Bacterial immunostimulants - mechanism of action and clinical application in respiratory diseases

Odporność przeciw chorobom zakaźnym powstaje w wyniku procesów naturalnych (zakażenie) lub w wyniku interwencji medycznej (szczepienia, podanie immunoglobulin, bakteryjnych preparatów immunostymulujących). Wykazano, że immunostymulatory bakteryjne (ISs) zawierające lizaty bakterii (OM-85 BV, LW 50020) lub elementy ich komórek (ekstrakt rybosomalny) indukują zarówno niespecyficzną, jak i swoistą (komórkową, humoralną) odpowiedź immunologiczną organizmu. Dwoistość ich aktywności immunomodulacyjnej naśladuje lub w pewnym stopniu powtarza odpowiedź immunologiczną rozwijającą się po wniknięciu patogenu do organizmu człowieka, która początkowo jest nieswoista i stopniowo nabywa cech odpowiedzi swoistej. Jednak kliniczna skuteczność ISs w zapobieganiu infekcjom dróg oddechowych (RTI) jest wciąż dyskutowana. W niniejszej pracy omówiono mechanizm działania immunomodulatorów i przeanalizowano wyniki dostępnych danych klinicznych u dzieci i dorosłych.Immunity towards bacteria might be achieved as a result of natural processes following infection, or as a consequence of medical intervention including vaccination, administration of immunoglobulins or therapy with immunostimulants derived from bacteria. Bacterial immunostimulants (ISs) containing bacterial lysate (OM-85 BV, LW 50020) or components of bacterial cells (ribosomal extracts) were shown to induce a non-specific response (i.e. intensification of phagocytosis) but also to orchestrate both cellular (B, T cell stimulation) and humoral responses (antibodies and proinflammatory cytokines production). Therefore, the duality of their immunomodulatory activity mimics or, to a certain extent, repeats the immune response evoked by the intrusion of a pathogen into the human body, which is initially non-specific, but subsequently becomes specific. However, their clinical efficacy in the prevention of respiratory tract infection (RTI) is still debated. This article reviews their mechanism of action, as well as the available clinical data, discussing the pros and cons of their use in the prevention of RITs in children and adults

Diagnostics of selected respiratory virus infections

Infekcje wirusowe, najpowszechniej występujące choroby zakaźne układu oddechowego, są związane z istotną śmiertelnością, zwłaszcza wśród dzieci i osób starszych, a także znacznym obciążeniem ekonomicznym dla systemu opieki zdrowotnej. Doświadczenia ostatnich lat wskazują, że zastosowanie szybkich metod diagnostycznych potwierdzających wirusową etiologię infekcji ułatwia zastosowanie właściwego leczenia, pozwala skrócić czas i koszty hospitalizacji oraz skutkuje znaczącym spadkiem śmiertelności wśród tych chorych. Nowoczesne metody laboratoryjne wykorzystują zróżnicowane techniki immunologiczne i molekularne do wykazania w materiale biologicznym pobranym od chorego obecności wirusa, jego antygenów lub kwasu nukleinowego oraz ich identyfikacji. Praca stanowi krytyczny przegląd tych metod ze szczególnym uwzględnieniem ich przydatności i wiarygodności klinicznej.Viral infections are the most common infectious diseases of the respiratory tract characterized by the considerable mortality (especially among children and elderly people) and considered as the significant economic burden. It has been demonstrated that implementation of rapid diagnostic methods enabled more appropriate treatment of respiratory viral infections, reduced mean hospitalization time and cost, as well as resulted in the significantly decreased mortality. Modern diagnostic methods effectively identify respiratory virus, its antigen or nucleic acids in biological samples by means of the immunological and molecular techniques. This article presents critical overview of those methods with particular emphasis on their clinical usefulness and clinical reliability

Rola probiotyków w profilaktyce i leczeniu chorób alergicznych

Fizjologiczna mikroflora przewodu pokarmowego zdominowana przez pałeczki kwasu mlekowego ma istotne znaczenie dla prawidłowego dojrzewania i pełnej sprawności układu odpornościowego człowieka. Z kolei eradykacja bakterii mlekowych na rzecz innych beztlenowców w mikrośrodowisku jelit wydaje się odgrywać istotną rolę w patomechanizmie wielu chorób, w tym rozwoju alergii. W pracy zaprezentowano rolę fizjologicznej mikroflory w procesach kształtowania reaktywności immunologicznej organizmu oraz jej potencjalne działania immunomodulacyjne. Stanowi również krytyczny przegląd badań oceniających przydatność suplementacji preparatami probiotycznymi, zawierającymi drobnoustroje wyselekcjonowane z flory jelitowej człowieka w profilaktyce i leczeniu chorób alergicznych. Pneumonol. Alergol. Pol. 2012; 80, 1: 65–76Physiological gastrointestinal microflora dominated by lactic acid bacteria is crucial for the maturation and proper functioning of human immune system. Thus, lactic acid bacteria eradication followed by intestinal colonization by other anaerobes seems to play an important role in the pathogenesis of numerous diseases, including allergy. This paper discusses the effect of physiological intestinal microflora on the physiological immune reactivity as well as its immunomodulatory potential. The critical review of current research on the effectiveness of probiotic dietary supplementation in the prevention and treatment of allergic diseases is provided. Pneumonol. Alergol. Pol. 2012; 80, 1: 65–7

Hypersensitivity pneumonitis recognised in a single pulmonary unit, between 2005 and 2015 — comparison with recently proposed diagnostic criteria

Introduction: Hypersensitivity pneumonitis (HP) is the third most common interstitial lung disease after idiopathic pulmonaryfibrosis and nonspecific interstitial pneumonia. Pathogenesis of HP is related to repeated exposure to inhaled environmentalantigens that sensitise the susceptible, genetically predisposed persons.The aim of the present retrospective study was to summarise the diagnostic methods used in consecutive patients with HP,recognised in a single pulmonary unit, between 2005 and 2015, and to compare them with current diagnostic criteria. Material and methods: 135 patients, 68 males, 67 females, median age 53 years (18–75 years), entered the study. Chest CTfeatures characteristic of HP were defined as: mosaic attenuation of lung parenchyma, air trapping and/or ill-defined centrilobularnodules. Lymphocytosis in BAL was defined as ≥ 30%. Results: Median time from first symptoms to diagnosis was 12 months. The exposure to one or more allergens was found in 94% ofpatients, chest CT features characteristic of HP have been reported in 87%, BAL lymphocytosis — in 86%.According to recent diagnostic criteria — in 54% of patients, clinical diagnosis of HP was confident, in 16% — probable, in 26% — possibleand in 4% — unlikely. The confirmation of HP with lung biopsy has been obtained in 36% of non-confident cases (16% of the study group). Conclusion: HP diagnosis was confirmed according to current diagnostic criteria in 70% of patients diagnosed between 2005 and2015. Contradictions to lung biopsy have been the main reason for inability to confirm HP in non-confident cases

Evaluation of humoral immune response against mycobacterial antigens in bronchoalveolar lavage fluid from patients with pulmonary tuberculosis confirmed by genetic and culture methods

Wstęp: Celem pracy była ocena stężenia przeciwciał przeciwko antygenom prątka gruźlicy w płynie uzyskanym podczas płukania oskrzelowo-pęcherzykowego u chorych na gruźlicę płuc potwierdzoną bakteriologicznie oraz porównanie przydatności metod serologicznych i metod genetycznych (łańcuchowa reakcja polimerazy) w rozpoznawaniu gruźlicy u tych chorych. Materiał i metody: Odpowiedź humoralną na antygeny prątka oceniono za pomocą testu immunoenzymatycznego, porównując stężenia przeciwciał różnych klas przeciwko rekombinowanym antygenom prątka 38kDa, 16kDa i LAM w materiale pochodzącym z płukania oskrzelowo-pęcherzykowego. Grupę badaną stanowili chorzy na gruźlicę płuc zdiagnozowaną przy użyciu metody BACTEC, a grupę kontrolną chorzy na inne choroby układu oddechowego. Przeprowadzono analizę czułości i swoistości zastosowanych testów. Wyniki: Czułość dla testu IgG anty38kDa + 16kDa wynosiła 49%, IgG anty38kDa + LAM - 33%, IgA anty38kDa + LAM - 100%, IgM anty38kDa + LAM - 35%. Swoistość użytych testów wyniosła dla antygenu IgA anty38kDa + LAM - 13%, IgM anty38kDa + LAM - 75%, IgG anty38kDa + 16kDa - 87%, IgG anty38kDa + LAM - 93%. Wnioski: Badane testy, oparte na przeciwciałach klasy IgG, mogą być przydatne, łącznie z innymi metodami diagnostycznymi, w rozpoznawaniu gruźlicy.Introduction: The resistance to TB is cells-mediated but humoral response is common and may be correlated with the lack of effective local cellular defence mechanisms. The goal of the study was to evaluate IgG, IgA and IgM mediated humoral immune response against 38kDa plus 16kDa and 38kDa plus lipoarabinomannan (LAM) mycobacterial antigens in BALF from patients with culture confirmed and PCR positive pulmonary tuberculosis (TB) compared to non-tuberculous controls (NTB). Material and methods: 79 BALF samples (46 TB and 30 NTB) were examined. In 25 BALF samples from TB patients nucleic acids from M. tuberculosis were detected by PCR method. Commercially available ELISA - based assays against proteins 38kDa and 16kDa or 38kDa plus LAM were used. Three different dilutions of BALF: 1 : 1 and 1 : 10 were tested. Mean IgG level against 38 + LAM was significantly higher in TB group compared to control (p < 0,0001). No difference was observed between TB and NTB group in titer of IgM antibodies. Results: Sensitivity of the tests based on IgG anti38kDa + 16kDa was 49%, IgG anti38kDa + LAM - 33%, IgA anti38kDa + LAM - 100%, IgM anti38kDa + LAM - 35%. Specificity of examined assays: IgA anti38kDa + LAM - 13%, IgM anti38kDa + LAM - 75%, IgG anti38kDa + 16kDa - 87%, IgG anti38kDa + LAM - 93%. The findings of the study indicate that TB is associated with the presence of detectable levels of antibodies in the BALF. Conclusions: Examined tests detecting IgG in BALF can be used in combination with other diagnostic methods to increase diagnostic accuracy of pulmonary TB

Markers of fibrosis and inflammation in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) of patients with pulmonary sarcoidosis - a pilot study

Introduction: Sarcoidosis is a disease of unknown etiology. Little is known of predictive factors of fibrosis. It was suggested that PAI-1, uPA, TGF-&#946;1, VEGF, IL-8, TNF-&#945; influence this process. Aims: To assess airway inflammatory and fibrosis markers in EBC in sarcoidosis and the effect of fiberoptic bronchoscopy (FOB), bronchoalveolar lavage fluid (BALF), transbronchial lung biopsy (TBLB) and bronchial mucosa membrane biopsy on their production in the airways. Material and methods: The study group consisted of 11 patients (5 women, 6 men; mean age 40 &#177; 9 yrs, mean &#177; SD) with sarcoidosis stage I-III. PAI-1 (ng/ml), uPA (ng/ml), TGF-&#946;1 (pg/ml), VEGF (pg/ml), IL-8 (pg/ml), TNF-&#945; (pg/ml) levels were measured in BALF and EBC collected before and 48 hours after FOB. Results: No significant changes in EBC levels of VEGF, PAI-1, TGF-&#946;1, TNF-&#945; (respectively: 8.02 &#177; 4.97 pg/ml; 1.1 &#177; 1.2 ng/ml; 2909.7 &#177; 206.6 pg/ml; 10.7 &#177; 19.9 pg/ml) after FOB were observed when compared to baseline. In contrast, IL-8 concentration in EBC (pg/ml) decreased after FOB (0.073 &#177; 0.13 v. 0.061 &#177; 0.1, p = 0.006) and was significantly lower than in BALF (BALF 0.95 &#177; 0.62, p < 0.05). Also, mean level of VEGF was higher in BALF than in EBC both pre- and post- FOB (BALF 66.38 &#177; 36.95, EBC pre-FOB 6.75 &#177; 3.67 and EBC post-FOB 8.02 &#177; 4.97). Significant relationship between TNF-&#945; in post-FOB EBC and BALF was also shown (b = 0.63, p = 0.04). Conclusions: FOB does not significantly affect levels of airway inflammation and fibrosis markers present in EBC before and after FOB; they were also comparable to the concentrations marked by BALF. The lack of correlation between markers levels in EBC and BALF indicates that these methods are not equivalent. Due to repeatibility, and less invasive, simple method of EBC test it seems reasonable to continue the research on the larger number of patients. Pneumonol. Alergol. Pol. 2010; 78, 5: 356-362Wstęp: Sarkoidoza to choroba o nieznanej etiologii. Nieznane są także czynniki rokownicze włóknienia. Uważa się, że PAI-1, uPA, TGF-&#946;1, VEGF, IL-8, TNF-&#945; mogą mieć związek z tym procesem. Cel: Głównym celem badania było określenie, czy markery włóknienia i zapalenia mogą być oznaczane w EBC pozyskiwanym od pacjentów z sarkoidozą oraz czy na stężenia tych markerów wpływają procedury diagnostyczne, takie jak: bronchofiberoskopia (FOB), płukanie oskrzelowo-pęcherzykowe (BAL), biopsja przezoskrzelowa płuc (TBLB) czy biopsja śluzówki oskrzeli. Materiał i metody: Do badania zakwalifikowano 11 pacjentów (5 kobiet oraz 6 mężczyzn), w średnim wieku 40 &#177; 9 lat, średnia &#177; SD) z sarkoidozą płuc w stadium I-III. Pomiarów PAI-1, uPA, TGF-&#946;1, VEGF, IL-8, TNF-&#945; dokonano w BALF oraz w EBC pozyskiwanym przed i 48 godzin po FOB. Wyniki: Nie zaobserwowano istotnych zmian w stężeniach VEGF, PAI-1, TGF-&#946;1, TNF-&#945; w EBC po FOB (odpowiednio: 8,02 &#177; 4,97 pg/ml; 1,1 &#177; 1,2 ng/ml; 2909,7 &#177; 206,6 pg/ml; 10,7 &#177; 19,9 pg/ml). W odróżnieniu od tego, stężenie IL-8 w EBC (pg/ml) było nieco niższe po FOB (0,073 &#177; 0,13 v. 0,061 &#177; 0,1, p = 0,006) i znamiennie niższe niż w BALF (BALF 0,95 &#177; 0,62, p < 0,05). Stężenie VEGF także było wyższe w BALF niż w EBC zarówno przed, jak i po FOB (BALF 66,38 &#177; 36,95, EBC przed FOB 6,75 &#177; 3,67 i EBC po FOB 8,02 &#177; 4,97). Zaobserwowano znaczącą korelację pomiędzy stężeniem TNF-&#945; w EBC po FOB oraz w BALF (&#946; = 0,63, p = 0,04). Wnioski: Nie wykazano istotnego wpływu FOB i innych analizowanych procedur diagnostycznych na stężenie markerów włóknienia i zapalenia oznaczane w EBC przed i po FOB, były one również porównywalne ze stężeniami oznaczanymi w BALF. Brak korelacji pomiędzy parametrami analizowanymi w EBC i BALF wskazuje, że metody te nie mogą być uważane za równoważne, jednak ze względu na powtarzalność, nieinwazyjność i prostą metodykę wykonania badania EBC wydaje się celowym kontynuowanie badań wśród większej liczby pacjentów. Pneumonol. Alergol. Pol. 2010; 78, 5: 356-36

Bacterial Immunostimulants—Mechanism of Action and Clinical Application in Respiratory Diseases

Immunity towards bacteria might be achieved as a result of natural processes following infection, or as a consequence of medical intervention including vaccination, administration of immunoglobulins or therapy with immunostimulants derived from bacteria. Bacterial immunostimulants (ISs) containing bacterial lysate (OM-85 BV, LW 50020) or components of bacterial cells (ribosomal extracts) were shown to induce a non-specific response (i.e., intensification of phagocytosis) but also to orchestrate both cellular (B, T cell stimulation) and humoral responses (antibodies and proinflammatory cytokines production). Therefore, the duality of their immunomodulatory activity mimics or, to a certain extent, repeats the immune response evoked by the intrusion of a pathogen into the human body, which is initially non-specific, but subsequently becomes specific. However, their clinical efficacy in the prevention of respiratory tract infection (RTI) is still debated. This article reviews their mechanism of action, as well as the available clinical data, discussing the pros and cons of their use in the prevention of RITs in children and adults

Markers of Fibrosis and Inflammation in Exhaled Breath Condensate (EBC) and Bronchoalveolar Lavage Fluid (BALF) of Patients with Pulmonary Sarcoidosis: A Pilot Study

Introduction: Sarcoidosis is a disease of unknown aetiology. Little is known of the predictive factors of fibrosis. It has been suggested that PAI-1, uPA, TGF-β1, VEGF, IL-8, TNF-α influence this process. The aim of the study was to assess airway inflammatory and fibrosis markers in EBC in sarcoidosis and the effects of fibreoptic bronchoscopy (FOB), bronchoalveolar lavage fluid (BALF), transbronchial lung biopsy (TBLB) and bronchial mu- cosa membrane biopsy on their production in the airways. Material and methods: The study group consisted of 11 patients (five women, six men, mean age 40 ± 9 yrs, mean ± SD) with sarcoidosis stage I–III. PAI-1 (ng/mL), uPA (ng/mL), TGF-β1 (pg/mL), VEGF (pg/mL), IL-8 (pg/mL), TNF-α (pg/mL) levels were measured in BALF and EBC collected before, and 48 h after, FOB. Results: No significant changes in EBC levels of VEGF, PAI-1, TGF-β1, TNF-α (respectively: 8.02 ± 4.97 pg/mL; 1.1 ± 1.2 ng/mL; 2909.7 ± 206.6 pg/mL; 10.7 ± 19.9 pg/mL) after FOB were observed when compared to baseline. In contrast, IL-8 concentration in EBC (pg/mL) decreased after FOB (0.073 ± 0.13 vs. 0.061 ± 0.1, p = 0.006) and was significantly lower than in BALF (BALF 0.95 ± 0.62, p &lt; 0.05). Also, the mean level of VEGF was higher in BALF than in EBC both pre- and post- FOB (BALF 66.38 ± 36.95, EBC pre-FOB 6.75 ± 3.67 and EBC post-FOB 8.02 ± 4.97). A significant relationship between TNF-a in post-FOB EBC and BALF was also shown (β = 0.63, p = 0.04). Conclusions: FOB does not significantly affect levels of airway inflammation and fibrosis markers present in EBC before and after FOB; they were also comparable to the concentrations marked by BALF. The lack of correlation between marker levels in EBC and BALF indicates that these methods are not equivalent. Due to the possibility of repetition, and the less invasive, simpler method of the EBC test, it would seem reasonable to continue this research on a larger number of patients

Factors Predictive for Immunomodulatory Therapy Response and Survival in Patients with Hypersensitivity Pneumonitis&mdash;Retrospective Cohort Analysis

Hypersensitivity pneumonitis (HP) is one of the interstitial lung diseases with clearly established diagnostic criteria. Nevertheless, pharmacologic treatment recommendations are still lacking. Most specialists use steroids as first-line drugs, sometimes combined with an immunosuppressive agent. Aim: The aim of the present retrospective study was to establish predictive factors for treatment success and survival advantage in HP patients. Methods: We analyzed the short-term treatment outcome and overall survival in consecutive HP patients treated with prednisone alone or combined with azathioprine. Results: The study group consisted of 93 HP patients, 54 (58%) with fibrotic HP and 39 (42%) with non-fibrotic HP. Mean (&plusmn; SD) VCmax % pred. and TL,co % pred. before treatment initiation were 81.5 (&plusmn;20.8)% and 48.3 (&plusmn;15.7)%, respectively. Mean relative VCmax and TL,co change after 3&ndash;6 months of therapy were 9.5 (&plusmn;18.8)% and 21.4 (&plusmn;35.2)%, respectively. The short-term treatment outcomes were improvement in 49 (53%) patients, stabilization in 16 (17%) patients, and progression in 28 (30%) patients. Among those with fibrotic HP, improvement was noted in 19 (35%) cases. Significant positive treatment outcome predictors were fever after antigen exposure, lymphocyte count in broncho-alveolar lavage fluid (BALF) exceeding 54%, RV/TLC &gt; 120% pred., and ill-defined centrilobular nodules in high-resolution computed tomography (HRCT). An increased eosinophil count in BALF and fibrosis in HRCT were significant negative treatment outcome predictors. The presence of fibrosis in HRCT remained significant in a multivariate analysis. A positive response to treatment, as well as preserved baseline VCmax (% pred.) and TLC (% pred.), predicted longer survival, while fibrosis in HRCT was related to a worse prognosis. Conclusion: Immunomodulatory treatment may be effective in a significant proportion of patients with HP, including those with fibrotic changes in HRCT. Therefore, future trials are urgently needed to establish the role of immunosuppressive treatment in fibrotic HP