Potek klopnega meningoencefalitisa pri bolnikih s protitelesi proti borelijam lymske borelioze v serumu

Velušček, Maša (author), Stupica, Daša (mentor)

Ozadje. Slovenija je endemična država za klopni meningoencefalitis (KME) in lymsko boreliozo (LB). Obe bolezni prenašajo klopi iz rodu Ixodes, zato so možne sočasne okužbe. Z različnih endemičnih področij Evrope in Rusije poročajo, da se sočasna borelijska okužba pojavlja pri 2–47 % bolnikov s KME. Doslej je bilo opravljenih malo raziskav, v katerih bi preučevali potek ter izid bolezni pri bolnikih s KME in sočasno borelijsko okužbo, in nimamo jasnih priporočil za obravnavo bolnikov s KME in možno sočasno borelijsko okužbo. To so bolniki s KME, ki imajo v serumu ali možganski tekočini prisotna borelijska protitelesa, vendar ne izpolnjujejo meril za potrjeno sočasno borelijsko okužbo. Namen. V retrospektivnem delu raziskave smo želeli opredeliti pogostost možne in potrjene sočasne borelijske okužbe pri bolnikih s KME v Osrednjeslovenski regiji, ki je endemično področje za obe bolezni, ter oceniti, ali je sočasna borelijska okužba povezana s potekom in izidom KME ter ali je antibiotično zdravljenje pri bolnikih s KME in možno sočasno borelijsko okužbo povezano z izidom bolezni. Slednje smo nameravali oceniti tudi v prospektivnem randomiziranem delu raziskave ter na podlagi rezultatov pripraviti priporočila za obravnavo bolnikov s KME in možno sočasno borelijsko okužbo. Metode. V retrospektivni del raziskave smo vključili bolnike s KME, hospitalizirane na Kliniki za infekcijske bolezni in vročinska stanja (KIBVS) Univerzitetnega kliničnega centra Ljubljana (UKCL), med letoma 2007 in 2013, v prospektivni del pa bolnike s KME in možno sočasno borelijsko okužbo (prisotnost borelijskih protiteles v serumu brez izpolnjenih meril za potrjeno sočasno borelijsko okužbo), ki so bili na KIBVS UKCL hospitalizirani med letoma 2014 in 2021. Za analizo smo uporabili demografske podatke, klinično oceno teže akutne bolezni ter izvide laboratorijskih in seroloških preiskav za borelije v serumu in možganski tekočini. Stanje bolnikov smo sledili ob kontrolnih pregledih dva, šest in dvanajst mesecev po hospitalizaciji, ko smo nepopolno okrevanje po akutni bolezni opredelili s prisotnostjo vsaj dveh simptomov po KME in/ali vsaj enega nevrološkega znaka po KME. V prospektivnem delu raziskave smo bolnike s KME in možno sočasno borelijsko okužbo randomizirali v dve skupini: bolniki iz prve skupine so prejeli peroralno antibiotično zdravljenje z doksiciklinom v odmerku 100 mg na 12 ur, 14 dni, bolniki iz druge skupine pa antibiotika niso prejeli. Rezultati. Med 684 bolniki s KME, vključenimi v retrospektivni del raziskave, jih je bilo 382 (55,8 %) brez sočasne borelijske okužbe, 62 (9,1 %) bolnikov je imelo KME in potrjeno sočasno borelijsko okužbo, 240 (35,1 %) bolnikov pa je imelo KME in možno sočasno borelijsko okužbo. Teža akutne bolezni je bila primerljiva med vsemi skupinami. Obeti za nepopolno okrevanje so se manjšali s pretekom časa po hospitalizaciji. Večji so bili pri ženskah, starejših bolnikih in tistih s težjim potekom akutne bolezni. Nepopolno okrevanje ni bilo povezano s potrjeno sočasno borelijsko okužbo (razmerje obetov (RO) 1,21; 95 % interval zaupanja (IZ) 0,49–2,95; p = 0,670) ali možno sočasno borelijsko okužbo (RO 0,95; 95 % IZ 0,55–1,65; p = 0,853). Med bolniki z možno sočasno borelijsko okužbo so starejši bolniki pogosteje prejeli antibiotično zdravljenje, vendar so bili obeti za nepopolno okrevanje primerljivi med bolniki, ki so prejeli antibiotik, in tistimi, ki antibiotika niso prejeli (RO 0,82; 95 % IZ 0,36–1,87; p = 0,630). V prospektivnem delu raziskave je 40 bolnikov s KME in z možno sočasno borelijsko okužbo prejelo antibiotično zdravljenje z doksiciklinom, 38 bolnikov pa antibiotika ni prejelo. Bolniki iz obeh skupin se niso razlikovali po zastopanosti med spoloma, starosti, seštevku pridruženih bolezni Charlson in teži akutne bolezni. Ker so se bolniki s težjo akutno boleznijo pogosteje udeležili kontrolnih pregledov po 6 in 12 mesecih, smo izid bolezni ocenili dva meseca po hospitalizaciji in ugotovili, da so imeli večje obete za nepopolno okrevanje bolniki s težjim potekom akutne bolezni (RO 1,14; 95 % IZ 1,04–1,27; p = 0,006), izid bolezni pa ni bil povezan z antibiotičnim zdravljenjem (RO 2,31; 95 % IZ 0,85–6,51; p = 0,099). Razlika tveganj za pojav serokonverzije med obema skupinama ni bila statistično značilna (2/40; 5 % vs. 0/38; 0 %; razlika 5,0 %; 95 % IZ –5,2 %–16,9 %). V retrospektivnem in prospektivnem delu raziskave se med 12-mesečnim sledenjem pri nobenem bolniku s KME in z možno sočasno borelijsko okužbo niso pojavili objektivni znaki LB ne glede na prejemanje antibiotičnega zdravljenja. Zaključki. V preučevani kohorti bolnikov s KME je bila sočasna borelijska okužba po pogostosti v vrhu glede na podatke z geografskih področij, kjer sta obe bolezni endemični. Tako sočasna borelijska okužba kot tudi antibiotično zdravljenje bolnikov z možno sočasno borelijsko okužbo nista bila povezana s potekom in izidom bolezni. Menimo, da bolniki s KME in možno sočasno borelijsko okužbo ne potrebujejo antibiotičnega zdravljenja. Za te bolnike se zdi bolj ustrezno 12-mesečno sledenje in uvedba antibiotičnega zdravljenja le v primeru pojava objektivnih kliničnih znakov LB.

• Language: Slovenian
• Keywords: klopni meningoencefalitis, lymska borelioza, sočasna okužba, antibiotično zdravljenje
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2024
• PID: 20.500.12556/RUL-154033
• Publication date in RUL: 21.01.2024

Secondary language

• Language: English
• Title: Clinical course of tick-borne encephalitis in patients with borrelial antibodies in serum

Abstract

Background. Slovenia is an endemic country for tick-borne encephalitis (TBE) and Lyme borreliosis (LB), which are both transmitted by ticks of the Ixodes genus, therefore co-infections are possible. According to previous studies from endemic areas across Europe and Russia, borrelial co-infections in patients with TBE occur in 2–47%. To date, few studies have been conducted evaluating the clinical course and outcome in patients with TBE and borrelial co-infection, and there are currently no clear recommendations for the management of patients with TBE and possible borrelial co-infection. These are patients with TBE and borrelial antibodies in serum or cerebrospinal fluid (CSF), yet not fulfilling criteria for confirmed borrelial co-infection. Aim. In the retrospective study we aimed to assess the frequency of possible and proven borrelial co-infection in patients with TBE in the central Slovenian region, which is endemic for both diseases, and assess the association between borrelial co-infection and clinical course and outcome of TBE, as well as the association between antibiotic therapy and long-term outcome in patients with TBE and possible borrelial co-infection. We aimed to assess the later also in a prospective randomised open-label study and based on our conclusions we planned to prepare recommendations for the management of patients with TBE and possible borrelial co-infection. Methods. The study was conducted at the Department of Infectious Diseases, University Medical Centre Ljubljana. In the retrospective study, we enrolled adult patients with TBE, hospitalized between 2007 and 2013. For the prospective part, adult patients with TBE and possible borrelial co-infection (anti-borrelial antibodies present in serum and/or CSF) were enrolled between years 2014 and 2021. Patients’ demographic data, clinical assessment of the severity of acute disease, serum and cerebrospinal fluid laboratory and microbiological tests’ results were analysed. We evaluated the outcome of the acute disease at follow up visits at 2, 6 and 12 months after hospitalization. Incomplete recovery was defined as presence of at least two post-TBE symptoms and/or at least one post-TBE neurologic sign. In the prospective study, patients with TBE and possible borrelial co-infection were randomized in two groups: patients in the first group received oral doxycycline 100 mg bid for 14 days, patients in the second group did not receive any antibiotic treatment. Results. In the retrospective part of the study 684 patients with TBE were enrolled: 382 (55.8%) had TBE alone, 62 (9.1%) had proven co-infection with borreliae and 240 (35.1%) had possible borrelial co-infection. The severity of acute illness was similar in all groups. The odds for incomplete recovery decreased during a 12-month follow-up. They were higher in women, older patients, and in those with more severe acute illness. Incomplete recovery was not associated with either proven (odds ratio (OR) 1.21 (95% confidence interval (CI) 0.49–2.95), p = 0.670) or possible borrelial co-infection (OR 0.95; 95% CI 0.55–1.65; p = 0.853). Among patients with possible borrelial co-infection, older patients more likely received antibiotics, but the odds for incomplete recovery were similar in those who received antibiotics and those who did not (OR 0.82; 95% CI 0.36–1.87; p = 0.630). In the prospective part of the study, 40 patients with TBE and possible borrelial co-infection received doxycycline and 38 patients were not treated with antibiotics. Patients from both groups did not differ regarding sex, age, Charlson comorbidity index, or severity of acute illness. Since patients with more severe acute disease attended follow-up visits at 6 and 12 months more often, outcome was assessed at the 2-month follow-up. The odds for incomplete recovery were higher in patients with more severe acute disease (OR 1.14; 95% CI 1.04–1.27; p = 0.006) but were not associated with antibiotic treatment (OR 2.31; 95% CI 0.85–6.51; p = 0.099). The risk difference for seroconversion of borrelial serum antibodies was not statistically significant between the two groups (2/40; 5% vs. 0/38; 0%; difference 5.0%; 95% CI –5.2%–16.9%). In the retrospective and prospective parts of the study, none of the patients with TBE and possible borrelial co-infection developed objective signs of LB during the 12-month follow-up, regardless of receiving antibiotic treatment. Conclusions. In the studied cohort of patients with TBE, the frequency of borrelial co-infection was in the upper range of frequencies reported previously from geographical areas endemic for both diseases. Borrelial co-infection in patients with TBE as well as anti-borrelial antibiotic treatment in patients with TBE and possible borrelial co-infection was not associated with the course and outcome of the disease. We think that antibiotic treatment of patients with TBE and possible borrelial co-infection may be deferred. In these patients, follow-up for 12 months and prescribing antibiotic treatment only if objective clinical manifestations of LB occur seem more appropriate.

• Keywords: tick-borne encephalitis, Lyme borreliosis, co-infection, antibiotic therapy