomical locations.

C O

N C

E P

T M

A P Microorganism enters upper airway

In�ammatory response

in upper airway In�ammation and oedema

Upper airway obstruction

Resistance to air �ow

Increased intrathoracic negative pressure

Collapse of upper airway

if swelling enough causes

initiates

causes

increases

results in

causes

FIGURE 25.28

The formation of upper airway obstruction with croup. Entry of the microorganisms causes upper airway inflammation, leading to airway obstruction and collapse.

alveoli and is required for maintaining their inflation. Without surfactant, which lowers surface tension, alveoli would tend to collapse at the end of each exhalation. Surfactant is not normally secreted by the alveolar cells until approximately 30 weeks gestation. In addition to the functional surfactant deficiency of the premature

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 745

Continued

lung, structural immaturity is a problem. Premature infants are born with many underdeveloped and small alveoli that are difficult to inflate. In the most extreme premature infants, the ‘alveoli’ have thick walls and inadequate capillary blood supply such that gas exchange is significantly impaired. In addition, the chest wall is weak and highly compliant and the rib cage tends to collapse inwards with ventilatory effort. The net effect of all these adverse factors is atelectasis (collapsed alveoli), which is difficult for the neonate to overcome because

it requires a significant negative inspiratory pressure to open the alveoli with each breath. The infant uses more oxygen to sustain the work of breathing and becomes hypoxaemic and hypercapnic (low blood oxygen and high carbon dioxide, respectively). Hypoxia and atelectasis cause pulmonary vasoconstriction and increase intrapulmonary resistance. This results in hypoperfusion of the lung and a decrease in effective pulmonary blood flow. The pathogenesis of respiratory distress syndrome is summarised in Fig. 25.31.

C O

N C

E P

T M A

Premature birth

presents with

results

leads to

leads to leads to

leads to

leads to develops

causes

manifest as

results in

causescontributes to

causes

causes worsens

Immature alveoli

Atelectasis

Respiratory failure

Increased pulmonary vascular resistance

Inactivation of surfactant

Protein leak into airspaces

Hypoxaemia

Pulmonary hypoperfusion

Hypoxic vasoconstriction

Ventilation-perfusion mismatch

Respiratory acidosis

Hypercapnia

Inadequate alveolar ventilation

Decreased expansion of alveoli

Decreased surfactant production

Decreased number of alveoli

Metabolic acidosis

Impaired cellular metabolism

Poor lung compliance

FIGURE 25.31

The pathogenesis of respiratory distress syndrome of the newborn. Premature birth leads to insufficient production of surfactant, poor lung compliance, insufficient number of alveoli and immature alveoli. Together, these lead to a complex series of events including lung collapse (atelectasis), hypoxaemia and respiratory failure.

746 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

CLINICAL MANIFESTATIONS Signs of respiratory distress syndrome appear within minutes of birth. Some neonates require immediate resuscitation because of asphyxia or severe respiratory distress. Characteristic signs are tachypnoea (respiratory rate over 60 breaths per minute), expiratory grunting, intercostal and subcostal retractions, nasal flaring and pale colour. The natural course is characterised by progressive hypoxaemia and dyspnoea. Apnoea and irregular respirations occur as the infant becomes fatigued from the difficulty of breathing. The typical chest x-ray shows diffuse, fine granular densities within the first 6 hours of life. In most cases the clinical manifestations reach a peak within 3 days, after which there is gradual improvement. EVALUATION AND TREATMENT Diagnosis is made on the basis of prematurity or other risk factors and chest x-rays. The ultimate treatment for respiratory distress syndrome would be prevention of premature birth; however, this is not always possible and often not foreseeable. Antenatal treatments with glucocorticoids are given to women at 24–34 weeks gestation for those at risk of premature delivery, and in preterm labour, unless delivery is imminent. Glucocorticoids induce a significant and rapid acceleration of lung maturation and there is extensive evidence that maternal steroid therapy significantly reduces the incidence of respiratory distress syndrome and death.75 Surfactant therapy should be considered complementary to antenatal corticosteroids. Supportive care includes oxygen and often continuous positive airway pressure or mechanical ventilation. Most infants survive respiratory distress syndrome with treatment. In many cases, recovery may be complete within 10–14 days. However, the incidence of subsequent chronic lung disease is significant among very low birth weight infants. Sudden infant death syndrome Sudden infant death syndrome (SIDS) remains a disease of unknown cause.76 It is defined as ‘sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene and review of the clinical history’.77

The incidence of SIDS is low during the first month of life but sharply increases in the second month and peaks at 3–4 months of age, then gradually declines.76 It is more common in males (60%) than females (40%). It almost always seems to occur during night-time sleep, when infants are least likely to be observed. A seasonal variation has been noted, with higher frequencies during the winter months. This has been related to a higher rate of respiratory tract infections during these months and, in fact, such infections are often reported to have preceded the death. Clinical risk groups include babies who were preterm or low birth weight, who were one of simultaneous multiple births and who had siblings die of SIDS. Nevertheless, about three-quarters of all SIDS cases have no known predisposing clinical risk factor. Additional risk factors fall into the categories of socioeconomic or maternal factors and factors in the baby’s sleeping situation. Maternal factors that predict increased risk are maternal smoking, young maternal age (under 20 years), less prenatal care, poverty and illicit drug use. Risk factors that relate to the baby’s sleeping situation are prone positioning, sleeping on a soft surface and overheating.78 Prone sleeping has been concluded to be a major and modifiable risk factor. Infants should sleep on their backs, even in preference to side sleeping. Other avoidable risk factors include sleeping on top of any soft surface and loose bedding. Overwrapping the infant or over-heating the room also appears to increase risk, particularly if the infant is sleeping prone. The aetiology of SIDS remains unknown but probably involves a combination of predisposing factors and external stressors.76,77

Currently, the best strategies for reducing SIDS seem to be avoidance of all the controllable risk factors. In Australia, infant mortality from SIDS has fallen to now being extremely rare, with only three babies dying of SIDS in 2012.79 The dramatic reduction from several hundred deaths in previous years was attributed to a successful national health education campaign that raised awareness of the risk factors and promoted safe infant sleeping practices, such as positioning the baby on their back during sleeping.

F O C U S O N L E A R N I N G

1 Describe the pathophysiology of croup.

2 Discuss how the alveoli and capillaries are affected by respiratory distress syndrome of the newborn.

3 List the risk factors for sudden infant death syndrome.

Alterations of pulmonary blood flow and pressure Blood flow through the lungs can be disrupted by disorders that occlude the vessels, increase pulmonary vascular resistance or destroy the vascular bed. The effects of altered pulmonary blood flow and pressure range from insignificant

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 747

• embolus with infarction: an embolus that is large enough to cause infarction (death) of a portion of lung tissue

• embolus without infarction: an embolus that is not severe enough to cause permanent lung injury

• multiple pulmonary emboli: may be chronic or recurrent. The pathogenesis of pulmonary embolism caused by a

thrombus is summarised in Fig. 25.33. If the embolus does not cause infarction in the lung

tissue that is not receiving blood, the clot will be dissolved by the fibrinolytic system (see Chapter 16) and pulmonary function will return to normal. If pulmonary infarction occurs, shrinking and scarring develops in the affected area of the lung.

C L I N I C A L MA N I F E S TAT I O N S In most cases, the clinical manifestations of pulmonary embolism are nonspecific, so evaluation of risk factors and predisposing factors is an important aspect of diagnosis. Although most emboli originate from clots in the lower extremities, specifically the iliac and femoral veins,80 deep vein thrombosis is often asymptomatic and clinical examination has low sensitivity for the presence of clot, especially in the thigh.

An individual with pulmonary embolism usually presents with the sudden onset of chest pain, dyspnoea, tachypnoea, tachycardia and unexplained anxiety. Occasionally syncope (fainting) or haemoptysis occurs. With large emboli, a pleural friction rub, pleural effusion, fever and leucocytosis may be noted. Recurrent small emboli may not be detected until progressive incapacitation, precordial pain (stabbing chest pain), anxiety, dyspnoea and right ventricular enlargement are exhibited. Massive occlusion causes severe pulmonary hypertension, shock and sudden death.

E VA LUAT I O N A N D T R E AT M E N T Routine chest x-rays and pulmonary function tests are not definitive for pulmonary embolism. On chest x-rays, the infarcted portion of the lung appears as a nonspecific infiltrate in a classic wedge shape bordering the pleura. Arterial blood gas analyses usually demonstrate hypoxaemia and hyperventilation (leading to respiratory alkalosis). A ventilation–perfusion scan, in which lungs are scanned after injection and inhalation of a radioactive substance, may indicate embolism (see Fig. 25.34). Today, the diagnosis is made by measuring elevated levels of D-dimer in the blood (an indicator of fibrinolysis) in combination with spiral CT scanning.81

The ideal treatment for pulmonary embolism is prevention through elimination of predisposing factors for individuals at risk. Venous stasis in hospital patients is minimised by leg elevation, bed exercises, position changes, early postoperative ambulation and pneumatic calf compression. Clot formation is also prevented by prophylactic low-dose anticoagulant therapy usually with low-molecular- weight heparin or warfarin.

Anticoagulant therapy is the primary treatment for pulmonary embolism. Intravenous administration of heparin

dysfunction to severe and life-threatening changes in ventilation/perfusion ratios.

Pulmonary embolism Pulmonary embolism is occlusion of a portion of the pulmonary vascular bed by an embolus (see Fig. 25.32), which can be a thrombus (blood clot), tissue fragment, lipids (fats), foreign body or an air bubble (air embolism). More than 90% of pulmonary emboli result from clots formed in the veins of the legs and pelvis.

Risk factors for pulmonary thromboembolism, or the obstruction of a pulmonary vessel by a thrombus, include conditions and disorders that promote blood clotting as a result of venous stasis (slowing or stagnation of blood flow through the veins), hypercoagulability (increased tendency of the blood to form clots) and injuries to the endothelial cells that line the vessels. No matter the source, a blood clot becomes an embolus when all or part of it breaks away from the site of formation and begins to travel in the bloodstream. Thromboembolism or deep vein thrombus is described further in Chapter 23.

Although the overall incidence of pulmonary embolism has declined (2 per 1000 people per year), it remains an important cause of death, especially in the elderly and hospitalised individuals. Trauma, especially head injuries and fractures of the lower extremities, spine or pelvis, confers a high risk for venous thromboembolism.

PAT H O P HYS I O LO G Y The impact or effect of the embolus depends on the extent of pulmonary blood flow obstruction, the size of the affected vessels, the nature of the embolus and the secondary effects. Pulmonary emboli can occur as any of the following: • massive occlusion: an embolus that occludes a major

portion of the pulmonary circulation (i.e. main pulmonary artery embolus)

FIGURE 25.32

Pulmonary embolism. Large pulmonary embolus (arrow) lying in the pulmonary artery (retracted back for visualisation).

748 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

PAT H O P HYS I O LO G Y Cor pulmonale develops as pulmonary hypertension and creates chronic pressure overload in the right ventricle, similar to that created in the left ventricle by systemic hypertension. (Hypertension is discussed in Chapter 23.) Pressure overload increases the work of the right ventricle and first causes hypertrophy of the normally thin-walled heart muscle, but eventually leads to dilation and failure of the ventricle. Acute hypoxaemia, as with pneumonia, can exaggerate pulmonary hypertension and dilate the ventricle as well. The right ventricle usually fails when pulmonary artery pressure equals systemic blood pressure.

is begun immediately and is followed by oral doses of warfarin. Studies suggest that low-molecular-weight heparins (e.g. enoxaparin) are as safe and effective as standard heparin but are easier to administer.82 If a massive life-threatening embolism occurs, a fibrinolytic agent is sometimes used and some individuals will require surgical thrombectomy.

Cor pulmonale Cor pulmonale consists of right ventricular enlargement (hypertrophy or dilation, or both) and failure. It is most commonly caused by pulmonary hypertension.

C O

N C

E P

T M

A P Venous stasisVessel injury

Hypercoagulability Predisposing factors

Predispose e.g. DVT

dislogdes

causes

leads to

manifest as

Formation of thrombus and occlusion of embolus

Conditions arising from occlusion of pulmonary vasculature

Signs and symptoms of pulmonary embolism

Thrombus formation

Portion of thrombus

Occlusion of part of pulmonary circulation

Hypoxic vasoconstriction Decreased surfactant

Release of neurohumoral and in�ammatory substances Pulmonary oedema

Atelectasis

Tachypnoea Dyspnoea Chest pain

Increased dead space Ventilation–perfusion

imbalances Decreased PaO2

Pulmonary infarction Pulmonary hypertension

Decreased cardiac output Systemic hypotension

Shock

FIGURE 25.33

The pathogenesis of massive pulmonary embolism caused by a thrombus (venous thromboembolism). A thrombus can form in another vessel, usually a deep vein thrombosis in the leg. From this, a fragment can dislodge and travel through the blood to the lungs, where it forms a pulmonary embolism. This blockage to the pulmonary vessel may lead to severe complications including severe impairment of gas exchange, pulmonary oedema and hypertension, and shock.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 749

C L I N I C A L MA N I F E S TAT I O N S The clinical manifestations of cor pulmonale may be obscured by primary respiratory disease and appear only during exercise testing. The heart may appear normal at rest, but with exercise, cardiac output falls. The electrocardiogram may show right ventricular hypertrophy. Increased pressures in the systemic venous circulation can cause jugular venous distension, hepatosplenomegaly (enlarged liver and spleen due to venous engorgement) and peripheral oedema.

E VA LUAT I O N A N D T R E AT M E N T Diagnosis is based on physical examination, radiological examination, electrocardiogram and echocardiography. The goal of treatment for cor pulmonale is to decrease the workload of the right ventricle by lowering pulmonary artery pressure. Treatment success depends on reversal of the underlying lung disease.

F O C U S O N L E A R N I N G

1 Describe how thrombus formation can lead to pulmonary embolism.

2 Describe cor pulmonale and the clinical manifestations.

alterations and their signs and symptoms. You should be familiar with the diseases and now need to consolidate your knowledge with an understanding of the clinical manifestations that individuals with pulmonary system alterations will exhibit.

Conditions caused by pulmonary alterations Pulmonary oedema One of the most serious conditions resulting from alterations to either the pulmonary system or the cardiovascular system is pulmonary oedema. Simply, pulmonary oedema is excess water in the lungs. The normal lungs are kept free from excess water by lymphatic drainage and a balance among capillary hydrostatic pressure, capillary oncotic pressure and capillary permeability (see Chapter 22). In addition, surfactant lining the alveoli repels water, keeping fluid from entering the alveoli. Predisposing factors for pulmonary oedema include heart disease, acute respiratory distress syndrome and inhalation of toxic gases. The pathogenesis of pulmonary oedema is shown in Fig. 25.35.

The most common cause of pulmonary oedema is heart disease. When the left ventricle fails, filling pressures on the left side of the heart increase and vascular volume redistributes into the lungs, subsequently causing an increase in pulmonary capillary hydrostatic pressure and a back-tracking of excess fluid into the lungs. When the hydrostatic pressure exceeds oncotic pressure (which holds fluid in the capillary), fluid moves out into the interstitial spaces (the spaces within the alveolar septum between the alveolus and capillary). When the flow of fluid out of the capillaries exceeds the lymphatic system’s ability to remove it, pulmonary oedema develops.

A B

FIGURE 25.34

Ventilation–perfusion scan. A Normal study with no defects visible. B Defects in scan showing lack of radioactive tracer uptake indicative of pulmonary embolism.

Clinical manifestations of pulmonary alterations So far in this chapter we have explored the pathophysiology of the major pulmonary system disorders. In the following sections we look at the manifestations of these disorders — the conditions that result from pulmonary system

750 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

Another cause of pulmonary oedema is capillary injury that increases capillary permeability, as in cases of acute respiratory distress syndrome. Capillary injury causes water and plasma proteins to leak out of the capillary and move into the interstitial spaces, increasing interstitial oncotic pressure, which is usually very low. As the interstitial oncotic pressure begins to equal capillary oncotic pressure, water moves out of the capillary and into the lungs. (This phenomenon is discussed in Chapter 22).

Clinical manifestations of pulmonary oedema include dyspnoea, hypoxaemia and increased work of breathing. Patients may also experience orthopnoea and paroxysmal nocturnal dyspnoea. Physical examination may reveal inspiratory crackles and dullness to percussion over the lung bases. In severe pulmonary oedema, pink frothy sputum is expectorated (coughed up) and oxygen levels decrease, while carbon dioxide levels increase, due to inadequate gas exchange.

The mainstay of therapy is supplemental oxygen. Individuals with pulmonary oedema usually require the delivery of a higher concentration of oxygen. The treatment of pulmonary oedema depends on its cause. If the oedema is caused by increased hydrostatic pressure that results from heart failure, therapy is geared towards improving cardiac output with diuretics (to reduce fluid volume), vasodilators (to redistribute blood to other areas of the body) and drugs that improve the contraction of the heart muscle (to allow normal blood flow throughout the systemic circulation).

If oedema is the result of increased capillary permeability resulting from injury, the treatment is focused on removing the offending agent and supportive therapy to maintain adequate ventilation and circulation. When oxygen therapy alone is inadequate to meet metabolic demand, positive- pressure mechanical ventilation may be needed to improve ventilation and oxygenation.

HYPOXAEMIA Hypoxaemia, or reduced oxygenation of arterial blood (reduced PaO2), is caused by respiratory alterations, whereas hypoxia, or reduced oxygenation of cells in tissues, may be caused by alterations of other systems as well. Although hypoxaemia can lead to tissue hypoxia, tissue hypoxia can result from other abnormalities unrelated to alterations of pulmonary function, such as low cardiac output.83

Hypoxaemia results from problems with one or more of the major mechanisms of oxygenation: • oxygen delivery to the alveoli

a oxygen content of the inspired air b ventilation of the alveoli

• diffusion of oxygen from the alveoli into the blood a balance between alveolar ventilation and perfusion b diffusion of oxygen across the alveolar–capillary

barrier • perfusion of pulmonary capillaries.

C O

N C

E P

T M

A P Valvular dysfunctionCoronary artery

disease Left ventricular

dysfunction

Injury to capillary endothelium

Blockage of lymphatic vessels

Increased left atrial pressure

can cause

leads to leads to leads to

causes causes

results in

results in results in

Increased pulmonary capillary hydrostatic

pressure

Pulmonary oedema

Movement of �uid and plasma proteins from capillary to interstitial space (alveolar

septum) and alveoli

Accumulation of �uid in interstitial space

Inability to remove excess �uid from interstitial space

Increased capillary permeability and

disruption of surfactant production by alveoli

FIGURE 25.35

The pathogenesis of pulmonary oedema. Pulmonary oedema can arise from increased pulmonary blood pressure, increased capillary permeability, or blockage of the lymphatic drainage.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 751

somewhat greater than ventilation in the lung bases and because some blood is normally distributed to the bronchial circulation. An abnormal ventilation/perfusion ratio is the most common cause of hypoxaemia (see Fig. 25.36). This is referred to as a ventilation–perfusion mismatch (clinically abbreviated to V̇/Q̇ mismatch). Hypoxaemia can be caused by inadequate ventilation of well-perfused areas of the lung (low ventilation–perfusion). Mismatching of this type occurs in atelectasis, in asthma as a result of bronchoconstriction and in pulmonary oedema and pneumonia when alveoli are filled with fluid. When blood passes through portions of the pulmonary capillary bed that receive no ventilation, blood is not oxygenated, resulting in hypoxaemia. Hypoxaemia can also be caused by poor perfusion of well-ventilated portions of the lung (high ventilation– perfusion), resulting in wasted ventilation. The most common cause of high ventilation–perfusion mismatching is a pulmonary embolus that impairs blood flow to a segment of the lung. An area where alveoli are ventilated but not perfused is termed alveolar dead space.

The second factor affecting diffusion of oxygen from the alveoli into the blood is the alveolar–capillary barrier. Diffusion of oxygen through the alveolar–capillary membrane is impaired if the membrane is thickened or the surface

The amount of oxygen in the alveoli is dependent on two factors. The first factor is the presence of adequate oxygen content in the inspired air. The amount of oxygen in inspired air is expressed as the percentage or fraction of air that is composed of oxygen. Anything that decreases the oxygen content of inspired air (such as high altitude) decreases oxygen in the alveoli. The second factor is the amount of alveolar minute volume (see Chapter 24 for alveolar ventilation). Hypoventilation results in an increased alveolar carbon dioxide and decreased oxygen such that diffusion across the alveoli is impacted. This type of hypoxaemia can be completely corrected if alveolar ventilation is improved by increasing the rate and depth of breathing. Hypoventilation causes hypoxaemia in unconscious individuals; in those with neurological, muscular or bone diseases that restrict chest expansion; and in individuals who have COPD.

Diffusion of oxygen from the alveoli into the blood is also dependent on two factors. The first is the balance between the amount of air getting into the alveoli and the amount of blood perfusing the capillaries around the alveoli. Normally, alveolar capillary lung units receive almost equal amounts of ventilation and perfusion. The normal ventilation/perfusion ratio is 0.8 : 0.9 because perfusion is

Airway Impaired ventilation

Hypoxaemia

Hypoxaemia Hypoxaemia

From pulmonary artery

Alveolocapillary membrane

Alveolus

To pulmonary vein

Normal ventilation–perfusion Low ventilation–perfusion

Shunt (very low) ventilation–perfusion

High ventilation–perfusion

Blocked ventilation

Collapsed alveolus

Alveolar dead space

Impaired perfusion

FIGURE 25.36

Ventilation–perfusion abnormalities. Normal ventilation–perfusion occurs when ventilation and perfusion are both ideal at the alveoli. Low ventilation–perfusion occurs due to impairments in ventilation. High ventilation–perfusion occurs due to impairments in perfusion.

752 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

2 Absorption atelectasis results from removal of air from obstructed or hypoventilated alveoli or from inhalation of concentrated oxygen or anaesthetic agents (see Fig. 25.37). Clinical manifestations of atelectasis are similar to those

of pulmonary infection including dyspnoea, cough and fever.

Atelectasis tends to occur after surgery. Postoperative patients may have received supplemental oxygen or inhaled anaesthetics and they are usually in pain, shallow breathe, are reluctant to change position and produce thick secretions that tend to pool in dependent portions of the lungs. Prevention and treatment of postoperative atelectasis usually include deep breathing, frequent position changes and early ambulation. Deep breathing opens connections between patent and collapsed alveoli, called pores of Kohn. This allows air to flow into the collapsed alveoli (collateral ventilation) and aids in the expulsion of intrabronchial obstructions.

Pneumothorax Pneumothorax is the presence of air or gas in the pleural space caused by a rupture in the visceral pleura (which surrounds the lungs) or the parietal pleura and chest wall. As air separates the visceral and parietal pleurae, it destroys the negative pressure of the pleural space and disrupts the equilibrium between the elastic recoil forces of the lung and chest wall. The lung then tends to recoil by collapsing towards the hilum (see Fig. 25.38).

Pneumothorax can occur spontaneously or secondary to trauma. The most common presentation of spontaneous pneumothorax occurs unexpectedly in healthy males aged 20–40 years. Secondary pneumothorax can result from rib fractures, COPD or chest stabbings or shootings.

area available for diffusion is decreased. Thickened alveolar– capillary membranes, as occur with oedema (tissue swelling) and fibrosis (formation of fibrous lesions), increase the time required for oxygen to diffuse from the alveoli into the capillaries. If diffusion is slowed enough, the oxygen in the alveoli and capillary blood do not have time to equilibrate and hence oxygenation of the blood is limited.

Hypercapnia Hypercapnia, or increased carbon dioxide in the arterial blood, is caused by hypoventilation of the alveoli. As discussed in Chapter 24, carbon dioxide is easily diffused from the blood into the alveolar space; thus, minute volume (ventilation rate × tidal volume) determines not only alveolar ventilation but also carbon dioxide levels in the blood.

There are many causes of hypercapnia. Most are a result of decreased drive to breathe or an inadequate ability to respond to ventilatory stimulation. Some of these causes include: (1) depression of the respiratory centre in the brainstem by drugs such as morphine and heroin; (2) diseases of the medulla, including infections of the central nervous system or trauma; (3) abnormalities of the spinal conducting pathways, as in spinal cord disruption; (4) diseases of the neuromuscular junction or of the respiratory muscles themselves, as in myasthenia gravis or muscular dystrophy; (5) thoracic cage abnormalities, as in chest injury or congenital deformity; (6) large airway obstruction, as in tumours or sleep apnoea; and (7) increased work of breathing or physiological dead space, as in emphysema.

Acute respiratory failure Respiratory failure is defined as inadequate gas exchange such that arterial oxygen levels are less than 50 mmHg or arterial carbon dioxide levels are greater than 50 mmHg with pH less than 7.25. Respiratory failure can result from direct injury to the lungs, airways or chest wall, or indirectly because of injury to another body system, such as the brain or spinal cord. It can occur in individuals who have an otherwise normal pulmonary system or in those with underlying chronic pulmonary disease. Most pulmonary diseases can cause episodes of acute respiratory failure. If the respiratory failure is primarily hypercapnic (i.e. due to high carbon dioxide levels), it is the result of inadequate alveolar ventilation. If the respiratory failure is primarily hypoxaemic (i.e. due to low oxygen levels), it is the result of inadequate exchange of oxygen between the alveoli and the capillaries. Many individuals will have combined hypercapnic and hypoxaemic respiratory failure.

Atelectasis Atelectasis is the collapse of lung tissue. It can occur due to lack of lung expansion, such as that experienced after surgery. There are two types of atelectasis: 1 Compression atelectasis is caused by external pressure

exerted by tumour, fluid or air in pleural space or by abdominal distension pressing on a portion of lung, causing alveoli to collapse.

Absorption Compression

FIGURE 25.37

Different forms of atelectasis. Lung collapse can occur by absorption, usually from decreased air flow through the lung, or from compression from outside of the lung.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 753

re-expands and the pleural rupture is healed, the chest tube is removed.

Pleural effusion Pleural effusion is the presence of excess fluid in the pleural space. The most common mechanism of pleural effusion is migration of fluids and other blood components through the walls of intact capillaries bordering the pleura. Pleural effusions that enter the pleural space from the intact blood vessels can be transudative (watery) or exudative (high in concentrations of white blood cells and plasma proteins). Mechanisms of pleural effusion are summarised in Table 25.6.

Small collections of fluid normally can be drained away by the lymphatics. Dyspnoea, compression atelectasis with impaired ventilation and mediastinal shift occur with large effusions. Pleural pain is present if the pleura are inflamed and cardiovascular manifestations occur in a large, rapidly developing effusion.

Diagnosis is confirmed by chest x-ray (see Fig. 25.39) and thoracentesis (needle aspiration), which can determine the type of effusion and provide symptomatic relief. If the effusion is large, drainage usually requires the placement of a chest tube.

Empyema Empyema (infected pleural effusion) is the presence of pus in the pleural space. It is thought to develop when the pulmonary lymphatics become blocked, leading to an outpouring of contaminated lymphatic fluid into the pleural space. Empyema occurs most commonly in older adults

Both spontaneous and secondary pneumothorax can present as either open or tension. In open pneumothorax, air pressure in the pleural space equals barometric pressure because air that is drawn into the pleural space during inspiration (through the damaged chest wall and parietal pleura or through the lungs and damaged visceral pleura) is forced back out during expiration. In tension pneumothorax, however, the site of pleural rupture acts as a one-way valve, permitting air to enter on inspiration but preventing its escape by closing up during expiration. As more and more air enters the pleural space, air pressure in the pneumothorax begins to exceed barometric pressure. Tension pneumothorax is life-threatening. Air pressure in the pleural space pushes against the already recoiled lung, causing compression atelectasis and against the mediastinum, compressing and displacing the heart and great vessels.

Clinical manifestations of spontaneous or secondary pneumothorax begin with sudden pleural pain, tachypnoea and dyspnoea (rapid breathing and difficulty breathing, respectively). The manifestations depend on the size of the pneumothorax. Physical examination may reveal absent or decreased breath sounds. Tension pneumothorax may be complicated by severe hypoxaemia, tracheal deviation away from the affected lung and hypotension (low blood pressure). Deterioration occurs rapidly and immediate treatment is required. Diagnosis of pneumothorax is made with chest x-rays and CT scans. Pneumothorax is treated with insertion of a chest tube that is attached to a water-seal drainage system with suction, such that negative pressure is restored. After the pneumothorax

Normal lung

Chest wall

Pleural space

Diaphragm

Mediastinum

Outside air enters because of disruption of chest wall and parietal pleura

Lung air enters because of disruption of visceral pleura

FIGURE 25.38

Pneumothorax. Air in the pleural space causes the lung to collapse around the hilus and may push mediastinal contents (heart and great vessels) towards the other lung.

754 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

1 and 3 years or in individuals whose normal swallowing mechanism and cough reflex are impaired by central or peripheral nervous system abnormalities. Predisposing factors include an altered level of consciousness caused by substance abuse, sedation or anaesthesia; seizure disorders; cerebrovascular accident; and neuromuscular disorders that cause dysphagia (see Chapter 27). The right lung, particularly the right lower lobe, is more susceptible to aspiration than the left lung because the branching angle of the right main stem bronchus is straighter than the branching angle of the left main stem bronchus (see Chapter 24).

Foreign bodies lodged in the larynx or upper trachea cause cough, stridor, hoarseness or inability to speak, respiratory distress and agitation or panic. The presentation is often dramatic and frightening.

Aspiration of acidic gastric fluid (pH of less than 2.5) may cause lung inflammation. Bronchial damage includes inflammation, loss of ciliary function and bronchospasm. In the alveoli, acidic gastric fluid damages the alveolar– capillary membrane, allowing plasma and blood cells to move from the capillaries into the alveoli. The lung becomes stiff and non-compliant as surfactant production is disrupted, leading to further oedema and collapse.

Preventive measures for individuals at risk are more effective than treatment of known aspiration. The most important preventive measures include the semi-recumbent position, the surveillance of enteral feeding and the avoidance of excessive sedation. Nasogastric tubes, which are often used to remove stomach contents, are used to prevent aspiration but can also cause aspiration if fluid and particulate matter are regurgitated as the tube is being placed.

Treatment of aspiration of foreign bodies may include bronchoscopy to remove the foreign body, if sneezing and coughing does not displace the object. More serious aspirations with either stomach contents or ingestion of

and children and usually develops as a complication of pneumonia, surgery, trauma or bronchial obstruction from a tumour.

Individuals with empyema present clinically with cyanosis, fever, tachycardia (rapid heart rate), cough and pleural pain. Diagnosis is made by chest x-rays, thoracentesis and sputum culture.

The treatment for empyema includes the administration of appropriate antimicrobials and drainage of the pleural space with a chest tube.

Aspiration Aspiration is the inhalation of fluid and solid particles into the lung. It tends to occur in children between the ages of

TABLE 25.6 Mechanisms of pleural effusion

TYPE OF FLUID/ EFFUSION SOURCE OF ACCUMULATION PRIMARY OR ASSOCIATED DISORDER

Transudate (hydrothorax)

Watery fluid that diffuses out of capillaries beneath the pleura (i.e. capillaries in the lungs or chest wall)

Cardiovascular disease that causes high pulmonary capillary pressures; liver or kidney disease that disrupts plasma protein production, causing hypoproteinaemia (decreased oncotic pressure in the blood vessels)

Exudate Fluid rich in cells and proteins (leucocytes, plasma proteins of all kinds; see Chapter 13) that migrates out of the capillaries

Infection, inflammation or malignancy of the pleura that stimulates mast cells to release biochemical mediators that increase capillary permeability

Pus (empyema) Debris of infection (microorganisms, leucocytes, cellular debris) dumped into the pleural space by blocked lymphatic vessels

Pulmonary infections, such as pneumonia; lung abscesses; infected wounds

Blood (haemothorax)

Haemorrhage into the pleural space Traumatic injury, surgery, rupture or malignancy that damages blood vessels

Chyle (chylothorax) Chyle (milky fluid containing lymph and fat droplets) that is dumped by lymphatic vessels into the pleural space instead of passing from the gastrointestinal tract to the thoracic duct

Traumatic injury, infection or disorder that disrupts lymphatic transport

FIGURE 25.39

Chest x-ray of a right-side pleural effusion. Note the arrows highlighting the extent of the effusion. This angle should be sharp and this blunting is due to fluid formation.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 755

Dyspnoea can occur transiently or can become chronic. One cause of dyspnoea is pulmonary congestion usually resulting from heart disease. Pulmonary congestion tends to cause dyspnoea when the individual is lying down (orthopnoea). The horizontal position redistributes body water, causes the abdominal contents to exert pressure on the diaphragm and decreases the efficiency of the respiratory muscles. Sitting up in a forward-leaning posture or supporting the upper body on several pillows generally relieves orthopnoea. Some individuals with pulmonary or cardiac disease wake up at night gasping for air and have to sit up or stand to relieve the dyspnoea (paroxysmal nocturnal dyspnoea).

Cough A cough is a protective reflex that cleanses the lower airways by an explosive expiration. Inhaled particles, accumulated mucus, inflammation or the presence of a foreign body initiates the cough reflex by stimulating the irritant receptors in the airways. There are only few of these receptors in the most distal bronchi and the alveoli, thus it is possible for significant amounts of secretions to accumulate in the distal respiratory tree without cough being initiated. The cough consists of inspiration, closure of the glottis and vocal cords, contraction of the expiratory muscles and reopening of the glottis, causing a sudden, forceful expiration that removes the offending matter. The effectiveness of the cough depends on the depth of the inspiration and the degree to which the airways narrow, increasing the velocity of expiratory gas flow.

Acute cough is cough that resolves within 2–4 weeks of the onset of illness or resolves with treatment of the underlying condition. It is most commonly the result of upper respiratory infections, acute bronchitis, pneumonia, heart failure, pulmonary embolus or aspiration.

Chronic cough is defined as cough that has persisted for more than 4 weeks in children and 8 weeks in adults. In non-smoking adults, the most common cause of chronic cough is rhinosinusitis, asthma or gastro-oesophageal reflux disease, in children it is asthma and protracted bacterial bronchitis.88,89 In smokers, chronic bronchitis is the most common cause of cough, although lung cancer must always be considered. Approximately 5–10% of Australians suffer from chronic cough and 20% of patients who take angiotensin-converting enzyme (ACE) inhibitors (see Chapter 23) develop a persistent dry cough, with some patients experiencing severe cough that requires the drug to be discontinued.

Management of chronic cough involves addressing the common issues of environmental exposures and the concerns of the patient and parents, then the institution of specific therapy.88,90

Hypoventilation and hyperventilation Hypoventilation is inadequate alveolar ventilation in relation to metabolic demand. Hypoventilation occurs when minute volume (tidal volume × ventilatory rate) is reduced. It is

solids or fluids into the lungs may necessitate supplemental oxygen, mechanical ventilation, fluid restriction and steroids. Bacterial pneumonia may develop as a complication of aspiration and must be treated with broad-spectrum antimicrobials.

F O C U S O N L E A R N I N G

1 Describe pulmonary oedema and list two causes.

2 Discuss the mechanisms that produce hypoxaemia and hypercapnia.

3 Differentiate the different levels of hypoxaemia and hypercapnia in acute respiratory failure.

4 Compare and contrast the two forms of atelectasis.

5 Compare and contrast open and tension pneumothorax.

6 Describe how pneumothorax differs from pleural effusion.

7 List causes of empyema.

8 Provide a list of 5 different causes of aspiration.

Signs and symptoms of pulmonary alterations Dyspnoea Dyspnoea is the subjective sensation of uncomfortable breathing, the feeling of not being able to get enough air. It is often described as breathlessness, air hunger, shortness of breath and laboured breathing. Everyone experiences dyspnoea at some stage. One of the most common non-pathological reasons is when you exercise heavily and become short of breath — that is dyspnoea. Our discussion here concerns dyspnoea that occurs at rest and is due to pulmonary system pathophysiology.

Dyspnoea can be caused by many pulmonary disorders. Disturbances of ventilation, gas exchange or ventilation– perfusion relationships can cause dyspnoea, as can increased work of breathing or any disease that damages lung tissue. One proposed mechanism for dyspnoea is a mismatch between sensory and motor input from the respiratory centre in the brainstem such that there is more urge to breathe than there is response by the respiratory muscles. Other causes of dyspnoea include stimulation of central and peripheral chemoreceptors and stimulation of afferent receptors in the lungs and chest wall.

The signs of dyspnoea include flaring of the nostrils, use of accessory muscles of ventilation and retraction (pulling back) of the intercostal spaces. In dyspnoea caused by lung tissue disease (e.g. pneumonia), retractions of tissue between the ribs may be observed, although retractions are more common in children than in adults. Dyspnoea can be quantified using scales (such as the Borg Dyspnoea Scale,84 the Medical Research Council (MRC) Dyspnoea Score85 and the Dyspnoea-12)86 and is frequently associated with significant anxiety.87

756 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

the brainstem is also a contributing factor. Cheyne- Stokes breathing indicates that severe pathophysiological disturbances have occurred and often is present immediately before death.

Haemoptysis Haemoptysis is the coughing up of blood or bloody secretions. This should not be confused with haematemesis, which is the vomiting of blood. Blood that is coughed up is usually bright red, has an alkaline pH and may be mixed with frothy sputum, whereas blood that is vomited is dark, has an acidic pH and is mixed with food particles. However, both are serious conditions.

Haemoptysis indicates a localised abnormality, usually infection or inflammation that damages the bronchi, such as bronchiectasis, or the lung tissue, such as tuberculosis and cancer. Bronchoscopy, combined with chest CT scans, is used to confirm the site of bleeding.

Cyanosis Cyanosis is a bluish discolouration of the skin and mucous membranes caused by increasing amounts of desaturated or reduced haemoglobin (which is bluish) in the blood. It generally develops when 5 g of haemoglobin is desaturated, regardless of haemoglobin concentration.

Cyanosis can be caused by decreased arterial oxygenation, ventilation–perfusion inequalities, decreased cardiac output, a cold environment or anxiety. In adults, cyanosis is not evident until severe hypoxaemia is present and therefore is an insensitive indication of respiratory failure. Severe anaemia (inadequate haemoglobin concentration) can cause inadequate oxygenation of tissues without causing cyanosis. However, individuals with polycythaemia (an abnormal increase in the numbers of red blood cells) may have cyanosis when oxygenation is adequate. Therefore, cyanosis must be interpreted in relation to the underlying pathophysiology. If cyanosis is suggested, the oxygen levels in the blood should be measured. Central cyanosis (decreased oxygen saturation of haemoglobin in arterial blood) is best seen in buccal (cheek) mucous membranes and lips. Peripheral cyanosis (slow blood circulation in fingers and toes) is best seen in nail beds.

caused by alterations in pulmonary mechanics or in the neurological control of breathing. When alveolar ventilation is normal, carbon dioxide is removed from the lungs at the same rate as that produced by cellular metabolism; therefore, arterial and alveolar carbon dioxide values remain at normal levels (between 35 and 45 mmHg). With hypoventilation, carbon dioxide removal does not keep up with carbon dioxide production and the level of carbon dioxide in the arterial blood increases, causing hypercapnia (a carbon dioxide level more than 45 mmHg). This results in respiratory acidosis (pH less than 7.35), which can affect the function of many tissues throughout the body. Blood gas analysis (i.e. measurement of the arterial carbon dioxide level) reveals hypoventilation.

Hyperventilation is alveolar ventilation exceeding metabolic demands. The lungs remove carbon dioxide faster than it is produced by cellular metabolism, resulting in decreased carbon dioxide levels in the blood, or hypocapnia (a carbon dioxide level less than 35 mmHg). Hypocapnia results in respiratory alkalosis (pH greater than 7.45), which also can interfere with tissue function. Like hypoventilation, hyperventilation can be determined by arterial blood gas analysis. Increased respiratory rate or tidal volume can occur with severe anxiety, acute head injury, pain and in response to conditions that cause insufficient oxygenation of the blood.

Abnormal breathing patterns Normal breathing (eupnoea) is rhythmic and effortless. The resting ventilatory rate in adults is usually between 8 and 16 breaths per minute and tidal volume (the amount of air in each breath) ranges from 400–800 mL. A short expiratory pause occurs with each breath and the expiratory phase is longer than inspiration, usually in a ratio of 1:2 (for inspiration time: expiration time). Disease states can alter this ratio.

Laboured breathing occurs whenever there is an increased work of breathing, especially if the airways are obstructed. If the large airways are obstructed, a slow ventilatory rate, large tidal volume, increased effort, prolonged inspiration and expiration, and stridor or audible wheezing (depending on the site of obstruction) are typical. In small airway obstruction like that seen in asthma and COPD, a rapid ventilatory rate, small tidal volume, increased effort and prolonged expiration are often present.

Strenuous exercise or metabolic acidosis induces Kussmaul breathing (slow deep breathing), or hyperpnoea (excessive breathing), which is characterised by an increased ventilatory rate, very large tidal volumes and no expiratory pause. Another abnormal breathing pattern is Cheyne-Stokes breathing, characterised by alternating periods of deep and shallow breathing. Apnoea lasting from 15 to 60 seconds is followed by breaths that increase in volume until a peak is reached; then breathing decreases again to apnoea. Cheyne-Stokes breathing results from any condition that slows the blood flow to the brainstem, which in turn slows impulses sending information to the respiratory centres of the brainstem. Neurological impairment above

F O C U S O N L E A R N I N G

1 List the primary signs and symptoms of pulmonary disease.

2 Discuss reasons why individuals may experience dyspnoea.

3 Differentiate between acute and chronic cough.

4 Differentiate between hypoventilation and hyperventilation.

5 Indicate reasons for haemoptysis.

6 Describe causes of cyanosis.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 757

chapter SUMMARY

Disorders of the pulmonary system • Obstructive airway diseases are characterised by

airway obstruction. Obstructive airway diseases can be acute or chronic in nature and include asthma and COPD.

• In asthma, the mechanisms causing airway obstruction include bronchoconstriction, bronchial inflammation, mucosal oedema and increased mucus production.

• Asthma control severity and control are used to determine therapy.

• Asthma is a common and important problem in children, adults and the elderly. Its origins are multifactorial, including genetic, allergic and viral-triggered mechanisms. Effective management is aimed at decreasing chronic inflammation in the lungs, eliminating known triggers from the environment, and early recognition and treatment of acute symptoms. Best practice asthma management includes effective pharmacotherapy, self-management education, the provision of a written asthma action plan and regular medical review.

• Childhood asthma is best classified by clinical patterns to support the spirometry results; different patterns of wheezing may be observed. Childhood asthma may be infrequent, frequent or persistent that progresses into adulthood. Viral infections are common triggers for childhood asthma.

• Chronic obstructive pulmonary disease (COPD) is an obstructive airway disease which involves the occurrence and the coexistence of chronic bronchitis and emphysema. Asthma COPD overlap is common particularly in older populations.

• COPD is an important cause of hypoxaemic and hypercapnic respiratory failure.

• Chronic bronchitis causes airway obstruction resulting from bronchial smooth muscle hypertrophy and production of thick, tenacious mucus.

• In emphysema, destruction of the alveolar septa and loss of passive elastic recoil lead to airway collapse and obstruct gas flow during expiration.

• Acute respiratory distress syndrome results from an acute diffuse injury to the alveolar–capillary membrane and decreased surfactant production, which increases membrane permeability and causes oedema and atelectasis. There is progressive respiratory distress with severe hypoxaemia and respiratory failure.

• Inhalation of noxious gases or prolonged exposure to high concentrations of oxygen can damage the bronchial mucosa or alveolar–capillary membrane and cause inflammation or acute respiratory failure.

• Pneumoconiosis, which is caused by inhalation of dust particles in the workplace, can cause pulmonary fibrosis, susceptibility to lower airway infection and cancers.

• Cystic fibrosis is an autosomal recessive genetic disease that affects many organ systems, especially the lungs and digestive system. Airway secretions are particularly thick and tenacious and the airways develop chronic bacterial infection with pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. Chronic infection, plugged airways and severe inflammation cause long- term lung damage and ultimately death. However, the prognosis is improving and most patients with cystic fibrosis now survive to adulthood.

• Bronchiectasis is an abnormal permanent dilation and distortion of the bronchi and bronchioles, resulting from chronic inflammation of the airways, and leading to progressive destruction of the bronchial walls and lung tissue.

Infections of the pulmonary system • Upper respiratory tract infections are the most common

cause of short-term disability in Australia and New Zealand.

• Serious lower respiratory tract infections occur most often in the elderly and in individuals with impaired immunity or underlying disease.

• Viral pneumonia can be severe, but is more often an acute self-limiting lung infection usually caused by the influenza virus.

• Tuberculosis is a lung infection caused by Mycobacterium tuberculosis.

• In tuberculosis, the inflammatory response proceeds to isolate colonies of bacterium by enclosing them in tubercles and surrounding the tubercles with scar tissue. These may remain dormant within the tubercles for life or, if the immune system breaks down, cause recurrence of active disease.

• Influenza is a common viral infection that affects large proportions of the population. This form is seasonal; however, more pathogenic forms of influenza involving mutations with avian and swine influenza have infected humans and may cause serious pandemics in the future.

Paediatrics and pulmonary infections • Bronchiolitis is the inflammatory obstruction of small

airways. It is most common in children.

Lung cancer • Lung cancer, the most common cause of cancer death in

Australia and New Zealand, is commonly caused by cigarette smoking.

Continued

758 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

• Cancer cell types include non-small cell carcinoma (squamous cell, adenocarcinoma and large cell) and small cell carcinoma. Each type arises in a characteristic site or type of tissue, causes distinctive clinical manifestations and differs in likelihood of metastasis and prognosis.

Obstructive sleep apnoea • Obstructive sleep apnoea syndrome is defined by partial

or complete upper airway obstruction during sleep with disruption of normal ventilation and normal sleep patterns. It affects a large percentage of adult males (typically middle-aged and older) and children.

• Risk factors for adults are obesity, age, smoking and gender; in children the most common cause is adenotonsillar hypertrophy.

Paediatrics and pulmonary disorders • Croup is an acute respiratory illness of young children,

usually caused by parainfluenza virus. This infection causes swelling of the upper trachea. The typical sign is a seal-like barking cough, which appears after a few days of rhinorrhoea, sore throat and low-grade fever.

• Respiratory distress syndrome of the newborn usually occurs in premature infants who are born before surfactant production and alveolar capillary development are complete. Atelectasis and hypoventilation cause hypoxaemia and hypercapnia. Prenatal steroids and postnatal surfactant are beneficial therapies.

• Sudden infant death syndrome (SIDS) is the leading cause of postnatal death for infants outside of the hospital setting and is associated with low birth weight, a prone sleeping position and other environmental factors. Some risk factors are modifiable — the prime example is the profound reduction in SIDS since widespread adoption of recommendations for supine positioning of infants during sleep.

Alterations of pulmonary blood flow and pressure • Pulmonary vascular diseases are caused by embolism or

hypertension in the pulmonary circulation. • Pulmonary embolism is occlusion of a portion of the

pulmonary vascular bed by a thrombus (most common), tissue fragment or air bubble. Depending on its size and location, the embolus can cause hypoxic vasoconstriction, pulmonary oedema, atelectasis, pulmonary hypertension, shock and even death.

• Cor pulmonale is right ventricular enlargement caused by chronic pulmonary hypertension. Cor pulmonale progresses to right ventricular failure if the pulmonary hypertension is not reversed.

Clinical manifestations of pulmonary alterations • Pulmonary oedema is excess water in the lungs caused

by disturbances of capillary hydrostatic pressure,

capillary oncotic pressure or capillary permeability. A common cause is left heart failure, which increases the hydrostatic pressure in the pulmonary circulation.

• Hypoxaemia is a reduced oxygen level in the blood caused by (1) decreased oxygen content of inspired gas, (2) hypoventilation, (3) diffusion abnormality or (4) ventilation–perfusion mismatch.

• Hypercapnia is an increased carbon dioxide level in the blood caused by hypoventilation.

• Atelectasis is the collapse of alveoli resulting from compression of lung tissue or absorption of gas from obstructed alveoli.

• Pneumothorax is the accumulation of air in the pleural space. It can be caused by spontaneous rupture of weakened pleural areas or it can be secondary to pleural damage caused by disease or trauma.

• Pneumothorax can be open, which means that the lung only partially collapses, or tension, which means that pressure builds up in the pleural space and can compress both the affected lung and the mediastinum.

• Pleural effusion is the accumulation of fluid in the pleural space, usually resulting from disorders that promote transudation or exudation from capillaries underlying the pleura but occasionally resulting from blockage or injury that causes lymphatic vessels to drain into the pleural space.

• Empyema (infected pleural effusion) is the presence of pus in the pleural space.

• Dyspnoea is the feeling of breathlessness and increased respiratory effort. It is a common pulmonary disorder symptom.

• Coughing is a protective reflex that expels secretions and irritants from the lower airways.

• Hypoventilation is decreased alveolar ventilation caused by airway obstruction, chest wall restriction or altered neurological control of breathing. Hypoventilation causes increased carbon dioxide levels.

• Hyperventilation is increased alveolar ventilation produced by anxiety, head injury or severe hypoxaemia. Hyperventilation causes decreased carbon dioxide levels.

• Abnormal breathing patterns are adjustments made by the body to minimise the work of the respiratory muscles. They include Kussmaul and Cheyne-Stokes breathing.

• Haemoptysis is expectoration of bloody mucus, which can be caused by bronchitis, tuberculosis, abscess, neoplasms and other conditions that cause haemorrhage from damaged vessels.

• Cyanosis is a bluish discolouration of the skin caused by desaturation of haemoglobin, polycythaemia or peripheral vasoconstriction.

CHAPTER 25 AlTeRATIOnS Of PulmOnARy funCTIOn ACROSS The lIfe SPAn 759

A D U L T Craig is 57 years old and has just been diagnosed with squamous cell lung cancer. Although he admits that he was well aware that lung cancer was a risk of smoking, he was not expecting such devastating news until he was much older. A large growth was found in the left primary bronchus, and metastasis has already occurred to another location within the lung tissue. His symptoms include cough and haemoptysis; it was haemoptysis which led to his diagnosis of cancer.

1 Compare the main features of the different types of lung cancer.

2 Explain the likely clinical progression of Craig’s condition. 3 Describe the relationship between cigarette smoking and

the p53 gene. 4 Discuss the potential reasons for encouraging Craig to

quit smoking, given that he already has lung cancer. 5 Lung cancer has a very high incidence and mortality in

Australia and New Zealand. Outline possible reasons why we do not have national lung cancer screening programs in our countries.

CASE STUDY

A G E I N G John is 73 years old with COPD. He is prescribed tiotropium bromide daily and salbutamol 2 puffs as required. He uses his salbutamol several times per day and his tiotropium as prescribed. His wife died 5 years ago and since then he has not been taking care of himself very well; he is no longer active and doesn’t like to go out too much. He presented to hospital with his daughter as she was concerned about him. She states that over the last 8 days he has experienced an increase in his symptoms; he had a fever, was increasingly breathless, and was coughing up green phlegm. She states that he had been increasingly irritable and not attending to his meals or personal care as he was too breathless. He had seen his doctor 4 days ago who had started oral amoxicillin for 7 days and had advised him to return if it did not get any better. The doctor also indicated that he should return once he was better for his influenza vaccine. She reported that this was the third time in the last 12 months that she needed to take her dad to the doctor or emergency department because of a flare-up of his breathing. Physical examination revealed decreased breath sounds throughout both lung fields with bibasal crackles, tachypnoea

(ventilatory rate: 32 breaths per minute) with accessory muscle use, temperature 37.9°C, pursed lip breathing, tachycardia (heart rate: 116 beats per minute), oxygen saturations of 84% and anxiety. Spirometry was performed in the emergency department; his FEV1was 44% of predicted, his FVC was 106% of predicted and his FEV1/VC ratio was 0.41. An urgent arterial blood gas was performed, which revealed mild hypercapnia PaCO2 (48 mmHg pH 7.35) and hypoxaemia (PaO2 78 mmHg). Oxygen prongs were applied at a flow of 2 L/ min and he was administered prednisolone and salbutamol via the pressurised metered dose inhaler and large volume spacer. 1 Describe the most probable reasons for John’s acute

exacerbation. 2 Describe why the arterial blood gas revealed respiratory

acidosis as it relates to COPD. 3 Explain the results of his spirometry test and the

implications of these results. 4 Based on the history discuss the impact of his previous

exacerbations. 5 Differentiate between the pathophysiology of upper

respiratory tract infections and asthma.

CASE STUDY

760 PART 4 AlTeRATIOnS TO bOdy mAInTenAnCe

1 Using changes in airflow characteristics, differentiate between obstructive and restrictive lung diseases.

2 Describe how smoking affects pulmonary function and how it contributes to the development of chronic obstructive pulmonary disease.

3 Differentiate between an upper respiratory tract infection and a lower respiratory tract infection. Provide examples to supplement your answer.

4 Compare the different types of bronchogenic lung cancer and the signs and symptoms that arise.

5 Provide a pathophysiological outline of the development of obstructive sleep apnoea.

6 Explain the pathogenesis of cystic fibrosis and why individuals develop clinical manifestations in other body systems.

7 Explain why pulmonary embolism is a potentially fatal condition.

8 Discuss how pulmonary oedema can arise and what treatment options are available.

9 Provide explanations outlining the differences between pneumothorax, pleural effusion and empyema.

10 Suggest why dyspnoea and cough are common symptoms of many pulmonary conditions.

REVIEW QUESTIONS

25 Alterations of pulmonary function across the life span

Chapter outline
Key terms
Introduction
Disorders of the pulmonary system

Obstructive airway diseases

Asthma

Pathophysiology
Clinical manifestations
Evaluation and treatment

Chronic obstructive pulmonary disease

Chronic bronchitis

Pathophysiology

Emphysema

Pathophysiology
Clinical manifestations of COPD
Evaluation and management of COPD

Cystic fibrosis

Pathophysiology
Clinical manifestations
Evaluation and treatment

Bronchiectasis

Restrictive airway diseases

Acute respiratory distress syndrome

Pathophysiology
Clinical manifestations
Evaluation and treatment

Inhalation disorders

Exposure to toxic gases
Pneumoconiosis

Infections of the pulmonary system

Pneumonia

Pathophysiology
Clinical manifestations
Evaluation and treatment

Tuberculosis

Pathophysiology
Clinical manifestations
Evaluation and treatment

Acute bronchitis
Influenza

Pathophysiology
Clinical manifestations
Evaluation and treatment

Lung cancer

Types of lung cancer

Non-small cell carcinoma
Small cell carcinoma

Pathophysiology
Clinical manifestations
Evaluation and treatment

Obstructive sleep apnoea

Pathophysiology
Clinical manifestations
Evaluation and treatment

Alterations of pulmonary blood flow and pressure

Pulmonary embolism

Pathophysiology
Clinical manifestations
Evaluation and treatment

Cor pulmonale

Pathophysiology
Clinical manifestations
Evaluation and treatment

Clinical manifestations of pulmonary alterations

Conditions caused by pulmonary alterations

Pulmonary oedema

Hypoxaemia

Hypercapnia
Acute respiratory failure
Atelectasis
Pneumothorax
Pleural effusion
Empyema
Aspiration

Signs and symptoms of pulmonary alterations

Dyspnoea
Cough
Hypoventilation and hyperventilation
Abnormal breathing patterns
Haemoptysis
Cyanosis

Review questions