Breathing new life into severe asthma

This article comes from the magazine Sciences et Avenir – La Recherche n ° 891 dated May 2021.

A small dry cough, shortness of breath, the inability to breathe deeply… These are all signs that asthmatics know all too well. But sometimes nothing, no symptoms. If this is not the fortuitous discovery, on auscultation, of typical whistles which will guide the diagnosis. In all cases, however, it is indeed asthma, from the Greek asthma (“difficult breathing”), the first description of which is in the iliad, the Greek epic poem describing the siege of Troy. If the breath of asthmatics becomes short, it is because the amount of air reaching their lungs is reduced due to several abnormalities: chronic local inflammation, thickening of the walls of the bronchi, all associated with a risk of bronchoconstriction. , at the origin of the crises. This year again, the World Day which takes place on May 4, 2021 will be an opportunity to recall that 330 million people are affected worldwide, including nearly four million in France. “However, there is not ‘one’ but ‘asthma’, warns Cécile Chenivesse, pulmonologist at the regional university hospital of Lille and member of the national research network on severe asthma Crisalis (Clinical Research Initiative in Severe Asthma).

Activated cells differ from patient to patient

Light, moderate, difficult, severe: as always, the nuances are important, the disease being very heterogeneous. And if inflammation with its complex cascade of events which remains to be fully deciphered is present in all asthmatics, we now know that the activated cells are not the same in all patients. In cases of severe asthma (5% of cases, around 200,000 patients), it has become possible to know precisely the specific pathway of inflammation for each patient. Interest: to offer, depending on the inflammatory profile, personalized therapy known as biotherapy. In fact, it is mainly these serious cases that research has focused in recent years.

In them, everything happens as if the disease “escaped” conventional inhaled treatments, when the maximum doses of conventional treatment have been reached. It is then necessary to add other corticosteroids taken orally, the long-term effects of which are not without risk (weight gain, arterial hypertension, diabetes, bone and skin fragility, etc.). It is at this level that biotherapies intervene by making it possible above all to reduce this intake of corticosteroids. Their complex mechanisms of action are based on the specific blockage of cells and agents involved in certain inflammatory pathways. The idea is to block these pathways in order to “break” the powerful inflammatory cascade as soon as possible and as efficiently as possible. Objective: to avoid its runaway, or at least to slow it down.


Half as many severe exacerbations

It all started about ten years ago with the first work on certain antibodies, immunoglobulins E (IgE). Very quickly, an anti-IgE (omalizumab) was developed and the first biotherapy in asthma was born. That was already over ten years ago. But while this molecule was felt to be universal, only 30% of severe asthmatics responded. This led to the conclusion that IgE was not the only trigger for inflammation and that other, as yet unknown, pathways were involved. This is how new “responsible”, all secreted by the immune system, have gradually been identified, including interleukins (IL) 4, 5, 13, 17, 33, TSLP (Thymic Stromal Lymphopoietin) … As many substances corresponding to inflammation pathways inhibited by biotherapies. Result, to date, several molecules are available. “All allow, on average, to halve the doses of oral corticosteroids and also to halve the number of severe exacerbations, these periods requiring oral corticosteroids for more than three days”, details Cécile Chenivesse.

Neither inhaled nor taken systemically, these molecules are injected once a month by the patient himself, mostly subcutaneously. So how do you know which molecule is best suited to your asthma? “The studies have schematically distinguished three profiles”, details Cécile Chenivesse. To determine a patient’s inflammatory profile, researchers use variable biomarkers depending on which pathway is preferentially activated. In practice, “for the first two, we use blood tests for IgE and eosinophils (a type of white blood cell), details the pulmonologist from Lille. For the third, it is a measurement in the exhaled air of a molecule synthesized at the bronchial level, nitrogen monoxide (NO) “. But again, nothing is simple or perfect: only 30% of patients respond to treatments. A fourth profile has just been described but no biotherapy has yet been developed. In addition, some asthmatics present mixed profiles because in the latter several pathways can be activated. Will one day have to combine several biotherapies to treat these cases? “The question is just starting to arise, continues the pulmonologist. But the most urgent today is to identify severe asthma. The lack of reaction to conventional treatment or the need to take oral corticosteroids more than twice a year are signs that should alert to make a balance, review everything and even reconsider the diagnosis. “ Indeed, “the worst situation is with those people who were once told ‘you have asthmatic bronchitis’ and who have been taking oral corticosteroids for years without these treatments being re-evaluated”, regrets Camille Taillé, pulmonologist at the Bichat-Claude-Bernard hospital, in Paris.

Most preventable deaths

Last possibility finally in the most complex cases: heat – a non-drug approach (see box below). Fortunately, for the vast majority of asthmatics (over 80%), the so-called classic basic treatment remains sufficient. Most often prescribed in the form of inhalers, it is based on a combination of two drug classes, that of so-called long-acting bronchodilators (to reduce the risk of bronchial spasm) and that of corticosteroids (to fight inflammation ), doses may be increased as needed. Note, however, that “these inhalers, very heterogeneous, are still badly handled by one in three patients”, specifies Valéry Trosini-Désert, pulmonologist and head of the bronchial endoscopy unit at the Pitié Salpêtrière hospital in Paris. Handling errors (less active dose delivered) which, associated with often irregular intake of treatments, explain the poor control of asthma. Furthermore, “Therapeutic education programs are not always offered by doctors, nor accessible everywhere on the territory”, adds Cécile Chenivesse. Education, however, always essential, whether the disease is mild or severe. Often silent outside of attacks, asthma also remains commonplace. As a result, we forget that he is responsible, in France, for nearly 1000 deaths each year. Deaths mostly preventable if the disease was better controlled. However, the support remains largely perfectible. “Less than 20% of all asthmatics have performed functional exploration tests (FR) reflecting the severity of the bronchial obstruction”, deplores Camille Taillé. In order to remedy these shortcomings, a white paper was presented in January at the last congress of the French-speaking pneumology society by a group of pulmonologists, learned societies and patient associations. It recommends around thirty concrete measures aimed at improving research and the course of asthmatics, regardless of the severity of their attack. Without forgetting the need to better support severe asthma and to fight against environmental factors.

65 ° C to unclog the bronchi

Treat asthma with heat. This is the principle of thermoplasty, a last resort technique reserved exclusively for severe uncontrolled asthma. Objective: destroy the thickened bronchial wall at 65 ° C under general anesthesia to increase the diameter of the ducts and thus the volume of circulating air. If its effects last ten years, as a study published in Lancet Respiratory Medicine, no learned society recommends it yet. “Three sessions are necessary to treat all the areas and work is underway to reduce the number of sessions.“, specifies Camille Taillé pulmonologist at the Bichat-Claude Bernard hospital (AP-HP), in Paris, one of the few centers * practicing the technique.

* Bordeaux, Lille, Lyon, Marseille, Nantes, Paris, Strasbourg, Toulouse.

How to handle your inhaler properly

“The cornerstone of asthma treatment are inhalers” , insists Valéry Trosini-Désert, head of the bronchial endoscopy unit at the Pitié-Salpêtrière hospital in Paris. But should you shake them before use, prime them, and how long to hold your breath? In short, how can you be sure to use them “well”? Very often the prescribing doctor does not have the time (or does not take it) to explain the operation of the device to the patient, and thinks that the relay will be taken over by the pharmacist who believes for his part that the doctor has already said everything . As a result, one in three patients makes mistakes. This is the reason why the pulmonologist created the Zéphir program. Initially, in 2012, in the form of a book and, since 2013, a digital format with videos viewable on the Internet and smartphone was developed. 61 devices (pressurized metered dose inhalers, dry powder inhalers) have so far been identified and more are to come. Much better than long and boring instructions, a short video format explains in images and for each device the precise sequence of actions to be performed. Regularly updated, these educational films are available on the website of the French-language Society of Pneumology. They have also recently been included in the prescriptions of certain hospitals in the form of a QR code printed on the prescription. This allows the patient with a smartphone to watch them as many times as necessary to use the medical device effectively.

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