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Fighting the shortage of air

Chemical messenger of the defense system regulates associated allergic reactions

LAURA BEATRIZOnly those who have woken up in the small hours with an anguishing sensation of suffocation or have experienced the inconvenience of prolonged crises of coughing after a small physical effort like going up two or three flights of stairs know well the upsets that asthma imposes. A chronic respiratory problem that affects from 150 million to 300 million people in the world, asthma consumes more than an important portion of the resources for healthcare. It steals life itself: it is estimated that every year 15 million asthma sufferers lose one year of healthy life. Described for the first time in a collection of Egyptian medical texts of 3,500 years ago, the Ebers Papyrus, even today challenges those who propose to understand the intricate chemical mechanisms that originate the sudden crises of shortage of air.

This is a picture that is beginning to change. Recent discoveries by researchers from Brazil and abroad are unveiling the role performed by messenger molecules of the defense system in controlling the production of allergic substances that trigger the asthma crises. It is early to know, but compounds that simulate or block the action of some of these molecules, the interleukins, may generate alternatives for controlling this chronic inflammatory disease that is becoming more and more frequent in the western countries. From 1980 until now, the occurrence of asthma has grown 60% in the United States, where the problem consumes US$ 6 billion a year in medical assistance and affects 11% of the population. It is a proportion similar to the one found in Brazil. It is reckoned that 11.4% of the Brazilians have asthma, and one in three shows some symptoms of the disease. Like breathing with difficulty and wheezing.

At the Federal University of Bahia (UFBA), lung doctor Álvaro Augusto Cruz has identified the regulatory role of interleukin-10, investigating the relationship between the occurrence of certain types of infection and the symptoms of asthma. They are studies to evaluate a curious hypothesis explored by German allergist Erika von Mutius: the hygiene hypothesis. In the 1990’s, she compared the rates of occurrence of allergies and asthmas in children of the former West Germany with those of children from East Germany. Her expectation was that these problems would be more frequent on the communist side, with its poorer, dirty, and apparently less healthy cities.

To her surprise, Erika found the opposite, and she went to find the explanation for this result in the difference in lifestyles of the two countries before reunification. In East Germany, the families were more numerous and from an early age the children would go to day nurseries, where they would be more exposed to infections caused by viruses and bacteria. Contact with this kind of infectious agent usually activates cells of the defense system that prompt a form of inflammation capable of inhibiting the development of allergy, while infections caused by worms usually trigger a reaction similar to allergy. It used to be believed that this equilibrium worked like scales with two pans, with the infections that activate inflammatory responses reducing the signs of asthma.

It is not always like that. The team from UFBA found that people infected with the HTLV1 virus really did show less intense allergic responses than people without this virus in their blood. But, different from the expectations, the reduction in the rates of infections – tuberculosis and measles – did not raise the levels of asthma; this was the finding of the group coordinated by Dirceu Solé, from the Federal University of São Paulo (Unifesp). When analyzing the immunological activity of bearers of Schistosoma mansoni, the worm that causes schistosomiasis, the group from Bahia also observed that the allergic response was paradoxically less intense than expected.

A messenger molecule of the immune system, interleukin-10, released in a greater quantity in people with S. mansoni, attenuates the allergic response. Apparently this interleukin alleviates the signs of asthma, according to a study published in the Journal of Infectious Diseases. With the teams of Edgar de Carvalho and Maria Ilma Araújo, from UFBA, and of Sérgio Oliveira, from the Federal University of Minas Gerais, Cruz is looking precisely for the proteins of S. mansoni that stimulate the production of interleukin-10, which, it is hoped, may assist in the control of asthma.

Added to this search are the advances in the comprehension of what asthma itself is. They are changes in concept that are beginning to reorient the therapy for this disease, so as to lead to a more effective prevention of the anguishing crises of asphyxia that leave the sensation that the lungs are about to be crushed. In the Heart Institute (InCor) of the University of São Paulo, the team of Rafael Stelmach and Alberto Cukier proved that the best way of preventing the crises of asthma is to associate two strategies for treatment used to fight apparently distinct problems. Adopted in the control of the inflammation that triggers asthma, the first strategy consists of the use of an anti-inflammatory applied in the mouth by means of a nebulizer and aspired into the bronchi and lungs. The second is the application of this medicine in the nose, with the objective of fighting rhinitis, an inflammation of the tissue that covers this organ internally.

Over four months, the team from InCor submitted 59 persons who had asthma and rhinitis for ten years to three forms of therapy with the anti-inflammatory beclomethasone. Separated into three groups, all the participants were given two kinds of flask. In one of them, there was a compound for nasal application, and in the other, a formulation to be nebulized in the mouth, the so-called pulmonary route. One group was given the anti-inflammatory by the nasal route and an innocuous compound (placebo) to be aspired by the mouth, while the other group took a placebo by the nasal route and the anti-inflammatory by the pulmonary route. Only the members of the third group were given beclomethasone by the nasal and pulmonary routes. Published last November in Chest, the results show that one month after starting the treatment, the volunteers showed fewer signs of asthma and rhinitis, an improvement that remained stable in the three following months.

An analysis of the damages that asthma and rhinitis caused in day-to-day life revealed, though, that those who took the anti-inflammatory by the nasal and pulmonary routes had to resort fewer time to emergency treatment, lost fewer days of work, and woke up less at night as a consequence of crises than the members of the other groups.

For Stelmach, asthma and rhinitis have to be understood as one and the same inflammation that affects different areas of the respiratory apparatus. It makes sense. After all, nose, trachea, bronchi and lungs are part of the same system. “Failing to fight rhinitis may impair the effective control of asthma”, says Stelmach.

Not always did people think like this. It has been known for about three centuries that the feeling of asphyxia typical of asthma is caused by the narrowing of the bronchi, the channels that take air to the lungs. But the chemical and biological mechanisms that trigger it off were only identified in the last 50 years. The entry into the organism of foreign bodies – like proteins from house mites and roaches found in household dust, components of cigarette smoke and of pollution, or even medicines – activates a complex chain of chemical reactions. These reactions activate the production of antibodies and release histamines, substances that bring about a contraction of the muscles that surround the bronchi and generate symptoms of allergy, such as swelling, redness, and the production of mucus inside the bronchi.

Until the 1970’s, it was believed that this was the only mechanism behind asthma, then seen as a sporadic allergic disease and, for this reason, combated only in the periods of crisis. Medicines were used that brought about the relaxation of the muscles around the bronchi – the bronchodilator inhalers, applied in the mouth using vaporizers known as “bombinhas” [little pumps] in Brazil – or of potent hormonal anti-inflammatories, corticosteroids administered by the oral or endovenous route. With an action on the whole organism, these corticosteroids should not be used for long periods, because they can cause high blood pressure, diabetes and bone fragility.

In the last 20 years, the use of a piece of medical equipment that makes it possible to observe the inside of the bronchi and to collect samples of the tissue has altered the understanding of the disease. It was found that the bronchi of asthma sufferers were continuously inflamed, and not just during the allergic reactions. This finding altered the way of treating asthma, regarded today as a chronic disease. The bronchodilators were not abandoned. They continue to be used at moments of crisis. The most important change was the adoption of inhaled corticosteroids, which act mainly on the bronchi and on the lungs, and are inactivated by the liver when they reach the bloodstream.

“We practically do not need any novelties to treat asthma”, says lung doctor Carlos Fritscher, from the PUC of Rio Grande do Sul. “The existing medicines are safe and control the disease in 90% of the cases.” If these anti-inflammatories are as good as all that, why does asthma continue to be one of the main causes of hospitalization in Brazil? In Fritscher’s opinion, the answer is clear: many people do not follow the treatment, which lasts a lifetime, and use the medicines only in the crises. Interested in observing whether people with asthma really follow the doctors’ prescriptions, Fritscher and José Miguel Chatkin carried out a study with 151 sufferers of moderate or serious asthma from 15 Brazilian states.

Guidance by telephone
Each participant was given the anti-inflammatory fluticasone and the bronchodilator salmeterol in sufficient quantity for 90 days of treatment. The researchers telephoned each volunteer of the first day, to give guidance on how to use the medicines, and, three months later, to verify whether they had taken the prescribed doses. Only half the participants followed the recommendations correctly, regardless of schooling, marital status, age and number of times they had already been hospitalized because of asthma. The only factor that improved their adhesion to the treatment was the seriousness of the disease.

It is like this not just in Brazil. In Latin America, where the prevalence of the problem is higher than the world average, the level of people who treat themselves correctly is lower still. Fritscher recently took part in a study that analyzed the control of asthma in 11 Latin American countries. Of the 2,184 persons interviewed, over half (56%) showed signs of asthma and had already been hospitalized because of the disease. But at the moment of the survey, only 6% were using anti-inflammatory corticosteroids, according to the data published in the Revista Panamericana de Salud Pública [Pan-American Public Health Magazine]. This same study suggests that the main problem is the lack of information of the population. Almost half the people with persistent asthma believed that their disease was under control, but the problem could be regarded as controlled from the medical point of view in only 2.4% of the cases. It is not so complicated or expensive to modify this situation. All that is needed is a few phone calls reinforcing the recommendations, as Chatkin and Fritscher.

They distributed anti-inflammatories and bronchodilators for three months’ therapy to 300 people with asthma, divided into two groups: the first received two phone calls – one on the first day of treatment, and one on the last – and the second was accompanied with a reinforcing call every fortnight. This simple measure increased to 74% the level of people who were treating themselves correctly.

“The treatment is the best way of living with the disease”, comments Ana Luisa Fernandes, a lung doctor from Unifesp. She proved that educational programs that teach the difference between anti-inflammatories and bronchodilators – or the right way of using these medicines – reduce hospitalizations. The result is not always immediate. Ana Luisa evaluated 121 participants from these programs and found that at least two months of proper treatment were needed for people with light or moderate asthma to begin to control the inflammation.

In the serious cases, with daily crises of shortage of air not controllable by inhaled anti-inflammatories, this period of time increased to four months. In Bahia, Álvaro Cruz is carrying out a program that has been improving the control of serious asthma. His team attends to 1,500 people in five referral centers of the Public Health System – four in Salvador and one in Feira de Santana. Those who join the program receive free of charge the medicines against asthma and make periodic consultations with physicians, nurses and psychologists. Already in the first year of full activity, this strategy has reduced hospitalizations by 40%,  Even being more complete than the SUS’s normal service, this program brings savings to the public health system. As there are fewer hospitalizations and emergency consultations, R$ 2,500 per patient per year is saved.