Alergija pelėsiams

Alergija pelėsiams

Įvadas

Pelėsiai – tai daugialąsčiai mikroorganizmai, priskiriami grybų karalystei.  Jie sudaryti iš siūlų, vadinamų hifais, kurie formuoja micelį, o dauginimasis vyksta sporomis. Pelėsiai dar vadinami grybeliais, mikroskopiniais grybais, siūliniais grybais, mikromicetais ar tiesiog grybais. Grybelių metabolizmas nėra panašus į gyvūnų ir augalų. Grybeliai sekretuoja fermentus į savo aplinką ir absorbuoja fermentų suskaidytas medžiagas [1]. Tai labai paplitusi mikroorganizmų grupė, kuri gali lengvai adaptuotis prie įvairių, net ir labai sudėtingų, aplinkos, oro ar mitybos sąlygų. Dėl didelio fermentinio aktyvumo, kaip mitybinę terpę, gali panaudoti net labai paprastą substratą, pavyzdžiui, plastiką [2]. Pelėsių sporos yra atsparios vandens trūkumui, todėl sausoje aplinkoje gali išgyventi daugelį metų ir su oro teršalais, dulkėmis nukeliauti tūkstančius kilometrų [3]. Pasikeitus aplinkos sąlygoms, padidėjus drėgmei, vėl pradeda augti ir aktyviai funkcionuoti. Grybeliai gerai ištveria nulinę ar net neigiamą žiemos temperatūrą, be to, dažnai nežūva 50 °C ir didesnės temperatūros sąlygomis. Jie paplitę visose Žemės rutulio klimatinėse zonose ir geografinėse platumose [4]. Gamtoje jie atlieka organinių medžiagų skaidymo funkciją, todėl didžiausias jų kiekis aptinkamas dirvožemyje. Sporas išnešioja vėjas. Miestuose, šalia magistralių, transporto sukeltas turbulentinis judėjimas gali skatinti grybelių patekimą į orą iš dirvos, greta esančių pastatų, medžių, todėl šalia judrių gatvių sporų koncentracija gali būti didesnė [5]. Pelėsiai naudojami ir pramonėje, pavyzdžiui, maisto, antibiotikų, fermentų gamyboje [6]. Grybelių sporų kiekis aplinkoje priklauso nuo sezono. Didžiausia jų koncentracija pasiekiama vasarą ir rudenį dėl gausaus maisto medžiagų kiekio dirvožemyje, tinkamos temperatūros ir drėgmės [7]. Aiški sezoninė grybelių koncentracijų kaita nustatyta Vilniaus ore. Žiemą ore buvo 3 kartus mažiau grybelių, palyginti su vasara. Iš Vilniaus oro išskirti ir nustatyti 402 rūšių grybeliai, kurių aptinkamumo dažnis įvairiu metų laiku buvo nevienodas. Daugiausia grybelių rūšių aptikta vasarą, mažiausiai – žiemą [5].  Dideli sporų kiekiai randami ne tik lauke, tačiau ir gyvenamosiose patalpose. Į vidų sporos patenka oru arba yra pernešamos žmonių bei gyvūnų. Geriausios sąlygos pelėsiui vešėti patalpose yra padidėjusi drėgmė, silpna ventiliacija ir saulės apšvita, patalpų kondicionavimo sistemų naudojimas [8, 9]. Tokios sąlygos yra rūsiuose, skalbimo, vonios kambariuose ir virtuvėse, o ūkiuose – vasarnamiuose, mediniuose nameliuose. Baseinų ir saunų lankytojai taip pat dažniau susiduria su šiais alergenais. Patalpose pelėsių augimo protrūkiai dažniausiai pastebimi ant drėgnų tapetų ar tarp plytelių esančio grunto [10]. Augalų auginimas namuose taip pat gali didinti pelėsio koncentraciją ore, nes, pavyzdžiui, Aspergillus grybelių sporų dažnai randama vazoninių augalų dirvožemyje [11]. Pelėsių kolonijos pastebimos kaip žalsvos, rudos ar juodos spalvos dėmės. Pelėsio taip pat gali būti randama ne tik gyvenamosiose patalpose, bet ir darbo vietose. Kai kurių profesijų atstovai susiduria su dideliu kiekiu pelėsių sporų ir toksinų. Dažniausiai tai yra maisto pramonės darbuotojai, ūkininkai, sodininkai, atliekų perdirbimo ir lentpjūvių darbuotojai [12–15].

 

Grybelių reikšmė alerginėms ligoms

Alergijas dažniausiai sukelia Alternaria, Cladosporium, Penicillium, Aspergillus genčių atstovai [16, 17]. Alergija šiems grybeliams gali pasireikšti ne tik įprastais kvėpavimo takų alergijos simptomais – alerginio rinito, konjunktyvito, astmos, bet ir daug sudėtingesnėmis alerginėmis kvėpavimo takų ligomis.

Nors alergija grybeliams aprašyta prieš 300 metų, tačiau ilgą laiką jų, kaip alergenų, svarba iki šių dienų vertinama kontroversiškai [18–20]. Grybeliai dažniausiai sukelia kvėpavimo takų ir odos simptomus, tačiau šiame straipsnyje plačiau aptarsime alergenų reikšmę kvėpavimo takams.

Epidemiologinių tyrimų duomenimis, patalpose ir lauke esantys grybeliai atlieka svarbų vaidmenį kvėpavimo takų ligų patogenezėje. Dažnesnis įsijautrinimas grybeliams nustatomas ne tik astma sergantiems asmenims, bet yra rizikos veiksnys astmai išsivystyti [21, 22]. Nustatyta, kad pelėsio kvapas namuose, patalpų drėgmė ir matomos pelėsių kolonijos yra susijusios su astmos išsivystymu vaikams ir simptomų sunkumu [23], nors kai kurie tyrimai šio ryšio nepatvirtina [24, 25]. Kitų studijų duomenimis, pelėsio vešėjimas patalpose yra rizikos veiksnys kosulio dažniui, padidėjusiam didžiausio iškvepiamo srauto kintamumui ir astmai [26–30]. Taip pat nustatyta sąsaja tarp sporų koncentracijos ir hospitalizacijos poreikio astmos gydymui ir buvo susijusi su astmos paūmėjimais, pasibaigusiais mirtimi. Tarkime, Čikagoje (JAV) mirčių nuo astmos skaičius buvo 2 kartus didesnis dienomis su didele sporų koncentracija ore, palyginti su dienomis, kai ji buvo maža [31].

Atmosferoje grybelių sporų yra nuolat [31]. Dėl didelio pelėsių rūšių spektro ir jų nustatymo  sudėtingumo žinių apie aplinkos grybelius ir jų svarbą vystantis alerginėms ligoms trūksta. Neseniai Korėjoje atliktu tyrimu nustatyta, kad ore yra 40 potencialiai alergiją sukeliančių pelėsių genčių [32].

Grybelių sporos į žmogaus organizmą gali patekti per kvėpavimo takus, virškinimo sistemą ar patekti ant odos [37]. Sporų dydis ir kiekis, sukeliantis simptomus, skiriasi tarp skirtingų grybelių rūšių. Paaiškėjo, kad sporų kiekio vertinimas ore nėra toks tikslingas, nes tyrimais nustatyta, jog ne tik sporos, bet ir grybelių fragmentai ir visai mažos jų dalelės gali būti pakankamas alergenų šaltinis, sukeliantis simptomus [34].

 

Grybelių alergenai

 

Šiuo metu Tarptautinis alergenų nomenklatūros subkomitetas yra patvirtinęs 107 alergenus, išskirtus iš 28 grybelių genčių [17]. Grybeliai produkuoja didelį kiekį su IgE reaguojančių molekulių, tačiau ne visos jos yra svarbios diagnostikoje. Pagrindinis veiksnys, lemiantis alergeno svarbą, yra dažnis, kai jam specifinių IgE randama pacientams, įsijautrinusiems tam grybeliui. Tuo remiantis, alergenai skirstomi į didžiuosius (randama >50 proc. pacientų) ir mažuosius (reaguoja <50 proc. pacientų) alergenus [17]. Duomenys apie grybelių alergenų molekulinę seką ir struktūrą formuoja supratimą apie jų biologinę ir imunologinę reikšmę ir yra svarbūs naujoms gydymo ir diagnostikos kryptims [35].

Žinios apie alergenų sandarą, jų panašumą į kitų baltymų seką yra svarbios, įvertinant kryžminių reakcijų galimybę. Kryžmiškumas gali pasireikšti ir tarp angliavandeninės alergeno struktūros dalies. Kryžminės reakcijos gali pasireikšti tarp to paties skyriaus atstovų baltymų, tarp skirtingų grybelių skyrių ar net nesusijusių baltymų [36], pavyzdžiui, žmogaus baltymų. Kliniškai kryžmiškumas pasireiškia IgE susidarymu prieš įvairius alergenus, net prieš mažą alerginį aktyvumą turinčias struktūras (pavyzdžiui, angliavandenines determinantes), todėl tyrimų rezultatai gali būti teigiami, bet neatspindėti tikrosios klinikinės svarbos.

 

Grybelių paplitimas Lietuvoje

Dažniausiai Lietuvos miestų ore buvo aptinkamos šios grybelių rūšys: Aspergilius niger (aptikimo dažnis – 84,2 proc.), Cladosporium herbarum (63,78 proc.), Alternaria alternata (62,99 proc.), Aspergillus fumigatus (57,48 proc.), Aureobasidium pullulans (56,69 proc.), Cladosporium cladosporioides (56,69 proc.), Botrytis cinerea (43,71 proc.), Penicillium funiculosum (42,52 proc.), Geotrichum candidum (33,07 proc.). Pagrindiniai šių ore randamų grybelių į orą patekimo šaltiniai yra dirva ir augalinės liekanos [5].

 

Alternaria

Alternaria (1 pav.) gentį sudaro daugiau nei 270 grybelių rūšių. Daugiausia jų – augalų patogenai (2 pav.) [37]. Alternaria yra lauko pelėsis, tačiau dažnai jį galima rasti ir patalpose [38, 39]. Alternaria grybelių sporos yra 20–40 µm dydžio ir, palyginti su kitų pelėsių sporomis, yra didesnės, todėl lengvai užsilaiko nosies ertmėje [40]. Gerai žinoma dažniausiai sutinkamo Alternaria rūšies grybelio, Alternaria alternata, kaip alergeno, reikšmė. Nustatyta stipri koreliacija tarp įsijautrinimo Alternaria rūšies pelėsiams ir alerginio rinito [41] bei astmos [42–46] išsivystymo, taip pat ir astmos sunkumo [47–49]. Alternaria grybeliams jautriems asmenims pasireiškia sunkūs astmos paūmėjimai [50, 51]. Be to, tyrimais nustatyta, kad tai svarbus aplinkos alergenas vaikams, nes yra susijęs su švokštimu sulaukus 2–3 mėnesių [52].

Alternaria pelėsis veši patalpose, kur drėgna aplinka, pavyzdžiui, vonioje ant vandens čiaupų ar nuolat drėkstančių sienų [53], tačiau alergeno reikšmė patalpose nėra gerai ištirta. Vidinė pelėsio koncentracija priklauso nuo jo koncentracijos lauke [54], todėl nuo aplinkos nepriklausomą vidinę koncentraciją  nustatyti sunku.

Alt a 1 yra svarbiausias ir specifiškiausias alergenas, kurio serologinis paplitimas yra 90 proc. tarp Alternaria alternata grybeliui įsijautrinusių individų [55]. Kitas svarbus alergenas yra Alt a 2–25 kD aldehido dehidrogenazė ir Alt a 5 – enolazė, kuri atpažįstama 20–50 proc. Alternaria alternata grybeliui jautrių individų [56, 57].

 

Cladosporium

Cladosporium gentį sudaro daugiau nei 750 grybelių rūšių [58]. Šie grybeliai formuoja alyvuogių žalumo ar rudas matomas kolonijas ir turi konidijų, suformuotų iš paprastųjų ar šakotųjų grandinių (3 pav.). Daug Cladosporium grybelių rūšių yra augalų patogenai (4 pav.) [59]. Cladosporium gentis tarp pelėsių yra viena labiausiai paplitusių, o Cladosporium herbarum – viena dažniausių sutinkamų aplinkos rūšių. Panašiai kaip ir Alternaria gentis, Cladosporium yra išorinės aplinkos pelėsis [38, 60], tačiau dažnai aptinkamas ir patalpų aplinkoje [53, 61]. Taip pat yra stipri koreliacija tarp išorinio ir vidinio pelėsio koncentracijos [54]. Klinikinė Cladosporium reikšmė yra panaši į Alternaria [6264], bet įtaka astmai silpnesnė. ECHRS (angl. European Community Respiratory Health Survey) duomenimis, teigiamų odos mėginių dažnis Cladosporium yra 1,7 proc., palyginti su Alternaria (3,3 proc.) [65]. Cladosporium koncentracijos, sukeliančios alergijos simptomus, slenkstis yra 3 000 sporų/m³, o Alternaria  100 sporų/m³ [66, 67].

Nepaisant to, kad daug pelėsio baltyminių alergenų yra identifikuota, pagrindinis specifinis šio pelėsio alergenas vis dar nėra rastas. Išskyrus Cla h 8, kiti nustatyti alergenai yra kryžmiškai reaguojantys mažieji alergenai [20]. Cla h 8  nuo NADPH priklausanti manitolio dehidrogenazė  atpažįstama 57 proc. pacientų, turinčių alergiją Cladosporium herbarum [20], ir turi 75 proc. sekos panašumą į Alt a 8  nuo NADPH priklausančią manitolio dehidrogenazę, randamą A. alternata [68]. Dėl šio natūralaus kryžmiškumo monosensibilizacija Cladosporium pelėsiui yra santykinai reta [69].

 

Penicillium

Gentis taip pavadinta dėl pelėsio struktūros, primenančios dailininko teptuką (lot. Penicillus) (5 pav.) [37]. Penicillium yra mėlynos ar žaliai mėlynos spalvos kolonijas formuojantis pelėsis, randamas vaisių ar daržovių paviršiuje (6 pav.) ir yra naudojamas mėlynojo pelėsio sūrio gamyboje. Penicillium genties pelėsių taip pat randama tiek lauke, tiek patalpose [38, 54.]. Vidinės aplinkos veiksniai, tokie kaip netinkamas šildymas, ventiliacija, gyvūnų laikymas, vandens nuotėkis ir saulės šviesos trūkumas, didina Penicillium pelėsio koncentraciją patalpose [70]. Alternaria ir Cladosporium pelėsių kiekis patalpose priklauso nuo koncentracijos lauke [54].  Penicillium rūšių randama visur, kur yra organinių medžiagų, ir gali augti sąlygomis, kai yra labai mažai vandens [57].

Nustatyta ir patvirtinta WHO-IUIS (angl. World Health Organization and International Union of Immunological Soceties) subkomiteto daugybė skirtingų Penicillium genties alergenų, tačiau specifiniai genčiai ar rūšiai nėra nustatyti. Šiuo metu pagrindiniai Penicillium alergenai yra šarminė ir vakuolių serino proteazės, kurios priskiriamos 13 ir 18 grupės alergenams [20, 70, 71]. Dėl šių alergenų panašumo į homologinius A. fumigatus alergenus (Asp 13, Asp f 18), monosensibilizacija Penicillium genties pelėsiams yra santykinai reta [69]. Penicillium taip pat gali sukelti alerginį pneumonitą [7274].

 

Aspergillus

Pavadinimas Aspergillus susijęs su mikroskopine pelėsio struktūra, kuri yra panaši į liturginį instrumentą, skirtą šlakstyti šventintą vandenį (lot. Aspergillum) (7 pav., 8 pav.) [75]. Pelėsis paplitęs visame pasaulyje, daugiausia jo randama dirvožemyje bei gendančio maisto paviršiuje [76]. Aspergillus fumigatus, A. terreus, A. nidulans ir A. niger yra rūšys, dažniausiai sukeliančios žmogaus ir gyvūnų ligas. A. fumigatus yra dažniausias oportunistinis grybelinės infekcijos sukėlėjas [77]. Įsijautrinimas A. fumigatus pelėsiui yra susijęs su sunkia persistuojančia suaugusiųjų astma [78]. Taip pat šis grybelis gali sukelti rinitą, alerginę bronchopulmoninę aspergiliozę [79], alerginį grybelinį rinosinusitą [80], alerginį pneumonitą [81], aspergiliomą [82] ir invazinę aspergiliozę [83].

Didelis A. fumigatus pelėsio patogeniškumas priklauso nuo jo termotolerancijos [84] (dėl ko pelėsis gali augti žmogaus organizmo temperatūroje) ir dėl mažo sporų dydžio (23 µm) [85], kurios sugeba pasiekti smulkiuosius kvėpavimo takus. Nepaisant to, kad A. fumigatus yra svarbus plaučių ligų patogenezėje ir kolonizuoja plaučius, tačiau A. fumigatus nėra aplinkoje dominuojantis Aspergillus genties pelėsis. Labiausiai paplitę pelėsiai iš Aspergillus genties yra A. niger, A. restrictus, A. versicolor ir A. ochroaceous [86]. Kelių studijų duomenimis, IgE sensibilizacija A. fumigatus ir / ar kvėpavimo takų kolonizacija astma sergantiems asmenims yra susijusi su sumažėjusia plaučių funkcija [8789] ir sunkesne ligos eiga [90].

Nustatyta daug Aspergillus genties alergenų. Kai kurie alergenų yra genčiai ar rūšiai specifiški, o kiti – panalergenai, kurie lemia kryžmiškumą būryje ar šeimoje [91]. Asp f 2 yra rūšiai specifiškas didysis A. fumigatus alergenas, kuriam įsijautrinimas siekia 96 proc. [92], Asp f 4 – kitas gerai ištirtas specifinis alergenas, kuriam įsijautrinimas siekia 92 proc. [93]. Daugumoje tyrimų plačiai nagrinėjami  Asp f 1, f 2, f 3, f 4 ir f 6 alergenai, kaip į diagnostiniai žymenys, svarbūs diagnozuojant alerginę bronchopulmoninę aspergiliozę (ABPA), tačiau duomenys yra kontroversiški [94]. Nors kai kurie alergenai, tokie kaip Asp f 9 [95] ir neseniai nustatytas Asp f 34 [96], turi santykinai didelį sekos specifiškumą A. fumigatus pelėsiui ir turi didelė klinikinę reikšmę sensibilizacijai tarp ABPA sergančių asmenų, tačiau dar trūksta tyrimų duomenų. Asp n 14 ir Asp n 25 iš A. niger ir Asp o 1 iš A. orizae nustatyti alergenai svarbūs profesinės alergijos atvejais. Pastebėtina, kad dauguma A. fumigatus alergenų buvo nustatyti naudojant žmonių, sergančių ABPA, serumą, todėl kiti alergenai, sukeliantys kvėpavimo takų alergijas, nėra gerai ištirti [16].

 

Alerginis rinitas, alerginis grybelinis rinosinusitas

Alerginis rinitas, sukeltas grybelio, paprastai simptomais nesiskiria nuo kitos etiologijos alerginio rinito. Tokie pacientai dažnai yra atopiški ir yra alergiški kitiems alergenams, tarkime, žiedadulkėms, todėl apie sensibilizaciją grybeliams retai pagalvojama [6].

Alerginis grybelinis rinosinusitas (AGRS) – tai neinvazinių grybelių sukelta sinusų liga, aprašyta prieš 40 metų ir šiuo metu išskiriama kaip atskira lėtinio rinosinusito forma, kuri yra unikali dėl organizmo sąveikos su pelėsiu [97]. Ši patologija sudaro 5–10 proc. visų lėtinių rinosinusitų atvejų ir sudaro 6–9 proc. lėtinių rinosinusito atvejų, kai yra reikalingas chirurginis gydymas [98] ir, vienų autorių duomenimis, apie 50 proc. [99], kitų – 37 proc. [100] pacientų kartu serga ir astma.

Liga gali pasireikšti nuo labai silpnų iki sunkių simptomų. Vangūs simptomai, tokie kaip beskausmė ir palaipsniui išsivystanti nosies obstrukcija, uoslės praradimas, padidėjusi gleivių gamyba, gali progresuoti metų metus [101] prieš atsirandant tokiems sunkiems simpotomams, kaip regos pakitimai [102]. Pacientai, sergantys AGRS, dažnai yra atopiški, turintys IgE sukeliamą sensibilizaciją įvairiems įkvepiamiems alergenams ir kartu sergantys alerginiu rinitu ir / ar astma. Nosies užburkimas, rinorėja, užnosinis gleivių tekėjimas – dažniausi simptomai, prasidedantys palaipsniui. Sergant šia liga, sinusuose gaminamos gleivės yra rudos, tirštos, kartais kraujingos, dažniausiai apibūdinamos kaip tirštas riešutų sviestas, ir tai yra skiriamasis AGRS požymis [99]. Gleivingas sekretas yra klampus, jį sudaro tankiai išsidėstę eozinofilai, dažnai su kitais degranuliacijos požymiais (pvz., Charcoto-Leydeno kristalai) bei grybelių hifais [103]. Šios gleivės plečiasi sinuso viduje, todėl plečiasi kaulinės ir audinių struktūros, galiausiai sukeldamos veido asimetriją, deformaciją, išverstakumą [104]. Daugumai pacientų ligos pradžioje ši diagnozė neįtariama, nebent gleivėse ar patologiniame mėginyje randama grybų elementų [97].

Lėtinio sinusito simptomai ir specifinių išskyrų radimas galėtų patvirtinti AGRS diagnozę, tačiau paciento sensibilizacija pelėsiui yra ligos priežastis ir būtinas radinys diagnostikoje. Tai gali būti patvirtinama atlikus odos dūrio mėginius ar specifinių IgE tyrimą. Nepaisant to, sensibilizacija gali būti nustatoma ir kitu lėtiniu sinusitu sergančiam žmogui. Bendrojo IgE kiekis yra gerokai didesnis AGRS atveju [105].

AGRS patogenezėje svarbiausi yra Aspergillus genties grybeliai, mažiau – Bipolaris, Curvularia ir Alternaria [106]. AGRS pirmą kartą 1976 metais diagnozuotas pacientui, sergančiam alergine bronchopulmonine aspergilioze, radus specifinių gleivių kamščius prienosiniuose ančiuose [107], todėl AGRS kartais apibūdinamas kaip viršutinių kvėpavimo takų alerginės bronchopulmoninės aspergiliozės versija, nors kartu šios ligos pasireiškia retai [79].

Diagnostikai taip pat svarbūs vizualiniai metodai – kompiuterinė tomografija ir magnetinio rezonanso tyrimas. Šiais metodais nustatomi AGRS būdingi specifiniai pokyčiai (išplitęs pažeidimas, dažniausiai su kaulo suplonėjimu ir / ar erozijomis. Kaulinė ir minkštųjų audinių invazija nebūdinga) [108].

Šio rinosinusito priežastis yra alergija grybeliui. Uždegimas, stebimas sergant AGRS, nėra paprastai paaiškinamas tradiciniu IgE sukeliamos reakcijos mechanizmu, tačiau nėra iki galo aiškus. Tai lėtinis, intensyvus Th2 medijuotas uždegimas, specifinių IgE gamyba prieš grybelį, putliųjų ląstelių degranuliacija, eozinofilų infiltracija. Grybeliui kolonizuojant ir proliferuojant sinusuose, sukeliamas stiprus imuninis atsakas, dėl kurio vyksta gleivių produkcija [109, 110].  

Pagrindiniai šios ligos diagnostikos kriterijai yra įsijautrinimas keletui pelėsių ir kitiems alergenams, nosies polipozė, specifiniai pokyčiai užfiksuoti kompiuterinės tomografijos tyrimu, eozinofilija gleivėse be aplinkinių minkštųjų audinių invazijos, grybeliai sinusų turinyje po operacijos [111113]. Mažieji kriterijai yra astmos anamnezė, vienpusė ligos eiga, radiologiniai kaulų erozijos duomenys, išaugintos grybelių kultūros, Charcoto-Leyedeno kristalai chirurgiškai pašalintam turinyje ir eozinofilija kraujyje. Diagnostikos kriterijai pagal Bent ir Kuhn pateikiami 1 lentelėje [114]. Pacientai turi atitikti visus didžiuosius kriterijus, o mažieji kriterijai yra tik pagalbiniai.

Šios ligos gydymas yra medikamentinis ir chirurginis. Dažniausiai pacientas kreipiasi jau išbandęs dalį medikamentų, neefektyviai gydadamas lėtinį rinosinusitą. Šios ligos atveju ankstyvas chirurginis gydymas yra labai svarbus, siekiant pašalinti kiek įmanoma daugiau grybelio bei gleivingų išskyrų, todėl medikamentinis gydymas veiksmingesnis. Visiškas gleivių išvalymas svarbus sustabdyti ir apsaugoti nuo galimų skeleto deformacijų, kurios būdingos progresuojant ligai. Taigi chirurginis gydymas yra svarbus pirmasis žingsnis, tačiau medikamentinis gydymas būtinas, siekiant išvengti ligos pasikartojimo. Daugybe medikamentų bandyta gydyti šį sinusitą – tiek sisteminiais, tiek vietiniais gliukokortikosteroidais (GKK), sisteminiais bei vietiniais vaistais nuo grybeių, leukotrienų antagonistais, specifine alergenų imunoterapija. GKK gydant šią ligą atlieka svarbų vaidmenį. Sisteminiai GKK padidina išgijimų dažnį tiems, kam liga kartojasi. Šio gydymo fone ligos eiga lengvesnė, prailgina laiką iki chirurginio gydymo, sumažina bendrojo IgE kiekį [115, 116]. Rekomenduojamas trumpas kursas sisteminiais GKK prieš operaciją, siekiant sumažinti polipus, gleivinės paburkimą ir t. t. [117], tačiau svarbiausia sisteminius GKK skirti pooperaciniu laikotarpiu, kol nebus galima skirti vietinių GKK [118]. Vietiniai GKK skiriami kuo greičiau po operacijos.

Tiek sisteminiai, tiek vietiniai vaistai nuo grybelio buvo bandyti plačiai naudoti šiai ligai gydyti, tačiau, tyrimų duomenimis, šis gydymas turi labai mažą įtaką ar visai jos neturi gydant AGRS [119].

Keletas studijų atlikta taikant specifinę alergenų imunoterapiją skelbia, kad imunoterapija galėtų būti efektyvus papildomas AGRS gydymo būdas. Šių studijų duomenimis, taikant alergenų specifinę imunoterapiją grybeliui, pagerėja gyvenimo kokybė, sumažėja GKK poreikis ir chirurginių intervencijų dažnis [120125]. Tačiau tikslių rekomendacijų ir rezultatų trūksta. Literatūros duomenimis, gydant leukotrienų antagonistais gautas geras atsakas [126], tačiau klinikinių duomenų trūksta.

 

Aspergillus grybelio indukuota astma, pelėsio sukelta sunki alerginė astma

Įvairių tyrimų duomenimis, nustatytas ryšys tarp alergijos grybeliui ir astmos pasireiškimo vaikystėje dažnio, epideminių astmos paūmėjimų bei sunkios astmos eigos. Literatūroje išskiriami terminai Aspergillus grybelio indukuota astma ir pelėsio sukelta sunki alerginė astma.

Aspergillus grybelio indukuota astma (AIA) – tai IgE medijuota padidėjusio jautrumo reakcija prieš Aspergillus genties alergenus, kuri pasireiškia astma. Tyrimais nustatyta koreliacija tarp sensibilizacijos Aspergillus ir bronchų obstrukcijos sunkumo. Atliktas tyrimas, kuriame dalyvavo 105 asmenys sergantys astma, iš jų 30 (28,5 proc.) buvo įsijautrinę Aspergillus genties grybeliams [127]. Nustatyta, kad šie pacientai sirgo sunkesne astmos forma nei kitiems alergenams įsijautrinę pacientai. Statistiškai patikimais duomenimis šių asmenų ligos trukmė buvo ilgesnė, pasižymėjo didesniu eozinofilų bei IgE kiekiu kraujyje ir didesniu suvartojamų sisteminių GKK kiekiu per metus. Todėl autoriai rekomenduoja visus pacientus, sergančius astma, tirti dėl įsijautrinimo Aspergillus. Naujaisiais duomenimis, nustatyta padidėjusi bronchektazių rizika asmenims, sergantiems AIA [128131].

Terminas pelėsio sukelta sunki alerginė astma apibūdina astma sergančius asmenis, kurie yra alergiški grybeliui (dažniausiai Aspergillus rūšims, bet nebūtinai). Jiems dažnai pasireiškia astmos paūmėjimai, kuriems gydyti reikalinga hospitalizacija [132]. Pelėsio sukeltai sunkiai alerginei astmai būdinga sunkiai kontroliuojama astma, nustatytas įsijautrinimas grybeliui ir padidėjusi bendro IgE koncentracija (bet ne >1 000 kU/l). Palyginti su alergine bronchopulmonine aspergilioze, nebūdingi gleivių kamščiai bronchuose, taip pat ABPA gali pasireikšti lengva ir vidutinio sunkumo astma sergantiems asmenims [133]. Nustatyta, kad pelėsio sukeltos sunkios alerginės astmos gydymui didelę reiškmę turi antigrybelinis gydymas itrakonazolu, o vorikonazolas efekto neturi. Autorių nuomone, tokie duomenys galėtų būti dėl itrakonazolo ir gliukokortikosteroidų tarpusavio sąveikos [134, 135].

 

Alerginė bronchopulmoninė aspergiliozė

ABPA yra imuniteto paskatinta plaučių liga, kurią sukelia padidėjęs organizmo jautrumas grybeliui, ir dažniausiai pasireiškia sergantiems astma ar cistine fibroze [136]. Nors pirmasis šios ligos atvejis buvo aprašytas 1952 metais Jungtinėje Karalystėje, tačiau išlieka dar daug neatsakytų klausimų ligos patogenezėje, kuriami standartizuoti diagnostikos kriterijai, gydymo protokolai. ABPA dažniausiai sukelia Aspergillus fumigatus grybelis, kuris pasižymi dideliu virulentiškumu, gebėjimu išgyventi įvairiomis aplinkos sąlygomis, dideliu fermentiniu aktyvumu. Ligą gali sukelti ir kitos rūšies grybelis. Tokiu atveju liga vadinama alergine bronchopulmonine mikoze [137]. Imuniteto sukeltas plaučių pažeidimas iki galo nėra aiškus. Grybelio alergenai, pakartotinai patekę į organizmą, sukelia polikloninį antikūnų atsaką, dėl ko padidėja IgE ir IgG antikūnų koncentracija prieš Aspergillus fumigatus grybelį [138, 139]. Kitų autorių duomenimis, su ligos patogeneze susijusios I, III ir IV tipo padidėjusio jautrumo reakcijos, be audinių invazijos [140].

Dėl nepatvirtintų vienodų diagnostikos kriterijų ir standartizuotų testų tikslų ligos paplitimą pasaulyje sudėtinga įvertinti. Remiantis tarptautiniais duomenimis, ABPA paplitimas astma sergančiųjų grupėje yra 6 proc. [141]. Cistine fibroze sergančių asmenų grupėje ABPA dažnis svyruoja nuo 2 iki 15 proc. [142]. David W. Denning apskaičiavo, kad šia liga serga apie 2,5 proc. astma sergančių suaugusiųjų [143].  

Šios plaučių ligos eiga dažniausiai yra vangi ir užsitęsusi. Klinika gali būti nuo lengvos astmos simptomų iki išplitusios plaučių ligos su kvėpavimo sutrikimu [144]. Negydant liga dažnai sukelia lėtinius fibrozinius plaučių pažeidimus, kurie panašūs į postuberkuliozinius plaučių pakitimus [145].  Be astmos, ABPA gali būti susijusi ir su kitomis atopinėmis ligomis. Nors atopija pasireiškia ankstyvo amžiaus pacientams, tačiau ABPA dažniausiai pasireiškia sulaukus 20–30 metų, nors gali pasireikšti ir vaikams [146, 147] ar net kūdikiams [148]. Gelsvai rudų skreplių iškosėjimas, ypač tarp sergančiųjų sunkiai kontroliuojama astma, ir eozinofilija kraujyje rodo didelę ABPA tikimybę [149]. Analizuojant 113 ABPA sergančių pacientų simptomus, kosulys ir dusulys buvo dažniausi simptomai ir pasireiškė 99 proc. pacientų, skrepliavimas – 98 proc., švokštimas – 97 proc., kraujo iškosėjimas – 41 proc. Nosies simptomai pasireiškė 45 proc., skreplių kamštukus iškosėjo 37 proc., o nosyje skreplių kamštukai pasireiškė 6 proc. pacientų. Šeiminė ar asmeninė atopinė anamnezė nustatyta 50 proc. pacientų [150].

Šiuo metu nėra vieno sutarimo, kuris patvirtintų bendrus diagnostinius kriterijus. Kelių autorių siūlomi kriterijai pateikiami 2 lentelėje. Nuo 1952 metais pirmojo ligos aprašyto atvejo buvo žinoma, kad ligai būdingi rentgenogramose matomi difuziniai trumpalaikiai plaučių infiltratai [151]. Šie pakitimai nustatomi daugumai ABPA sergančių pacientų, todėl Rosenbergas ir Patersonas šį požymį įtraukė į didžiųjų ABPA kriterijų sąrašą [152]. Tiriant 1 340 rentgenogramų, padarytų 113 pacientų, sergančių ABPA, trumpalaikiai šešėliai nustatyti 89 proc. atvejų [150]. Šie praeinantys plaučių infiltratai, matomi rentgenogramoje, atspindi ligos aktyvumą ir dažniausiai stebimi ūmios ligos ar paūmėjimo atvejais. Nėra tokios plaučių vietos, kurios negalėtų pažeisti ši patologija, tačiau pažeidimas dažniausiai stebimas viršutinėse plaučių skiltyse [153]. Pakitimai dažnai painiojami su tuberkulioziniu pažeidimu. Kompiuterinė tomografija svarbi norint įvertinti plaučių pokyčius dėl bronchektazių. Centrinės bronchektazės yra svarbus diagnostinis kriterijus. Be bronchektazių, dar būdingi visiškai okliuzuotų bronchų vaizdai, būdingi gleivių kamščiai, kurie nustatyti 28 proc. pacientų, sergančių ABPA [154]. ISHAM (angl. nternational Society for Human and Animal Mycology) darbo grupė šį radinį traktuoja kaip patognomoninį ABPA ir sieja su gerokai didesne eozinofilų koncentracija kraujyje, bendrojo IgE kiekiu ir specifinių IgE koncentracija [155]. Diagnozuojant ABPA, įsijautrinimas A. fumigatus turi būti patvirtintas odos dūrio mėginiais, nors šiuo atveju tyrimas nėra labai specifiškas, nes, kai kurių autorių duomenimis, įsijautrinimas nustatomas net 40 proc. sergančiųjų astma ir 56 proc. – cistine fibroze [156].

Diagnostikoje ne mažiau svarbūs ir laboratoriniai tyrimai. Vienas kriterijų – eozinofilija. Per ligos paūmėjimus eozinofilų kiekis kraujyje gali siekti 1 000–3 000/µl. ISHAM darbo grupė šį kriterijų priskyrė prie kitų kriterijų, nes eozinofilija gali pasireikšti ir kitų ligų, susijusių su grybeliais, metu, taip pat išnykti vartojant sisteminius GKK. Bendrojo IgE kieko padidėjimas kraujyje – vienas iš diagnostikos kriterijų, būtinas patvirtinant šią diagnozę, tačiau vis dar išlieka skirtinga nuomonė dėl koncentracijos slenksčio. Pagal Rosenbero-Pattersono ir ISHAM darbo grupės siūlomus diagnostinius kriterijus, bendrojo IgE koncentracija turėtų viršyti 1 000 IU/ml [152], o Greenbergeno kriterijuose nurodoma 417 IU/ml riba [80]. Svarbus specifinių IgE ar IgG, susidariusių prieš A. fumigatus, nustatymas.

Pagrindiniai medikamentai gydant ABPA yra GKK [157]. Šiuo metu šis gydymas laikomas efektyviausiu, nors tikslių duomenų trūksta. Antigrybelinis gydymas taikomas kaip pagalbinis, derinant su GKK. Daug žadantis gydymas omalizumabu – monokloniniu antikūnu prieš IgE. Pradinių tyrimų duomenimis, gydymas omalizumabu sumažino hospitalizacijų dažnį dėl ABPA paūmėjimo cistine fibroze  sergantiems asmenims, sumažino sisteminių GKK poreikį [158–161].

 

Apibendrinimas

IgE sukeliama alergija grybeliams dažnai yra susijusi su astma, ypač sunkia astmos forma, kuria gali sirgti tiek vaikai, tiek suaugusieji. Klinikinių simptomų paūmėjimus, pasireiškiančius dėl alergijos Alternaria ir Cladosporium genčių grybeliams, galima nuspėti, nes jų sporų kiekis aplinkoje priklauso nuo klimatinių sąlygų. Tuo tarpu termotolerantiški Aspergillus ir Penicillium rūšies grybeliai priklausomybės nuo klimato sąlygų neturi, o dėl galimybės kolonizuoti apatinius kvėpavimo takus gali sukelti sudėtingas alergines kvėpavimo takų ligas. Standartizuotų tyrimų, diagnostikos ir gydymo protokolų trūkumas lemia prastesnę šių ligų diagnostiką, nors tyrimų duomenys rodo, kad šio tipo alergija nėra tokia ir reta, tik nelabai dažnai diagnozuojama.

1 lentelė. Alerginio grybelinio rinosinusito diagnostikos kriterijai

Didieji kriterijai

Mažieji kriterijai

I tipo padidėjęs jautrumas grybeliui (patvirtintas ODM, specifiniais IgE)

Nosies polipozė

Specifiniai radiniai kompiuterinės tomografijos metodu

Eozinofilinės gleivės be invazijos į aplinkinius audinius

Grybelių radimas gleivėse

Astma

Vienpusis pažeidimas

Kaulų erozijos

Išaugintos grybų kultūros

Charcoto-Leyedeno kristalai

Eozinofilija kraujyje

 ODM – odos dūrio mėginiai.

2 lentelė. Alerginės bronchopulmoninės aspergiliozės diagnostiniai kriterijai

Rosenbergo-Pattersono kriterijai [19]

Didieji kriterijai:

· Astma

· Rentgenogramose matomi difuziniai trumpalaikiai plaučių infiltratai

· Teigiamas alerginis odos mėginys Aspergillus antigenu

· Padidėjęs bendrojo IgE kiekis

· Precipituojantys antikūnai prieš Aspergillus

· Eozinofilija kraujyje

· Padidėjęs kiekis IgE ir IgG prieš Aspergillus fumigatus

· Centrinės bronchektazės su normaliais distaliniais bronchais

Mažieji kriterijai:

· Gelsvai rudų skreplių iškosėjimas

· Skrepliuose aptinkama Aspergillus

· Padidėjęs odos jautrumas  Aspergillus

Minimalūs būtinieji kriterijai [24]

· Astma

· Teigiamas alerginis odos mėginys Aspergillus antigenu

· Padidėjęs bendrojo IgE kiekis (417 kU/l)

· padidėjęs IgE/IgG prieš Aspergillus fumigatus

· centrinės bronchektazės, nesant distalinių bronchektazių

Tikrieji minimalieji kriterijai [1]:

· Astma

· Teigiamas alerginis odos mėginys Aspergillus antigenui

· Padidėjęs bendro IgE kiekis (417 kU/l)

· Centrinės bronchektazės, kai nėra distalinių bronchektazių

ISHAM (angl. International Society for Human and Animal Mycology) darbo grupės kriterijai [30]

Predisponuojančios būklės:

· Astma

· Cistinė fibrozė

Privalomieji kriterijai:

· Teigiamas alerginis odos mėginys Aspergillus antigenui (greitojo tipo) ar specifiniai IgE susidarę prieš Aspergillus fumigatus

· Padidėjęs bendrojo IgE kiekis

Kiti kriterijai (≥2):

· Precipituojantys ar IgG antikūnai prieš A. fumigatus

· ABPA būdingi rentgenologiniai pokyčiai

· Eozinofilų kraujyje skaičius >500 ląst./µl (nevartojus gliukokortikosteroidų)

 

Simona Kašinskaitė

Lietuvos sveikatos mokslų universiteto ligoninės Kauno klinikų Imunologijos ir alergologijos klinika

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