Odnos otpora dišnih puteva i krivulje protok-volumen u djece s astmom

Pavlov, Neven (2003) Odnos otpora dišnih puteva i krivulje protok-volumen u djece s astmom. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Maximal expiratory flow in low parts of FVC is a sensitive indicator of small airways resistance. Clinical asymptomatic anatomic changes of small airways (SA) cannot be discovered by standard functional tests: FEV1, FVC and FEV1%FVC. Increased resistance of small airways is the key point in asthma and it can be diagnosed by flow-volume curve (FV-C) early. HYPOTHESIS. The parameters used in asthma diagnosis and control: FEV1, FVC, FEV1%FVC and PEF are not sensitive enough and this results in hypodiagnosis and insufficient treatment of asthma in children. The consequence can be the existence of unidentified hyperinflation with the development of irreversible bronchial changes. My hypothesis is that more intensive usage of more sensitive inflamation markers in asthma: biological (IgE, ECP) and physiological (FEF75 and FEF50) significantly improves diagnosis and control of asthma in children and cuts down the danger of appearance of irreversible changes. AIMS. The discovery of the airway obstruction at an early, reversible stage of asthma aiming at an early stage treatment. Evaluation of hyperinflation level in children with mild and moderate asthma cured and controled according to GINA guidelines. Using the prospective follow up we want to determine the effects of the treatment in asmathic children, sensitivity, specificity, predictive value of positive (PPV) and negative (NPV) test results of biological and physiological markers which are used in diagnosis and control of asthma in children. Evaluation of persistance of ventilation/perfussion disorders in children with mild and moderate asthma and determining its influence on TLC and treatment response. SUBJECTS: Out of total of 298 children, 81 healthy children were in the Control group (aged 10.7±2.2 ), 217 children with mild and moderate asthma were in the Asthma group (aged 10.2±3.1). All of them were patients of the Clinic for Allergy and Pulmology of the Pediactric Clinic at the Clinical Hospital Split. According to the treatment I established three groups: ICS group:121 children treated with inhaled steroid IS: fluticasone propionate (100-200 mg daily), Ketotifen group: 65 children treated with ketotifen (2 mg daily) and Salbutamol group: 31 children treated with salbutamol as needed (100-200 mg). METHODS. In the prospective study (1996-2002) in all the children the following items were measured: ·Biological markers: 1 Total and specific IgE (RAST), eosinophil cationic protein (ECP), myeloperoxidase (MPO), · Physiological markers: 1 Sat.O2, pO2, pH and pCO2 before lung function tests, 2 Flow-volume curve (FV-C), 3 Airway resistance (Rtot, plathysmographic), 4 Diffusing lung capacity TLCO (single breath method with carbone monoxyde), alveolar volume (VA), transfer coefficient (KCO), 5 Residual volume (RV), total lung capacity (TLC) and RV%TLC: 5.1 Plethysmographic and 5.2 By diffusion. All parameters presented above (FV-C, Rtot, RV, TLC, TLCO) were repeated after bronchodilatation test (BT, salbutamol). In the Control group all the measurements were done once, while in the asthma groups measurements (in total 4) were repeated at intervals of 3-6 months. RESULTS. The parameters of highest sensitivity and NPV in children with mild and moderate asthma are: FEF75 (60.9%) and FEF50 (52.2%). They, as parameters of mid-expiratory flow on FV-C, reflect the flows through small airways. Repeated FV-C measurements in children with mild and moderate asthma proved better efficiency of IS treatment compared to ketotifen and salbutamol. The biggest measurement differences before and after BT were noticed in ICS group for all FV-C parameters which suggests that b2-receptors in children treated with IS have better therapeutic approachability. Children with mild and moderate asthma in ICS group show significantly lower values of FEF25 in all measurements in spite of IS therapy. It suggests their hypotreatment and the necessity of add-therapy (B2-agonists, increase of IS dose). It confirms reversible increase of total airway resistance established by plethysmographic measurements in ICS group which considerably decreased with IS therapy and salbutamol inhalation.Asmatic children treated with IS (p=0.014, p<0.001, p=0.004) showed significant reduction of concentration of total IgE, specific IgE on D. pteronyssinus and level of ECP in serum, unlike the children treated with salbutamol and ketotifen. Plethysmographic measurements of TLC, RV and RV%TLC did not prove the existence of hyperinflation in children with mild and moderate asthma (p>0.05), unlike diffusion measurements of identical parameters which showed significant level of hyperinflation in asthmatic children (p<0.001). Diffusion measurements of RV, TLC and RV%TLC showed significantly higher level of sensitivity and NPV compared to plethysmographic, which makes diffusing measurement of the lung function parameters a better method of diagnosis and control of asthma in children. Children with asthma had significantly higher TLCO (p<0.0001), VA (p=0.005) and KCO (p<0.0001) at the begginning of the treatment which normalized during the treatment and after BT. Apart from reversibility of inflammatory changes and their good response to bronchodilatation therapy, it shows the disorder of ventilation/perfusion in children with mild and moderate asthma. CONCLUSIONS. Children with mild and moderate asthma, treated according to GINA guidelines, are hypodiagnosed and hypotreated. It is the consequence of insufficient sensitivity of parameters used in diagnosis and control of treatment: FEV1, FVC and FEV1%FVC. I suggest a supplement to the algorhythm of tests used so far, introduction of parameters of mid-expiratory flow which reflect changes of small airways: FEF75 and FEF50 as the most sensitive, highly specific and parameters of high PPV and NPV values which would result in improvement of diagnosis and control even in asymptomatic asthma. Children with mild and moderate asthma show the presence of reversible hyperinflation which diminishes with bronchodilatation therapy and IS treatment. The estimation of the hyperinflation degree through diffusion shows significantly higher sensitivity and NPV compared to plethysmographic measurement. In case of disparity between clinical symptoms and FV-C results I suggest to rule out the presence of hyperinflation by diffusion measurement of RV and RV%TLC. With regard to proved significant decrease of total and specific IgE after IS treatment, it is useful to treat children who have mild asthma together with high level of IgE and even higher level of hypersensitivity on D. Pteronyssinus (RAST ³4), even in absence of symptons and spirometric disorders, with short and preventive IS cure (3 months), aiming at the decrease of risks of further sensibilisation and appearance of the desease. In available literature I have not found similar opinions on therapeutical prevention of these occurrences. I have found the ventilation/perfusion disorder even in children with mild and moderate asthma: increased level of TLCO, VA and KCO. My opinion is that that due to the ventilation/perfusion disorder the rest of alveolar-cappilary units are included of which in literature I have not found similar experience in children with asthma. Good response to bronchodilatation therapy and IS treatment confirms the reversibility of inflammatory changes. Comparing sensitivity, specificity, PPV and NPV of biological and physiological markers used in diagnosis and control of asthma in children I found out that the most useful tests are those of highest sensitivity and NPV: IgE, RV%TLC determined by diffusion (d), RVd, FEF75 and FEF50. Using these tests together with already used parameters: FVC, FEV1 and FEV1%FVC, it is possible to achieve further improvement in diagnosis and asthma control in children.

Abstract in Croatian

Najveći ekspiracijski protok pri nižim dijelovima FVC osjetljiv je indikator otpora u MDP. Klinički asimptomatske anatomske promjene MDP ne mogu se otkriti primjenom standardnih funkcionalnih testova: FEV1, FVC, FEV1%FVC. Povećanje otpora MDP ključ je zbivanja u astmi, a njihov porast moguće je rano dijagnosticirati putem KP-V. HIPOTEZA. Parametri koji se koriste u dijagnostici i nadzoru astme: FEV1, FVC, FEV1%FVC i PEF, nedovoljno su osjetljivi, što rezultira hipodijagnosticiranjem i nedovoljnim liječenjem djece s astmom. Posljedica može biti opstojanje neprepoznate hiperinflacije, s razvojem ireverzibilnih promjena bronha. Pretpostavljam kako bi korištenjem osjetljivijih markera upale u astmi: bioloških (IgE, ECP) i fizioloških (FEF75 i FEF50) značajno poboljšali dijagnostiku i nadzor astme u djece, čime bi smanjili opasnost pojave ireverzibilnih promjena. CILJEVI. Otkrivanje opstrukcije MDP u ranom, reverzibilnom stadiju astme u cilju pravovremenog liječenja. Procjena stupnja hiperinflacije u djece s blagom i srednje teškom astmom, liječene i nadzirane prema GINA smjernicama. Prospektivnim praćenjem može se odrediti učinak liječenja u djece s astmom, osjetljivost, specifičnost, PPV i NPV bioloških i fizioloških markera koji se koriste pri dijagnostici i nadzoru astme u djece. Treba procijeniti postoji li u djece s blagom i srednje teškom astmom poremećaj ventilacije/perfuzije, odrediti njegov utjecaj na TLCO i odgovor na liječenje. ISPITANICI. Od ukupno 298 djece, Kontrolnu skupinu sačinjavalo je 81 zdravo dijete (dobi 10.7±2.2 god.), Astma skupinu 217 djece s blagom i srednje teškom astmom (dobi 10.2±3.1 god.), pacijenti Alergološko-pulmološke ambulante Klinike za dječje bolesti K.B. Split. Prema liječenju ustanovio sam 3 skupine: ICS skupina: 121 dijete, liječeni IS: flutikazon propionat (100-200 mg dnevno), Ketotifen skupina: 65 djece, liječene ketotifenom (2 mg dnevno) i Salbutamol skupina: 31 dijete, liječeni salbutamolom (Ventolin) prema potrebi (100-200 mg). METODE. U prospektivnom istraživanju (1996.-2002.) u sve sam djece odredio: · Biološke markere: Ukupni i specifični IgE (RAST), eozinofilni kationski protein (ECP), mijeloperoksidazu (MPO), · Fiziološke markere: 1. Sat.O2, pO2, pH i pCO2 prije svakog određivanja testova plućne funkcije, 2. Krivulju protok-volumen (KP-V), 3. Otpore dišnih puteva (Rtot, pletizmografski), 4. Difuzijski kapacitet pluća TLCO (metoda jednog udaha sa CO), alveolarni volumen (VA), koeficijent difuzije (KCO), 5. Rezidualni volumen (RV), totalni plućni kapacitet (TLC) i RV%TLC: 5.1 . pletizmografski, i 5.2. preko difuzije. Sve prethodno navedene testove (KP-V, Rtot, RV, TLC, TLCO) ponavljao sam poslije bronhodilatacijskog (BT, Ventolin) testa. U skupinama djece s astmom mjerenja (ukupno 4) ponavljao sam u intervalu od 3-6 mjeseci, dok sam u Kontrolnoj skupni sva mjerenja radio jednom. REZULTATI. Parametri najveće osjetljivosti i NPV u djece s blagom i srednje teškom astmom su: FEF75 (60.9%) i FEF50 (52.2%). Oni kao parametri srednjeg ekspiracijskog protoka na KP-V odražavaju protoke kroz MDP. Ponavljanim mjerenjima KP-V u djece s blagom i srednje teškom astmom ustvrdio sam veću učinkovitost liječenja IS u usporedbi s ketotifenom i salbutamolom. Najveće razlike prije i poslije BT u ICS skupini za sve parametre KP-V govore o boljoj terapijskoj dostupnosti b2-receptora u djece liječene IS. U djece s blagom i srednje teškom astmom u ICS skupini održavaju se značajno niže vrijednosti FEF25 za sva mjerenja unatoč terapiji IS, što upućuje na njihovo nedovoljno liječenje i potrebu za dodatnom terapijom (b2-agonisti, povišenje doze IS). To potvrđuje reverzibilno povišenje ukupnog otpora dišnih puteva, ustvrđeno pletizmografskim mjerenjem u ICS skupini, koje se terapijom IS i nakon inhalacije Ventolinom značajno snizilo. Koncentracija ukupnog IgE, specifičnog IgE na D. pteronyssinus i ECP u krvi značajno se smanjuje u djece liječene IS (p=0.014, p<0.001, p=0.004), ali ne i u djece liječene ketotifenom, odnosno salbutamolom. letizmografskim mjerenjem TLC, RV i RV%TLC nisam ustvrdio postojanje hiperinflacije u djece s blagom i srednje teškom astmom (p>0.05), za razliku od difuzijskog mjerenja identičnih parametara, kojim putem sam ustvrdio značajnu razinu hiperinflacije u djece s astmom (p<0.001). Difuzijsko određivanje RV, TLC i RV%TLC pokazalo je znatno veću osjetljivost i NPV u odnosu na pletizmografsko, što daje prednost difuzijskom određivanju parametara plućne funkcije pri dijagnostici i nadzoru astme u djece. Djeca s astmom imala su značajno povišen TLCO (p<0.0001), VA (p=0.005) i KCO (p<0.0001) na početku liječenja, koji se tijekom liječenja i nakon BT normalizirao, što osim reverzibilnosti upalnih promjena i njihovog povoljnog odgovora na bronhodilatacijsku terapiju, govori u prilog poremećaja ventilacije/perfuzije u djece s blagom i srednje teškom astmom. ZAKLJUČCI. Djeca s blagom i srednje teškom astmom liječena prema GINA smjernicama, hipodijagnosticirana su i nedovoljno liječena. To je posljedica nedovoljne osjetljivosti parametara koji se koriste u dijagnostici i nadzoru liječenja: FEV1, FVC i FEV1%FVC. Predlažem dopunu algoritma pretraga tj. uz do sada korištene, uvođenje parametara srednjeg ekspiracijskog protoka koji odražavaju promjene MDP: FEF75 i FEF50 kao najosjetljivijih, visoko specifičnih i parametara visoke PPV i NPV vrijednosti, što bi značajno poboljšalo dijagnostiku i nadzor čak i u asimptomatskoj astmi. U djece s blagom i srednje teškom astmom prisutna je hiperinflacija, koja je reverzibilna i povlači se na bronhodilatacijsku terapiju i liječenje IS. Procjena stupnja hiperinflacije putem difuzije pokazala je znatno veću osjetljivost i NPV u odnosu na pletizmografsko mjerenje. Predlažem, u slučaju nepodudaranja kliničkih simptoma i nalaza KP-V, difuzijskim mjerenjem RV i RV%TLC isključiti nazočnost hiperinflacije. S obzirom na dokazano značajno sniženje ukupnog i specifičnog IgE pri liječenju IS, korisno je djecu s blagom astmom, visokim IgE i većim stupnjem preosjetljivosti na D. pteronyssinus (RAST ³4), čak i u odsustvu simptoma i spirometrijskih poremećaja, podvrći kratkotrajnom preventivnom liječenju IS (3 mjeseca), u cilju smanjenja rizika daljnje senzibilizacije i očitovanja bolesti. U dostupnoj literaturi nisam našao slične stavove o terapijskoj prevenciji spomenutih zbivanja. Čak i u djece s blagom i srednje teškom astmom ustvrdio sam poremećaj ventilacije/perfuzije: povišen TLCO, VA i KCO. Mišljenja sam kako uslijed poremećaja ventilacije/perfuzije dolazi do uključivanja preostalih alveolo-kapilarnih jedinica, o čemu u literaturi nisam naišao na slična iskustva u djece s astmom. Povoljan odgovor na terapiju bronhodilatatorom i IS potvrđuje reverzibilnost upalnih promjena. Usporedbom osjetljivosti, specifičnosti PPV i NPV bioloških i fizioloških markera koji se koriste u dijagnostici i nadzoru astme u djece, ustvrdio sam kako su najkorisniji testovi visoke osjetljivosti i NPV: IgE, RV%TLCd, RVd, FEF75 i FEF50. Njihovim korištenjem, uz do sada upotrebljavane parametre: FVC, FEV1 i FEV1%FVC, moguće je postići daljnji napredak u dijagnostici i liječenju astme u djece.

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