Vpliv starosti na klinični potek ter serološki in vnetni odziv pri bolnikih z zgodnjo lymsko boreliozo

Boršič, Katarina (author), Stupica, Daša (mentor)

Ozadje. Okužbe pri starejših osebah pogosto potekajo z drugačnimi kliničnimi simptomi in znaki ter vnetnim odzivom kot pri mlajših osebah. Povezava med starostjo bolnikov in klinično sliko ter imunskim odzivom v obdobju zgodnje lymske borelioze (LB) je slabo raziskana. Namen. Namenili smo se preučiti povezavo med starostjo in kliničnimi značilnostmi ter dolgoročnim izidom zdravljenja zgodnje LB v obliki erythema migrans (EM) pri odraslih bolnikih. Pri podskupini bolnikov z EM, ki so imeli iz kože izolirano Borrelia afzelii, smo se namenili preučiti tudi povezavo med starostjo in prirojenim ter pridobljenima imunskima odzivoma Th1 in Th17 ter povezavo med serumsko koncentracijo vnetnih mediatorjev in simptomi, povezanimi z LB. Metode. Povezavo med starostjo bolnikov (mladi [18-44 let] vs. srednjih let [45-64 let] vs. starejši [? 65 let]) in kliničnimi ter mikrobiološkimi značilnostmi in dolgoročnim izidom zdravljenja smo preučevali v prospektivno spremljani skupini 1220 bolnikov z EM, obravnavanih v Univerzitetnem kliničnem centru Ljubljana. Bolnike smo ocenili ob vključitvi in jih spremljali dvanajst mesecev. V podskupini 96 bolnikov z EM (48 bolnikov, starih ? 50 let, 48 bolnikov, starih < 50 let), povzročenim z B. afzelii, smo ob vključitvi z metodo Luminex določili tudi koncentracijo 15-ih sistemskih vnetnih mediatorjev (citokinov/kemokinov) v serumu, ki posredujejo prirojeni ter pridobljena imunska odziva Th1 in Th17. Rezultati. Starejši bolniki so imeli v primerjavi z mlajšimi pogosteje okužbo povzročeno z B. burgdorferi in B. garinii ter pozitiven izvid seroloških testov za borelije, redkeje so imeli multiple EM, daljši čas do izzvenetja EM po zdravljenju, pričakovano so pogosteje navajali predhodno prebolelo LB in imeli pridružene bolezni. Po dvanajstih mesecih spremljanja smo ugotovili nepopolno okrevanje, opredeljeno s prisotnostjo simptomov po LB, pri 59 od 989 (6,0 %) bolnikov. Verjetnost za nepopolno okrevanje se je zmanjševala s časom spremljanja (razmerje obetov (RO) 0,48; 95 % interval zaupanja (IZ) 0,37?0,63; p < 0,001 za primerjavo pri dveh mesecih vs. 14 dneh; RO 0,5; 95 % IZ 0,36?0,68; p < 0,001 pri šestih mesecih vs. dveh mesecih in RO 0,47; 95 % IZ 0,32?0,7; p < 0,001 pri dvanajstih mesecih vs. šestih mesecih) in je bila večja ob večji starosti bolnikov (RO 1,57; 95 % IZ 1,04?2,37; p = 0,031 pri bolnikih srednjih let vs. mladih in 1,94; 95 % IZ 1,12?3,37; p = 0,018 pri starejših vs. mladih), pri ženskah (RO 1,43; 95 % IZ 1,01?2,02; p = 0,041), pri bolnikih z diseminirano obliko bolezni (RO 1,67; 95 % IZ 1,08?2,58; p = 0,022) in pri bolnikih s simptomi, povezanimi z LB ob vključitvi (RO 8,47; 95 % IZ 5,79?12,38; p < 0,001). Simptomi, povezani z LB, so predstavljali najpomembnejši napovedni dejavnik za nepopolno okrevanje. Povprečne serumske koncentracije citokinov/kemokinov so bile nizke. Ob upoštevanju deleža bolnikov s koncentracijami citokinov/kemokinov pod mejo zaznave in po prilagoditvi analize za večkratne primerjave smo pri starejših v primerjavi z mladimi bolniki ugotovili nižje serumske koncentracije le za IL-23 (p = 0,033), ki je mediator pridobljenega imunskega odziva Th17. Pri primerjavi bolnikov z in brez simptomov, povezanih z LB, nismo našli razlik v sistemskem imunskem odzivu ob vključitvi. Zaključki. Naše ugotovitve, da so imeli starejši bolniki v primerjavi z mlajšimi pogosteje okužbo povzročeno z B. burgdorferi in B. garinii, manj pogosto multiple EM, pogosteje predhodno prebolelo LB, pozitiven izvid seroloških testov za borelije ob vključitvi in daljši čas do izzvenetja EM po zdravljenju ter večjo verjetnost nepopolnega okrevanja, podpirajo hipotezo, da so klinične značilnosti ter dolgoročni izid zdravljenja zgodnje LB v obliki EM povezani s starostjo bolnikov. Odsotnost pomembnih razlik v serumskih koncentracijah izbranih sistemskih vnetnih mediatorjev med podskupinama bolnikov z EM, povzročenim z B. afzelii, starih ? 50 let in starih < 50 let, ne podpira hipoteze, da so sistemski vnetni mediatorji ključni v patogenezi kliničnih razlik zgodnje LB, povezanih s starostjo, ali simptomov, povezanih z LB. V tem pogledu so morda pomembnejši lokalni imunski odzivi v koži ali drugi patogenetski mehanizmi.

• Language: Slovenian
• Keywords: /
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2023
• PID: 20.500.12556/RUL-144369
• COBISS.SI-ID: 146984963
• Publication date in RUL: 17.02.2023

Secondary language

• Language: English
• Title: Vpliv starosti na klinični potek ter serološki in vnetni odziv pri bolnikih z zgodnjo lymsko boreliozo

Abstract

Background. Infected elderly people often present with signs and symptoms and immune responses that differ from those in younger adults. There are limited data on the association between patient age, presentation and host immune responses in early LB. Aim. We aimed to investigate how age is associated with the clinical and long-term outcome of treatment parameters in adult patients with early LB manifested as erythema migrans (EM). Additionally, we aimed to investigate the association between age and systemic innate, Th1 and Th17 immune responses in patients with skin culture‐positive Borrelia afzelii EM and to explore the association between markers of serum immune responses and LB-associated symptoms. Methods. The association between patient age (young [18-44 years] vs. middle-aged [45-64 years] vs. elderly [⡥ 65 let]) and disease course, microbiological characteristics and the long-term treatment outcome was assessed in 1220 prospectively enrolled adult patients with EM at a single university hospital. Patients were assessed at enrolment and followed up for twelve months. In addition, 15 cytokine and chemokine levels, representative of innate, Th1, and Th17 immune responses, were determined using a bead-based Luminex multiplex assay in acute sera from a subgroup of 96 patients with skin culture-positive B. afzelii EM; 48 patients were aged ⡥ 50 years and 48 patients were < 50 years old. Results. Older age was associated with more frequent infection with B. burgdorferi and B. garinii, lower frequency of multiple EM and longer time to resolution of EM after starting antibiotic treatment. As expected, older patients more frequently reported previous LB, had positive Borrelia serological test results at enrollment, and higher frequency of comorbidities than younger patients. At 12 months, 59/989 (6.0%) patients showed incomplete recovery. The odds for incomplete recovery decreased with time from enrolment (odds ratio (OR) of 0.48, 95% confidence interval (CI) 0,37‒0,63, p < 0,001, 0.50, 95% CI 0,36‒0,68, p < 0,001, and 0.47, 95% CI 0,32‒0,7, p < 0,001 for 2-month vs. 14-days, 6-month vs. 2-month, and 12-month vs. 6-month follow-up visits, respectively), but were higher with higher age (OR 1.57; 95% CI 1,04‒2,37; p = 0,031 for middle aged vs. young, and OR 1.94; 95% CI 1,12‒3,37; p = 0,018 for elderly vs. young), in women (OR 1.4, 95% CI 1,01‒2,02; p = 0,041), in patients with disseminated disease (OR 1,67; 95 % CI 1,08‒2,58; p = 0,022), and in patients who reported LB-associated symptoms at enrolment (OR 8,47; 95 % CI 5,79‒12,38; p < 0,001). The presence of LB-associated symptoms at enrolment was the strongest predictor of incomplete recovery. Mean serum cytokine and chemokine levels were low. After accounting for the proportion of patients with cytokine or chemokine concentrations below the lowest limit of detection and adjusting analysis for multiple comparisons, only levels of IL-23, representative of the Th17 immune response, differed between the two age groups of patients with lower concentrations detected in older patients (p = 0,033). In addition, we found no differences in systemic inflammatory responses when comparing patients with and those without LB‐associated symptoms at enrolment. Conclusions. Our findings that older patients had more frequently infection caused by B. burgdorferi and B. garinii, previous LB and positive Borrelia serological test results at enrollment, less frequently multiple EM, longer time to resolution of EM after starting treatment, and higher probability of incomplete recovery, support the hypothesis that the clinical characteristics and long-term outcome of treatment of early LB in the form of EM are associated with the patient age. The absence of significant differences in serum concentrations of selected systemic inflammatory mediators between subgroups of patients with B. afzelii-caused EM, aged ⡥ 50 years and aged < 50 years, does not support the hypothesis that systemic inflammatory mediators are pivotal in the pathogenesis of age-associated clinical differences in early LB, or symptoms associated with LB. In this respect, local immune responses in the skin or other pathogenetic mechanisms may be more important.

• Keywords: /