Gasping millions

Asthma, the bane of modern life, stalks the young ones and the affluent. It will strike 32 million people in India by 2010. The silent strangler has a propensity to waylay its victims, striking with stealth. An analysis into what triggers the killer which garrottes nearly 500 victims every day and leaves several others suffering a life of anticipated terror

 
Last Updated: Sunday 07 June 2015 | 21:11:47 PM

Gasping millions

-- LIKE A FISH out of water, she chokes and gasps. Writhes. She struggles to snatch a lungful of air, while watching television she suddenly hits a vacuum. She is asthmatic. She is just about anybody. One of the 150 million that are reminded the hard way that life in today's world is just a breath away from turning into a statistical entry in the death register.

But asthma doesn't discriminate, not between sexes, at least. She could just as well be a boy. The medical fraternity is sure though, asthma does prefer the affluent and the children of affluence, more so. It is the curse of modernity. A morbid attendant at the door to the new world, waiting to catch the entrant unawares. A murderer that chokes 180,000 people to death each year. And the lists of its victims only grow longer each year with humans increasingly embracing a lifestyle that is too cushioned to resist the onslaught of allergen. Doctors try to fathom the method to the madness, predict a trend. But trends emerge as chaotic as the life of an asthmatic.

If you are not an asthma patient here's how you can experience the misery of one: take a deep breath. No, do not exhale. Not just now. Hold it for 20 seconds. Now exhale. But only for two seconds. Inhale again, holding it this time for 15 seconds. Repeat this for intervals by holding your breath for 10-15 seconds more. Never before did oxygen feel this precious. To slip from the precipice into an abyss, just about. To be pulled back, finding your feet grounded again, only to fall back once more. Repeatedly. Millions of people, often children, regularly endure this near death experience. Attacks occur suddenly, without any provocation. Today in India, about 15-20 million asthmatics daily live this encumbering reality. One out of 10 children in the country are asthmatic. In Delhi alone 700,000 people live under the spectre of asthma.

Asthma is more prevalent in Australia, the UK and New Zealand. In the US, asthma cases have shot up by 75 per cent between 1980 and 1994. The disease kills 5,000 US citizens each year. The rates of affliction are much lower in Asia - about eight per cent on an average, compared to the global average of 14 per cent. Across countries in Asia, and within each country, significant variations exist.

But experts are unanimous that in case of India the disease is one of the most underreported ones. In fact, nine out of 10 cases of asthma in children go undetected say some guesstimate. And while children may be the primary targets, asthma in adults too seems to be on the rise. The British Medical Journal reports on a Scotland-based study that showed asthma in adults to have doubled in the past two decades.

Baffled by figures
And the rate of those inflicted with the debilitating disease increases by 12 per cent every decade. This is the world average and it is a conservative figure. Real figures, however, may never emerge. Diagnosing asthma is never easy.

A plethora of triggers bring the disease into play. Just as the number of those afflicted rises, so does the list of triggers. Environmental triggers like diesel, lifestyle-related ones like junk food consumption - the range is maddening and frustrating for the patient, the doctor and the researcher.

In India, data on asthmatics is not collected officially. The data bank created could help find patterns - trends that help focus medical and pharmacological research. So a comprehensive picture of the disease continues to elude experts. Elsewhere, there is a great wealth of research on asthma, but with little consensus. Some report that smoking, exposure to allergen, dust mite or cockroaches cause asthma. Others report that there is a genetic link. While one section of the research looks for reasons behind asthma's spread, the other tries to find cures and disease mitigating drugs.

An asthmatic, trying to figure out just what triggers the spasmodic dance of the devil inside, cannot wait for a medical breakthrough or a cure. The asthmatic learns to live with whatever drug regime is affordable, whatever provides some solace. This moment.

Trigger happy
Asthma is easily caused. Innumerous allergen, from pollen grains to dust mite, play havoc, exacerbating the disease. While experts are unable to reach a consensus, one thing's clear: modern lifestyle contributes to this disease

ASTHMA affects people of all ages, runs in families and can be severely debilitating, even fatal. It picks on the vulnerable children. Recent research suggests that genetic, lifestyle, medical and environmental factors combine together, often inextricably, to cause asthma. This is undisputed. Researchers are now investigating other triggers and risk factors such as family size, exertion, housing, socioeconomic status and allergen in air and food that contribute to its onset and severity. Genetic causes
ATOPY: The propensity, usually genetic, for developing immunoglobin E (IgE) mediated responses to allergen is probably the strongest identifiable risk factor for asthma development. A review of clinical evidence by Adnan Custovic of Wythenshawe hospital in the UK in 1998 showed most asthma patients to be atopic - they are prone to producing abnormal amounts of IgE when exposed to allergen like domestic mite, animal proteins, pollen and fungi. Atopy occurs in 30-50 per cent of the population, but overall asthma prevalence is usually much lower. In other words, most asthmatics are atopic but only some with atopy will develop asthma. Yet, when expressed in the lower airways, atopy remains among the strongest predisposing factors for developing asthma. J K Suri, head of respiratory medicine at Safdarjung Hospital, Delhi, says, "While environmental factors aggravate asthma, they cannot be supported without a strong genetic base."

ETHNICITY: Asthma occurs among all races. Yet marked ethnic differences have been observed. Minority groups are not only asthma-prone, they also are more likely to die. African Americans are 2.5 times more likely to die of asthma than whites. Puerto Ricans have asthma rates 2-3 times more than whites while, paradoxically, Mexican Americans have rates significantly lower than whites, says Malcolm Blumenthal, a professor of medicine at the University of Minnesota-Twin Cities. Another study observed that in the group aged 5-34 years, asthma mortality rates were 0.5 per 100,000 in Chinese, 1.3 per 100,000 in Indians, and 2.5 per 100,000 in Malay subjects. Similar variations were seen for other age groups. In the 1960s, there was a rise in death rates in New Zealand, Australia and the UK, and a decade later a second epidemic of deaths was observed in New Zealand disproportionately affecting Maoris. Scientists suggest western lifestyle may partly explain such differences, but exact reasons remain unknown.

AGE AND GENDER: That children are becoming increasingly vulnerable to asthma is now confirmed. But the reasons are poorly understood. Childhood asthma is more prevalent in boys than in girls. However, this increased risk seems more related to narrower airways and increased airway tones in boys, which predispose them to enhanced airflow limitation.

GROWTH OF THE CHILD: Asthma evolution depends on the age of onset and possibly on the etiology of the disease. Disproportionate foetal growth (large head and small trunk), that is often associated with a birth weight of less than 2,500 gramme may carry an increased risk of developing asthma during childhood or adolescence. Poor nutrition in underweight babies may also impair basic immunological mechanisms. There is a correlation of early wheeze with reduced lung function before the development of symptoms suggesting that small lungs may be responsible for some infant wheezing that resolves with the child's growth. Asthma may disappear in 30-50 per cent of children at puberty, but often reappears in adult life and up to two-thirds of children with asthma continue to suffer through puberty and adulthood.

Lifestyle factors
AFFLUENCE: The prevalence of childhood asthma and atopy varies widely between countries. Alistair Stewart doing a study for the International Study on Asthma and Allergy in Childhood (ISAAC) studied the correlation between gross national product (GNP) and the symptoms of asthma and other allergies in children from across 56 countries. A moderately strong correlation was established between GNP per capita and the prevalence of asthma. This means the more the income per capita, the greater the prevalence of asthma.

High-income countries like the US, Canada, New Zealand, Australia and the UK have an asthma prevalence rate of between 20-30 per cent in these age groups. Many Latin American countries like Brazil, Costa Rica and Peru have an unusually high prevalence rate of around 20 per cent. Though India and China have a lower prevalence rate (between 4.2-6 per cent), the total number of asthmatics is very high. Also asthma cases are underreported and poorly diagnosed in India and China because of the stigma attached to the disease.

Writing in Thorax, a medical journal published from the UK, Adeola Olusola Faniran compared the prevalence of symptoms in Australian and Nigerian children and found that wheeze and persistent cough were less prevalent in Nigeria (10.2 per cent and 5.1 per cent respectively) than in Australia (21.9 per cent and 9.6 per cent, respectively). Though there was no significant difference in the overall prevalence of atopy between the two countries (Australia 32.5 per cent, Nigeria 28.2 per cent), atopy was a strong risk for wheeze in both countries. Despite this, Australian children had a higher prevalence of asthma symptoms. This could be related to various environmental factors, allergen exposure or to different racial susceptibility, genetic predisposition and environmental factors.

But the story is not as simple as it sounds. Hospital records suggest that people of low socioeconomic status (SES) experience higher mortality and morbidity in comparison with people belonging to higher SES. A study done in London found the severity of asthma cases being more prevalent in the poorer sections. The poor seek treatment and admission only when there is a crisis. They rarely follow a planned treatment procedure and are under-users of primary healthcare facilities. The attendance rate in casualty departments by the poor during acute asthma attacks is four times more than other user groups. Evidently, while the poor may suffer lower incidence of asthma, when the disease does strike, it leaves them in a worse situation than the rich.

Another study shows how the prevalence of severe asthmatic crisis increases inversely with the declining SES of the patients. In Korea, mortality avoidable by medical intervention, defined as 'mortality wholly or substantially avoidable by adequate medical care' decreases with the growth in socioeconomic conditions and health services. These studies show that inequalities in health do exist. Are the poor more susceptible and more exposed to trigger agents? If so, is it possible to modify some of these determinants of disease severity? But how does this conform to the findings of the ISAAC study on the inverse correlation between income (GNP terms) and asthma prevalence? It is time to design our health policies based on epidemiological studies and demographic distribution.

SMOKING: There is now proof that while passive smoking causes increased incidence of wheezing illnesses in the first few years, it does not increase the risk of sensitisation to common aeroallergens, an important risk factor for asthma that onsets later. Surveys show that wheeze and asthmatic attacks are more prevalent in children whose parents smoke.

DIET: The role of dietary factors is under scrutiny, but no clear results have emerged. A recent paper in Thorax by Nariman Hijazi investigated dietary and other factors for asthma in Saudi Arabia where major lifestyle differences are found in different communities. It found that family history, atopy and eating fast food were significant risk factors for wheezy illness, as were the lowest intakes of milk and vegetables and of fibre, vitamin E, calcium, magnesium, sodium and potassium. Studies show that low intake of fish may weaken asthma resistance and evidence suggests that intake of omega-3, a fatty acid found in fish oil, may help keep the disease away.

It is also widely believed that food allergies are common asthma triggers, though evidence is rare. Some food and additives, including salicylates, food preservatives, monosodium glutamate and some food-colouring agents, cause asthma symptoms in some patients.

OBESITY: Obesity is associated with asthma symptoms regardless of ethnicity. The association is consistent with the basal metabolic rate because obese children are more advanced in their maturation than other children. There is some evidence that this association is stronger in girls than in boys.

Environmental triggers
ALLERGIES: The most important allergen are probably inhaled allergen, like mite, fur of animals, fungi and pollens. Allergen sensitise atopic persons by stimulating the development of specific T lymphocyte cell clones and the production of specific IgE antibodies. Once a person is sensitised (that is, has developed memory T lymphocytes and specific IgE), they are likely to develop allergic inflammation upon re-exposure to the same allergen.

The introduction of mite, the presence of large numbers of insects and cockroaches in tropical countries are some important episodes in the history of asthma. Climate is important because it is directly related to the amount of allergen present in the environment. For example, a damp and warm climate is favourable to mite and mould growth. Sensitisation to allergen by exposure to sources like house-dust mite, cats, dogs, cockroaches and smoke is strongly established, while other factors are less strongly correlated.

According to S K Kabra, an asthma specialist with the All India Institute of Medical Sciences in Delhi, in the general population of India, 60 per cent of the patients suffer from asthma due to viral infections and 40 per cent of the cases are due to allergen, pollens or seasonal variations.

URBANISATION: Universally, levels of asthma in urban communities seem to be higher than in rural ones. Yet, urbanisation involves so many changes in environment and lifestyle that a definitive explanation for this has so far been elusive. Urbanisation with accompanying pollution appears to be more directly related to increase in allergy. For example, in polluted Swedish and Chilean cities, asthma has increased drastically in the last two decades. In Japan, the increased allergy to Cryptomeria japonica, soft wood pine, has been attributed to sensitisation to urban diesel exhausts.

The trigger happy asthma needs just as many treatments to catch it before it hits hard and to limit its effects.It is, one must remember, controllable, even if not completely comprehensible.

Breathing easy

-- (Credit: Pradeep Saha / CSE)WITH increasing patients and many of them in industrialised nations the market for asthma drugs is growing rapidly. It is the eighth largest selling drug market and possibly the most profitable venture for pharmaceutical companies, at par with profits made from cancer and heart diseases related drugs.

In the absence of evidence of the global growth of asthma, sales of drug and medicines to treat asthma are a good indicator of how fast the disease is actually growing. According to the US-based Asthma and Allergy Foundation, USA, spends US $2 billion annually seeking asthma and allergy relief and globally the market is estimated to be at US $4.8 billion. Singulair, Merck's once-a-day leukotriene-antagonist medicine, alone grosses worldwide sales worth US $860 million.

But compare this to the budget spent on research and development of drugs for asthma and one comes to know why the disease is not finding any adequate response in the thousands of prescriptions being handed out daily. The Pharmaceutical Research and Manufacturers of America (PhRMA) estimates the total budget of asthma research is only US $1 billion of the total US $80 billion industry. The revenues from asthma drugs comprise about a healthy nine per cent of the total sales in western markets according the World Pharmaceutical Outlook 2000. Just 15 years ago, in 1985, asthma drugs commanded only 1.5 per cent of the total global revenue. Against this backdrop, one can evaluate the drugs, therapies and treatments present today in the market for asthmatics.

Medication for asthma
Asthma is not yet curable and neither does any convincing evidence exist yet to prove that it could be prevented. It can, however, be treated and controlled. Good care and a regimen of some expensive drugs can convert asthma from a major handicap to a minor nuisance.

Treatment for asthma is based on the severity of the problem faced by the particular patient. Three main types of treatments are usually recommended. The first set of medicinal treatments is called bronchodilators. These make the muscles around the airways relax. As this happens, air tubes open up, making it easier for the patient to breathe. The other group of medicines reduce swelling and irritation in the airways and are collectively called anti-inflammatory drugs. Corticosteroids are an example of such anti-inflammatory steroids and are used very frequently. Anti-inflammatory medicines help to control the inflammation of airways and prevent the onset of asthma attacks. They work to reduce the swelling in air tubes and keep them open for passage of air. Consequently they also decrease the mucus.

Inhaled corticosteroids, which help relax the muscles around the airways, are the most favoured these days. They dominate the asthma market, accounting for one-third of major-market sales of asthma medication. They are the most effective long-term preventive medications since a greater percentage of the dose is able to target the inflamed lungs. Doctors also commonly prescribe other anti-inflammatory medicines like cromolyn sodium and nedocromil.

Interestingly, sensitising to low doses of trigger antigens can also be helpful in preventing asthma attacks. But this treatment is rarely done in India as it is too expensive and requires a long treatment time with no assured relief. The risk also exists of the patient suffering adverse reactions to the allergen.

Four steps to well being
Based upon a set of symptoms, a stepwise approach is advised for deciding the medication regime. A predetermined set of symptoms is used to grade the severity of asthma attack. The number of drugs used, type of drugs, dosage levels and the frequency of medication, all depend upon where the patient stands on these four 'steps' (see box: Asthma control regime).

As in other medicines, the drugs are sold under brand names and not generic names. They come in different forms, including sprays, pills, powders, liquids and shots. When corticosteroids are inhaled as in a spray, the risk of serious side effects is minimised if not done away with completely. The chance of suffering side effects increases when these medicines are taken in the form of pills or as a liquid and that too over a long period. In case of pills or liquids the patient needs to go for regular check-ups by a doctor to make sure that the medicine works the best way. The medicines ease the asthmatic condition but demand that a lot of attention be paid to the usage and after care.

Although most medications aim to improve the lung function when administered regularly, they differ in their mechanisms of action, in their offset of effect and how they actually resolve inflammation. On breaking the performance of medications into subcategories of response, differences can be observed.

There does exist another kind of treatment that may be helpful if asthma attacks are triggered by allergies. This treatment is called hyposensitisation therapy or allergy shots. In India however, Kabra says, hyposensitisation therapy is practised very rarely as patients are rarely subjected to allergy tests. Quite often, patients through their own experiences are able to identify the allergen.

Advances in medicine
A host of new medicines are also under development. Some of them seek to better the node of delivery, while others seek to optimise the chemical balances. Of all the therapies and medicines under development, omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody from Genentech/Novartis, holds the greatest promise, believe experts. The medicine is currently awaiting marketing approval. Dr Reddy's Laboratories' zafirlukast, a non-steroidal leukotriene modifier launched recently in India, too holds some potential. Leukotrienes are pro-inflammatory substances released during pathogenesis of asthma resulting in bronchoconstriction, oedema and inflammation. By selectively and competitively blocking leukotriene receptors, zafirlukast helps in effectively controlling a range of asthma symptoms and improves lung function. Available in oral pill form, just two doses a day of the drug could provide 24-hour protection from asthma attacks, claims the company. It remains to be seen how effective this new oral dosage treatment will be, given the physician's existing preference for inhalers to treat chronic patients.

Industry observers believe that the long-acting beta2 agonist-corticosteroid combination agents (which ease muscles around the airways) will become the most popular choice, replacing the single-agent inhaled corticosteroids and long-acting beta2 agonists. Both combination agents offer more convenient treatment regimens.

Therapeutically speaking, managing the disease has improved enormously over the past 20 years due to advances in both drugs and in the way these drugs are delivered. Pharmacological treatment for asthma relies heavily on -agonists and corticosteroids. The development of both classes of drug combined with a general improvement in management means that most patients with mild or moderate asthma can have a relatively symptom-free life. Nasal sprays that treat allergies have been improving. Older versions of the nose sprays frequently caused allergic reactions because they were essentially allergen in a water solution. Using a spray, patients would endure allergy symptoms until their bodies built up a tolerance to the allergen at hand. But researchers have learned that giving patients a spray of cromolyn sodium first can stifle a nasal spray's allergy-inducing response, while still providing protection against the allergen.

Other areas of developments involve the hunt for novel allergy targets. Some also see room for improvement in existing therapies. Innovating upon the allergy-shot method, a hi-tech US-based lab recently cloned the genes for allergen contained in cat dander and ragweed pollen. With genes in hand, they isolated the most potent portions of the allergen and then used just those portions to create refined allergy shots. In theory, these shots will deliver more therapeutic punch-over the course of just a few weeks and with fewer side effects.

Many experts believe that for a complex disease like asthma such an approach would work only for a few allergen.

While the researchers practicing allopathic medicine experiment with a handful of chemicals, trying to develop the best possible mix for a drug that will be more effective and have less or no side reactions, asthmatics have survived the agony of a million gasps by trusting other schools of medicine. These complementary and alternative medicine systems work out to be cheaper and more accessible, especially in India's case.

Alternative medicine
Complementary and alternative medicine (CAM) systems may not be a part of the mainstream and conventional therapy but their popularity has only increased over time. Homeopathy, yoga, herbal medicine and nutritional therapies - all are finding an increasing number of asthma patients converting to the fold, looking for long-term and cheaper solutions.

And there are innumerable such options for the suffering to explore. Take for instance the ayurvedic herb, Coleus forskholii, which has a bronchodilating effect or the Chinese wonder herb Ginkgo biloba and Tylophora asthmatica, which improve pulmonary function.

While allopathic practitioners continue to doubt the efficacy of herbal drugs, two drugs have already been launched in the previous year -Resipicare (developed by Bafco) and Asmon (developed by the Indian Institute of Chemical Biology, Kolkata). Both manufacturers claim that their medicines effectively control asthma without any side effects. Doctors assert that herbal drugs cannot replace steroids and at best can be used along with an allopathic drug.

While these doubts may persist, a comparative study of CAM approaches done by George Lewith in Thorax finds that yoga breathing exercises - pranayama in a particular modification (called the Pink City lung exercise) is an effective therapy.

"Homeopathy too helps in improving the immunity of the patient," contends Chanda Shah, a practising homeopath in Mumbai and an asthma patient herself. She, however, recommends the usage of injections or a nebuliser in case of severe asthma attack.

Awareness, the ultimate tool
But the most important weapon in the fight against asthma, believe doctors, is education. "Education should be our top priority" says S K Chhabra. "Asthma guidelines are given to general physicians abroad by associations like the British Thoracic Society or global protocols like the World Health Organisation. These should be observed here too and taught in the medical curriculum. This would go a long way in the correct diagnosis of the disease."

And it is not only about educating the asthmatics but about the doctors and medical researchers also learning more about the disease. Government agencies and research institutions in India need to wake up. The US government has specialised agencies like the National Allergy and Infectious Diseases, which specialises in research and creating awareness in public. Even the Environment Protection Agency educates about allergen like pollution due critical periods. Australia and New Zealand have special helplines and warning centres during the 'allergy seasons'. The least that the Indian government can do is enforce protocols like asthma management and create a platform for educating patients. This is true for the entire world also. Building a global research protocol on the epidemiology of the disease remains an imperative that is yet not paid attention to.

Meanwhile, scientists continue to seek a cure, attacking asthma from new directions, using a variety of disciplines - genetics, physiology, cell biology, epidemiology and immunology - to converge on the problem. That's a big change from years ago, when only allergists and lung experts studied the disease. The real challenge lies in comprehending the confounding number of triggers that push the millions of asthmatics into a paroxysm of gasps. It seems that there is no silver bullet despite so many triggers. Till one is found the sufferer will need to wait, with bated breath.

With inputs from Sarita, DBManisha, Chandrachur Ghosh, Apurva Narain, Jennifer O'Riley, Rachita Jha (in Delhi) and Pujita Krishna (in Hyderabad)

Future stock
Asthma drugs still in the pipeline
Generic name Company Age group targeted
Xopenex Sepracor 4-11 years
Xolair Tanox biosystems 6 years and older
Flovent Glaxo SmithKline 4-11 years
Azmacort Aventis Not known
Ventolin Glaxo SmithKline 4-11 years
Seretide Glaxo SmithKline Paediatric patients
Advair Glaxo SmithKline Not known
Asmanex Schering-Plough 2-12 years
Aerobid Forest laboratories 6 years and older
Xopenex Sepracor Newborn – 6 years
Pediavent Ascent pediatrics 2 years and older
Foradil Novartis 5 years and older
Asmanex twisthaler Schering-plough 4-12 years
Oxsodrol recombinant human superoxide dismutase Bio-technology general Premature infants
Ciclesonide Aventis Not known
Source: Pharmaceutical Research and Manufacturers of America (PhRMA) website : www.phrma.org,asthma,asthma-cures.htm (as of Dec 23, 2001)

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