Asthma is one of the most common diseases among adults. According to Asthma UK, doctors currently treat around 4.3 million adults for asthma. Of these, 700,000 are over the age of 65 years. Those figures are sobering enough. However, many cases of asthma among adults, especially in older people, remain undiagnosed.
Two main factors are largely responsible for the under-diagnosis. First, asthma’s symptoms overlap with several other conditions, which complicates diagnosis. Second, older people who feel breathless or wheezy may not seek their doctor’s help, mistakenly regarding the symptoms as the inevitable price of growing older. However, breathlessness and wheeze are certainly not always age-related: they’re often signs of asthma, COPD or another disease. So, it’s important to get yourself checked if you start wheezing or feeling breathless.
Asthma’s natural history
Against this background, asthma’s natural history in adults tends to follow one of three routes. Estimates vary from study to study, but between 30 and 80 per cent of adults with asthma have suffered from the disease since childhood. Others develop asthma for the first time as adults. In one study, by Loerbroks and colleagues, almost one in 50 (1.8 per cent) of a group of people aged between 40 and 65 years developed asthma over, on average, 8.5 years.
The final group experienced wheeze and other asthma symptoms when they were children, then recovered during adolescence only for the condition to re-emerge in later life. Recurrence of childhood symptoms is probably as common as new cases of asthma among adults. Of course, some people may not recall that they suffered asthma as a child. In other cases of ‘adult-onset asthma’, myself included, hindsight reveals possible symptoms during childhood. So, gaining an accurate picture is difficult. Nevertheless, to understand why some adults suffer from asthma and how we can cope with the disease, we need to start by looking at a healthy pair of lungs.
Inside our lungs
Unless something goes wrong – or we pant after running for a bus or after the kids in the park – we rarely think much about breathing. Respiration is one bodily function – like the beating of our heart – that remains remarkably reliable throughout life, even without conscious control. However, we consciously control breathing when we speak, sing or hold our breath.
At rest, we typically breathe 12 to 20 times each minute. The normal tidal volume – the amount of air that moves in and out of our lungs during inspiration and expiration when we do not make any extra effort – is around 500 ml. A normal pair of adult lungs can expel between 3 and 5 litres of air (vital capacity) after taking the deepest breath we can.
Our lungs do not expand fully each time we take a breath: we only use a small fraction of our vital capacity during each breath. A quarter of the air we inhale remains in the airways that connect the mouth and the alveoli (see below), where we exchange toxic carbon dioxide for the oxygen our cells need to remain alive, repair damage and divide.
Almost all cells contain mitochondria – essentially the cell’s power-house. Mitochondria use oxygen to generate a chemical called adenosine triphosphate (ATP), the fuel for the cell’s various activities. Without a steady supply of ATP, the processes that keep cells alive grind to a halt, and eventually the cell dies.
As everyone knows, you have two lungs: one on the left of your body, the other on the right. The left lung lies over your heart. So, the right lung is slightly larger and has three sections (lobes), while the smaller left lung consists of two lobes. Your ribcage surrounds and protects the spongy, fragile lungs and anchors some of the muscles you use to breathe (see figure 1.1).
Figure 1.1 Anatomy of the lungs
Muscles and breathing
Usually, you rely on two sets of muscles to breathe: the diaphragm and the intercostals:
- The diaphragm – a thick sheet of muscle – lies under the lungs, anchored to the lower part of the ribcage, the base of the sternum (breastbone) and the spine.
- The intercostal muscles run between each rib.
Underneath the ribs, two thin moist membranes – the pleura – cover each lung. These membranes slide over each other when you exhale and inhale. (‘Pleurisy’ refers to an inflammation of the pleura usually following an infection, such as flu.)
When relaxed, the diaphragm is dome-shaped. When you inhale, your diaphragm contracts and flattens. Meanwhile, the intercostals contract and shorten. Together, the two sets of muscles pull the ribcage up and out, which increases the space in the chest. So, the pressure inside the airways is lower than that outside. As a result, air flows through your mouth and nose, along your windpipe (trachea) and into your lungs. The diaphragm and intercostals then relax. The lungs and chest wall are elastic, so when the muscles relax the chest springs back to its original shape. This expels the air in the lungs, now rich in carbon dioxide.
Several other muscles aid breathing, especially when you exercise. For example:
- Three pairs of neck muscles, called the scalenes, lift and help expand the ribcage during inspiration (breathing in).
- The sternocleidomastoids, which connect your head to your shoulder, aid breathing especially during exercise and stress.
- Even if you don’t have a six-pack, your abdominal muscles are very powerful. (They have to be strong to resist the pressure exerted by the intestines and stop your belly from bulging outwards.) During rigorous exercise, abdominal muscles contract, which pushes the diaphragm against the lungs and expels more air.
Many people do not use their breathing muscles correctly – as you’ll soon find out if you learn meditation, tai chi or one of the other martial arts. Most people have sufficient lung reserve to overcome their bad habits. However, in people with asthma this ‘improper use’ can exacerbate their symptoms.
From the nose to the alveoli
After the mouth and nose, air flows along the trachea, which is about 10 to 16 cm long and about 2 cm wide. Horseshoe-shaped rings of cartilage – rather like the rings on a vacuum cleaner hose – protect the trachea from crushing. The body’s temperature warms the air as it travels. (As we’ll see, cold air is one of the most common asthma triggers.) The trachea forks into two major bronchi, one to each lung. Each major bronchus divides another 10 to 25 times into bronchi and then bronchioles. Bronchi have cartilage to strengthen their walls and support the airways. The final few branches of the respiratory tree, called bronchioles, do not have cartilage in their walls, and together end in between 300 million and 500 million alveoli. Each alveolus, which looks like a cauliflower floret, is about 0.1 to 0.2 mm in diameter (Figure 1.2).
Figure 1.2 The alveoli
As they lack cartilage, bronchioles and alveoli rely on the surrounding tissues for the support they need to remain open. (Emphysema – a debilitating form of COPD – destroys these delicate tissues.
The bronchial tree’s shape packs a vast area into a relatively small volume. Overall, our lungs contain approximately 1,500 miles of airways. In an adult, the alveoli’s surface area is about 70 m2 – roughly the same as a single tennis court. A network of around 620 miles of capillaries – small, thin blood vessels – surrounds the alveoli (Fig. 1.2). Oxygen dissolves in the fluid covering the thin alveoli and crosses into the bloodstream.
Red blood cells (erythrocytes) pick up and carry oxygen to the tissues around your body. Red blood cells collect some of the ‘waste’ carbon dioxide produced by cells, which they transport back to the lungs. However, 90 per cent of the carbon dioxide produced during respiration reaches the lungs dissolved, or combined with water, in blood.
Our bodies need to keep levels of oxygen and carbon dioxide within tight limits. The respiratory centre at the base of the brain controls our breathing subconsciously. Sensors in the brain and certain blood vessels (aorta and carotid arteries) detect changes in levels of carbon dioxide and oxygen in the blood. Increased levels of carbon dioxide trigger us to breathe more rapidly and deeply. When carbon dioxide levels decline, we breathe less frequently and more shallowly. However, the breathing of older people – even if they don’t suffer from asthma or another lung disease – tends to show a less marked response to decreased oxygen and increased carbon dioxide levels than is typical among younger people. This impaired response is one of several age-related changes in our breathing that form the backdrop against which adult asthma develops.
Anaemia and breathlessness
People with anaemia have too little haemoglobin, the iron-containing protein in red blood cells that carries oxygen. Some anaemic people produce too few red blood cells. Each red blood cell survives for 100 to 120 days, and the body destroys old, inefficient erythrocytes. However, in some anaemic patients the body destroys too many red blood cells, including some that are healthy and efficient. Numerous factors can trigger anaemia, such as deficiencies in vitamin B12 or iron, chronic inflammation and certain malignancies.
Anaemia’s symptoms arise from a mismatch between the demand for oxygen by tissues and the supply by haemoglobin. As a result, an anaemic person may feel fatigued and weak or suffer headaches, chest pains and palpitations. If an anaemic person breathes normally, his or her body ‘senses’ that oxygen levels are too low. So, he or she feels breathless – a trigger to inhale more oxygen – and exercise becomes more difficult. Anaemia is one of several conditions that doctors may need to rule out when determining whether someone has asthma.
Age-related changes in breathing
As you get older, almost every organ in your body changes – and your lungs are no exception. For example, age-related changes to the larynx (voice box) probably altered your voice’s pitch, loudness and quality over the years. As you age, your voice may become quieter, slightly hoarse and ‘weaker’. With age the pitch usually deepens in women and rises in men.
The lung matures until about a woman reaches about 20 and a man around 25 years of age. During childhood, lungs grow by increasing the number of bronchioles and alveoli. However, most of our complement of alveoli has emerged by around ten years of age and relatively few develop during adolescence. After our mid-20s, alveoli numbers decline. Obviously, this reduces the surface area available for gas exchange. While the decline in alveoli number is inevitable, environmental factors – especially smoking – can speed their destruction.
Muscles also weaken with age. As this includes your diaphragm and intercostals, older people typically generate less force during inspiration. Our chest and lungs also become less elastic, partly because we produce less ‘elastin’. As this protein’s name suggests, elastin allows skin, tendons, ligaments and other tissues to spring back into their ‘normal’ shape after stretching or contracting. In the lungs, the elastic recoil helps force air from the airways when we exhale. So, we drive air from the lungs less forcibly as we age.
Meanwhile, changes in bones and muscles often increase the depth of the chest. For example, along with the rest of the skeleton, bone mass in the ribs and vertebrae declines as we age, which predisposes to osteoporosis (brittle bone disease) and so increases the risk of breaking a bone. Oral steroids – used to treat asthma – can hasten the decline in our skeletal strength.These and other age-related changes can alter the shape of the spine and the chest is less able to stretch during breathing.
Measurements of lung function reflect these age-related changes. For example, the rate at which air flows through the bronchi declines after around 30 years of age, and vital capacity (the maximum amount of air you can exhale) peaks around the age of 20 years and then falls by around 250 cc each decade. Fortunately, we normally have more lung function than we need for most activities. This ‘reserve’ means that elderly people should still be able to perform the activities of daily life. Indeed, many people still breathe reasonably well after having one of their lungs surgically removed.
Nevertheless, these age-related changes help to explain why asthma and other lung diseases can pose a particular problem for adults. One study compared two groups of otherwise similar asthma patients. One group was aged, on average, 35 years. The other group – whose average age was 60 years – showed a greater variation in peak flow (a measure of lung function, over the course of the day. This suggests that their asthma control was worse than that of their younger counterparts. The older people also reported more symptoms during the night – another indicator of poor control.
The age-related changes also help explain why childhood asthma can re-emerge in middle-aged or elderly adults despite disappearing during adolescence. Young children may not have enough lung reserve to cope with mild airway obstruction, so they suffer asthmatic symptoms. As they reach adolescence and young adulthood, improved lung function compensates for mild airway obstruction and the symptoms seem to resolve. But lung function declines as they age and symptoms re-emerge in later life.
Symptoms of asthma
The term ‘asthma’ derives from an ancient Greek word meaning ‘breathless’ or ‘breathing with an open mouth’. Ancient Greeks used the term more widely than to describe only the constellation of symptoms (recurrent bouts of coughing, wheezing, chest tightness and breathlessness) we now call asthma.
While doctors first described the symptoms of asthma millennia ago, the cause remained largely a mystery until the twentieth century. We now know that allergies and several other factors trigger excessive inflammation in the lungs. This inflammation contracts the ring of muscles around the airways, which narrows the bronchi and bronchioles (Fig. 1.3). The narrowing obstructs the flow of air as we breathe in and out. Airway inflammation occurs at all stages of asthma, from newly diagnosed people with mild symptoms to those dying from intractable asthma. Indeed, the lungs remain inflamed even when the person is symptom-free. But as the inflammation increases in intensity, the severity of the symptoms worsens. (See Figure 1.3.)
Figure 1.3 Normal (a) and asthmatic (b) airways
The airway obstruction in asthma is largely reversible, as the attack abates or with treatment. But as you get older, the chance that the airway obstruction will not be totally reversible increases (we’ll see why later), which can complicate diagnosis and treatment. In general, however, reversible airway obstruction produces asthma’s four hallmark symptoms:
- cough, which may be the main or only symptom in mild asthma;
- wheeze: a whistling, sighing sound caused when air passes through a narrow tube; asthmatic wheeze tends to be worse in the morning, when the airways are naturally narrower, during exercise or in cold air;
- shortness of, or gasping for, breath – night-time breathlessness may be a particularly reliable indicator of asthma in adults from early middle age onwards;
- chest tightness: some people describe this as a band around their chest.
Bronchial hyper-responsiveness – another hallmark of asthma – refers to the tendency of asthmatic airways to narrow excessively and too readily when exposed to numerous non-allergic triggers, such as cold air, fog, perfume and tobacco smoke. Everyone’s airways narrow in a smoky room to protect the lungs. However, in people with asthma, the narrowing is much more marked and occurs when you are exposed to much lower levels of the trigger than people with healthy lungs. Indeed, people with asthma tend to show increased bronchial hyper-responsiveness even before symptoms emerge. And those patients with more severe bronchial hyper-responsiveness tend to endure worse asthma symptoms than people with less reactive airways.
Asthma’s sex divide
During childhood, boys are more likely to develop asthma than girls. The sex difference then switches. Middle-aged women are more likely to develop asthma than men of the same age. However, the difference between the sexes then declines again. The Lung and Asthma Information Agency points out that one study found that around 5 per cent of older men and 2 per cent of older women have asthma. But there are too few studies to know definitely whether elderly men are more likely to have asthma than women or vice versa. As you might expect, the pattern of bronchial hyper-responsiveness parallels the sex divide in asthma. The airways of boys are more responsive than those of girls, adult women are more responsive than men, and older men show broadly the same degree of responsiveness as older women.
A variable disease
No two asthma patients show exactly the same pattern of symptoms or endure the same impact on their life, health and well-being. And the severity of asthma and the frequency of attacks often varies over time in the same person. The variation in symptoms is especially marked in young children and older adults.
Occasionally people endure all four symptoms all the time. Some people experience debilitating attacks of all four symptoms, but only occasionally. Others endure just a troublesome cough and only during the night. Others find that they’re symptom-free until they take part in certain activities – such as at work or during exercise.
Not surprisingly, this variation can complicate diagnosis, especially as the person may seem well and have near normal lung function between attacks. To complicate matters further, several diseases cause symptoms similar to asthma. So, doctors cannot diagnose asthma definitively using symptoms alone.
For instance, some asthmatics never wheeze audibly, and not everyone who wheezes suffers from asthma. Any disease that narrows the airways can cause wheeze:
- People with asthma and COPD tend to wheeze when they exhale.
- In some diseases – such as cancer in the trachea – wheeze tends to occur when the person breathes in.
- People develop reversible airway obstruction – and therefore wheeze and cough – when they contract a viral or bacterial lung infection.
This overlap in symptoms between asthma and other diseases further complicates diagnosis – especially as people may suffer from more than one disease.
Coughing up blood
If you cough up blood (the medical term is haemoptysis), you should seek medical attention as soon as possible. Haemoptysis may be the first sign of lung cancer and may allow doctors to detect the tumour when it remains small enough for surgery to cure. Several other serious diseases can cause haemoptysis, including tuberculosis and some other lung infections, chronic bronchitis and pulmonary oedema (fluid in the lungs).
When to seek urgent medical help
Never underestimate the severity of an asthma attack. During some severe asthma attacks, the airways become completely blocked and the person can suffocate, a potentially fatal condition called status asthmaticus. Ironically, people with the most severe asthma often have the worst perception of their symptoms’ intensity. So, you should phone 999 immediately if you have any of the symptoms in the box below.
But try not to panic. Deaths from asthma are rare and effective prompt treatment prevents most fatalities. Furthermore, asthma attacks rarely strike out of the blue – although it can appear that way. Severe asthma attacks usually (but not always) develop over between 6 and 48 hours. This means that remaining alert to changes in your symptoms and regularly measuring your peak flow (see Chapter 5) might allow you to detect the decline and use your medication to prevent a serious attack. You and your doctor should agree a self-management plan to deal with changes in symptom severity. A frank chat with your doctor or asthma nurse should help you keep your fears in perspective.
When to call 999 - in the UK (911 in US)
You (or someone around you) should call 999 if:
- you feel your bronchodilator (reliever) is not really helping your symptoms;
- the wheeze, cough or chest tightness is severe and constant. Wheeze may be especially loud or, ironically, absent in very severe asthma, when there is insufficient airflow to produce the sound. Medical schools traditionally warned doctors to ‘beware of the silent chest’;
- you are too breathless to speak, or talk in words rather than sentences;
- your pulse is racing;
- you feel agitated or restless;
- you feel drowsy or confused;
- your lips or fingernails look blue.
Some people hunch forward during a severe attack, which offers a further clue.
Suffering a severe asthma attack is terrifying and debilitating. One severe asthma attack left me unable to pick up the phone to call for an ambulance, let alone have a conversation. So, it’s worth letting your partner, carer or colleagues know how to recognize the symptoms of a severe attack, and when to call 999. You could photocopy the box above and pin it to a notice board at home or work.
What goes wrong in asthma?
After a typhoon devastated the Pacific island of Tokelau, the authorities evacuated some children to New Zealand. Researchers discovered that asthma was just as common among the evacuated children as among kids born in New Zealand. However, asthma was much less common among children who remained on Tokelau than in the ex-pats or those born in New Zealand. Similarly, asthma and other allergic diseases became more common in people who moved from the former East to West Germany during the 1990s.
Clearly, environmental factors contribute to asthma. However, not everyone exposed to any particular environmental trigger develops asthma. For example, around 2 per cent of people develop asthma during their first year of working with animals. So, 49 in every 50 people working with animals don’t develop asthma.
The pattern of genes we inherit helps determine whether or not we develop asthma when exposed to a potential trigger. Essentially, asthma arises when this combination of environmental factors and genes results in the airways’ defences becoming ‘over-protective’.
Every breath we take carries millions of potentially harmful micro-organisms (viruses, bacteria and fungi), potential allergens (immune triggers such as pollen or cat hair) and irritants (for example, tobacco smoke and pollutants) deep into our lungs. After all, micro-organisms are everywhere. Each square centimetre of human skin harbours around 10 million bacteria, New Scientist reported. Indeed, we breathe in about two heaped tablespoons of dust, pollen, mould, smoke, carbon, tar, rubber, metals and bacteria each day, along with countless chemicals.
To protect our delicate respiratory system and our bodies generally, our lungs evolved several lines of defence. For example, goblet cells lining the bronchi produce sticky mucus, which traps particles and pathogens. Tiny ‘hairs’ – called cilia – on the outside of cells lining the airways waft the mucus from the airways into your mouth. After you swallow the mucus, enzymes in your gut and acid in your stomach destroy the infection or particle. Coughing also removes mucus, particles and pathogens.
Poorly controlled asthma can damage this ‘mucociliary escalator’, which may leave you more vulnerable to lung infections. In turn, these infections can trigger an asthma attack. Smoking also damages the mucociliary escalator, one of the links between passive and active smoking and lung diseases such as asthma and COPD.
Second, a ring of muscle surrounds each airway. When this ring of muscle contracts, it squeezes and narrows the airway. This ‘bronchoconstriction’ prevents harmful particles from penetrating deep into the lungs and reaching and potentially damaging the delicate alveoli. Smoking, for example, triggers bronchoconstriction in people without asthma. However, bronchial hyper-responsiveness (see above) means that people with asthma react excessively to non-allergic triggers such as smoking, cold air and pollution.
Inflammation offers a further line of defence in the airways and elsewhere in your body. During inflammation, blood vessels supplying the injured or infected area swell (dilate) and become leaky, which produces several characteristic changes:
- The increased blood flow makes the inflamed areas look red and feel warm.
- The movement of fluid from leaky blood vessels into the surrounding inflamed tissues causes swelling.
- The leaky vessels allow white blood cells and other components of the immune system to move into the damaged or infected tissue. For example, one type of white blood cell (phagocytes) engulfs and destroys invading micro-organisms and particles.
- The fluid contains chemicals that trigger pain, which stops you moving the injured area, so helping to prevent further damage.
So, inflammation starts healing. However, you can have too much of a good thing.
Too much of a good thing …
Inflammation usually subsides as an injury heals or the immune system eradicates an infection. Similarly, asthmatic symptoms resolve as the inflammation subsides, spontaneously or after treatment. However, while most lung infections last only a few days, sensitive people may be exposed to their asthma triggers continually (such as house dust mites) or for protracted periods (pollen, for instance). This means that people with asthma develop long-lasting (chronic) inflammation.
Over time, chronic inflammation alters the airway’s structure – a process called remodelling. For example, chronic inflammation can destroy the delicate cilia and increase the number of goblet cells. The resulting rise in mucus production can create ‘plugs’ that block the airways. The damage to the mucociliary escalator makes these plugs difficult to remove.
Chronic inflammation also scars and thickens the airway walls. The more severe the asthma, the thicker the airway wall becomes. Indeed, Elias remarked, compared to people without asthma, the thickness of the airway wall increases by between 50 and 300 per cent in people who die from asthma. Even in non-fatal asthma, wall thickness can increase by between 10 and 100 per cent. As a result, remodelling permanently reduces the diameter of the airways in people with asthma, which makes a severe attack more likely. Furthermore, these changes tend to be irreversible. So, while doctors generally regard asthmatic airway obstruction as reversible, remodelling can cause at least partially irreversible symptoms.
Two main types of asthma
Doctors recognize several asthma subtypes that may differ in cause, symptoms, response to treatment and long-term outcome. Broadly, doctors split asthma into two types. First, in many people – especially children – asthma arises from an allergy (allergic asthma). However, in many adults, asthmatic inflammation seems to arise without an allergic reaction – so-called ‘intrinsic’ asthma. Some other forms of asthma – such as nocturnal and exercise-induced symptoms – overlap with these two main types.
Atopic (allergic) asthma
Allergic asthma’s causes are very complex and scientists still haven’t worked out all the details. Essentially, however, allergic triggers (allergens) travel deep into the lungs and come to rest on the thin layer of cells that lines the airways. This cell layer – called the respiratory epithelium – forms a barrier that stops disease-causing bacteria, viruses, fungi and other airborne hazards from entering the body. The respiratory epithelium also keeps the airways moist and contains mucus-producing goblet cells, which, as mentioned earlier, are an important defence against pathogens.
Specialist ‘dendritic’ cells in the respiratory epithelium engulf and ingest allergens and invading micro-organisms. Enzymes inside the dendritic cell degrade proteins in the allergen or pathogen into small fragments, called peptides. (Enzymes are specialized proteins that control biochemical reactions.) Dendritic cells then move to the local lymph nodes. These glands produce lymph, a liquid that bathes cells, and certain white blood cells that target the peptide fragments. (The same mechanism causes lymph nodes around your neck to swell during an infection. That’s why a doctor feels your glands when you’re unwell.)
Red, white and other blood cells
Blood contains many different types of cell. Red blood cells (erythrocytes) carry oxygen from your lungs to your tissues. Platelets help your blood clot. And white blood cells fight infections. For instance, lymph nodes produce several members of a family of white blood cells called T-lymphocytes. Each of the several T cell types has a specialized function:
- Memory T-lymphocytes help the body respond rapidly to micro-organisms that it’s encountered before.
- Cytotoxic T cells destroy the invading pathogen.
- T suppressor cells inhibit the immune response, helping to prevent it from raging out of control and destroying healthy tissue.
We’re interested in another member of this family: T-helper cells (Th cells). Dendritic cells bind to and activate Th cells. In turn, Th cells release chemicals (cytokines) that stimulate another group of white blood cells (B cells), which form in the bone marrow.
B cells have two main actions. First, B cells produce antibodies, which allow your body to remember and respond rapidly to allergens and pathogens you have encountered before. The human immune system contains hundreds of millions of different B cells, each of which recognizes a different antigen or pathogen. Second, B cells activate other defensive white blood cells. (See Figure 1.4.)
Figure 1.4 The immune response
Essentially, your immune system produces two main types of Th cells:
- Th1 cells help the immune system tackle some bacteria and certain viruses.
- Th2 lymphocytes evolved to protect against certain parasitic infections, especially gastrointestinal worms.
Many common allergens – such as house dust mites, pollen, animal dander (dead skin and fur) and fungal spores – contain proteases. These enzymes damage the respiratory epithelium, which activates the Th2 response.
The first time you encounter an allergen you generally do not experience any symptoms. However, your immune system is ‘primed’ (sensitized). So, when you next encounter the allergen, you quickly produce large amounts of antibodies.
This rapid response helps the immune system tackle infections. The first time you encounter a pathogen – such as chickenpox or a flu strain – you can suffer unpleasant, even serious, symptoms. However, sensitization means that your immune system swings into action and eradicates the infection much more quickly when you next encounter the pathogen, in many cases before you develop symptoms. This is, essentially, the same process as vaccination. The jab primes your immune system.
In allergies, however, this ‘priming’ means that the immune system produces symptoms when sensitive patients encounter triggers that most people find innocuous, such as cat or dog hair or grass pollen. In asthma, the reaction causes allergic symptoms in the lungs. In rhinitis and eczema, symptoms develop in the nose and skin respectively.
B cells produce five families of antibody (called IgA, IgD, IgE, IgG and IgM), each of which controls a different aspect of the immune response. For instance, we evolved immunoglobulin E (IgE) to tackle certain parasites, including tapeworms. However, people with asthma triggered by cat dander produce IgE specific for cat dander. Those asthmatics sensitive to grass pollen produce IgE specific for grass pollen.
In general, IgE does not cross-react between allergens. So, IgE for cat dander won’t trigger an allergic response when you encounter grass pollen. But there are occasional exceptions. For example, some pollens (such as birch) contain proteins that have a very similar structure to those in other plants, including apples, oranges, potatoes and tomatoes. This means that someone who produces IgE to, say, birch pollen may also develop allergic symptoms when peeling potatoes. Doctors call these proteins ‘pan-allergens’.
IgE binds to yet another type of white blood cell, called mast cells. The great German scientist Paul Ehrlich noted during the 1870s that mast cells accumulate in inflamed areas. Ehrlich believed that the cells helped meet the inflamed tissue’s increased nutritional requirements. So, he called them ‘mast’ cells – the German for ‘fattening’ or ‘suckling’.
But we now know that mast cells are central to the immune response. IgE’s binding triggers the release of mast cells’ stores of inflammatory mediators, of which histamine is the best known. When IgE binds, mast cells also freshly make several other mediators that promote inflammation. Meanwhile, IgE also binds to basophils, another type of white blood cell, which trigger the release of yet more inflammatory mediators.
Some mediators released by mast cells and basophils attract other types of white blood cells into the inflamed tissue. These late-arriving cells add still more mediators into the cocktail, which help maintain the inflammation. The late-arriving cells also release enzymes and other chemicals that start breaking down inflamed tissue. This attack on inflamed tissue helps destroy invading pathogens, but also contributes to airway remodelling in asthma.
One type of late-arriving white blood cell, the eosinophil, seems to be especially important in asthma. Mediators and other chemicals released by eosinophils promote airway obstruction, contribute to remodelling and increase bronchial hyper-responsiveness in asthma. Indeed, eosinophils are present in the airway wall across all severities of asthma, from mild to life-threatening, and seem to be one of the key cells driving asthma.
Uncontrolled inflammation could spread from the site of exposure and destroy the surrounding healthy tissue. So, the body evolved ‘anti-inflammatory’ mechanisms. For example, some mediators damp down the inflammation, limiting the immune response to damaged or infected tissue. Low levels of these mediators – as well as high levels of pro-inflammatory chemicals – can contribute to COPD and asthma. Furthermore, as mentioned on page 15, T suppressor cells help limit any collateral damage to healthy tissue during an inflammatory reaction. These mechanisms mean that the inflammation gradually subsides once your exposure to the allergen ends or the infection resolves.
Immune changes with age
Several aspects of the immune response change with advancing age. For example, the T cell response seems to be less active in elderly adults compared to younger people. In particular, memory T-lymphocytes seem to become less responsive. This may contribute to allergies’ declining importance as an asthmatic trigger in adults compared to children. Interestingly, women usually have lower levels of total and allergen-specific IgE than men. This observation ties in with the typical patient with intrinsic asthma: a middle-aged woman.
The early and late allergic reactions
This immune reaction creates two ‘peaks’ in allergic symptoms. The early response in people with allergic asthma (driven, predominantly, by mast cells) reaches a peak after about 20 minutes of exposure to the allergen. Eosinophils and other late-arriving white blood cells usually take several hours to reach significant numbers in the inflamed tissue. As a result, allergic symptoms may re-emerge later, usually between 6 and 12 hours after the first exposure to the allergen. This is the so-called ‘late-phase reaction’.
Allergic (sometimes called extrinsic) asthma generally occurs in younger people, depends on IgE and tends to emerge in people whose immune system is highly sensitive to a particular allergen. In contrast, intrinsic asthma tends to occur in older people, doesn’t involve IgE and shows a strong relationship with several non-allergic triggers, including certain respiratory infections, chronic sinusitis and recurrent bronchitis. Virchow notes that in one study, recurrent bronchitis preceded 17 per cent of cases of intrinsic asthma. Furthermore, 32 per cent of patients reported suffering a flu-like infection, while 51 per cent had chronic sinusitis and nasal polyps. Typically, these conditions developed into persistent cough and then airway obstruction and wheeze.
Your age when symptoms first emerged may offer a clue as to whether you suffer from intrinsic or extrinsic asthma. Intrinsic asthma usually emerges in people aged between 40 and 50 years. Indeed, some doctors suggest regarding asthma that emerges before the age of 30 years as allergic until proven otherwise. On the other hand, they suggest considering asthma that emerges after the age of 40 years as intrinsic until proven otherwise. Sex offers another clue: three adult women suffer from intrinsic asthma for every two men with the disease. In part, this sex difference may reflect the impact of female hormones, an issue we’ll return to later.
Children with allergic asthma often report that their siblings have allergic rhinitis (an allergy affecting the nose – hay fever is the best-known example), allergic asthma or allergic eczema (an allergic skin rash). With allergies’ declining importance as a cause of asthma, such reports become less common in people whose asthma symptoms begin in later life. Nevertheless, many people with adult-onset (and, therefore, supposedly intrinsic) asthma report that they or another member of their family or both suffer from allergic diseases. Indeed, Virchow comments that one study showed that levels of IgE to house dust mite rose – remember, increased IgE is supposedly the hallmark of allergic asthma – before men with an average age of 64 years started wheezing. In another study, 21 per cent of people with ‘intrinsic asthma’ showed elevated levels of IgE. However, showing IgE circulating in your blood doesn’t necessarily mean that the immune response triggered by the allergen was sufficient to cause asthmatic symptoms. And in some people both mechanisms may play a role. If you think this sounds confusing – you’re right! No clear picture emerges.
In the end, however, persistent inflammation drives intrinsic and allergic asthma. In addition, the lungs show similar changes – including reversible airway obstruction, exercise-induced symptoms, variations in lung function over the course of the day and raised levels of eosinophils – whether the asthma is intrinsic or allergic. So, the distinction between allergic and intrinsic asthma usually has little influence on diagnosis or treatment. Nevertheless, if you suffer from allergic asthma, identifying the cause may help you avoid the trigger.
Genes and asthma
Asthma, especially allergic asthma, runs strongly in families. Indeed, genetic factors may account for up to 60 per cent of the risk of developing asthma, according to Moffat and co-workers. Doctors describe the 30 to 40 per cent of the population with a tendency to produce excessive levels of IgE, especially when inherited, as ‘atopic’. Allergic rhinitis (which includes hay fever) and the allergic forms of asthma and eczema are the ‘atopic’ diseases.
Researchers believe that more than 100 genes increase the risk of developing allergy and asthma. Rather than one gene strongly influencing the risk of developing asthma and allergies, several genes, each of which produces a moderate effect, seem to interact. Some of these genes increase the risk of asthma irrespective of age. A gene is an instruction that tells the cell to make a particular protein. For example, some of the age-independent genes code for proteins that ‘report’ damage to the airway epithelium to the immune system. These ‘reports’ activate inflammation driven by Th2 cells, Moffat and co-workers remark.
Other genes linked to asthma throughout life produce proteins that down-regulate the immune system. In other words, the genes code for a protein that puts a brake on the airway inflammation. If the gene encodes an abnormal version of this protein, the inflammation will be poorly controlled. Finally, some genes determine the extent of airway remodelling whether you’re 6 or 60 years old.
Other genes seem to influence the risk of developing asthma during childhood but not as an adult, or vice versa. Your cells contain 23 pairs of chromosomes. You inherited one copy of the chromosome in each pair from your mother, the other from your father. This means that you have 46 chromosomes. (Down’s syndrome and certain other genetic diseases are exceptions to this rule. Down’s Syndrome, for example, arises when the child inherits an additional copy of part or all of chromosome 21 during conception.)
One study looked for genes linked to asthma across all 23 pairs of chromosomes. Moffat and colleagues found a particularly strong link between a region on chromosome 17 and asthma in children. In contrast, a region on chromosome 6 exerted an important influence on the risk of adult-onset asthma and seemed to code for a protein that influences the immune response provoked by bacterial or other non-atopic (non-allergic) triggers. These genetic variations underscore, once again, that in some cases asthma in children and adults may be very different diseases, despite the superficial similarity in symptoms.
Human DNA has contained most – if not all – of the genes linked to asthma for thousands – if not millions – of years. But the number of cases of allergic asthma and other atopic diseases rose dramatically in children during the twentieth century. The Lung and Asthma Information Agency estimates that the number of children with asthma increased by about half between the early 1970s and the mid 1980s. (The agency also notes that there are too few studies to assess whether the number of adults with asthma increased.) Moreover, the number of people with allergic eczema increased between two- and three-fold in the last 30 years of the twentieth century.
Alterations in our genetic code could not account for the rapid rise in these allergic diseases. In any case, as mentioned at the start of this chapter, the interaction between genes and environment determines your risk of developing asthma. Against this background, the ‘hygiene hypothesis’ (see below) helps explain the marked rise in asthma and other atopic diseases.
Studying asthma’s genetics helps researchers understand the causes of the disease and may lead to new treatments. However currently, doctors cannot look at your genetic code and determine your risk of developing asthma. They can’t predict the course of your asthma, your response to treatment or the severity of your symptoms after analysing your genetic code and risk factors.
Nevertheless, in the future doctors may be able to scan a person’s genetic code, characterize a person’s chance of developing asthma, predict the severity and ascertain which treatment will be the most effective and least likely to cause side effects. We have only just scratched the surface of the potential offered by genetic studies into asthma.
The ‘hygiene hypothesis’
Whether an immature Th cell becomes a Th1 or Th2 lymphocyte depends on the hazards in the environment. Many bacterial infections ‘programme’ the immune system to produce Th1 cells. Th2 cells protect against certain parasites and several other infections. During the twentieth century, improved sanitation, better nutrition and vaccinations reduced the risk of infections. So, ‘idling’ Th2 cells started responding to allergens.
This means that the bacteria, viruses and other pathogens that you encounter in early life seem to influence your risk of going on to develop asthma. For example, most studies (although not all) suggest that infections with parasitic worms protect against asthma and other allergies. The Th2 cells target the parasite rather than the lung. Furthermore, the respiratory syncytial virus (RSV) causes the common cold in adults and bronchiolitis (inflammation of the bronchioles) in children. RSV infections augment Th2 responses, and therefore seem to be a risk factor for developing asthma later in life.
On the other hand, certain microbes boost the Th1 response. So there are fewer Th2 cells, which may reduce the risk of asthma. This probably partly explains why children with older brothers and sisters are less likely to be asthmatic than those without elder siblings. Younger children are more likely to catch a childhood infection, and therefore have fewer Th2 cells and a lower risk of asthma.
In other words, the person’s particular pattern of exposure to allergens and microbes in early childhood may programme the immune system to ‘favour’ a particular Th pattern and therefore influence the risk of developing allergic asthma. As our homes and environment became cleaner, as our nutrition improved and as vaccinations prevented many of the diseases most feared by our parents and grandparents, the patterns of exposure to pathogens changed. These changes contributed to the rise in asthma and, probably, the other atopic diseases during the twentieth century. However, other factors – including alterations in diet – probably also contributed to the changing risk of allergies.