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No breath to catch

Respiratory tract alterations thwart improvement in cases of severe asthma

Fatal asthma tissue bank at USP: thinly-sliced pulmonary tissue for histological analysis

Léo Ramos Fatal asthma tissue bank at USP: thinly-sliced pulmonary tissue for histological analysisLéo Ramos

People with the severest forms of asthma suffer almost daily bouts of a shortness of breath so intense that it renders them unable to walk quickly across a room or pick something up from the floor. Most of them fail to respond to even the most powerful treatments available today – and we are now beginning to understand why. Recent studies conducted by two research teams at the University of São Paulo (USP) have detected alterations in the structure of these people’s airways and alveoli, respectively the ducts that convey air in our bodies and the microscopic sacs that make up our lungs. In the most serious cases, representing about 5% of all asthma patients, both the respiratory tract and the alveoli are stiffer and thicker than normal. The researchers believe that these alterations are a consequence of persistent respiratory inflammation early in life, probably in childhood.

The groups led by pulmonologist Rafael Stelmach and pathologist Thais Mauad, both from the USP School of Medicine, are arriving at this conclusion after thoroughly analyzing the respiratory systems of two groups of people. The first consisted of patients suffering from severe asthma, on whom medication did not have the desired effect of keeping the disease under control. The second group consisted of people who had died of asphyxia as a result of asthma. Though globally rare, these deaths remain frequent in Brazil, where three out of 200,000 people die of suffocation due to asthma attacks. This mortality rate has only started to decline in the past decade, after it became mandatory for the country’s public healthcare system to distribute free anti-inflammatory medication for asthma. Even so, between 1998 and 2009, the number of asthma-related deaths only diminished in the richest regions of Brazil. A recent survey by the research team led by pulmonologist Álvaro Cruz from the Federal University of Bahia (UFBA) indicates that deaths by asthma actually increased in that period in Brazil’s North and Northeast.

Maximum dose
Seven years ago in São Paulo, Stelmach initiated a thorough investigation into the respiratory system of severe asthmatics when he noticed that a considerable number of the 2,500 patients treated by the pulmonology department of USP’s Heart Institute (InCor) failed to improve even when they received the maximum doses of the most widely used asthma medications. This treatment usually consists of powerful hormonal anti-inflammatories known as corticoids, associated with long-acting bronchodilators that alleviate asphyxia by relaxing the muscles around the airways. The price tag on this costly combination of drugs is about R$100 per month, a completely unaffordable expense in a country where half of the employed population earns a monthly income of R$650 or less. “We wanted to find out why these people’s asthma could not be controlled, even when they received the most effective treatment available,” says Stelmach.

He and his team then decided to select a group of 74 patients suffering from severe asthma and offer them the best possible treatment for 12 weeks, before repeating an extensive battery of tests to check if anything had changed with the therapy. The doctors provided the medications and closely monitored the participants. The subjects were assessed every two weeks to check whether they were taking their medication correctly and at the indicated dosages. When the treatment was complete, pulmonologist Regina de Carvalho-Pinto observed that even after receiving maximum doses of the medications, two thirds of the patients showed no improvement and continued to present asthma symptoms almost daily.

After comparing some characteristics of each patient group – such as number of years with the disease, intensity of allergic reactions, respiratory capacity, and level of respiratory inflammation – the researchers found only one significant difference. Those who showed no improvement continued to show much lower respiratory capacity than those who had responded as expected to the therapy. According to Stelmach, 30% of the treatment-resistant group showed respiratory capacities equivalent to that of a smoker who has consumed one pack a day for 20 years who ended up developing irreversible respiratory tract alterations. The studies indicate that by age 45, severe asthmatics have only half the respiratory capacity of a healthy individual. This is akin to saying that they have the use of only one lung. “This functional alteration can afflict the entire respiratory system, including bronchi and alveoli,” says Stelmach.

Stiffened bronchi
Biopsies of a specific region of the study participants’ bronchi showed that in highly treatment-resistant cases, the musculature of the bronchial walls is thicker than normal. This can elicit stronger bronchial contractions during asthma attacks, usually triggered by allergic or infectious agents. Not only are they thicker, but the bronchial walls of these patients also appear to be stiffer. Immunologist Diogenes Seraphim Ferreira, a member of the research team headed by Thais Mauad, who collaborates with Stelmach’s group, has identified higher levels of a specific type of collagen in the bronchi of people who do not respond to treatment. This protein organizes itself into long chains that make the body’s tissues tougher and more rigid. “Thicker bronchial musculature and higher collagen levels are a sign of structural alteration that is probably a result of long-term inflammation,” says Ferreira. “The bronchi become stiffer,” says the immunologist, who presented these data in May 2013 at the international conference of the American Thoracic Society in Philadelphia.

According to Stelmach, some functional markers suggest that the structural alteration observed in the bronchi can be found even in the most peripheral parts of the respiratory system, near the alveoli in the lungs. “When you add them up, these results indicate that people whose condition does not improve with treatment have either had the disease since childhood, or they have a much more severe form of asthma than other patients,” he says.

The inflammation and structural alterations recently observed in cases of severe, treatment-resistant asthma had also been identified in the past by pathologists Thais Mauad, Marisa Dolhnikoff, and Paulo Saldiva in the respiratory systems of people who died of asphyxia during an asthma attack, in what is known as fatal asthma. Though the two situations may differ in severity, the information revealed by one complements the other. Death is asthma’s most extreme possible outcome, but it’s impossible to know whether these people had a more serious form of the disease than those who do not respond to treatment.

ILLUSTRATION: PEDRO HAMDAN / INFOGRAPHIC: ANA PAULA CAMPOSSince 1998, Mauad, Dolhnikoff and Saldiva have been investigating what was wrong with the respiratory systems of about 130 people in the city of São Paulo who had asthma when they died and who underwent autopsies by the Death Certification Service of the City of São Paulo (SVOC), which analyzes cases of death by natural – but undetermined – causes. During each autopsy, the researchers collected small samples from 30 to 40 different areas of the respiratory system. Upon analyzing this material, they observed that the respiratory systems of deceased asthmatics showed significant, widespread inflammation, extending all the way from their nasal mucosas to the farthest reaches of their lungs and everywhere in between (bronchi and bronchioli).

The elastic fibers in the inner layers of their bronchial and bronchiolar walls had ruptured. In addition, the musculature around their respiratory passages was about 50% thicker than normal (see Pesquisa FAPESP Issue No. 165). More recently, Mauad collaborated with Alan James from the University of Western Australia in a study that revealed differences between the respiratory tract musculatures of people with fatal and non-fatal asthma. Published in 2012 in the American Journal of Respiratory and Critical Care Medicine, the study showed that in both cases, the volume of each muscular cell was enlarged – in medical terms, they were hypertrophic. In the case of people who had asthma when they died, the muscle cells were not only larger, but also much greater in number (hyperplasia). “These alterations were observed regardless of the amount of time that asthma had been present, so we believe that they begin very early in life,” says Mauad.

But these are not the only changes. Mauad, along with Canadian and Australian colleagues, found that the walls of an asthmatic’s bronchi – the network of increasingly narrow channels that convey air from the trachea to the lungs – contain more mucous glands and that these glands contract more strongly, according to a paper published in the journal Thorax. “In narrower airways, mucus can accumulate and create a plug that completely prevents the passage of air,” Ferreira explains. “The shortness of breath experienced by these people causes a feeling of near-death that cannot be understood by people who have never suffered this problem,” he says.

Blood vessels are also more abundant around the bronchi of an asthmatic. Mauad and her collaborators found an increased number of inflammation-related immune system cells near these vessels. According to the pathologist, these cells release compounds that can change the contractile power of bronchial muscle tissue and contribute to shortness of breath in severe cases of asthma.

As researchers accumulate evidence that these respiratory tract alterations – known as remodeling in the medical jargon – may start very early in life, their focus of attention is shifting from treatment to prevention. “It is becoming increasingly clear that we should focus on discovering the time window in which action is possible, in an attempt to prevent the alterations that lead to remodeling,” says Mauad. If the stage of childhood in which the alterations begin can be determined, pediatricians could start monitoring children whose genetic backgrounds favor the development of asthma, and parents could start limiting their children’s exposure to environmental factors that increase the risk of asthma, such as viral respiratory infections. But as Mauad reminds us, “it is very difficult to completely avoid exposure to these environmental factors.”

Scientific articles
CARVALHO-PINTO, R.M. et al. Clinical characteristics and possible phenotypes of an adult severe asthma population. Respiratory Medicine. v. 106, p. 47-56. 2012.
JAMES, A. L. et al. Airway Smooth Muscle Hypertrophy and Hyperplasia in Asthma. American Journal of Respiratory and Critical Care Medicine. v. 185 (10), p. 1058-64. May 15, 2012.
GREEN, F.H.Y. et al. Increased myoepithelial cells of bronchial submucosal glands in fatal asthma. Thorax. v. 65, p. 32-3. 2010.
SHIANG, C. et al. Pulmonary periarterial inflammation in fatal asthma. Clinical and Experimental Allergy. v. 39, p. 1.499-1507. 2009.