Asthma

Asthma is a common chronic inflammatory condition of the airways whose cause is incompletely understood. Symptoms include wheeze, chest tightness, cough and shortness of breath, often worse at night. Asthma commonly starts in childhood between the ages of 3 and 5 years and may either worsen or improve during adolescence. Classically asthma has three characteristics:

Airflow limitation which is usually reversible spontaneously or with treatment

Airway hyperresponsiveness to a wide range of stimuli (see below)

Bronchial inflammation with T lymphocytes, mast cells, eosinophils with associated plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging and epithelial damage.

In chronic asthma, inflammation may be accompanied by irreversible airflow limitation as a result of airway wall remodelling that may involve large and small airways and mucus impaction.

Prevalence

In many countries, the prevalence of asthma is increasing. This increase is particularly marked in children and young adults where this disease may affect up to 15% of the population. There is also geographical variation, with asthma being commoner in more developed countries. Some of the highest rates are in the UK, New Zealand and Australia, with much lower rates in Far Eastern countries such as China and Malaysia, Africa and Central and Eastern Europe. Long-term follow-up in developing countries suggests that asthma may become more frequent as individuals adopt a more ‘westernized’ lifestyle, but the environmental factors accounting for this remain unknown. Studies of occupational asthma suggest that a large proportion of the workforce (15–20%) may become asthmatic if exposed to potent sensitizers. Worldwide, approximately 300 million people have asthma and this is expected to rise to 400 million by 2025.

Classification

Asthma is a complex disorder of the conducting airways that was often classified into extrinsic and intrinsic asthma but there is considerable overlap.

Extrinsic asthma occurs most frequently in atopic individuals: i.e. those with positive skin-prick reactions to common inhalant allergens such as dust mite, animal danders, pollens and fungi; 90% of children and 70% of adults with persistent asthma have positive skin-prick tests to inhalant allergens. Childhood asthma is often accompanied by eczema (atopic dermatitis) (see p. 1206). Sensitization to chemicals or biological products in the workplace is a frequently overlooked cause of late-onset asthma in adults.

Intrinsic asthma often starts in middle age. Nevertheless, many patients with adult-onset asthma show positive allergen skin tests and on close questioning some of these will give a history of childhood respiratory symptoms suggesting they have extrinsic asthma.

Non-atopic individuals may develop asthma in middle age from extrinsic causes such as sensitization to occupational agents such as toluene diisocyanate, intolerance to non-steroidal anti-inflammatory drugs such as aspirin or because they were given β-adrenoceptor-blocking agents for concurrent hypertension or angina that block the protective effect of endogenous adrenergic agonists. Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.

Aetiology and pathogenesis

The two major factors involved in the development of asthma and many other stimuli that can precipitate attacks are shown in Figure 15.29.

Figure 15.29 Causes and triggers of asthma. RSV, respiratory syncytial virus; NSAIDs, non-steroidal anti-inflammatory drugs.

Atopy and allergy

The term ‘atopy’ was coined in the early twentieth century to describe a group of disorders, including asthma and hayfever, which appeared:

to run in families

to have characteristic wealing skin reactions to common allergens in the environment

to have circulating allergen-specific antibodies (later shown to be IgE).

Allergen-specific IgE is present in 30–40% of the UK population, and there is a link between serum IgE levels and both the prevalence of asthma and airway hyperresponsiveness. Genetic and environmental factors affect serum IgE levels.

Genetic

There is no single gene for asthma, but several genes, in combination with environmental factors, appear to influence the development of asthma.

Genes controlling the production of the cytokines IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF – which in turn affect mast and eosinophil cell development and longevity as well as IgE production – are present in a cluster on chromosome 5q31-33 (the IL-4 gene cluster).

Polymorphic variation in proteins along the IL-4/-13 signalling pathway is strongly associated with allergy and asthma.

Novel asthma genes identified by positional cloning from whole genome scans are the PHF11 locus on chromosome 2 (that includes genes SETDB2 and RCBTB1) and transcription factors, which are implicated in IgE synthesis and associated more with atopy than asthma.

ADAM 33 (a disintegrin and metalloproteinase) on chromosome 20p13 is associated with airway hyperresponsiveness and tissue remodelling.

Other genes associated with asthma are those that encode neuropeptide S receptor (GPRA or GPR154) on chromosome 7p15, HLA-G on chromosome 6p21, dipeptidyl peptidase 10 on chromosome 2q14 and ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum, on chromosome 17q21.

Environmental factors

Early childhood exposure to allergens and maternal smoking has a major influence on IgE production. Much current interest focuses on the role of intestinal bacteria and childhood infections in shaping the immune system in early life. It has been suggested that growing up in a relatively ‘clean’ environment may predispose towards an IgE response to allergens (the ‘hygiene hypothesis’). Conversely, growing up in a ‘dirtier’ environment may allow the immune system to avoid developing allergic responses. Components of bacteria (e.g. lipopolysaccharide endotoxin, immunostimulatory CpG DNA sequences, flagellin), viruses (e.g. SS- and DS-RNA) and fungi (e.g. chiton, a cell wall component) stimulate various toll-like receptors (TLRs) expressed on immune and epithelial cells to direct the immune and inflammatory response away from the allergic (Th2) towards protective (Th1 and Treg) pathways. Th1 immunity is associated with antimicrobial protective immunity whereas regulatory T cells are strongly implicated in tolerance to allergens. Thus early life exposure to inhaled and ingested products of microorganisms, as occurs in livestock farming communities and developing countries, may reduce the subsequent risk of a child becoming allergic and/or developing asthma.

The allergens involved in allergic asthma are similar to those implicated in rhinitis although pollens are relatively less implicated in asthma. Most allergic asthmatics are sensitized to house-dust mite allergens. Cockroach allergy has been implicated in asthma in US inner-city children, while allergens from furry pets (especially cats) are increasingly common causes. The fungal spores from Aspergillus fumigatus cause a range of lung disorders, including asthma (see p. 852). Many allergens, including those from Aspergillus, have intrinsic biological properties, e.g. enzymes with proteolytic function which may increase their sensitizing capacity.

FURTHER READING

Holgate ST, Roberts G, Arshad HS et al. The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis. Proc Am Thor Soc 1009; 6:655–659.

Increased responsiveness of the airways of the lung (airway hyperresponsiveness)

Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma and can be demonstrated by asking patients to inhale gradually increasing concentrations of histamine or methacholine (bronchial provocation tests). This induces transient airflow limitation in susceptible individuals (approximately 20% of the population); the severity of BHR can be graded according to the provocation dose (PD) or concentration (PC) of the agonist that produces a 20% fall in FEV₁ (PD₂₀ FEV₁ or PC₂₀ FEV₁). Patients with clinical symptoms of asthma respond to very low doses of methacholine, i.e. they have a low PD₂₀ FEV₁. BHR can also be assessed by exercise testing or inhalation of cold dry air, mannitol or hypertonic saline. These are indirect tests that release endogenous mediators such as histamine, prostaglandins and leukotrienes which then cause bronchoconstriction. Indirect measures of BHR correlate more closely with symptoms and diurnal peak expiratory flow rate (PEFR) variation than PC₂₀ histamine or methacholine: both are useful in diagnosing asthma if there is doubt and in guiding controller treatment.

Some patients also react to methacholine but at higher doses, e.g. those with:

attacks of asthma only on extreme exertion, e.g. winter sports enthusiasts

wheezing or prolonged periods of coughing following a viral infection

seasonal wheeze during the pollen season

allergic rhinitis, but not complaining of lower respiratory symptoms until specifically questioned

and some subjects with no respiratory symptoms.

Although the degree of BHR can be influenced by allergic mechanisms (see p. 826 and Fig. 15.32), its pathogenesis and mode of inheritance involve a combination of airway inflammation and tissue remodelling.

Precipitating factors

Occupational sensitizers (Table 15.13)

Over 250 materials encountered at the workplace can cause occupational asthma, which accounts for about 15% of all asthma cases. These are recognized occupational diseases in the UK, and patients in insurable employment are eligible for statutory compensation provided they apply within 10 years of leaving the occupation in which the asthma developed.

Table 15.13 Occupational asthma

Cause	Source/Occupation
Low molecular weight (non-IgE related)
Isocyanates	Polyurethane varnishes
	Industrial coatings
	Spray painting
Colophony fumes	Soldering/welders
Colophony fumes	Electronics industry
Wood dust
Drugs
Bleaches and dyes
Complex metal salts, e.g. nickel, platinum, chromium
High molecular weight (IgE related)
Allergens from animals and insects	Farmers, workers in poultry and seafood processing industry; laboratory workers
Antibiotics	Nurses, health industry
Latex	Health workers
Proteolytic enzymes	Manufacture (but not use) of ‘biological’ washing powders
Complex salts of platinum	Metal refining
Acid anhydrides and polyamine hardening agents	Industrial coatings

Asthma can be due to:

Low molecular weight compounds, e.g. reactive chemicals such as isocyanates and acid anhydrides that bond chemically to epithelial cells to activate them as well as provide haptens recognized by T cells.

High molecular weight compounds, e.g. flour, organic dusts and other large protein molecules involving specific IgE antibodies

The risk of developing some forms of occupational asthma increases in smokers. The proportion of employees developing occupational asthma depends primarily upon the level of exposure. Proper enclosure of industrial processes or appropriate ventilation greatly reduces the risk. Atopic individuals develop occupational asthma more rapidly when exposed to agents causing the development of specific IgE antibody. Non-atopic individuals can also develop asthma when exposed to such agents, but after a longer period of exposure.

FURTHER READING

Kogevinas M, Zock JP, Jarvis D et al. Exposure to substances in the workplace and new onset asthma: an international prospective population based study (ECRHS-II). Lancet 2007; 370:336–341.

Nonspecific factors

The characteristic feature of BHR in asthma means that, as well as reacting to specific antigens, the airways will also respond to a wide variety of nonspecific direct and indirect stimuli.

Cold air and exercise

Most asthmatics wheeze after prolonged exercise or inhaling cold dry air. Typically, the attack does not occur while exercising but afterwards. Exercise-induced wheeze is driven by release of histamine, prostaglandins (PGs) and leukotrienes (LTs) from mast cells as well as stimulation of neural reflexes when the epithelial lining fluid of the bronchi becomes hyperosmolar owing to drying and cooling during exercise. The phenomenon can be shown by exercise, cold air and hypertonic (e.g. saline or mannitol) provocation tests.

Atmospheric pollution and irritant dusts, vapours and fumes

Many patients with asthma experience worsening of symptoms on contact with tobacco smoke, car exhaust fumes, solvents, strong perfumes or high concentrations of dust in the atmosphere. Major epidemics have been recorded when large amounts of allergens are released into the air, e.g. soybean dust in Barcelona. Asthma exacerbations increase during summer and winter air pollution episodes associated with climatic temperature inversions. Epidemics of asthma have occurred in the presence of high concentrations of ozone, particulates and NO₂ in the summer and particulates, NO₂ and SO₂ in the winter.

Diet

Increased intakes of fresh fruit and vegetables have been shown to be protective, possibly owing to the increased intake of antioxidants or other protective molecules such as flavonoids. Genetic variation in antioxidant enzymes is associated with more severe asthma.

Emotion

It is well known that emotional factors may influence asthma both acutely and chronically, but there is no evidence that patients with the disease are any more psychologically disturbed than their non-asthmatic peers. An asthma attack is a frightening experience, especially when of sudden and unexpected onset. Patients at special risk of life-threatening attacks are understandably anxious.

Drugs

Non-steroid anti-inflammatory drugs (NSAIDs). NSAIDs, particularly aspirin and propionic acid derivatives, e.g. indometacin and ibuprofen, are implicated in triggering asthma in approximately 5% of patients. NSAID intolerance is especially prevalent in those with both nasal polyps and asthma and is not infrequently associated with rhinitis and flushing on drug exposure. NSAIDs inhibit arachidonic acid metabolism via the cyclo-oxygenase (COX) pathway, preventing the synthesis of certain prostaglandins. In aspirin-intolerant asthma there is reduced production of PGE₂ which, in a sub-proportion of genetically susceptible subjects, induces the overproduction of cysteinyl leukotrienes by eosinophils, mast cells and macrophages. In such patients there is evidence for genetic polymorphisms involving the enzymes and receptors of the leukotriene generating pathway (Fig. 15.30). Interestingly, asthma in intolerant patients is not precipitated by COX-2 inhibitors, indicating that it is blockade of the COX-1 isoenzyme that is linked to impaired PGE₂ production.

Figure 15.30 Arachidonic acid metabolism and the effect of drugs. The sites of action of NSAIDs (e.g. aspirin, ibuprofen) are shown. The enzyme cyclo-oxygenase occurs in three isoforms, COX-1 (constitutive), COX-2 (inducible) and COX-3 (in brain). PG, prostaglandin; BLT, B leukotriene receptor; CysLT, cysteinyl leukotriene receptor.

Beta-blockers. The airways have a direct parasympathetic innervation that tends to produce bronchoconstriction. There is no direct sympathetic innervation of the smooth muscle of the bronchi, and antagonism of parasympathetically induced bronchoconstriction is critically dependent upon circulating epinephrine (adrenaline) acting through β₂-receptors on the surface of smooth muscle cells. Inhibition of this effect by β-adrenoceptor-blocking drugs such as propranolol leads to bronchoconstriction and airflow limitation, but only in asthmatic subjects. Selective β₁-adrenergic-blocking drugs such as atenolol may still induce attacks of asthma; ideally alternative drugs should be used to treat hypertension or angina in asthmatic patients.

Allergen-induced asthma

The experimental inhalation of allergen by atopic asthmatic individuals leads to the development of different types of reaction, as illustrated in Figure 15.31. Much of our knowledge of asthma mechanisms comes from studies of allergen inhalation, but it must always be remembered this is only a model of the disease.

Figure 15.31 Different types of asthmatic reactions following challenge with allergen. M, midnight; N, noon.

Immediate asthma (early reaction). Airflow limitation begins within minutes of contact with the allergen, reaches its maximum in 15–20 minutes and subsides by 1 hour.

Dual and late-phase reactions. Following an immediate reaction many asthmatics develop a more prolonged and sustained attack of airflow limitation that responds less well to inhalation of bronchodilator drugs such as salbutamol. Isolated late-phase reactions with no preceding immediate response can occur after the inhalation of some occupational sensitizers such as isocyanates. BHR increases during and for several weeks after the exposure, which may explain persisting symptoms after allergen exposure.

Pathogenesis

The pathogenesis of asthma is complex and not fully understood. It involves a number of cells, mediators, nerves and vascular leakage that can be activated by several different mechanisms, including exposure to allergens (Fig. 15.32). The varying clinical severity and chronicity of asthma is dependent on an interplay between airway inflammation and airway wall remodelling. The inflammatory component is driven by Th2-type T lymphocytes which facilitate IgE synthesis through production of IL-4 and eosinophilic inflammation through IL-5 (Fig. 15.32). However, as the disease becomes more severe and chronic and loses its sensitivity to corticosteroids, there is greater evidence of a Th1 response with release of mediators such as TNF-α and associated tissue damage, mucous metaplasia and aberrant epithelial and mesenchymal repair.

Figure 15.32 Inflammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unit. Epithelial damage alters the set point for communication between bronchial epithelium and underlying mesenchymal cells, leading to myofibroblast activation, an increase in mesenchymal volume, and induction of structural changes throughout airway wall.

(Adapted from Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006; 368: 780–793, with permission from Elsevier.)

Inflammation

Several key cells are involved in the inflammatory response that characterizes all types of asthma.

Mast cells (see also p. 53). These are increased in the epithelium, smooth muscle and mucous glands in asthma and release powerful preformed and newly generated mediators that act on smooth muscle, small blood vessels, mucus-secreting cells and sensory nerves, such as histamine, tryptase, PGD₂ and cysteinyl leukotrienes, which cause the immediate asthmatic reaction. Mast cells are inhibited by sodium cromoglycate and β₂ agonists, which may partly explain their ability to prevent acute bronchoconstriction triggered by indirect challenges. Mast cells also release an array of cytokines, chemokines and growth factors that contribute to the late asthmatic response and more chronic aspects of asthma.

Eosinophils. These are found in large numbers in the bronchial wall and secretions of asthmatics. They are attracted to the airways by the eosinophilopoietic cytokines IL-3, IL-5 and GM-CSF as well as by chemokines which act on type 3 C-C chemokine receptors (CCR-3) (i.e. eotaxin, RANTES, MCP-1, MCP-3 and MCP-4). These mediators also prime eosinophils for enhanced mediator secretion. When activated, eosinophils release LTC₄, and basic proteins such as major basic protein (MBP), eosinophil cationic protein (ECP) and eosinophils peroxidase (EPX) that are toxic to epithelial cells. Both the number and activation of eosinophils are rapidly decreased by corticosteroids. Sputum eosinophilia is of diagnostic help as well as providing a biomarker of response to therapy

Dendritic cells and lymphocytes. These cells are abundant in the mucous membranes of the airways and the alveoli. Dendritic cells have a role in the initial uptake and presentation of allergens to lymphocytes. T helper lymphocytes (CD4⁺) show evidence of activation (Fig. 15.32) and the release of their cytokines plays a key part in the migration and activation of mast cells (IL-3, IL-4, IL-9 and IL-13) and eosinophils (IL-3, IL-5, GM-CSF). In addition, production of IL-4 and IL-13 helps maintain the proallergic Th2 phenotype, favouring switching of antibody production by B lymphocytes to IgE. In mild/moderate asthma there is selective upregulation of Th2 T cells with reduced evidence of the Th1 phenotype (producing gamma-interferon, TNF-α and IL-2), although Th1 cells are more prominent in more severe disease. This polarization is mediated by dendritic cells and involves a combination of antigen presentation, co-stimulation and exposure to polarizing cytokines. The activity of both macrophages and lymphocytes is influenced by corticosteroids but not β₂-adrenoceptor agonists.

Remodelling

A characteristic feature of chronic asthma is an alteration of structure and functions of the formed elements of the airways. Together, these structural changes interact with inflammatory cells and mediators to cause the characteristic features of the disease. Deposition of matrix proteins, swelling and cellular infiltration expand the submucosa beneath the epithelium so that for a given degree of smooth muscle shortening there is excess airway narrowing. Swelling outside the smooth muscle layer spreads the retractile forces exerted by the surrounding alveoli over a greater surface area so that the airways close more easily. Several factors contribute to these changes.

The epithelium. In asthma the epithelium of the conducting airways is stressed and damaged with loss of ciliated columnar cells. Metaplasia occurs with a resultant increase in the number and activity of mucus-secreting goblet cells. The epithelium is a major source of mediators, cytokines and growth factors that enhance inflammation and promote tissue remodelling (Fig. 15.32). Damage and activation of the epithelium make it more vulnerable to infection by common respiratory viruses (e.g. rhinovirus, coronavirus) and to the effects of air pollutants. Increased production of nitric oxide (NO), due to the increased expression of inducible NO synthase, is a feature of epithelial damage and activation. Measurement of exhaled NO is proving useful as a non-invasive test of continuing inflammation (p. 829).

Epithelial basement membrane. A pathognomonic feature of asthma is the deposition of repair collagens (types I, III and V) and proteoglycans in the lamina reticularis beneath the basement membrane. This, along with the deposition of other matrix proteins such as laminin, tenascin and fibronectin, causes the appearance of a thickened basement membrane observed by light microscopy in asthma. This collagen deposition reflects activation of an underlying sheath of fibroblasts that transform into contractile myofibroblasts which also have an increased capacity to secrete matrix. Aberrant signalling between the epithelium and underlying myofibroblasts is thought to be the principal cause of airway wall remodelling, since the cells are prolific producers of a range of tissue growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF)-α and -β, connective tissue-derived growth factor (CTGF), platelet-derived growth factor (PDGF), endothelin (ET), insulin-like growth factors (IGF), nerve growth factors and vascular endothelial growth factors (Fig. 15.32). The same interaction between epithelium and mesenchymal tissues is central to branching morphogenesis in the developing fetal lung. It has been suggested that these mechanisms are reactivated in asthma, but instead of causing airway growth and branching, they lead to thickening of the airway wall (remodelling, Fig. 15.32). Increased deposition of collagens, proteoglycans and matrix proteins creates a microenvironment which encourages ongoing inflammation since these molecules also possess cell-signalling functions, which aid cell movement, prolong inflammatory cell survival and prime them for mediator secretion.

Smooth muscle. Another prominent feature of asthma is hyperplasia of the helical bands of airway smooth muscle. In addition to increasing in amount, the smooth muscle alters in function so it contracts more easily and stays contracted because of a change in actin–myosin cross-link cycling. These changes allow asthmatic airways to contract too much and too easily at the least provocation. Asthmatic smooth muscle also secretes a wide range of cytokines, chemokines and growth factors that help sustain the chronic inflammatory response. The asthma gene ADAM33 has been implicated in driving increased airway smooth muscle and other features of remodelling through increased availability of growth factors.

Nerves. Neural reflexes, both central and peripheral, contribute to the irritability of asthmatic airways. Central reflexes involve stimulation of nerve endings in the epithelium and submucosa with transmission of impulses via the spinal cord and brain back down to the airways where release of acetylcholine from nerve endings stimulates M₃ receptors on smooth muscle causing contraction. Local neural reflexes involve antidromic neurotransmission and the release of a variety of neuropeptides. Some of these are smooth muscle contractants (substance P, neurokinin A), some are vasoconstrictors (e.g. calcitonin gene-related peptide, CGRP) and some vasodilators (e.g. neuropeptide Y, vasoactive intestinal polypeptide). A polymorphism of the neuropeptide S receptor (GPR 154) is associated with asthma susceptibility. Bradykinin generated by tissue and serum proteolytic enzymes (including mast cell tryptase and tissue kallikrein) is also a potent stimulus of local neural reflexes involving (nonmyelinated) nerve fibres.

FURTHER READING

Tschumperlin DJ. Physical forces and airway remodelling in asthma. N Engl J Med 2011; 364:2058–2057.

Clinical features

The principal symptoms of asthma are wheezing attacks and episodic shortness of breath. Symptoms are usually worst during the night, especially in uncontrolled disease. Cough is a frequent symptom that sometimes predominates, especially in children in whom nocturnal cough can be a presenting feature. Attacks vary greatly in frequency and duration. Some patients only have one or two attacks a year that last for a few hours, while others have attacks lasting for weeks. Some patients have chronic persistent symptoms, on top of which there are fluctuations. Attacks may be precipitated by a wide range of triggers (Fig. 15.29). Asthma is a major cause of impaired quality of life with impact on work and recreational, as well as physical activities, and emotions.

Investigations

There is no single satisfactory diagnostic test for all patients with asthma.

Lung function tests

Peak expiratory flow rate (PEFR) measurements on waking, prior to taking a bronchodilator and before bed after a bronchodilator, are particularly useful in demonstrating the variable airflow limitation that characterizes the disease (Fig. 15.14). The diurnal variation in PEFR is a good measure of asthma activity and is of help in the longer-term assessment of the patient’s disease and its response to treatment.

Spirometry is useful, especially in assessing reversibility. Asthma can be diagnosed by demonstrating a greater than 15% improvement in FEV₁ or PEFR following the inhalation of a bronchodilator. However, there may be less reversibility when asthma is in remission or in severe chronic asthma when little reversibility can be demonstrated or if the patient is already being treated with long-acting bronchodilators.

The carbon monoxide (CO) transfer test is normal in asthma.

Exercise tests

These have been widely used in the diagnosis of asthma in children. Ideally, the child should run for 6 minutes on a treadmill at a workload sufficient to increase the heart rate above 160 beats per minute. Alternative methods use cold air challenge, isocapnic hyperventilation (forced overbreathing with artificially maintained P_ACO₂) or aerosol challenge with hypertonic solutions. A negative test does not automatically rule out asthma.

Histamine or methacholine bronchial provocation test (see p. 824)

This test indicates the presence of airway hyperresponsiveness, a feature found in most asthmatics, and can be particularly useful in investigating those patients whose main symptom is cough. The test should not be performed on individuals who have poor lung function (FEV₁ <1.5 L) or a history of ‘brittle’ asthma. In children, controlled exercise testing as a measure of BHR is often easier to perform.

Trial of corticosteroids

All patients who present with severe airflow limitation should undergo a formal trial of corticosteroids. Prednisolone 30 mg orally should be given daily for 2 weeks with lung function measured before and immediately after the course. A substantial improvement in FEV₁ (>15%) confirms the presence of a reversible element and indicates that the administration of inhaled steroids will prove beneficial to the patient. If the trial is for ≤2 weeks, the oral corticosteroid can be withdrawn without tailing off the dose, and should be replaced by inhaled corticosteroids in those who have responded.

Exhaled nitric oxide (NO)

A measure of airway inflammation and an index of corticosteroid response; used in children to assess the efficacy of corticosteroids.

Blood and sputum tests

Patients with asthma sometimes have increased numbers of eosinophils in peripheral blood (>0.4 × 10⁹/L) but sputum eosinophilis is a more specific diagnostic finding.

Chest X-ray

There are no diagnostic features of asthma on the chest X-ray, although overinflation is characteristic during an acute episode or in chronic severe disease. A chest X-ray may be helpful in excluding a pneumothorax, which can occur as a complication, or in detecting the pulmonary infiltrates associated with allergic bronchopulmonary aspergillosis.

Skin tests

Skin-prick tests (SPT) should be performed in all cases of asthma to help identify allergic trigger factors. Allergen-specific IgE can be measured in serum if SPT facilities are not available, if the patient is taking antihistamines or no suitable allergen extracts are available.

Allergen provocation tests

Allergen inhalation challenge is a useful research tool, and is required when investigating of patients with suspected occupational asthma, but not in ordinary asthma.

Management

The aims of treatment are to:

Abolish symptoms

Restore normal or best possible lung function

Reduce the risk of severe attacks

Enable normal growth to occur in children

Minimize absence from school or employment.

This involves:

Patient and family education about asthma

Patient and family participation in treatment

Avoidance of identified causes where possible

Use of the lowest effective doses of convenient medications to minimize short-term and long-term side-effects.

Many asthmatics join self-help groups whose aim in order to improve their understanding of the disease and to foster self-confidence and fitness.

Control of extrinsic factors

Measures must be taken to avoid causative allergens such as pets, moulds and certain foodstuffs (see allergic rhinitis), particularly in childhood. Avoidance of house-dust mite is very difficult. There is little evidence for the effectiveness of current physical or chemical measures to control house-dust mite levels. The use of covers for bedding and changes to living accommodation has no beneficial effect on outcomes. Active and passive smoking should be avoided, as should beta-blockers in either tablet or eye drop form. Individuals intolerant to aspirin should avoid NSAIDs, although they may tolerate COX-2 inhibitors. Other agents (e.g. preservatives and colouring materials such as tartrazine) should be avoided if shown to be a causative factor. About one-third of individuals sensitized to occupational agents may be cured if they are kept permanently away from exposure. The remaining two-thirds will continue to have symptoms, and in half of these the symptoms may be as severe as when exposed to materials at work, especially if they were symptomatic for a long time before the diagnosis was made.

This emphasizes that:

The rapid identification of extrinsic causes of asthma and their removal is necessary wherever possible (e.g. occupational agents, family pets).

Once extrinsic asthma is initiated, it may become self-perpetuating, possibly by non-immune mechanisms.

Drug treatment

The mainstay of asthma therapy is the use of therapeutic agents delivered as aerosols or powders directly into the lungs (see Practical Box 15.3). The advantages of this method of administration are that drugs are delivered direct to the airways and first-pass metabolism in the liver is avoided; thus lower doses are necessary and systemic unwanted effects are minimized.

Practical Box 15.3

Inhaled therapy

Patients should be taught how to use inhalers and their technique checked regularly.

Use of a metered-dose inhaler

1. The canister is shaken.

2. The patient exhales to functional residual capacity (not residual volume), i.e. normal expiration.

3. The aerosol nozzle is placed to the open mouth.

4. The patient simultaneously inhales rapidly and activates the aerosol.

5. Inhalation is completed.

6. The breath is held for 10 seconds if possible. Even with good technique, only 15% of the contents is inhaled and 85% is deposited on the wall of the pharynx and ultimately swallowed.

Spacers

These are plastic cones or spheres inserted between the patient’s mouth and the inhaler. Some inhalers have a built-in spacer extension. These are designed to reduce particle velocity so that less drug is deposited in the mouth. Spacers also diminish the need for coordination between aerosol activation and inhalation. They are useful in children and in the elderly and reduce the risk of candidiasis.

Both national and international guidelines have been published on the stepwise treatment of asthma (Box 15.3), based on three principles:

Asthma self-management with regular asthma monitoring using PEF meters and individual treatment plans that are discussed with each patient and written down.

The appreciation that asthma is an inflammatory disease and that anti-inflammatory (controller) therapy should be started even in mild cases.

Use of short-acting inhaled bronchodilators (e.g. salbutamol and terbutaline) only to relieve breakthrough symptoms. Increased use of bronchodilator treatment to relieve increasing symptoms is an indication of deteriorating disease.

Box 15.3

The stepwise management of asthma

Step	PEFR	Treatment
1. Occasional symptoms; less frequent than daily	100% predicted	As-required short-acting β₂ agonists If used more than once daily, move to step 2
2. Daily symptoms	<80% predicted	Regular inhaled preventer therapy: Anti-inflammatory drugs: inhaled low-dose corticosteroids up to 800 µg daily Leukotriene receptor antagonists (LTRA), theophylline and sodium cromoglycate are less effective If not controlled, move to step 3
3. Severe symptoms	50–80% predicted	Inhaled corticosteroids and long-acting inhaled β₂ agonist Continue inhaled corticosteroid Add regular inhaled long-acting β₂ agonist (LABA) Still not controlled, add either LTRA, modified release oral theophylline or β₂ agonist If not controlled, move to step 4
4. Severe symptoms uncontrolled with high-dose inhaled corticosteroids	50–80% predicted	High-dose inhaled corticosteroid and regular bronchodilators Increase high-dose inhaled corticosteroids up to 2000 µg daily Plus regular long-acting β₂ agonists Plus either LTRA or modified release theophylline or β₂ agonist
5. Severe symptoms deteriorating	≤50% predicted	Regular oral corticosteroids Add prednisolone 40 mg daily to step 4
6. Severe symptoms deteriorating in spite of prednisolone	≤30% predicted	Hospital admission

Short-acting bronchodilator treatment taken at any step on an as-required basis.

A list of drugs used in asthma is shown in Box 15.4. These are given in a stepwise fashion as indicated in Box 15.3.

Box 15.4

Drugs used in asthma

Short-acting relievers

Inhaled β₂ agonists (e.g. salbutamol (albuterol in USA), terbutaline)

Long-acting relief/disease controllers

Inhaled long-acting β₂ agonists (e.g. salmeterol, formoterol)

Inhaled corticosteroids (e.g. beclometasone, budesonide, fluticasone)

Compound inhaled salmeterol and fluticasone

Sodium cromoglycate

Leukotriene modifiers (e.g. montelukast, zafirlukast, zileuton)

Other agents with bronchodilator activity

Inhaled antimuscarinic agents (e.g. ipratropium, oxitropium)

Theophylline preparations

Oral corticosteroids (e.g. prednisolone 40 mg daily)

Steroid-sparing agents

Methotrexate

Ciclosporin

Intravenous immunoglobulin

Anti-IgE monoclonal antibody – omalizumab

Etanercept (p. 72), infliximab, lebrikizumab

Once asthma is brought under control, for at least 2–3 months, the drug regimen should be reassessed in order to reduce the dosage of inhaled steroids.

β₂-Adrenoceptor agonists

The most widely used bronchodilator preparations contain β₂-adrenoceptor agonists that are selective for the respiratory tract and do not stimulate the β₁ adrenoceptors of the myocardium. These drugs are potent bronchodilators because they relax the bronchial smooth muscle. They are very effective in relieving symptoms but do little for the underlying airways inflammation. Their usage is as follows:

Mildest asthmatics with intermittent attacks. Only these people should rely on bronchodilator treatment alone. Short-acting β agonists (SABAs) such as salbutamol (100 µg), (called albuterol in the USA), or terbutaline (250 µg) should be prescribed as ‘two puffs as required’. Some patients use nebulizers at home for self-administration of salbutamol or terbutaline. Such treatment is effective, but patients should not rely on repeated home administration of nebulized β₂-adrenoceptor agonists for worsening asthma, and should seek medical advice urgently if their condition does not improve. Excessive use of SABAs was linked to two epidemics of asthma mortality in the 1960s and 1980s.

SABAs can be taken at any step, as and when required from step 1 to step 5 (see above).

Poorly controlled asthmatics on standard doses of inhaled steroids. These patients require salmeterol or formoterol, which are highly selective and potent long-acting β₂-adrenoceptor agonists (LABAs) effective by inhalation for up to 12 hours, thereby reducing the need for administration to once or twice daily. LABAs improve symptoms and lung function and reduce exacerbations in patients. They should never be used alone but always in combination with an inhaled corticosteroid. Increasingly, these drugs are administered as fixed-dose combinations with corticosteroids (salmeterol/fluticasone and formoterol/budesonide) in the same inhaler (step 3).

To help those who cannot coordinate activation of the aerosol and inhalation, several breath-activated or dry powder devices have been developed.

Antimuscarinic bronchodilators

Muscarinic receptors are found in the respiratory tract; large airways contain mainly M₃ receptors whereas the peripheral lung tissue contains M₃ and M₁ receptors (see p. 793). Non-selective muscarinic antagonists – ipratropium bromide (20–40 µg three or four times daily) or oxitropium bromide (200 µg twice daily) – by aerosol inhalation can be useful during asthma exacerbations, but they are less useful in stable asthma.

Anti-inflammatory drugs

Sodium cromoglycate and nedocromil sodium prevent activation of many inflammatory cells, particularly mast cells, eosinophils and epithelial cells, but not lymphocytes, by blocking a specific chloride channel which in turn prevents calcium influx. These drugs are effective in patients with milder asthma (step 2) but have fallen out of favour in recent years.

Inhaled corticosteroids

All patients who have regular persistent symptoms (even mild symptoms) need regular treatment with inhaled corticosteroids delivered in a stepwise fashion (from step 2 upwards) or as a high dose followed by a reduction to maintenance levels. Beclometasone dipropionate (BDP) is the most widely used inhaled steroid and is available in doses of 50, 100, 200 and 250 µg per puff. Other inhaled steroids include budesonide, fluticasone, mometasone and triamcinolone.

Much of the inhaled dose does not reach the lung but is either swallowed or exhaled. Deposition in the lung varies between 10% and 25% depending on inhaler technique and the technical characteristics of the aerosol device. Drug which is deposited in the airways reaches the systemic circulation directly, through the bronchial circulation, while any drug that is swallowed has to pass through the liver before it can reach the systemic circulation. Gram for gram, fluticasone and mometasone are more potent than beclometasone with considerably less systemic bioavailability, owing to their greater sensitivity to hepatic metabolism. Absorption of beclometasone and budesonide does not seem to present a risk at doses up to 800 µg/day, but fluticasone or mometasone may be preferred because of their lower bioavailability when high-dose inhaled steroids are needed. The dose-response curve for inhaled corticosteroids is flat beyond 800 µg beclometasone or equivalent, and in patients with moderate asthma who are taking this daily, addition of a LABA is more effective than doubling the dose of inhaled corticosteroid.

Unwanted effects of inhaled corticosteroids include oral candidiasis (5% patients), and hoarseness. Subcapsular cataract formation is rare but can occur in the elderly. Osteoporosis is less likely than with oral steroids but can occur with high-dose inhaled corticosteroids (beclometasone or budesonide >800 µg daily). In children, inhaled corticosteroids at doses >400 µg daily have been shown to retard short-term growth, but final heights are not affected. Inhaled corticosteroid use should be stepped down once asthma comes under control (p. 830). Candidiasis and GI absorption can be reduced by using spacers, mouthwashing and teeth cleaning after use. Inhaled corticosteroids that are esterified in the lung, thereby reducing systemic effects, are also used (e.g. ciclesonide 80 µg daily).

Asthmatic patients who smoke are less responsive to inhaled corticosteroids due to induction of a range of genes and proteins in their respiratory epithelium. Assistance with smoking cessation should be offered, and additional therapy, e.g. with leukotriene receptor antagonists or theophylline, is required.

A functional GLCCI1 variant is associated with a decreased response to inhaled corticosteroids.

Many patients with anything more than mild/moderate asthma benefit from combination LABA/corticosteroid therapy and there is some evidence that the two drugs interact therapeutically.

Oral corticosteroids and steroid-sparing agents

Oral corticosteroids are needed for individuals not controlled on inhaled corticosteroids (step 5). The dose should be kept as low as possible to minimize side-effects. The effect of short-term treatment with prednisolone 30 mg daily is shown in Figure 15.14 (p. 804). Some patients require continuing treatment with oral corticosteroids. Several studies suggest that treatment with low doses of methotrexate (15 mg weekly) can significantly reduce the dose of prednisolone needed to control the disease in some patients, and ciclosporin also improves lung function in some steroid-dependent asthmatics. Several other steroid-sparing strategies including ciclosporin and immunoglobulin have also been tried, but with varying success.

Cysteinyl leukotriene receptor antagonists (LTRAs)

This class of anti-asthma therapy targets one of the principal asthma mediators by inhibiting the cysteinyl LT₁ receptor. A second receptor (cyst LT₂) has been identified on inflammatory cells. Montelukast, pranlukast (only available in South-east Asia) and zafirlukast are given orally and are effective in a subpopulation of patients. However, it is not possible to predict which individuals will benefit: a 4-week trial of LTRA therapy is recommended before a decision is made to continue or stop. LTRAs should be tried in any patient who is not controlled on low to medium doses of inhaled steroids (step 2). Their action is additive to that of long-acting β₂ agonists. LTRAs are particularly useful in patients with aspirin-intolerant asthma, in those patients requiring high-dose inhaled or oral corticosteroids and in asthmatic smokers. Because these drugs are orally active they are helpful in asthma combined with rhinitis and in young children with asthma and/or virus-associated wheezing.

Monoclonal antibodies

Omalizumab, a recombinant humanized monoclonal antibody directed against IgE, chelates free IgE and downregulate the number and activity of mast cells and basophils. It is given subcutaneously every 2–4 weeks, depending on total serum IgE level and body weight. Although expensive, it is cost-effective in patients with frequent exacerbations requiring hospital admission. Proof-of-concept trials have shown that anti-TNF therapy (infliximab or etanercept) may be helpful in severe corticosteroid-refractory asthma. There is still a need to examine other biological agents as potential new controller therapies for the 5–10% of patients with severe disease, who account for a high proportion of the health costs of asthma.

Lebrikizumab, a monoclonal antibody to IL-3, showed improvement in lung function in one recent study.

Antibiotics

Although wheezing frequently occurs in infective exacerbations of COPD, there is little evidence that antibiotics are helpful in managing patients with asthma. During acute exacerbations, yellow or green sputum containing eosinophils and bronchial epithelial cells may be coughed up. This is normally due to viral rather than bacterial infection and antibiotics are not required. Occasionally, mycoplasma and Chlamydia infections can cause chronic relapsing asthma and macrolide antimicrobials may be helpful if a bacterial diagnosis has been established by culture or serology.

Asthma attack

Although these may occur spontaneously, asthma exacerbations are most commonly caused by lack of treatment adherence, respiratory virus infections associated with the common cold, and exposure to allergen or triggering drug, e.g. an NSAID. Whenever possible, patients should have a written personalized plan that they can implement in anticipation of or at the start of an exacerbation that includes the early use of a short course of oral corticosteroids. If the PEFR is >150 L/min, patients may improve dramatically on nebulized therapy and may not require hospital admission. Their regular treatment should be increased, to include treatment for 2 weeks with 30–60 mg of prednisolone followed by substitution by an inhaled corticosteroid preparation. Short courses of oral prednisolone can be stopped abruptly without tailing down the dose.

Acute severe asthma

The term acute severe asthma is used to mean an exacerbation of asthma that has not been controlled by the use of standard medication.

Patients with acute severe asthma typically have:

the inability to complete a sentence in one breath

a respiratory rate of ≥25 breaths/min

Tachycardia ≥110 beats/min (pulsus paradoxus is not useful as it is only present in 45% of cases)

PEFR <50% of predicted normal or best.

Features of life-threatening attacks are:

A silent chest, cyanosis or feeble respiratory effort

Exhaustion, confusion or coma

Bradycardia or hypotension

PEFR <30% of predicted normal or best (approximately 150 L/min in adults).

Arterial blood gases should always be measured in asthmatic patients requiring admission to hospital, with particular attention paid to the P_aCO₂. Pulse oximetry is useful in monitoring oxygen saturation during the admission and can reduce the need for repeated arterial puncture. Features suggesting very severe life-threatening attacks are:

a high P_aCO₂ >6 kPa

severe hypoxaemia P_aO₂ <8 kPa despite treatment with oxygen

a low and falling arterial pH.

Treatment (Emergency Box 15.2) consists of nebulized short-acting bronchodilators; nebulized antimuscarinics (e.g. ipratropium bromide) are also helpful. A chest X-ray is useful to exclude pneumothorax and other causes of dyspnoea. Intravenous hydrocortisone is useful, and in very severe cases, β₂-adrenoceptor agonists and/or magnesium sulphate are also given intravenously. Oral prednisolone (40–60 mg daily) should be given orally. Ventilation is required for patients who deteriorate despite this initial regimen.

Emergency Box 15.2

Treatment of severe asthma

At home

1. The patient is assessed. Tachycardia, a high respiratory rate and inability to speak in sentences indicate a severe attack.

2. If the PEFR is <150 L/min (in adults), an ambulance should be called. (All doctors should carry peak flow meters.)

3. Nebulized salbutamol 5 mg or terbutaline 10 mg is administered.

4. Hydrocortisone sodium succinate 200 mg i.v. is given.

5. Oxygen 40–60% is given if available.

6. Prednisolone 60 mg is given orally.

At hospital

1. The patient is reassessed.

2. Oxygen 40–60% is given.

3. The PEFR is measured using a low-reading peak flow meter, as an ordinary meter measures only from 60 L/min upwards.

Measure O₂ saturation with a pulse oximeter.

4. Nebulized salbutamol 5 mg or terbutaline 10 mg is repeated and administered 4-hourly.

5. Add nebulized ipratropium bromide 0.5 mg to nebulized salbutamol/terbutaline.

6. Hydrocortisone 200 mg i.v. is given 4-hourly for 24 hours.

7. Prednisolone is continued at 60 mg orally daily for 2 weeks.

8. Arterial blood gases are measured; if the P_aCO₂ is >7 kPa, ventilation may be required.

9. A chest X-ray is performed to exclude pneumothorax.

10. One of the following intravenous infusions is given if no improvement is seen:

Salbutamol 3–20 µg/min, or

Terbutaline 1.5–5.0 µg/min, or

Magnesium sulphate 1.2–2 g over 20 min.

11. No improvement – urgent; transfer to ITU

Depending on progress, patients may go home after receiving nebulized therapy. More severe cases should be kept in hospital for 2–5 days with regular monitoring of oxygen saturation and peak flow rates. Downstream assessment of patients admitted with asthma should address trigger factors and aim to reduce the risk of readmission. Bronchial thermoplasty is a novel approach for moderate to severe persistent asthma is. This bronchoscopic procedure reduces the mass of airway smooth muscle, reducing bronchoconstriction, and is being evaluated.

Management of catastrophic sudden severe asthma (brittle asthma)

A small minority of patients with asthma suffer sudden life-threatening attacks despite being well controlled between attacks. These attacks may occur within hours or even minutes, and can cause sudden death. Such patients require a carefully worked out management plan agreed by patient, primary care physician hospital emergency services and the respiratory physician, which may include:

Optimization of standard therapy

Emergency supplies of medications at home, in the car and at work

Oxygen and resuscitation equipment at home and at work

Nebulized β₂-adrenoceptor agonists at home and at work

Self-injectable adrenaline (epinephrine): two autoinjectors of 0.3 mg adrenaline at home, at work and to be carried by the patient at all times

Prednisolone tablets 60 mg

Medic Alert bracelet.

On developing wheeze, the patient should attend the nearest hospital immediately. Direct admission to intensive care may be required.

Prognosis of asthma

Although asthma often improves in children as they reach their teens, the disease frequently returns in the 2nd, 3rd and 4th decades. In the past, the data indicating a natural decrease in asthma through teenage years have led to childhood asthma being treated as an episodic disorder. However, airway inflammation is present continuously from an early age and usually persists even if the symptoms resolve. Moreover, airways remodelling accelerates the process of decline in lung function over time. This has led to a reappraisal of the treatment strategy for asthma, mandating the early use of controller drugs and environmental measures from the time asthma is first diagnosed.

FURTHER READING

British Thoracic Society. British guidelines on the management of asthma. Thorax 2008; 63(SIV):1–121.

Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med 2006; 355:2226–2235.

Holgate ST, Polosa R. The mechanisms, diagnosis and management of severe asthma in adults. Lancet 2006; 368:780–793.

SIGNIFICANT WEBSITE

Scottish Intercollegiate Guidelines Network. Guideline No. 101. British Guideline on the Management of Asthma. 2011 update: http://www.sign.ac.uk/guidelines/fulltext/101/index.html

Pneumonia

Pneumonia is defined as inflammation of the substance of the lungs. It is usually caused by bacteria but can also be caused by viruses and fungi. Clinically, it usually presents as an acute illness with cough, purulent sputum, breathlessness and fever together with physical signs or radiological changes compatible with consolidation of the lung (Fig. 15.33). However, it can present with more subtle symptoms, particularly in the elderly. About 50% of pneumonia is pneumococcal.

Figure 15.33 Chest X-ray showing lobar pneumonia.

Pneumonia is usually classified by the setting in which the person has contracted their infection, e.g.

In the community setting or community-acquired pneumonia (CAP) by a person with no underlying immunosuppression or malignancy

In a hospital or other institution such as a nursing home – hospital-acquired pneumonia (HAP)

In a patient whose immune system is compromised, through either genetic defect, immunosuppressive medication, or acquired immunodeficiency such as HIV infection.

Community-acquired pneumonia (CAP)

Community-acquired pneumonia occurs across all ages, but is commoner at the extremes of age. There has been an increase in rates of hospital admission due to community-acquired pneumonia over the last 10 years, reflecting changes in clinical practice and an ageing population, rather than a true increase in incidence.

Pneumonia can be classified either according to the organism responsible for infection or by the site of disease; Pneumococcus is the commonest cause overall; however, in 30–50% cases no organisms is identifiable while in about 20% of cases more than one organism is present. Infection can be localized with the whole of one or more lobes affected (‘lobar pneumonia’) or diffuse, when the lobules of the lung are mainly affected, often due to infection centred on the bronchi and bronchioles (‘bronchopneumonia’).

Pathophysiology

Several different microorganisms commonly cause CAP. Infection is spread by respiratory droplets. Both the clinical presentation and the range of causative organisms vary with age and with the effectiveness of the host’s immune response and innate defence mechanisms. Factors which increase the risk of developing CAP are shown in Box 15.5.

Box 15.5

Risk factors for community-acquired pneumonia

Age: <16 or >65 years

Co-morbidities: HIV infection, diabetes mellitus, chronic kidney disease, malnutrition, recent viral respiratory infection

Other respiratory conditions: cystic fibrosis, bronchiectasis, COPD, obstructing lesion (endoluminal cancer, inhaled foreign body)

Lifestyle: cigarette smoking, excess alcohol, intravenous drug use

Iatrogenic: immunosuppressant therapy (including prolonged corticosteroids)

Other causes of pneumonitis are listed below:

Chemical insult, such as in the aspiration of vomit (see p. 838)

Radiotherapy (see p. 838)

Allergic mechanisms (see p. 852).

Clinical features of CAP

The clinical presentation varies according to the immune state of the patient and the infecting agent.

Cough: this may be dry or productive and haemoptysis can occur. In pneumococcal pneumonia, sputum is characteristically rust-coloured.

Breathlessness: the alveoli become filled with pus and debris, impairing gas exchange. Coarse crackles are often heard on auscultation, due to consolidation of the lung parenchyma. Bronchial breath sounds may be heard over areas of consolidated lung.

Fever: this can be as high as 39.5–40°C. If swinging fevers are present this often indicates empyema (see Complications).

Chest pain: this is commonly pleuritic in nature and is due to inflammation of the pleura. A pleural rub may be heard early on in the illness.

Extrapulmonary features (Box 15.6): these are more common in certain infections and are not universal. Sometimes the presence of these symptoms gives a clinical clue as to the aetiology.

– Haemolysis due to cold agglutinins occurs (in approximately 50% cases of Mycoplasma pneumonia). Thrombocytopenia is relatively common.

Other features: in the elderly, CAP can present with confusion or nonspecific symptoms such as recurrent falls. CAP should always be considered in the differential diagnosis of sick elderly patients given their frequently atypical presentation.

Where symptoms have been present for several weeks or have failed to respond to standard antibiotics, the possibility of tuberculosis should always be remembered.

Box 15.6

Extrapulmonary features of community-acquired pneumonia

Myalgia, arthralgia and malaise are common, particularly in infections caused by Legionella and Mycoplasma

Myocarditis and pericarditis are cardiac manifestations of infection, most commonly in Mycoplasma pneumonia

Headache is common in Legionella pneumonia. Meningoencephalitis and other neurological abnormalities also occur but are much less common

Abdominal pain, diarrhoea and vomiting are common. Hepatitis can be a feature of Legionella pneumonia

Labial herpes simplex reactivation is relatively common in pneumococcal pneumonia

Other skin rashes such as erythema multiforma and erythema nodosum are found in Mycoplasma pneumonia. Stevens–Johnson syndrome (p. 1231) is a rare and potentially life-threatening complication of pneumonia

Investigation and management of CAP

The clinical presentation varies between different causative organisms, but there is considerable overlap. Streptococcus pneumoniae (pneumococcus) is the commonest single cause, and all treatment and investigation strategies need to cover this. The most likely causative pathogens must be treated while considering alternative less common infectious causes (such as tuberculosis) or an alternative pathology (e.g. lung cancer). The treatment plan can always be refined and focused later. Pneumonia caused by endobronchial obstruction due to lung cancer is the main underlying problem.

Initial assessment

The type and extent of investigation depends on the severity of the illness, which also guides where the patient should be managed and predicts their outcome. Diagnostic microbiological tests are not needed in mild infection, which should be treated at home with standard antibiotics (amoxicillin or clarithromycin for those with a history of penicillin allergy). Where patients have mild disease, chest X-ray is not routinely recommended unless they fail to improve after 48–72 hours. Antibiotics can be administered orally.

Severity is commonly assessed by CURB-65 or the CRB-65 score (Box 15.7). These give a guide to the likely risk of fatal outcome but they are not mandatory and antibiotic choice must always be tempered by clinical assessment and judgement, taking into account other factors associated with increased rates of mortality (Box 15.8). The CRB-65 score is used in the community where the serum urea level is not usually available (Fig. 15.34). Other severity scores are available to predict mortality and where a patient should be cared for such as the Pneumonia Severity Index (PSI), which is used more widely in the USA. Figure 15.34 illustrates a suggested diagnostic and treatment algorithm in CAP. It incorporates treatment recommendations extracted both from the British Thoracic Society Guidance for the management of CAP (2009) and the Infectious Diseases Society of America/American Thoracic Society Guidance 2007.

Box 15.7

CURB-65 score

C: confusion present (abbreviated mental test score <8/10)

U: (plasma) urea level >7 mmol/L

R: respiratory rate >30/min

B: systolic BP <90 mmHg; diastolic BP <60 mmHg

65: age >65

1 point for each of the above:

Score 0–1: Treat as outpatient

Score 2: Admit to hospital

Score 3+: Often require ICU care

Mortality rates increase with increasing score.

Box 15.8

Other markers of severe community-acquired pneumonia

Chest X-ray: more than one lobe involved

P_aO₂ <8 kPa

Low albumin (<35 g/L)

White cell count (<4 × 10⁹/L or >20 × 10⁹/L)

Blood culture – positive

Other co-morbidities

Absence of fever in the elderly

Figure 15.34 Algorithm for the assessment and treatment of CAP. CRB, confusion, respiratory rate, blood pressure.

Investigations

All patients admitted to hospital should have a chest X-ray, blood tests and microbiological tests.

Chest X-ray

This must be repeated 6 weeks after discharge unless complications occur to rule out an underlying bronchial malignancy predisposing to pneumonia by causing obstruction.

Strep. pneumoniae. Consolidation with air bronchograms, effusions and collapse due to retention of secretions can all be seen. Radiological abnormalities can lag behind clinical signs. A normal chest X-ray on presentation should be repeated after 2–3 days where CAP is suspected

Mycoplasma. Usually one lobe is involved but infection can be bilateral and extensive.

Legionella. There is lobar and then multi-lobar shadowing, with the occasional small pleural effusion. Cavitation is rare.

Blood tests

Full blood count, urea and electrolytes, biochemistry and C-reactive protein are helpful.

Strep. pneumoniae. White cell count is >15 × 10⁹/L (90% polymorphonuclear leucocytosis); inflammatory markers significantly elevated: ESR >100 mm/hour; CRP >100 mg/L.

Mycoplasma. White cell count is usually normal. In the presence of anaemia, haemolysis should be ruled out (direct Coombs’ test and measurement of cold agglutinins).

Legionella. There is lymphopenia without marked leucocytosis, hyponatraemia, hypoalbuminaemia and high serum levels of liver aminotransferases.

Other tests

The causative organism must be identified:

Sputum culture and Gram-stain are required for all patients:

– S. pneumoniae: Gram-positive diplococci

– S. aureus: Gram-positive organisms commonly in clusters like a bunch of grapes

– Also diagnostic in infections caused by S. aureus, H. influenzae, M. catarrhalis, Gram-negative organisms

Blood culture should be done for all patients who have moderate to severe CAP, ideally before antibiotics are administered. In S. pneumoniae infection, positive blood culture indicates more severe disease with greater mortality.

Table 15.14 highlights more specific diagnostic tests used to identify the causative organism in patients with moderate to severe CAP.

Table 15.14 Specific diagnostic tests in patients with moderate to severe community-acquired pneumonia (CAP)

Organism	Diagnostic confirmatory test
Streptococcus pneumoniae	Counter-immunoelectrophoresis (CIE) of sputum, urine and serum is 3–4 times more sensitive than sputum or blood cultures
	Urinary antigen test detects C-polysaccharide. This is rapid and unaffected by antibiotics; sensitivity is 65–80% and specificity about 80%
	Pneumococcal PCR (not routinely recommended as inferior to blood cultures and low sensitivity)
Mycoplasma pneumoniae	PCR of respiratory tract samples (throat swab/sputum/BAL fluid) – higher detection rates than serological assays
	PCR on serum under assessment and likely to become more available
	Complement fixation test (CFT) (though sensitivity and specificity low) – measure paired samples 10–14 days apart and look for rising titres or single level approximately 7 days after onset of illness
Legionella spp. (also termed Legionnaire’s disease)	Urinary antigen test detects only serogroup 1, which accounts for most of these infections. Sensitivity (~80%) and specificity are high (almost 99%)
	Direct immunofluorescent staining of organism in the pleural fluid, sputum or bronchial washings is carried out
	Serum antibodies are less reliable. Paired serum antibody titres 10–14 days apart (or single level 7 days after onset of illness)
	Culture on special media is possible but takes up to 3 weeks. This gives valuable information on antibiotic sensitivity and should be performed if urinary antigen positive
	Legionella is not visible on Gram-staining
Chlamydophila pneumoniae	Paired serum antibody titres 10–14 days apart
	Antigen detection (DIF) on throat swabs/respiratory samples
	CFT usually only weakly positive and less reliable than in C. psittaci
Chlamydophila psittaci	Paired serum antibody titres 10–14 days apart
	CFT relatively sensitive and specific
	Antigen detection (DIF) not available for C. psittaci
Coxiella burnetti (Q fever)	Paired serum antibody titres 10–14 days apart
All respiratory viruses including influenza A and B	PCR of respiratory tract samples (throat swab/sputum/bronchoalveolar lavage, BAL fluid)

Pulse oximetry and arterial blood gas analysis is necessary if oxygen saturation is below 94%.

HIV testing: since pneumonia is a common initial presenting illness in patients with previously undiagnosed HIV infection, a test should be offered to all patients with pneumonia unless the patient is unable to give consent or comfort measures alone are implemented due to poor prognosis.

General management of pneumonia

Oxygen. Supplemental oxygen should be administered to maintain saturations between 94% and 98% provided the patient is not at risk of carbon dioxide retention, due to loss of hypoxic drive in COPD. In patients with known COPD, oxygen saturations should be maintained between 88% and 92%; normally with controlled oxygen via fixed percentage delivery mask.

Intravenous fluids. Required in hypotensive patients showing any evidence of volume depletion.

Antibiotics. The first dose of antibiotic should be administered within 4 hours of presentation in hospital and treatment should not be delayed while investigations are awaited.

– Parenteral antibiotics should be switched to oral once the temperature has settled for a period of 24 hours, provided there is no contraindication to oral therapy.

– If patients fail to respond to initial treatment, microbiological advice should be sought and alternative diagnoses considered (e.g. S. aureus pneumonia, which requires addition of flucloxacillin/fusidic acid, and possibly cover for MRSA infection. Causes of failure are shown in Table 15.15.

– The antibiotic regimen should be adjusted specifically once culture and sensitivity results are available. There is an increased incidence of Clostridium difficile associated diarrhoea (CDAD) associated with some antibiotics, e.g. cephalosporins, which should be avoided if possible. The risk of MRSA increases with antibiotic overuse.

Thromboprophylaxis. If admitted for >12 hours subcutaneous low molecular weight heparin should be prescribed unless contraindications exist and TED (thromboembolus deterrent) stockings fitted.

Physiotherapy. Chest physiotherapy is not needed unless sputum retention is an issue.

Nutritional supplementation. The need for this is assessed, particularly in severe disease, by a dietician.

Analgesia. Simple analgesia such as paracetamol or non-steroidal anti-inflammatory medication helps treat pleuritic pain, thereby reducing the risk of further complications due to restricted breathing because of pain (e.g. sputum retention, atelectasis or secondary infection).

Table 15.15 Causes of slow resolving pneumonia

Incorrect or incomplete antimicrobial treatment	Underlying antibiotic resistance
	Inadequate dose/duration
	Non-adherence
	Malabsorption
Complication of CAP	Parapneumonic pleural effusion (exudative)
	Empyema
	Lung abscess
Underlying neoplastic lesion or other lung disease	Obstructing lesion
	Bronchoalveolar cell carcinoma
	Bronchiectasis
Alternative diagnosis	Pulmonary thromboembolic disease
	Cryptogenic organizing pneumonia
	Eosinophilic pneumonia
	Pulmonary haemorrhage

Complications

Complications of pneumonia must be excluded, especially if the patient does not respond quickly to initial treatment (see Table 15.17).

Prevention of further episodes

Cigarette smoking is an independent risk factor for CAP; if the patient still smokes, cessation advice and support should be given.

Vaccination against influenza is recommended for at-risk groups. All patients over the age of 65 who have not previously been vaccinated and are admitted with CAP should have the pneumococcal vaccine before discharge from hospital.

Types of pneumonia (Table 15.16)

The clinical presentation of pneumonia varies according to the causative organism but there is considerable overlap. Pneumococcal disease is typically acute in onset, with prominent respiratory symptoms and a high fever. Pneumonia due to the so-called atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila) tends to have a slower onset, often with more prominent extrapulmonary symptoms and complications. The radiographic appearances are indistinguishable from those of CAP caused by pneumococcal pneumonia. The other atypical feature is that these organisms do not respond to penicillin, because they lack a cell wall. Erythromycin and tetracycline are usually effective.

Table 15.16 Types of pneumonia and their clinical features

Organism	Features
Streptococcus pneumoniae	Acute onset, often preceded by flu-like symptoms. Cough with rust coloured sputum High fevers and pleuritic chest pain common Bacteraemia more common in females, excess alcohol, dry cough and COPD, diabetes or HIV infection
Mycoplasma pneumoniae	Usually mild disease in young patient; occurs in cycles every 3–4 years Usually prominent extrapulmonary symptoms (headache, malaise, myalgia); complications common: haemolytic anaemia, erythema multiforme, hepatitis, meningoencephalitis
Legionella spp. (Legionnaire’s disease)	Usually Legionella pneumophila but other species implicated in around 10% of cases Causes more severe disease with need for early intensive care Usually acquired by inhaling water mist containing bacteria Neurological symptoms frequently seen, along with GI involvement and deranged liver enzymes, elevated creatine kinase More common in smokers, males and in young people with no co-morbidities
Staphylococcus aureus	Evidence of recent influenza found in up to around 40–50% patients (increasing frequency with greater severity disease) Usually meticillin-sensitive strains (MSSA) but increasing incidence of meticillin-resistant disease (MRSA) which can produce Panton Valentine leucocidin (PVL) and result in necrotizing cavitating pneumonia and bilateral infiltrates
Chlamydophila pneumoniae	Unclear whether this is a causative or associated organism Generally causes mild disease but with prolonged prodrome
Haemophilus influenzae; Moraxella catarrhalis	More common in pre-existing structural lung disease (CF, bronchiectasis, COPD) and the elderly
Chlamydophila psittaci	Acquired from birds (only 20% have positive history) Can be person-to-person spread; usually mild illness
Coxiella burnetti (Q fever)	Tends to occur more commonly in young men. History of dry cough and high fever Recognized cause of endocarditis
Gram-negative organisms
Klebsiella pneumonia	More common in men and those with history of excess alcohol (bacteraemia more likely), poor dental hygiene, diabetes and other co-morbidities; often present with low platelet and white cell count. Systemic upset is usual; high mortality
Pseudomonas aeruginosa	Cavitation and abscess formation seen Infection is associated with underlying lung disease (cystic fibrosis, bronchiectasis, COPD) or immune suppression
All respiratory viruses	Infection more likely in elderly with subsequent staphylococcal pneumonia Usually causes mild disease; not admitted to hospital
Varicella zoster	Causes pneumonitis which heals leaving characteristic small calcified or non-calcified nodules
Influenza A and B	Approximately 10% of adults with confirmed influenza infection have coincident S. aureus disease Fever, malaise and myalgia common
Other
Influenza A (H5N1)	Does not usually affect humans Can be transmitted from poultry (causes avian flu) Fever, breathlessness, cough, diarrhoea Lymphopenia and thrombocytopenia High mortality

Complications of pneumonia (Table 15.17)

Parapneumonic effusion and empyema

Effusions commonly occur with pneumonia and complicate around one-third to a half of cases of CAP. The majority of these are simple exudative effusions but empyema may also develop (where purulent fluid collects in the pleural space). Early indications of empyema are ongoing fever, and rising or persistently elevated inflammatory markers, despite appropriate antibiotic therapy.

Table 15.17 Complications of pneumonia

General	Respiratory failure
General	Sepsis – multi-system failure
Local	Pleural effusion
	Empyema
	Lung abscess
	Organizing pneumonia

Thoracocentesis should be performed to make a diagnosis. Fluid should be aspirated under ultrasound guidance and sent for Gram-stain, culture, fluid protein, glucose and LDH (with comparison to serum levels). Light’s criteria (see p. 863) can be applied to assess whether an effusion is transudative or exudative. An exudative effusion with pleural fluid pH <7.2 is strongly suggestive of empyema. Pathogens are often detectable; sensitivity analysis will help guide antimicrobial therapy.

If an empyema develops, the fluid should be urgently drained to prevent further complications such as development of a thick pleural rind or prolonged hospital admission. The presence of empyema further increases mortality risk. The duration of antibiotic administration will usually need to be extended. Whenever possible, the choice of antimicrobial should be guided by the results of cultures. Thoracic surgical intervention is necessary in severe cases.

Lung abscess

This term is used to describe severe localized suppuration within the lung associated with cavity formation visible on the chest X-ray or CT scan, often with a fluid level (which always indicates an air-liquid interface).

There are several causes of lung abscess (Box 15.9).

Aspiration pneumonia: rarely, abscesses develop as a complication of aspiration pneumonia. A history of excessive alcohol consumption or impaired swallowing in a patient with pneumonia suggests aspiration.

Tuberculosis: see pages 839-841.

Pneumonia caused by certain species, particularly Staphylococcus aureus or Klebsiella pneumonia.

Septic emboli usually containing staphylococci: these can cause multiple lung abscesses. The presence of multiple lung abscesses in an injecting drug user should prompt investigation for infective endocarditis of the tricuspid (or rarely pulmonary) valves. Infarcted areas of lung (due to pulmonary emboli) occasionally cavitate and become infected.

Spread from an amoebic liver abscess: amoebic lung abscesses occasionally develop in the right lower lobe following transdiaphragmatic spread.

Bronchial obstruction by an endoluminal cancer

Foreign body inhalation.

Box 15.9

Common causative organisms in lung abscess

Klebsiella pneumonia

Staphylococcus aureus

Gram-negative enteric bacilli

Mycobacterium tuberculosis

Streptococcus milleri

Anaerobic bacteria (post aspiration)

Haemophilus influenzae

In the latter two, a fibreoptic bronchoscopy and CT scan are performed. Chronic or subacute lung abscesses may follow inadequate treatment of pneumonia.

Clinical features

The clinical features are usually persisting or worsening pneumonia associated with the production of large quantities of sputum, which is often foul-smelling owing to the growth of anaerobic organisms. There is usually a swinging fever; malaise and weight loss frequently occur. On examination, there may be little to find in the chest. Clubbing occurs in chronic suppuration. Patients have a normocytic anaemia and/or raised inflammatory markers (ESR/CRP).

Treatment

Treatment should be guided by available culture results or clinical judgement and is often prolonged (4–6 weeks). Surgical drainage is sometimes necessary.

Pneumonia in other settings

Hospital-acquired pneumonia (HAP)

This is defined as new onset of cough with purulent sputum along with a compatible X-ray demonstrating consolidation, in patients who are beyond 2 days of their initial admission to hospital or who have been in a healthcare setting within the last 3 months (including nursing/residential homes as well as acute care facilities such as hospitals). HAP is the second most common form of hospital-acquired infection after urinary tract and carries a significant mortality risk, particularly in the elderly or those with co-morbidities such as stroke, respiratory disease or diabetes. In HAP, the causative organisms differ from those causing CAP (Box 15.10). Viral or fungal pathogens are not responsible in immunocompetent hosts. Aerobic Gram-negative bacilli are commonly involved (e.g. P. aeruginosa, E. coli, Klebsiella pneumoniae and Acinetobacter species). Staphylococcus aureus is increasingly recognized in HAP, particularly meticillin-resistant S. aureus (MRSA), both in Europe and the USA. HAP due to S. aureus is more common in patients with diabetes mellitus, head trauma, and patients in intensive care units. Empirical antimicrobial therapy should be tailored accordingly. Other conditions should be excluded, including aspiration of gastric contents due to impaired swallowing or bulbar weakness.

Box 15.10

Organisms implicated in hospital-acquired pneumonia

Gram-negative bacteria (Pseudomonas spp., Escherichia spp., Klebsiella spp.)

Anaerobic bacteria (Enterobacter spp.)

Staphylococcus aureus (including MRSA)

Acinetobacter spp.

Elderly residents of long-term care facilities who develop pneumonia have a similar range of pathogens to those found in HAP. In the USA, S. aureus, Gram-negative rods, pneumococcus and Pseudomonas species are the commonest causes of pneumonia acquired in nursing homes. Pneumonia associated with ventilation has the same range of organisms as other forms of HAP (p. 894). Piperacillin-tazobactam is commonly used in severe HAP.

Aspiration pneumonia

Acute aspiration of gastric contents into the lungs can produce an extremely severe and sometimes fatal illness owing to the intense destructiveness of gastric acid. This can complicate anaesthesia, particularly during pregnancy (Mendelson’s syndrome). Because of the bronchial anatomy, the most usual sites for aspirated material to end up are the right middle lobe and apical or posterior segments of the right lower lobe. The persistent pneumonia is often due to anaerobes and progresses to lung abscess or even bronchiectasis if protracted. It is vital to identify any underlying problem, since without appropriate corrective measures aspiration will recur.

Treatment should be directed specifically against positive cultures if available. If not, then use co-amoxiclav for mild to moderate disease which covers Gram-negative and anaerobic bacteria. Treatment needs to be escalated where there is a lack of response or in severe cases.

Rare causes of pneumonia

Pneumonia can occur as a minor feature during infection by Bordetella pertussis, typhoid and paratyphoid bacillus, brucellosis, leptospirosis and a number of viral infections including measles, chickenpox and glandular fever. Details of these infections are described in Chapter 4.

FURTHER READING

Lim WS, Baudouin SV, George RC et al. British Thoracic Society Guidelines for the management of community-acquired pneumonia in adults: update 2009. Thorax 2009; 64(Suppl III):iii1–iii55.

Loke YK, Kwok CS, Niruban A et al. Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis. Thorax 2010; 65(10):884–890.

Pneumonia in Immunocompromised patients

Patients who are immunosuppressed (either iatrogenically or due to a defect in host defences) are at risk not only from all the usual organisms which can cause pneumonia but also opportunistic pathogens which would not be expected to cause disease. These opportunistic pathogens can be commonly occurring microorganisms (i.e. ubiquitous in the environment) or bacteria, viruses and fungi that are found less often (see Table 4.56). The symptom pattern may resemble CAP or be more nonspecific. A high degree of clinical suspicion is therefore necessary when assessing an ill patient who is immunocompromised.

Pneumocystis jiroveci

Pneumocystis pneumonia (PCP) is one of the most common opportunistic infections encountered in clinical practice. It affects patients on immunosuppressant therapy such as long-term corticosteroids, monoclonal antibody therapy or methotrexate for autoimmune disease, those on anti-rejection medication post-solid organ transplantation or following stem cell transplantation, and patients infected with HIV; those at particular risk have CD4 counts <200/mm³. Pneumocystis jiroveci is found in the air, and pneumonia arises from re-infection rather than reactivation of persisting organisms acquired in childhood.

Clinically, the pneumonia is associated with a high fever, breathlessness and dry cough. A characteristic feature on examination is rapid desaturation on exercise or exertion. The typical radiographic appearance is of a diffuse bilateral alveolar and interstitial shadowing beginning in the perihilar regions and spreading out in a butterfly pattern. Other chest X-ray appearances include localized infiltration, nodules, cavitation or a pneumothorax. Empirical treatment is justified in very sick high-risk patients, but wherever possible the diagnosis should be confirmed by indirect immunofluorescence on induced sputum or bronchoalveolar lavage fluid. First-line treatment of PCP is with high-dose co-trimoxazole (see p. 188).

FURTHER READING

Lawn SD, Zumla AI. Tuberculosis. Lancet 2011; 378:57–72.

Tuberculosis

Epidemiology

It is estimated that one-third of the world’s population are infected with tuberculosis (see also p. 135). The World Health Organization (WHO) declared TB a world emergency in 1993. There were almost 9 million new and relapsed cases of TB worldwide in 2010. Its incidence had been increasing by around 1% per year to a peak in 2005, but since then the global incidence per capita has started to slowly decline. The majority of cases (around 65%) are seen in Africa and Asia (India and China). Co-infection with HIV remains a problem, not only because this is a huge health burden on resource-poor nations, but also because of the growing incidence of multi- and extremely-drug resistant strains and the high mortality of the two co-existent diseases. TB was responsible for 1.4 million deaths in 2010 and a quarter of these were in HIV co-infected individuals. There are a number of factors affecting the prevalence and risk of developing TB (Box 15.11).

Box 15.11

Factors affecting the prevalence and risk of developing tuberculosis in the developed world

Contact with high-risk groups:

– Originated from a high incidence country (defined as >40/100 000)

– Frequent travel to high incidence areas

Immune deficiency

– HIV infection

– Corticosteroids or immunosuppressant therapy

– Chemotherapeutic drugs

– Nutritional deficiency (vitamin D)

– Diabetes mellitus

– Chronic kidney disease

– Malnutrition/body weight >10% below ideal body weight

Lifestyle factors:

– Drug/alcohol misuse

– Homelessness/hostels/overcrowding

– Prison inmates

Genetic susceptibility (twin studies of gene polymorphisms)

Pathophysiology

Tuberculosis is caused by four main mycobacterial species collectively termed Mycobacterium tuberculosis complex (MTb):

Mycobacterium tuberculosis

Mycobacterium bovis

Mycobacterium africanum

Mycobacterium microti.

These are obligate aerobes and facultative intracellular pathogens, usually infecting mononuclear phagocytes. They are slow growing with a generation time of 12–18 hours. Due to high lipid content in the cell wall, they are relatively impermeable and stain only weakly with Gram-stain. Where stained with dye combined with phenol and washed with acidic organic solvents, they resist decolorization and therefore are termed ‘acid-fast bacilli’.

Pathogenesis

Tuberculosis is an airborne infection spread via respiratory droplets. Only a small number of bacteria need to be inhaled to develop infection but not all those who are infected develop active disease. The outcome of exposure is dictated by a number of factors including the host’s immune response (Fig. 15.35).

Figure 15.35 The consequences of exposure to TB.

Primary tuberculosis

‘Primary tuberculosis’ describes the first infection with MTb. Once inhaled into the lung, alveolar macrophages ingest the bacteria; the bacilli then proliferate inside the macrophages and cause the release of neutrophil chemoattractants and cytokines, resulting in an inflammatory cell infiltrate reaching the lung and draining hilar lymph nodes. Macrophages present the antigen to the T lymphocytes with the development of a cellular immune response. A delayed hypersensitivity-type reaction occurs, resulting in tissue necrosis and formation of a granuloma.

Granulomatous lesions consist of a central area of necrotic material called caseation, surrounded by epithelioid cells and Langhans’ giant cells with multiple nuclei, both cells being derived from the macrophage. Lymphocytes are present and there is a varying degree of fibrosis. Subsequently, the caseated areas heal completely and many become calcified. Some of these calcified nodules contain bacteria, which are contained by the immune system (and the hypoxic acidic environment created within the granuloma) and are capable of lying dormant for many years. The initial focus of disease is termed the ‘Ghon focus’.

On a chest X-ray, the Ghon focus is evident as a small calcified nodule often within the upper parts of the lower lobes or the lower parts of the upper lobes, seen in the mid-zone. A focus can also develop within the regional draining lymph node (primary complex of Ranke).

Upon initial contact with infection <5% of patients develop active disease. This percentage increases to 10% within the first year of exposure.

Latent tuberculosis

In the majority of people who are infected by Mycobacterium spp., the immune system contains the infection and the patient develops cell-mediated immune memory to the bacteria. This is termed latent tuberculosis.

Reactivation tuberculosis

The majority of TB cases are due to reactivation of latent infection. The initial contact usually occurred many years or decades earlier. In patients with HIV infection newly acquired TB infection is also common. There are several factors implicated in the development of active disease. (Box 15.12). The clinical features of latent and reactivation TB are contrasted in Table 15.18.

Box 15.12

Factors implicated in the reactivation of latent TB

HIV co-infection

Immunosuppressant therapy (chemotherapy/monoclonal antibody treatment) including corticosteroids

Diabetes mellitus

End-stage chronic kidney disease

Malnutrition

Ageing

Table 15.18 Some features contrasting latent infection with active tuberculous disease

Latent infection	Active disease
Bacilli present in Ghon focus	Bacilli present in tissues or secretions
Sputum smear and culture negative	Sputum commonly smear and culture positive in pulmonary disease MTb can usually be cultured from infected tissue
Tuberculin skin test usually positive	Tuberculin skin test usually positive (and can ulcerate)
Chest X-ray normal (small calcified Ghon focus frequently visible)	Chest X-ray shows signs of consolidation/cavitation/effusion in pulmonary disease
Asymptomatic	Symptomatic – night sweats, fevers, weight loss and cough common
Not infectious to others	Infectious to others if bacilli detectable in sputum

Clinical features and diagnosis

Any of the manifestations of disease shown in Table 15.19 occur in primary or reactivation disease but extrapulmonary involvement is far less common in primary disease and is usually only seen in regions of high endemnicity.

Table 15.19 Common sites of TB infection with relevant radiological findings and appropriate diagnostic investigations

Pulmonary, pleural and laryngeal	Smear and culture of: Sputum (≥2 samples increase diagnostic yield) Induced sputum (inhale hypertonic saline which induces coughing) diagnostic yield comparable to bronchoscopic samples Bronchoalveolar lavage fluid if cough unproductive and induced sputum not possible Aspiration of pleural fluid and pleural biopsy Gastric aspirates may be useful in paediatric disease Nasoendoscopic or bronchoscopic examination/biopsy of vocal cords with biopsy for smear/culture and histology in laryngeal disease

Miliary TB	CNS TB	Lymph node TB

Blood cultures Bronchoalveolar lavage fluid (usually smear negative but culture-positive) Lumbar puncture should be performed in all cases unless contraindicated to assess for CNS involvement (affects treatment duration) – see below	Lumbar puncture if no contraindication. Characteristics of lumbar puncture: CSF protein may be very high (usually >2–3 g/L) CSF glucose < blood glucose	All samples should be sent for Histocytopathological examination as well as culture and smear:
		Fine needle aspiration or biopsy of an involved lymph node usually under radiological guidance Mediastinal nodal sampling (endobronchial ultrasound transbronchial needle aspiration, mediastinoscopy/mediastinotomy)
Sampling of other involved organs often necessary	CSF lymphocytosis

In all cases of suspected TB, substantial effort should be made to obtain tissue or fluid for microscopy, smear and culture to obtain information on sensitivities. Tissue samples should also be sent for histopathological examination.

Pulmonary TB

Patients are frequently symptomatic with a productive cough and occasionally haemoptysis along with systemic symptoms of weight loss, fevers and sweats (commonly at the end of the day and through the night). Where there is laryngeal involvement, hoarse voice and a severe cough are found. If disease involves the pleura, then pleuritic pain is a frequent presenting complaint.

The chest X-ray (Fig. 15.36) demonstrates several findings: consolidation with or without cavitation, pleural effusion or thickening or widening of the mediastinum caused by hilar or paratracheal adenopathy.

Figure 15.36 Chest X-ray showing tuberculosis of left upper lobe with cavitation.

Lymph node TB

The next commonest site for infection is lymph node TB. Extrathoracic nodes are more commonly involved than intrathoracic or mediastinal. Usually this presents as a firm non-tender enlargement of a cervical or supraclavicular node. The node becomes necrotic centrally and can liquefy and be fluctuant if peripheral. The overlying skin is frequently indurated or there can be sinus tract formation with purulent discharge but characteristically there is no erythema (cold abscess formation). Nodes typically can be enlarged for several months prior to diagnosis. On CT imaging, the central area appears necrotic (see image).

Other forms of TB

Gastrointestinal

See page .833

TB of bone and spine

See pages 533 and 534

Miliary TB

Miliary disease occurs through haematogenous spread of the bacilli to multiple sites, including the central nervous system in 20% cases.

Systemic upset is the rule, with respiratory symptoms in the majority. Other findings are liver and splenic microabscesses with deranged liver enzymes or cholestasis and GI symptoms.

The chest X-ray demonstrates multiple nodules which appear like millet seeds, hence the term ‘miliary’.

Central nervous system TB

See this chapter.

Pericardial TB

See page 774.

Skin

See page 1198.

Microbiological diagnosis

Rapid identification of the presence of bacteria by immediate stains is essential and should be performed within 24 hours; culture of the sample allows determination of the antibiotic sensitivity of the infecting strain.

Stains

Auramine-rhodamine staining is more sensitive (though less specific) than Ziehl–Neelsen; as a result it is more widely used. It requires fluorescence microscopy and highlights bacilli as yellow-orange on a green background.

Culture

The majority of the developed world uses liquid/broth culture of mycobacteria in addition to solid media (Lowenstein–Jensen slopes or Middlebrook agar) as time to culture is shorter than for solid culture (1–3 weeks compared with 3–8 weeks). Using liquid culture in the presence of anti-mycobacterial drugs (usually first-line therapy initially) establishes the drug sensitivity for that strain and usually takes approximately 3 weeks).

The use of microscopic-observation drug-sensitivity (MODS) assay allows detection of bacteria and susceptibility rapidly by comparing growth in multiple wells with anti-mycobacterial drugs within liquid media. This technique has the advantage of being relatively inexpensive (although is labour-intensive and operator dependent) and is therefore more widely used in resource-poor areas.

Nucleic acid amplification (NAA)

NAA is increasingly used for rapid identification of MTb complex and is useful in differentiating between MTb and non-tuberculosis mycobacteria (NTM) as well as identifying TB in smear-negative sputum specimens. Culture and staining is still necessary and should not be replaced by PCR. PCR is only useful at the initial stage of diagnosis as it frequently remains positive despite treatment due to the detection of dead organisms. This test has a high specificity and moderate sensitivity on cerebrospinal fluid and should be routinely looked for in suspected CNS TB.

The identification of mycobacterial DNA is becoming increasingly useful in facilitating rapid commencement of treatment and also rapid identification of drug resistance. Genetic mutations in bacterial DNA conferring rifampicin-resistance are highly predictive of multi-drug resistance. The development of a highly specific probe designed to detect this mutation thereby allows rapid identification of resistant disease and appropriate therapy to be commenced sooner than waiting for cultures to complete (may take up to 8 weeks).

Molecular testing for drug resistance has also become possible using PCR to detect genetic mutations associated with rifampicin resistance.

Management

Patients with fully sensitive TB require 6 months of treatment, excluding TB of the central nervous system, for which the recommended duration is at least 12 months. Shorter duration courses are being studied, aiming at reducing the duration of treatment and increasing the armamentarium against resistant strains. In CNS and pericardial disease, corticosteroids are used as an adjunct at treatment initiation to reduce long-term complications. Table 15.20 summarizes standard recommended regimens.

Table 15.20 Usual treatment and duration in fully sensitive TB

Site of disease	Duration of therapy	Drug choice
Pulmonary^a Extrapulmonary (excluding CNS disease) Miliary (excluding CNS involvement)	6 months (may be extended to 9 months in certain situations):	Fully sensitive strain: 2HRZE + 4HR^b Or 2HRZE + 7HR
	patient smear positive 2 months into treatment
	some patients with HIV co-infection
	high burden of disease
CNS TB	12 months	2HRZE + 10HR
		Plus
		Prednisolone (20–40 mg o.d.) weaning over 2–4 weeks
Latent TB	3 months	3RH
	Or	Or
	6 months	6H

CNS, central nervous system; E, ethambutol; H, isoniazid; R, rifampicin; Z, pyrazinamide.

a For pulmonary TB, 2HRZE + 4(HR)₃, i.e. 3x weekly for 4HR is acceptable.

b 2HRZE + 4HR, 2 months of HRZE + 4 months of HR.

Directly observed therapy (DOT) is widely recommended and employed with an aim to achieve treatment-completion rates of over 85%. DOT is defined as treatment supervised by a healthcare professional or family member where the person is observed swallowing their medication. WHO advocates universal DOT as one of their strategies to reduce the incidence of TB worldwide, partly because the majority of relapsed disease or treatment failure is due to lack of adherence, interrupted therapy or incorrect treatment (Box 15.13). Where used, the dosing frequency may be reduced to three-times per week to make DOT more convenient. Success rates are comparable for thrice-weekly DOT as for standard daily unsupervised therapy.

Box 15.13

Criteria for implementation of directly observed therapy for TB

Patients thought unlikely to comply

– History of serious mental illness

– History of non-adherence to TB therapy in past or during current treatment course

Street or shelter-dwelling homelessness

Multi-drug resistant TB

Unwanted effects of drug treatment

Rifampicin induces liver enzymes, which may be transiently elevated in the serum of many patients. The drug should be stopped only if the serum bilirubin becomes elevated or if transferases are >3 times elevated, which is uncommon. Induction of liver enzymes means that concomitant drug treatment may be made less effective (see Ch. 16). Thrombocytopenia has been reported. Rifampicin stains body secretions pink and the patients should be warned of the change in colour of their urine, tears (contact lens) and sweat. Oral contraception will not be effective, so alternatie birth-control methods should be used. Rifabutin, a rifamycin, is similar and is used for prophylaxis against M. avium-intracellulare complex infection in HIV patients with CD4 counts <200 mm³.

Isoniazid has very few unwanted effects. At high doses it may produce a polyneuropathy due to a B₆ deficiency as isoniazid interacts with pyridoxal phosphate. This is extremely rare when the normal dose of 200–300 mg is given daily. Nevertheless, it is customary to prescribe pyridoxine 10 mg daily to prevent this. Occasionally, isoniazid gives rise to allergic reactions, e.g. a skin rash and fever, with hepatitis occurring in fewer than 1% of cases. The latter, however, may be fatal if the drug is continued.

Pyrazinamide may cause hepatic toxicity, though this is much rarer with present dosage schedules. Pyrazinamide reduces the renal excretion of urate and may precipitate hyperuricaemic gout.

Ethambutol can cause a dose-related optic retrobulbar neuritis that presents with colour blindness for green, reduction in visual acuity and a central scotoma (commoner at doses of 25 mg/kg). This usually reverses provided the drug is stopped when symptoms develop; patients should therefore be warned of its effects. All patients prescribed the drug should be seen by an ophthalmologist prior to treatment and doses of 15 mg/kg should be used.

Streptomycin can cause irreversible damage to the vestibular nerve. It is more likely to occur in the elderly and in those with renal impairment. Allergic reactions to streptomycin are more common than to rifampicin, isoniazid or pyrazinamide. This drug is used only if patients are very ill, have multidrug-resistant TB or are not responding adequately to therapy.

Drug resistance

Worldwide, drug resistance is an increasing problem, with an estimated incidence of 444 000 cases in 2008, responsible for around 150 000 deaths (Fig. 15.37). It arises due to incomplete or incorrect drug treatment and can be spread from person to person. In developed countries, the incidence of multi-drug resistance (resistance to both rifampicin and isoniazid, termed MDR-TB) is relatively low (around 1%) and only a handful of extensively drug-resistant (XDR-TB) cases have been seen, though most countries have reported at least one case. XDR-TB is defined as high level resistance to rifampicin, isoniazid, fluoroquinolones and at least one injectable agent such as amikacin, capreomycin or kanamycin. Total drug resistance (TDR) has now been reported from Italy, Iran and Mumbai (India) in a few cases. Mono-resistance is reasonably common, for example the incidence is approximately 10% in the UK. A risk assessment for drug resistance should be routinely performed (Box 15.14).

Figure 15.37 Worldwide incidence of MDR-TB, 2009.

(Reproduced with permission from WHO.)

Box 15.14

Factors associated with an increased risk of drug-resistant TB

History of prior drug treatment of TB (particularly if unsupervised, self-administered treatment)

Co-infection with advanced HIV and previous TB treatment

Infection acquired in region with high rates of drug resistance

Contact with a known case of resistant TB

Failure to respond to empiric TB therapy despite documented adherence

Exposure to multiple courses of fluoroquinolone antibiotics for presumed community acquired pneumonia

Healthcare workers exposed to cases of resistant TB

TB in special situations

HIV co-infection

The increase in TB seen over recent decades has occurred to a considerable extent in association with the incidence of HIV infection, with high levels seen in Africa (particularly sub-Saharan Africa), the Indian subcontinent and parts of Eastern Europe and Russia. The incidence of HIV infection in TB worldwide is around 15% and TB is responsible for around one-quarter of AIDS-related deaths.

Alongside the increased morbidity and mortality of co-infection, there are specific issues relating to the treatment of TB in HIV: namely, the incidence of drug interactions and intolerability, the increased risk of treatment toxicity and the higher incidence of drug resistance. TB/HIV infection should be managed by experts in TB (respiratory or infectious disease physicians) alongside HIV specialists.

Chronic kidney disease (CKD)

CKD is a risk factor for reactivation of latent TB infection due to relative immune paresis. Patients due to undergo renal transplantation may need to be screened for LTBI and need to be given complete chemoprophylaxis if necessary before undergoing their procedure. The presence of chronic kidney disease also complicates the treatment regimen as there is an increased risk of toxicity due to altered pharmacokinetics, which necessitates dosage adjustments and therapeutic drug level monitoring. Management should be undertaken by TB specialists in conjunction with renal physicians.

Latent TB Infection

The diagnosis of latent TB infection (LTBI) involves demonstration of immune memory to mycobacterial proteins. Two tests are available.

Tuberculin skin test (TST)

A positive result is indicated by a delayed hypersensitivity reaction evident 48–72 hours after the intradermal injection of purified protein derivative (PPD) resulting in:

A raised indurated lesion >6 mm diameter in non-vaccinated adults

A raised indurated lesion >15 mm in BCG-vaccinated adults.

False negative (anergic) TSTs are common in immunosuppression due to HIV infection (CD4⁺ <200/mm³), sarcoidosis, drugs (chemotherapy, anti-TNF therapy, steroids), at the extremes of age and in active disease. False positives occur due to cross-reactivity with non-tuberculous mycobacteria (NTM) and BCG vaccination.

Interferon-gamma release assays (IGRAs)

IGRAs detect T-cell secretion of interferon-gamma (IFN-γ) following exposure to M tuberculosis-specific antigens (ESAT-6, CFP-10,). Where a person has been infected (previously or currently) with TB, activated T cells within their extracted whole-blood secrete quantifiable levels of interferon-gamma in response to re-exposure to TB-specific antigens. The test does not differentiate between active and latent infection. However, it is highly specific compared with the TST and has a similar or better sensitivity.

Global TB strategy

Part of the global strategy is an increase in the identification and treatment of latent TB infection (LTBI), thereby reducing the risk of conversion to active disease and transmission to others. In certain groups with LTBI, chemoprophylaxis is offered to reduce the risk of active infection (Box 15.15).

Box 15.15

People who should be treated for latent TB infection (after excluding active TB)

People aged ≤35 years with positive TST or IGRA

Healthcare workers with positive TST or IGRA

Patients commencing anti-TNF therapy with positive IGRA

HIV-positive people with positive IGRA

People with evidence of previous TB on chest X-ray and inadequate treatment.

Active case finding forms part of a number of programmes:

Contact tracing: carried out after diagnosis of a new case of TB; involves identifying close contacts who are at risk of infection or who may have active infection and not yet sought medical attention

Screening of healthcare workers: as part of an occupational health programme, with BCG vaccination of those with no evidence of previous TB exposure

Screening of new entrants: those arriving from a country of high incidence of TB should be offered screening for latent or active infection and vaccination if not infected and previously unvaccinated

Street-homeless or hostel dwellers: these groups are at increased risk of active TB and should be offered opportunistic screening for active infection

Immunocompromised people:

– Patients due to commence monoclonal antibody therapy for autoimmune conditions should be screened for active or latent infection and should be given appropriate treatment before commencing immunosuppressive therapy as they are at a particularly high risk for reactivation of LTBI

– People with HIV infection (see above)

– People with underlying haematological malignancies or solid-organ transplants or undergoing chemotherapy require screening.

BCG vaccination

BCG is a live attenuated vaccine derived from M. bovis that has lost its virulence. It has variable efficacy but is still recommended in certain situations in developed countries (but not the USA), though no longer offered routinely to all due to the lack of cost-efficacy. It has been shown to reduce the risk of disseminated and CNS TB in babies and children and is therefore used worldwide. There are safety concerns in babies with HIV. Its efficacy in adults is very variable.

Non-tuberculous mycobacterial infection (NTM)

NTM occur in soil and water and are not usually pathogenic due to their lack of virulence. However, where there is a breach of the normal host defence mechanisms, certain strains have the potential to become pathogenic (Table 15.21). Factors associated with increased risk of pulmonary NTM infection are shown in Box 15.16. Treatment is suggested if there is a compatible clinical picture and (a) the organism is isolated from an invasive sample or (b) if an NTM is isolated from more than one sputum sample obtained at different times.

Table 15.21 Some non-tuberculous mycobacteria strains implicated in disease

Strain	Site of disease
M. avium intracellulare complex (MAC)	Pulmonary (nodular and interstitial infiltrates in middle lobe in women or fibrocavitary disease in smoking middle-aged males)
	Disseminated (usually in HIV)
	Hypersensitivity pulmonary disease (‘hot-tub lung’)
	Lymphadenitis in children
M. kansasii	Pulmonary (similar presentation to MTb, usually in middle-aged males)
M. kansasii	Disseminated disease (in HIV)
M. abscessus	Skin, soft tissue and bone disease
M. abscessus	Pulmonary (usually in bronchiectasis, older, non-smoking females)
M. chelonae	Skin, bone and soft tissue
M. chelonae	Pulmonary (similar to M. abscessus)
M. fortuitum	Pulmonary (similar to M. abscessus)
M. gordonae	Only rarely pathogenic (can be significant in immunocompromised host)
M. xenopi	Pulmonary (fibrocavitary disease in COPD)
M. xenopi	Contaminated surgical instruments causing bone/soft tissue infection
M. malmoense	Pulmonary
M. malmoense	Lymph node
M. marinum	Soft tissue, skin and bone
M. szulgai	Pulmonary (similar to TB)

Box 15.16

Factors associated with increased risk of pulmonary infection with non-tuberculous mycobacteria

Structural lung disease:

– COPD

– Bronchiectasis

• subgroup of women with bronchiectasis, scoliosis, pectus excavatum, mitral valve prolapse and hypermobile joints at particular risk

– Cystic fibrosis

– Prior TB

HIV infection (CD4 <50/mm³)

Genetic defects of interferon-γ/interleukin-12 pathway

FURTHER READING

Diel R, Goletti D, Ferrara G et al. Interferon-γ release assays for the diagnosis of latent Mycobacterium tuberculosis infection: a systematic review and meta-analysis. Eur Respir J 2011; 37(1):88–99.

Kaufmann SHE et al. New vaccines for tuberculosis. Lancet 2010; 375:2110–2119.

SIGNIFICANT WEBSITES

National Institute for Health and Clinical Excellence: Tuberculosis. Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. http://www.nice.org.uk/nicemedia/live/13422/53638/53638.pdf

World Health Organization Global tuberculosis control 2011: http://www.who.int/tb/publications/global_report/en/index.html

Asthma

Prevalence

Classification

Aetiology and pathogenesis

Atopy and allergy

Genetic

Environmental factors

Increased responsiveness of the airways of the lung (airway hyperresponsiveness)

Precipitating factors

Occupational sensitizers (Table 15.13)

Nonspecific factors

Cold air and exercise

Atmospheric pollution and irritant dusts, vapours and fumes

Diet

Emotion

Drugs

Allergen-induced asthma

Pathogenesis

Inflammation

Remodelling

Clinical features

Investigations

Lung function tests

Exercise tests

Histamine or methacholine bronchial provocation test (see p. 824)

Trial of corticosteroids

Exhaled nitric oxide (NO)

Blood and sputum tests

Chest X-ray

Skin tests

Allergen provocation tests

Management

Control of extrinsic factors

Drug treatment

Use of a metered-dose inhaler

Spacers

Short-acting relievers

Long-acting relief/disease controllers

Other agents with bronchodilator activity

Steroid-sparing agents

β2-Adrenoceptor agonists

Antimuscarinic bronchodilators

Anti-inflammatory drugs

Inhaled corticosteroids

Oral corticosteroids and steroid-sparing agents

Cysteinyl leukotriene receptor antagonists (LTRAs)

Monoclonal antibodies

Antibiotics

Asthma attack

Acute severe asthma

At home

At hospital

Management of catastrophic sudden severe asthma (brittle asthma)

Prognosis of asthma

Pneumonia

Community-acquired pneumonia (CAP)

Pathophysiology

Clinical features of CAP

Investigation and management of CAP

Initial assessment

Investigations

Chest X-ray

Blood tests

Other tests

General management of pneumonia

Complications

Prevention of further episodes

Types of pneumonia (Table 15.16)

Complications of pneumonia (Table 15.17)

Parapneumonic effusion and empyema

Lung abscess

Clinical features

Treatment

Pneumonia in other settings

Hospital-acquired pneumonia (HAP)

Aspiration pneumonia

Rare causes of pneumonia

Pneumonia in Immunocompromised patients

Pneumocystis jiroveci

Tuberculosis

β₂-Adrenoceptor agonists