KLINIČNE ZNAČILNOSTI IN IMUNSKI ODZIVI PRI POSTENCEFALITISNEM SINDROMU PO PREBOLELEM KLOPNEM MENINGOENCEFALITISU

Izhodišča. O dejavnikih, ki določajo, kakšna bosta potek in izid klopnega meningoencefalitisa (KME), o (dolgo)trajnih posledicah prebolele bolezni (postencefalitisni sindrom) in o mehanizmih, ki so povezani z neugodnim potekom in izidom bolezni, je malo znanega. Namen. Namen raziskave je opredeliti klinične značilnosti akutne bolezni, ugotoviti, kateri klinični in/ali laboratorijski parametri so povezani s težjim potekom bolezni in/ali neugodnim izidom, oceniti (dolgo)trajne posledice, ki jih pušča prebolela bolezen, in osvetliti osnovne imunske značilnosti KME. Metode dela. V raziskavo smo vključili 717 odraslih bolnikov, ki so bili v obdobju od 1. 1. 2007 do 31. 12. 2012 na Kliniki za infekcijske bolezni in vročinska stanja zdravljeni zaradi KME. Pri podskupini 420 bolnikov, ki smo jih povabili na kontrolni pregled leta 2014, 2–7 let po prebolelem KME, smo ocenili dolgoročni izid bolezni. V raziskavo smo vključili tudi kontrolno skupino oseb, ki so se z bolniki ujemale glede na starost in v preteklosti niso prebolele KME. Imunske odzive smo v obdobju akutne bolezni ocenili v serumu in možganski tekočini, 2 meseca in 2–7 let po preboleli bolezni pa le v serumu. Določili smo koncentracije 24 citokinov/kemokinov, ki zastopajo prirojene ter pridobljene Th1-, Th17- ter B-celične odzive. Rezultati. Multipla regresija je pokazala, da so s težjim potekom KME značilno povezani višja starost bolnikov (razmerje obetov (RO) 1,26, 95 % interval zaupanja (IZ) 1,11–1,44 P = 0,001), predhodno cepljenje proti KME (RO 14,23, 95 % IZ 1,72–117,87 P = 0,014), nizka koncentracija protiteles IgG proti virusu KME v serumu (RO 0,85, 95 % IZ 0,75–0,96 P = 0,009), večja koncentracija levkocitov v krvi (RO 1,45, 95 % IZ 1,13–1,85 P = 0,004) ter večja koncentracija C-reaktivnega proteina v serumu (ocenjeni koeficient 1,20, 95 % IZ 0,48–1,91 P = 0,001). Pogostost postencefalitisnega sindroma se zmanjšuje s časom in se stabilizira 12 mesecev po preboleli bolezni, ko ima postencefalitisni sindrom tretjina bolnikov kasneje se zmanjšuje le še njegova teža. Neugoden izid 6 mesecev po preboleli bolezni je povezan s koncentracijo levkocitov v možganski tekočini (RO 1,43, 95 % IZ 1,07–1,93, P = 0,017), po 12 mesecih z izidom bolezni po 6 mesecih (RO 497,89, 95 % IZ 39,42–6289,16, P < 0,001) in 2–7 let po preboleli bolezni z izidom bolezni po 12 mesecih (RO 38,56, 95 % IZ 8,40–177,14, P < 0,001). Bolniki so 2&#8210 7 let po prebolelem KME navedli večje število nespecifičnih simptomov v primerjavi s kontrolnimi preiskovanci, ki niso preboleli KME, prisotnost vsakega od ponujenih simptomov pa bolj pogosto in bolj stalno. Slabše so ocenili tudi kakovost telesnega in duševnega zdravja, vendar so bile razlike med skupinama majhne in niso bile statistično značilne. Koncentracije velike večine citokinov/kemokinov v serumu in možganski tekočini se v času akutne bolezni značilno razlikujejo: koncentracije citokinov/kemokinov prirojenega in Th1-pridobljenega imunskega odziva so večje v možganski tekočini, tiste, povezane s pridobljenim Th17- in B-celičnim imunskim odzivom, pa v serumu. Večina predstavnikov prirojenega in pridobljenega Th1-imunskega odziva je povezana s težo akutne bolezni, z neugodnim izidom bolezni pa nismo dokazali statistično značilnih povezav. Sklep. Raziskava, temelječa na velikem številu dobro definiranih odraslih bolnikov s KME, je omogočila določitev dejavnikov, ki so povezani s težkim potekom in neugodnim izidom KME, ter oceno pogostosti in kliničnih značilnosti postencefalitisnega sindroma. Omogočila je tudi vpogled v imunske značilnosti akutne bolezni ter v vnetne parametre, povezane s težko akutno boleznijo in neugodnim izidom. Background. Information on parameters associated with the severity of tick-borne encephalitis (TBE), on the long-term outcome (post-encephalitic syndrome), and on the mechanisms responsible for the unfavorable clinical course and outcome of TBE are limited. Aims. The aims of the study were to describe the clinical characteristics of acute TBE, to determine the clinical and/or laboratory parameters associated with the severity of acute illness and/or unfavorable outcome, to assess the frequency and severity of post-encephalitic syndrome at different time points after TBE, and to highlight the basic immune characteristics of TBE. Methods. Seven hundred seventeen adult patients, diagnosed with TBE and hospitalized at the Department of Infectious Diseases, University Medical Centre Ljubljana, in the period from 1. 1. 2007 to 31. 12. 2012, qualified for the study. In a subgroup of 420 patients who participated in a follow-up visit in 2014, i.e. 2–7 years after TBE, we assessed the long-term outcome of the disease. The study also included control group of subjects of the same age (± 5 years). Immune responses were evaluated in serum and cerebrospinal fluid in the period of acute illness, and in the serum 2 months and 2–7 years after the onset of illness. The concentrations of 24 cytokines /chmokines that represent innate and adaptive Th1, Th17 and B cell responses were determined. Results. Multivariate regression showed that patient age (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.11–1.44 P = 0.001), previous vaccination against TBE (OR 14.23, 95% CI 1.72–117.87 P = 0.014), low level of specific TBE virus serum IgG antibodies (OR 0.85, 95% CI 0.75–0.96 P = 0.009), blood leukocyte count (OR 1.45, 95% CI 1.13–1.85 P = 0.004), and serum C-reactive protein level (estimated coefficient 1.20, 95% CI 0.48–1.91 P = 0.001) were associated with severe acute illness. The frequency of post-encephalitic syndrome diminished over time and stabilized 12 months after the acute illness when it was present in one-third of patients whereas the severity of post-encephalitis syndrome continued to decline. Unfavourable outcome at 6 months was associated with cerebrospinal fluid leukocyte count (OR 1.43, 95% CI 1.07–1.93, P = 0.017), at 12 months with the disease outcome at 6 months (OR 497.89, 95% CI 39.42–6289.16, P < 0.001), and at the final visit with disease outcome at 12 months (OR 38.56, 95% CI 8.40–177.14, P < 0.001). Unspecific symptoms 2–7 years after TBE were more frequent and more constant in patients than in the control group. Similarly, patients have poorly assessed their physical and mental health, but the differences between the groups were small and were not statistically significant. The concentrations of most cytokines/chemokines in serum and cerebrospinal fluid were significantly different during the time of acute illness: cytokines and chemokines associated with innate immune responses and Th1 adaptive immune responses were significantly higher in cerebrospinal fluid, whereas mediators associated with Th17 and B cell immune responses were generally higher in serum. The majority of studied cytokines/chemokines of innate and adaptive Th1 immune responses were associated with the severity of acute illness, while statistically significant correlations with the unfavorable outcome of the disease have not been found. Conclusion. A study based on a large number of well-defined adult patients with TBE enabled the identification of parametrs associated with the severity of acute illness and/or unfavourable (long-term) outcome of TBE, and the assessment of the frequency and severity of postencephalitic syndrome. It also provided an insight into the immune characteristics of acute illness and inflammatory parameters associated with severe acute illness and an unfavorable outcome of TBE.