Status of leukotrienes in the pathophysiology of asthma. Necessity for antileukotrienes treatment

Asthma is a chronic inflammatory airway disease in which many inflammatory cells and mediators participate. Inhaled corticosteroids (ICs) are recommended as the most effective anti-inflammatory medications currently available for the treatment of asthma. However, some patients don’t achieve asthma control even when these agents are used in high doses in monotherapy or in combination with long-acting beta2-mimetics. During asthmatic inflammation various cellular pathways are activated. Among them, leukotriene synthesis pathway is of great importance. Leukotrienes, such as leukotriene C4, D4, E4 (named "cysteinyl-leukotrienes") are known as both strong bronchoconstrictors and inflammation stimulators. They increase vascular permeability, mucus production in bronchi and may contribute to airway remodeling. Their chemotactic effect on various inflammatory cells (eosinophils, mast cells, neutrophils) contributes to the maintenance of chronic inflammation in the airways. These biological activities suggest a prominent role of leukotrienes in the pathogenesis of asthma. Although ICs suppress many of the components of asthmatic inflammation, they don’t affect the leukotriene synthesis. Thus, additional therapy with leukotriene antagonists, may be beneficial for this group of asthmatics. It is well documented that antileukotrienes have anti-inflammatory and bronchoprotective effects. They are particularly effective in patients with aspirin-sensitive asthma and those with concomitant allergic rhinitis. Antileukotrienes are also used in the prevention of exercise- and cold-air-induced bronchoconstriction. Less effective in monotherapy, as add-on therapy to ICs, antileukotrienes improve asthma control resulting in the reduction of the frequency of asthma exacerbations and the use of short-acting beta2-mimetics as well as the improvement in lung function. This review summarizes current knowledge on the role of leukotrienes in the pathogenesis of asthma and clinical aspects of therapy with antileukotrienes.Astma jest przewlekłą chorobą zapalną dróg oddechowych, w której uczestniczy wiele komórek zapalnych i mediatorów. Obecnie rekomenduje się wziewne glikokortykosteroidy, jako najbardziej skuteczne leki przeciwzapalne dostępne w leczeniu astmy. Niektórzy pacjenci nie osiągają jednak kontroli choroby, mimo stosowania dużych dawek wziewnych glikokortykosteroidów w monoterapii lub skojarzeniu z długodziałającymi beta2-mimetykami. W przebiegu zapalenia astmatycznego ulegają aktywacji różne szlaki komórkowe. Szczególnie ważna jest ścieżka prowadząca do syntezy leukotrienów. Leukotrieny, takie jak leukotrien C4, D4, E4 (zwane leukotrienami cysteinylowymi), są znane z silnego działania prozapalnego oraz kurczącego oskrzela. Leukotrieny zwiększają przepuszczalność naczyń krwionośnych i produkcję śluzu w oskrzelach oraz mogą przyczyniać się do niekorzystnej przebudowy oskrzeli (remodelingu). Ich działanie chemotaktyczne na różne komórki zapalne (eozynofile, mastocyty, neutrofile) przyczynia się do podtrzymywania przewlekłego zapalenia w drogach oddechowych. Te biologiczne działania leukotrienów wskazują na ich ważną rolę w patogenezie astmy. Chociaż wziewne glikokortykosteroidy hamują wiele składowych zapalenia astmatycznego, to nie wpływają one na syntezę leukotrienów. W związku z tym dodatkowa terapia za pomocą antagonistów leukotrienów może okazać się korzystna dla tej grupy astmatyków. Dobrze udokumentowano działanie przeciwzapalne i bronchoprotekcyjne antyleukotrienów. Są one szczególnie skuteczne u pacjentów z astmą aspirynową i tych ze współistniejącym alergicznym nieżytem nosa. Leki antyleukotrienowe są także stosowane w zapobieganiu skurczowi oskrzeli wywołanym wysiłkiem i zimnym powietrzem. Mniej skuteczne w monoterapii, jako terapia dodana do wziewnych glikokortykosteroidów, poprawiają kontrolę astmy, powodując zmniejszenie liczby zaostrzeń choroby, zużycia krótkodziałających beta2-mimetyków oraz poprawę funkcji płuc. Artykuł podsumowuje obecną wiedzę na temat roli leukotrienów w patogenezie astmy oraz aspektów klinicznych terapii lekami antyleukotrienowymi

The statement of the Polish Society of Allergology experts on the treatment of difficult-to-treat asthma

The main objective of asthma treatment is to control symptoms of the disease; however, despite the availability of guidelines and many groups of medications, the degree of control of this condition is insufficient. In difficult-to-treat asthma, the optimal control cannot be achieved due to reasons independent of the disease. Factors worsening asthma control include: inadequate treatment plan (low therapy adherence and compliance), inappropriate inhalation technique, insufficient symptom control using the available classes of medications, incomplete response to treatment (non-responders, steroid-resistance), incorrect diagnosis of asthma or comorbidities, and environmental factors. In order to achieve the optimal asthma control, it is recommended to: take therapeutic decisions with the patient, assess the probability of non-compliance, perform detailed diagnostics and initiate treatment of concomitant diseases, carry out differential diagnosis of conditions mimicking asthma, educate the patient as to the inhalation technique and check it, eliminate unfavourable environmental factors, and modify current treatment. New treatment options for patients with asthma include: ultra-long-acting beta2-agonists, long-acting muscarine receptor antagonists (LAMA), monoclonal antibodies, and non-pharmacological interventions. The only LAMA approved for treatment of asthma is tiotropium bromide. The analyses performed demonstrated a high efficacy of tiotropium in terms of improved lung function parameters and prolonged time to the first asthma exacerbation. It is recommended as an add-on therapy at asthma treatment steps 4 and 5 according to GINA (Global Initiative for Asthma) 2014. The optimal asthma control is important from the medical as well as the economical point of view.The main objective of asthma treatment is to control symptoms of the disease; however, despite the availability of guidelines and many groups of medications, the degree of control of this condition is insufficient. In difficult-to-treat asthma, the optimal control cannot be achieved due to reasons independent of the disease. Factors worsening asthma control include: inadequate treatment plan (low therapy adherence and compliance), inappropriate inhalation technique, insufficient symptom control using the available classes of medications, incomplete response to treatment (non-responders, steroid-resistance), incorrect diagnosis of asthma or comorbidities, and environmental factors. In order to achieve the optimal asthma control, it is recommended to: take therapeutic decisions with the patient, assess the probability of non-compliance, perform detailed diagnostics and initiate treatment of concomitant diseases, carry out differential diagnosis of conditions mimicking asthma, educate the patient as to the inhalation technique and check it, eliminate unfavourable environmental factors, and modify current treatment. New treatment options for patients with asthma include: ultra-long-acting beta2-agonists, long-acting muscarine receptor antagonists (LAMA), monoclonal antibodies, and non-pharmacological interventions. The only LAMA approved for treatment of asthma is tiotropium bromide. The analyses performed demonstrated a high efficacy of tiotropium in terms of improved lung function parameters and prolonged time to the first asthma exacerbation. It is recommended as an add-on therapy at asthma treatment steps 4 and 5 according to GINA (Global Initiative for Asthma) 2014. The optimal asthma control is important from the medical as well as the economical point of view

PrzeciweozynofilowedziałanieIL-12 w hodowanej tkance ludzkiego polipa nosa

Rationale: Tissue eosinophilia is an important pathophysiological issue in bronchial ashma and nasal polyps. Its magnitude is regulated by several mechanisms, including selective migration of eossinophils to peripheral tissues and prolongation of survival. A key role in this processes is assigned to Th2 originating cytokines: IL-3, IL-5, GM-CSF. It has been previously demonstrated that IL-12 diminishes tissue eosinophilia in an animal model, and Hofstra showed that Il-12 together with IL-18 prevents allergen-induced increase bronchial hyperresponsiveness, BAL eosinophilia and the development of allergen-specific Th2 cells. Methods: Nasal polyps were obtained during routine surgery and were cultured in fragments of approximately 30 mg for 2, 6, and 15 days in RPMI 1640 in the absence or presence of IL-12. Afterwards a dose-dependency was tested at day 2 of culture. Polyp tissue from cultures was than processed to slides, stained with Giemsa and cells were counted in light microscopy (400x). Results: Eosinophils represented 62,8 &plusmn; 21,3% of residing cells in nasal polyps at the day 0. IL-12 (1 &#956;g/ml) caused a significant time-dependent decrease in the percentage of Eos after 2 and 6 days. The effect of IL-12 at day 2 was concentration-dependent: control, 28,2 &plusmn; 2,9; at 10 ng/ml, 13,9 &plusmn; 6,4 (n = 4, p < 0,05); at 100 ng/ml, 11,6 &plusmn; 2,1 (p < 0.01); at 1 &#956;g/ml, 7,5 &plusmn; 1,5 (p < 0,005). Conclusion: IL-12 acts as potent topical antieosinophilic agent. Its action can be seen in a cultured polyp environment. It is visible already after two days and is concentration-dependent. Further study is needed to elucidate tissue mechanisms of this action

Small airways in obstructive lung diseases

Określenie drobne drogi oddechowe (DDO) dotyczy oskrzeli poniżej 7. generacji, o średnicy mniejszej niż 2 mm. W artykule przedstawiono dowody, że ta część drzewa oskrzelowego charakteryzuje się pewnymi odmiennymi cechami zarówno w kontekście budowy, fizjologii, jak i patofizjologii. Szczególnie ważną funkcję odgrywają DDO w chorobach obturacyjnych układu oddechowego. U zdrowych osób opór DDO nie jest większy niż 10% całkowitego oporu dróg oddechowych, natomiast u pacjentów chorych na choroby obturacyjne, poprzez nałożenie się elementu zapalnego i skurczowego ich opór może stanowić nawet 60% oporu całkowitego. Zmiany w DDO w astmie oskrzelowej i przewlekłej obturacyjnej chorobie płuc (POChP) są odpowiedzialne także za powstawanie tak zwanej pułapki powietrznej, szczególnie w POChP. Nie ma obecnie doskonałych metod diagnostyki DDO, w zależności od doświadczeń własnych w różnych ośrodkach przeprowadza się tomografię komputerową wysokiej rozdzielczości, badanie pletyzmograficzne całego ciała (stosunku objętości zalegającej/całkowitej ilości zawartego w płucach powietrza [RV/TLC] lub innych parametrów). Pewne nadzieje wiąże się obecnie z połączeniem oscylometrii impulsacyjnej, testu wypłukiwania azotu w jednym wydechu i pomiaru wydychanego tlenku azotu(eNO). Ze względu na coraz szerszą wiedzę o istotnej roli DDO w patofizjologii chorób obturacyjnych, stworzono superdrobne aerozole, których cząstki zarówno teoretycznie, jak i praktycznie (doświadczenia na impaktorze kaskadowym, skany ozonowe po inhalacjach) mogą wnikać do tej części dróg oddechowych. Autorzy przedstawiają wybrane badania z dwiema grupami leków &#8212; agonistami receptora b2-adrenergicznego (BA) i wziewnymi glikokortykosteroidami (wGKS). W przypadku tych pierwszych nie udowodniono, że tak głęboka depozycja w drogach oddechowych przekłada się na poprawę efektu klinicznego. Natomiast w przypadku wGKS, głęboka depozycja ultradrobnego aerozolu powoduje możliwość zmniejszenia dawki leku (nawet ponad dwukrotnej) przy utrzymaniu tego samego efektu terapeutycznego (poprawa indeksu terapeutycznego). Reasumując, DDO wydają się być miejscem podstawowych procesów w rozwoju chorób obturacyjnych i w związku z tym celem potencjalnych terapii.The term small airways (SA) applies to the bronchi below 7th generation with diameter smaller than 2 mm. This paper presents data showing that this part of the respiratory system is distinct in terms of its architecture, physiology and pathophysiology. The most important role SA play in obstructive airway diseases. In healthy subjects SA resistance accounts for 10% of the total airway resistance while in patients with obstructive disease, due to the constriction of the airways together with airway inflammation, SA are responsible even for 60% of the total resistance. Changes in SA in asthma and COPD are responsible for air trapping especially prominent in the latter disease. There are no precise tools to diagnose SA. Depending availability and experience HRCT, body pletysmography (RV/TLS plus other parameters) are frequently used. Some hope for the future is placed in combined use of oscilometry, multiple (or single) breath nitrogen wash-out and eNO concentration measurement. Due to our increasing knowledge on the role of SA in airway obstruction ultra-fine particle aerosols have been developed that penetrate to this compartment of the respiratory system (deposition confirmed in cascade impactors as well as by ozone scans after aerosol inhalation). Authors present selected publications investigating whereas deep drug penetration influences its clinical efficacy. For LABAs deposition in SA doesn&#8217;t seem to increase their bronchodilating effect. Using ultrafine CS aerosol allows to maintain clinical effects even with half the dose of the active steroid, however. In summary, SA seem to be crucial in obstructive diseases of the airways and therefore constitute an important target for therapy

Potential Saving of Antibiotics for Respiratory Infections in Several European Countries: Insights from Market Research Data

Antibiotics represent an essential pillar in the treatment of respiratory infections (RI). Overuse of antibiotics in avoidable cases and inappropriate application in bacterial infections facilitate treatment resistance, threatening their effectiveness and causing a significant healthcare challenge. We therefore assessed the savings potential for antibiotics in ambulant care of selected RI (bronchitis and cough, pharyngitis, rhinosinusitis) in several European countries based on market research data for the year 2019. Number of antibiotic packages sold in pharmacies varied, with highest values in Serbia and France, and lowest in Sweden and Switzerland. Selected RI contributed nearly half of overall ambulant antibiotic prescriptions, with around one fifth given for bronchitis and cough; the vast majority was estimated to be of viral origin with potentially avoidable antibiotic use. Antibiotic consumption for selected RI in eight European countries (Austria, Belgium, the Czech Republic, France, Germany, Poland, Slovakia, and Switzerland) amounted to nearly 100 million, with an overall savings potential between 66.2 and 83.7 million packages. The highest estimated volume of avoidable antibiotics was in France (44.7 million, 0.80 per capita), and lowest in Switzerland (1.4 million, 0.18 per capita). Due to substantial savings potential, prudent use of antibiotics and adequate application of alternatives should be promoted in daily practice

The strategies to support the COVID-19 vaccination with evidence-based communication and tackling misinformation

COVID-19 vaccinations are about to begin in various countries or are already ongoing. This is an unprecedented operation that is also met with a loud response from anti-vaccine communities—currently using all available channels to manipulate public opinion. At the same time, the strategy to educate on vaccinations, explain their mechanism of action, and build trust in science is subdued in different world parts. Such actions should go much beyond campaigns promoting the COVID-19 vaccines solely on the information provided by the health institutions and national authorities. In this paper, actions provided by independent expert groups needed to counteract the anti-vaccine propaganda and provide scientific-based information to the general public are offered. These actions encompass organizing groups continuously communicating science on COVID-19 vaccines to the general public; tracking and tackling emerging and circulating fake news; and equipping celebrities and politicians with scientific information to ensure the quality of messages they communicate, as well as public letters, and statements of support for vaccination by healthcare workers, recognized scientists, VIPs, and scientific societies; and no tolerance to false and manipulated claims on vaccination spread via traditional and social media as well as by health professionals, scientists, and academics. These activities should be promptly implemented worldwide, regardless of the current status and availability of the COVID-19 vaccine in a particular region. If we are about to control the pandemic for the sake of public benefit, it is high time to collectively speak out as academic and medical societies with support from decision-makers. Otherwise, the battle will be lost to those who stand against scientific evidence while offering no feasible solution to the problem

Integrated care for patients with advanced chronic obstructive pulmonary disease

Przewlekła obturacyjna choroba płuc (POChP) jest trzecią przyczyną zgonów i trzecią przyczyną niesprawności (mierzonej za pomocą wskaźnika DALY) u osób powyżej 60. roku życia. Ciężką lub bardzo ciężką postać POChP (wskaźnik FEV1, odpowiednio, poniżej 50% i 30% należnej wartości) rozpoznaje się u mniej więcej jednej piątej ogółu chorych. Chorzy na zaawansowaną POChP z reguły cierpią z powodu fizycznej i umysłowej niepełnosprawności, w wielu przypadkach źle radzą sobie z problemami wynikającymi z choroby i współistniejących schorzeń. To z kolei stwarza duże ryzyko zaostrzeń POChP, które prowadzą do pogorszenia przebiegu choroby, istotnego zwiększenia kosztów medycznej opieki oraz zwiększenia ryzyka zgonu. Obecna organizacja medycznej opieki dla tej grupy chorych nie zapewnia odpowiednich warunków zdrowotnych i socjalnych. Wydaje się jednak, że zastosowanie modelu zintegrowanej opieki, zalecanego przez Światową Organizację Zdrowia stworzyłoby możliwość poprawy sytuacji chorych na zaawansowane POChP. W Polsce ta forma opieki jest realizowana od kilkunastu lat w zakładach medycyny paliatywnej i hospicjach w odniesieniu do chorych na zaawansowane nowotwory. Wykorzystanie tych doświadczeń powinno pomóc w integracji działań wokół lekarzy rodzinnych i wyspecjalizowanej pielęgniarki, z jednoczesnym zapewnieniem dostępu do specjalistów w zależności od indywidualnych potrzeb chorego. Powinno także umożliwić szersze wykorzystanie pracowników pomocniczych, jak: pracownicy socjalni, pomocnicy medyczni oraz wolontariusze, a także psycholodzy i duchowni (zwłaszcza w końcowej fazie choroby). Pneumonol. Alergol. Pol. 2010; 78, 2: 126-132Chronic obstructive pulmonary disease (COPD) is the third cause of mortality and disability (assed by DALY) among patients above 60 year old. Severe and very severe COPD (FEV1 = equal or less than 50% and 30% of expected value, respectively) is estimated at 20% of all COPD patients. Advanced COPD usually leads to physical and mental deterioration, the patients often manage with the problems caused by the disease and other comorbidities poorly. This leads to increased risk of COPD exacerbations and further deterioration of the patient&#8217;s status, increased costs of medical care and eventually increased risk of death. Current organization of medical care for those patients does not provide adequate health and social support for them. However, it seems that introducing an integrated approach proposed by World Health Organization, could improve the situation of advanced COPD patients. In Poland, this kind of care has been provided in advanced cancer patients throughout stationary palliative care units and hospices during the last several years. This experience should be helpful in integrating actions of general practitioners and specialized nurses, as well as providing access for the specialists&#8217; consultations according to the individual needs of the patients. It should also allow for broad cooperation with auxiliary staff, such as social workers, medical assistants and volunteers, as well as psychologists and clergymen (especially in the terminal phase of the disease). Pneumonol. Alergol. Pol. 2010; 78, 2: 126-13

Formation of management skills in students of higher medical educational establishments in the period of health care reforming

The paper focuses on formation of managerial skills in students of higher medical educational institutions within the framework of developing the doctor’s competencies in the light of European health policy and reconsideration of existing mechanisms of health care management