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Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive impairment after bacterial meningitis

Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive... Background: Patients with pneumococcal meningitis are at risk for death and neurological sequelae including cog- nitive impairment. Functional genetic polymorphisms of macrophage migration inhibitory factor (MIF) alleles have shown to predict mortality of pneumococcal meningitis. Methods: We investigated whether MIF concentrations during the acute phase of disease were predictive for death in a nationwide prospective cohort study. Subsequently, we studied whether individual ex vivo MIF response years after meningitis was associated with the development of cognitive impairment. Results: We found that in the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were pre- dictive for mortality (p = 0.009). Cognitive impairment, examined 1–5 years after meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared to 1 of 63 (2%) in controls, and was consistently associ- ated with individual variability in MIF production by peripheral blood mononuclear cells after ex vivo stimulation with various infectious stimuli. Conclusions: Our study confirms the role of MIF in poor disease outcome of pneumococcal meningitis. Inter-indi- vidual differences in MIF production were associated with long-term cognitive impairment years after pneumococ- cal meningitis. The present study provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. Keywords: Macrophage migration inhibitory factor, Bacterial meningitis, Pneumococcal meningitis, Cognitive impairment Background associated with mortality ranging from 6 to 24% and a Acute bacterial meningitis is a life-threatening disease substantial morbidity ranging from 23–29% [3–8]. Com- that ranks among the top 10 infectious causes of death mon neurological sequelae after pneumococcal men- [1]. Streptococcus pneumoniae is the most common cause ingitis are focal cerebral deficits (11–36%), hearing loss of bacterial meningitis, accounting for 75% of cases in (22–69%) and, seizures (4–31%) [4, 9–12]. developed countries [2, 3]. Pneumococcal meningitis is Cognitive impairment occurs in 14–32% after pneumo- coccal meningitis and even in those with apparent good clinical outcome [13–15]. A long-term follow up of adults *Correspondence: d.vandebeek@amsterdamumc.nl with bacterial meningitis included in a randomized con- Department of Neurology, Amsterdam UMC, University of Amsterdam, trolled study on the adjunctive dexamethasone therapy, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The showed no difference in neuropsychological outcome Netherlands Full list of author information is available at the end of the article between dexamethasone- and placebo treated patients © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kloek et al. acta neuropathol commun (2021) 9:4 Page 2 of 10 [16]. However, in a cross-sectional study, we recently at −  70 or −  80 degrees  ºC. Patients in this study were described that pneumococcal meningitis patients treated included in the MeninGene study as well, a nation-wide with dexamethasone had less frequent cognitive impair- Dutch prospective cohort study analyzing genetic risk ment compared to patients not treated with dexametha- factors in bacterial meningitis, described elsewhere [3]. sone [15]. Clinical data and outcome were prospectively collected Macrophage migration inhibitory factor (MIF) plays by the attending physicians, mostly neurologists, in an an important role in our innate immune system as a pro- online database. Outcome was scored at discharge by inflammatory cytokine and a neuro-endocrine mediator the Glasgow Outcome Scale (GOS) score, a score rang- [17, 18]. MIF is expressed by cells of the immune system ing from 1 to 5, a score of 1 indicating death, 2 is persis- but also by cells of the central nervous system and vari- tent vegetative state, 3 is severe disability, 4 is moderate ous other organs [19]. It stimulates cytokine production disability (capable of living independently but unable to of macrophages and enhances Toll-like receptor 4 expres- return to work or school) and, 5 is mild or no disabil- sion on macrophage surface increasing phagocytosis and ity (able to return to work or school) [23]. Patients were inhibiting apoptosis [17]. It also acts as an endogenous included during the acute phase of the illness and pro- counter-regulator of glucocorticoid immunosuppressive vided written informed consent for participation for both action [18]. MIF has been implicated as playing a causa- the MeninGene and the serial sampling study. tive role in many disease states, including sepsis, pneu- monia, diabetes, rheumatoid arthritis, inflammatory Patient cohort and controls of recall study bowel disease, cancer, and inflammatory skin disease Participants in the recall study had been included in the [20]. MIF also has been associated with the develop- MeninGene study between October 2011 and March ment of cognitive impairment, mainly in Alzheimer’s dis- 2015. Patients in this study were older than 16  years of ease [20]. We previously have identified MIF as genetic age and had a community-acquired acute bacterial men- marker of patient’s outcome in community-acquired ingitis confirmed by CSF cultures, or a positive CSF PCR bacterial meningitis [21]. In a prospective, nationwide in combination with typical CSF abnormalities. On the cohort of patients with pneumococcal meningitis, we informed consent form of the MeninGene study, the showed high-expression MIF alleles were associated with patient was asked whether they allowed the research- disease severity and death [21]. In patients with pneumo- ers to approach them for follow-up studies on long-term coccal meningitis MIF cerebrospinal fluid (CSF) values neurological sequelae. Patients eligible for the current were increased and high CSF MIF levels are associated follow-up study provided this consent and had been with systemic complications and death [21, 22]. admitted with pneumococcal meningitis 1–5 years prior Here, we further define the role of MIF on outcome in the follow-up study. The control group consisted of the pneumococcal meningitis. We investigated associations partners or other proxies of the patients. Before partici- between serial MIF blood levels and outcome in the acute pation patients and controls were questioned about their illness. Furthermore, we evaluated the long-term cog- medical history, medication use, and ongoing illness. If nitive outcome of these patients and determined asso- patients had ongoing infections or felt ill they could not ciations between the inter-individual variability of MIF participate in the study. Patients who gave permission to concentrations after ex vivo stimulatory experiments and participate in this follow-up study were recalled to the cognitive impairment. Academic Medical Center for a blood withdrawal and neuropsychological examination. Methods Serial blood sampling in bacterial meningitis patients Whole blood and PBMC stimulation experiments Patients with bacterial meningitis admitted between In the Recall study blood from patients and controls April 2014 and January 2017 in one of our 12 participat- was collected in heparin tubes. To isolate peripheral ing centers in the Netherlands were included. Inclusion blood mononuclear cells (PBMCs) the whole blood was criteria were a clinical suspicion on bacterial meningi- 1:1 diluted with Dulbecco’s phosphate-buffered saline tis and one of the following CSF characteristics: pleio- (D-PBS) and thereafter centrifuged with Ficoll . Isolated cytosis > 1000 cells per 3  mm , glucose < 1.9  mmol/L, PBMCs were washed three times with D-PBS before protein > 2.20  g/L or a positive Gram stain. Bacterial diluted in Roswell Park Memorial Institute (RPMI) meningitis needed to be confirmed with either a posi - medium. Whole blood and isolated PBMCs were stim- tive CSF culture of positive blood culture. Blood samples ulated at 37  ºC with RPMI, lipopolysaccharide (LPS) were withdrawn on day 0, 1, 2 and 7 of admission and 10  ng/ml, lipoteichoic acid (LTA) 1000  ng/ml and ultra- 3  months after discharge. Blood samples were immedi- violet (UV) killed S. pneumoniae strains D39 (serotype 2) ately processed in the participating hospitals and stored multiplicity of infection (MOI) 10 and 6303 (serotype 3) K loek et al. acta neuropathol commun (2021) 9:4 Page 3 of 10 MOI 5. After 24  h stimulated samples were centrifuged causative pathogen in 38 of these 54 (70%) episodes. for 10 min at 400 × G and supernatant was collected and On admission, 20 of 54 (41%) presented with the classic stored at − 80 ºC until further use. triad of fever, neck stiffness and decreased conscious - ness (defined as Glasgow coma scale score of < 14) and 12 of 54 (22%) were comatose. Twelve of 54 patients Cytokine measurements (22%) died. Human MIF, IL-6 and IL-10 levels in the blood sam- To investigate whether MIF concentrations were asso- ples of the serial sampling and the stimulation experi- ciated with outcome we obtained serial blood samples. ments were measured with the Luminex technology by Plasma samples were obtained on day 0 from 30 of 56 using an assay of Bio-Techne. Measurements were done (54%) available episodes, on day 1 from 47 of 55 (85%) according manufacturing protocol. The lower and upper episodes, day 2 from 50 of 52 (96%) episodes, on day 7 limit of detection  for MIF were respectively 219  pg/ml from 37 of 56 (66%) episodes, and of patients alive after and 55,600 pg/ml. 3  months from 32 of 42 (76%) available episodes. MIF concentration during early admission (day 0) did not Neuropsychological examination differ with the convalescent samples that were taken Cognitive functioning was tested with the Cognitive 3  months after discharge (Fig.  1a). On the contrary, for Basic Assessment Test set (COGBAT) of the Vienna Test IL-6 concentrations, a clear increase was observed in the System (VTS), Schuhfried, Mödling, Austria. Details of early phase of disease. In line with previous results on this test set are previous described [15]. All VTS COG- high-expression MIF alleles and cerebrospinal fluid con - BAT normative test scores were expressed as z-scores centrations [21], higher plasma concentrations of MIF on corrected for age and education with the control group admission were associated with mortality (median MIF as a reference. The value of the z-score represents the blood level of survivors 8,244  pg/ml [IQR 7463–11,465] distance between the patient score and the mean con- vs deceased patients 14,623  pg/ml [IQR 12,949–18,020], trol group score, in units of the standard deviation. p = 0.009; Fig.  1b). In the following days the same trend The z-score is negative when the patient score is below was visible but the larger spread of measurements led the mean control group score and positive when above. to a non-significant difference. Limiting the analysis to To compare differences in MIF concentration between the 38 pneumococcal meningitis patients showed simi- groups with worse versus good scores on cognitive lar results, with higher plasma concentration of MIF on performance, the groups were divided in < − 1 SD (z admission being associated with mortality (p = 0.039). score < − 1, worse scores) versus ≥ − 1 SD (z score ≥ − 1, Subsequently, we investigated whether variability of MIF good scores). concentration after ex  vivo stimulation was associated with cognitive impairment after pneumococcal meningitis Statistical analyses in a long-term follow up study. Patient enrollment in this Data was analyzed by using IBM SPSS statistics (version study have been described elsewhere [15]. For this study 24). Differences in MIF concentration between groups we included 79 patients, 1–5  years after pneumococcal were calculated with the t test or Mann Whitney U test meningitis, and 63 controls. Gender and age were simi- depending respectively on a normal or skewed distribu- lar between patients and controls (Table  2). As described tion. If not normal distributed, MIF concentrations in previously, multivariate analysis of covariance showed sig- the stimulation experiments were converted to a normal nificant differences in overall test scores of neuropsycho - distribution with a log transformation. The Friedman test logical testing between patients and controls (p = 0.008) was used to compare paired samples in all groups (> 2) [15]. Of the cognitive domains, alertness (p = 0.01) and and the Wilcoxon signed rank test was used to compare cognitive flexibility (p = 0.03) were most affected [15]. two related samples. All tests were two-tailed and p val- Of the patients who underwent neuropsychological ues of < 0.05 were considered as statistical significant. evaluation, whole blood or fresh isolated PBMCs were Statistical analyses to examine difference in cognitive stimulated with RPMI (negative control), LTA, LPS, functioning between patients and controls are described and two different UV-killed S. pneumoniae strains: in a previous study [15]. D39, and ATCC 6303. As a major component of the membrane (cell wall) of all Gram positive bacteria, LTA Results is important for bacterial survival, growth, and patho- From April 2014 to December 2017 54 patients com- genicity. LPS is a major component of the outer mem- prising 56 bacterial meningitis episodes were included brane of Gram negative bacteria and plays a key role in in our multicenter prospective serial sampling study host–pathogen interactions with the innate immune (Table 1). Of these 54 patients, 35 (65%) were male and system. the median age was 62  years. S. pneumoniae was the Kloek et al. acta neuropathol commun (2021) 9:4 Page 4 of 10 Table 1 Clinical characteristics of  the  54 patients with  bacterial meningitis and  38 patients with  pneumococcal meningitis in the serial sampling study Characteristics Patients (n = 54) Pneumococcal n/N (%) meningitis patients (n = 38) n/N (%) Male 35/54 (65%) 22/38 (58%) Age in years, mean (SD) 54 (21) 61 (18) Symptoms and predisposing conditions Duration of symptoms < 24 h 22/52 (42%) 19/38 (50%) Sinusitis/otitis media 16/53 (30%) 13/37 (35%) Pneumonia 3/48 (6%) 2/32 (6%) Immunocompromised state 10/53 (19%) 31/38 (82%) Clinical characteristics on admission Classic triad 20/49 (41%) 19/34 (56%) Coma 12/54 (22%) 11/38 (29%) Focal neurologic deficits 12/53 (23%) 10/37 (27%) Causing pathogen S. pneumoniae 38/54 (70%) 100% N. meningitidis 5/54 (9%) – Other 11/54 (21%) – Laboratory characteristics on admission** C-reactive protein (mg/L) 141 (54–267) 141 (59–293) Blood leukocyte count (× 10^9 cells/L) 18.3 (11.9–23.8) 18.3 (11.9–26.6) CSF leukocyte count (× 10^6 cells/L) 2874 (685–7877) 2462 (511–6170) Standard dose of dexamethasone therapy 43/49 (88%) 32/33 (97%) Clinical course/complications Circulatory shock 6/47 (13%) 6/33 (18%) Intensive care admission 23/52 (44%) 21/35 (60%) Cerebral infarction 6/47 (13%) 6/32 (19%) Outcome at discharge GOS 1 12/54 (22%) 11/38 (29%) GOS 3 5/54 (9%) 4/38 (11%) GOS 4 7/54 (13%) 4/38 (11%) GOS 5 30/54 (56%) 19/38 (50%) Mortality at 3 months 14/54 (26%) 13/38 (34%) ** CRP, blood leukocyte count, CSF leukocyte count were known in respectively all, 53 of 54 (pneumococcal 37 of 38) and 50 of 54 (pneumococcal 34 of 38) patients, data are median (interquartile range) IL-6 and IL-10 concentration were increased 24  h Discussion after ex vivo stimulation with LTA, LPS and both pneu- Our study confirms the role of MIF in poor disease mococcal strains, as compared to the negative con- outcome in the acute phase of pneumococcal men- trol samples with RPMI (Additional file  1: Fig.  1b and ingitis. Our findings are in line with a previous study c). MIF concentration was not increased after whole that described high-expression MIF alleles to be asso- blood and PBMC stimulation with LTA, LPS or pneu- ciated with disease severity and death in patients mococci, compared to negative control samples with with pneumococcal meningitis. We found that higher RPMI (Additional file  1: Fig.  1a). However, in whole plasma MIF concentrations during the early phase of blood stimulation experiments patients showed higher disease were predictive for mortality in bacterial men- MIF responses than control subjects for all stimuli ingitis. Our findings are consistent with the harmful (respectively p = 0.031, p = 0.004, p = 0.018, p = 0.042, consequences of robust pro-inflammatory cytokine Fig. 2). Whole blood stimulation showed no differences responses on brain edema and neuronal damage in the in MIF response between patients and control subjects, course of bacterial meningitis [1]. MIF has also shown but MIF concentrations after PBMC stimulation were to be markedly and persistently upregulated and to higher in patients with a worse performance on the be  associated with  increased disease severity and early most affected cognitive domain alertness (Fig. 3 ). death in patients with sepsis [24, 25]. Administration K loek et al. acta neuropathol commun (2021) 9:4 Page 5 of 10 ab c 20000 250 100000 150 0 0 Survived Died *0.009 Fig. 1 Cytokine concentrations at day 0, 1, 2 and 7 of admission and 3 months after admission. A Scatter plot of cytokine concentration in pg/ml of 56 bacterial meningitis episodes. Black lines are medians with interquartile ranges, a MIF, b IL-6, c IL-10. B MIF concentration in pg/ml at day 0, 1, 2 and 7 of admission of survivors versus deceased patients. White bars: survivors, black bars: patients that died during admission. Bars are presented as medians with interquartile ranges (lines in grey) of recombinant MIF protein in a murine sepsis model is currently unknown. In a prospective cohort study, increased mortality following LPS administration [26]. baseline data, including clinical characteristics, and cyto- Several experimental sepsis studies in mice showed biochemical parameters of blood and cerebrospinal fluid that the neutralization of MIF reduced pro-inflamma - between patients with or without cognitive impairment tory cytokine production and organ injury, and thereby after meningitis were similar [14]. In patients with clini- increased the survival rate [21, 27, 28]. Therefore, MIF cal pre-dementia disease stage, MIF has been associ- modulation is an interesting adjunctive therapy to ated with biomarkers of Alzheimer’s disease pathology improve outcome of pneumococcal meningitis. and predicted cognitive impairment [30]. MIF cerebro- Our study shows that individuals with an increased spinal fluid (CSF) levels in even moderately cognitively pro-inflammatory response consisting of a higher MIF impaired subjects were higher compared to participants expression after PBMC stimulation, are at risk for worse with normal cognition [30]. Experimental studies showed cognitive functioning. Previous studies showed that that MIF deficient mice had reduced astrocyte activation pneumococcal meningitis patients were at risk to develop and tau hyperphosphorylation in Alzheimer’s disease cognitive impairment [13–16, 29]. The pathophysiology models [31]. of cognitive impairment after pneumococcal meningitis Day 0 Day 1 Day 2 Day 7 3 months Day 0 Day 1 Day 2 Day 7 3 months Day 0 Day 0 Day 1 Day 1 Day 2 Day 2 Day 7 Day 7 Day 0 Day 1 Day 2 Day 7 3 months MIF concentration MIF concentration pg/ml IL-6 concentration IL-10 concentration Kloek et al. acta neuropathol commun (2021) 9:4 Page 6 of 10 Table 2 Clinical characteristics of the 80 patients with pneumococcal meningitis and 69 controls in the follow up study Characteristics Patients (n = 80) Controls (n = 69) n/N (%) n/N (%) Male 39/80 (49%) 35/69 (51%) Age in years* 63 (56–69) 65 (54–68) Predisposing conditions before admission Duration of symptoms < 24 h 35/79 (44%) Sinusitis/otitis media 44/79 (55%) Pneumonia 10/78 (13%) Immunocompromised state 16/80 (20%) Clinical characteristics on admission Classic triad 35/76 (44%) Coma 4/80 (5%) Focal neurologic deficits 18/79 (23%) Laboratory characteristics on admission* Blood leukocyte count (× 10^9 cells/L) 17.5 (13.3–23.6) CSF leukocyte count (× 10^6 cells/L) 3492 (1298–7805) Standard dose of dexamethasone therapy 69/80 (86%) Clinical course/complications Seizures 12/76 (15%) Circulatory shock 1/73 (1%) Intensive care admission 26/77 (33%) Cerebral infarction 7/69 (9%) Outcome at discharge GOS 3 2/80 (3%) GOS 4 17/80 (21%) GOS 5 61/80 (76%) Years from discharge to testing* 2.5 (1.1—4.6) Median (IQR 25–75) High MIF responsiveness may persist for a long time showing increased MIF production is associated with after the acute disease. Blood MIF levels on admis- Alzheimer disease and mild cognitive impairment sug- sion were not different than those among survivors gesting that MIF is involved in the neuro-inflammatory 3 months after infection, although we did not test MIF process occurring in cognitive decline [36, 37]. One levels in control subjects. However, even years after study has shown MIF can bind to the  amyloid protein, the disease, patients had higher MIF responsiveness on possibly leading to accumulation of amyloid-beta in infectious stimuli compared to controls. A study with Alzheimer disease [38]. patients suffering from sepsis showed consistent results Our study has several limitations. The most impor - with higher ex  vivo MIF release by PBMCs in patients tant limitation is selection bias. First, we did not versus healthy control subjects [32]. Furthermore, sample all patients in the acute phase of disease. Sam- murine models of sepsis have shown low-grade brain ples from early time points were missed because of inflammation persists after recovering from sepsis, sug - informed consent procedures. At later time points gesting a severe infection is able to induce in microglia some patients had died. These two factors led to selec - a primed-like state [33, 34]. The persistent brain inflam - tion bias leading to underrepresentation of the most mation was associated with increased levels of amyloid- severely ill patients. This might have caused an under - beta peptide and long-term cognitive deficits in sepsis estimation of the predictive effect of MIF concentra - survivors [33]. Likewise in patient studies it is known tions. Second, all patients in our prospective study that severe sepsis in the older population is indepen- underwent lumbar puncture. Since lumbar punc- dently associated with substantial and persistent new ture in some cases cannot be done in the most severe cognitive impairments [35]. Although with this study patients, this may also have led to an underestimation we cannot prove  a causal relationship, we hypothesize of the rate of unfavorable outcome and death in our that prolonged MIF upregulation contributes to the cohort. Third, the patients in the follow up study were cognitive impairments of survivors of pneumococcal a selected group of patients with relatively good con- meningitis. This hypothesis is strengthened by studies dition after disease, which could have underestimated K loek et al. acta neuropathol commun (2021) 9:4 Page 7 of 10 a b RPMI LTA * p= 0.031 40000 * p= 0.004 cd S. pneumoniae 6303 S. pneumoniae D39 * p= 0.018 80000 * p= 0.042 Fig. 2 MIF concentration after 24 h whole blood stimulation of patients versus controls. Bars are boxplot with medians and interquartile ranges a after RPMI stimulation of WB of patients 19,459 pg/ml [IQR 15,880–26755] versus that of controls 16,182 pg/ml [IQR 13,334–23006], p = 0.031; b after LTA stimulation of WB of patients 12,461 pg/ml [IQR 10,649–16253] versus that of controls 9932 pg/ml [IQR 7718–12592], p = 0.009; c after S. pneumoniae 6303 stimulation of WB of patients 22,042 pg/ml [IQR 16,505–33155] versus that of controls 18,588 pg/ml [IQR 14,974–23099], p = 0.018; d after S. pneumoniae D39 stimulation of WB of patients 22,889 pg/ml [IQR 16,057–31820] versus that of controls 18,805 pg/ml [IQR 16,063–22865], p = 0.042. See Additional file 1: Figs. 2.1 and 2.2 for IL-6 and IL-10 concentrations after 24 h WB stimulation of patients versus controls (no significant differences) the rate of cognitive impairment, decreasing the study subpopulations for our ex  vivo stimulation experi- power to detect meaningful associations between indi- ments. Stimulation of specific cell population would vidual MIF responsiveness and cognitive impairment. likely have increased our study power, providing more Another limitation is that we did not use specific cell specific information [39]. Interestingly, stimulation Patients Controls Patients Controls Patients Controls Patients Controls MIF (pg/ml) MIF (pg/ml) MIF (pg/ml) MIF (pg/ml) Kloek et al. acta neuropathol commun (2021) 9:4 Page 8 of 10 ab LTA stimulated samples LPS stimulated samples 50000 30000 * p= 0.033 * p= 0.017 0 0 Cognitive testing Cognitive testing cd S. pneumoniae D39 stimulated S. pneumoniae 6303 stimulated samples samples * p= 0.024 * p= 0.025 Cognitive testing Cognitive testing Fig. 3 MIF concentration after 24 h PBMC stimulation versus performance on cognitive testing. MIF concentration in pg/ml after 24 h PBMC stimulation in groups with good performance on cognitive testing (test score ≥ − 1SD) and worse performance on cognitive testing (test score < − 1 SD). a After stimulation with LTA. b After stimulation with LPS. c After stimulation with S. pneumoniae 6306. d After stimulation with S. pneumoniae D39. Grey lines are medians and interquartile ranges. See Additional file 1: Figs. 3.1 and 3.2 for IL-6 and IL-10 concentrations after 24 h PBMC stimulation in groups divided on performance on cognitive testing (no significant differences) ≥ ≥ -1 SD < -1 SD ≥≥ -1 SD < -1 SD ≥ ≥ -1 SD < -1 SD ≥ ≥ -1 SD < -1 SD MIF pg/ml MIF pg/ml MIF pg/ml MIF pg/ml K loek et al. acta neuropathol commun (2021) 9:4 Page 9 of 10 University of Amsterdam, Nieuwe Achtergracht 129 B, 1001 NK Amsterdam, experiments showed consistent results for all stimuli The Netherlands. Department of Epidemiology and Data Science, Amster- which may suggest that our results are robust—at least dam UMC, University of Amsterdam, Amsterdam Public Health, Meibergdreef between different stimuli. 9, 1105 AZ Amsterdam, The Netherlands. Department of Medical Microbiol- ogy and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity, Meibergdreef 9, 1105 AZ Amsterdam, Conclusions The Netherlands. Department of Medical Microbiology and Infection Our study shows that high MIF concentrations in the Prevention, The Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam Infection and Immunity, Meibergdreef 9, 1105 AZ Amsterdam, early phase of acute bacterial meningitis predict poor The Netherlands. Department of Neurology, Amsterdam UMC, University outcome of disease. Furthermore, we found associa- of Amsterdam, Amsterdam Neuroscience, PO Box 22660, 1100DD Amsterdam, tions between high MIF levels and occurrence of cogni- The Netherlands. tive impairment, suggesting MIF contributes to cognitive Received: 3 November 2020 Accepted: 6 December 2020 impairments in pneumococcal meningitis. Both results suggest MIF modulating therapy could be an interest- ing new target to influence outcome of pneumococcal meningitis. References 1. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E (2016) Community-acquired bacterial meningitis. Nat Rev Dis Primers Supplementary Information 2:16074 The online version contains supplementary material available at https ://doi. 2. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community- org/10.1186/s4047 8-020-01100 -7. acquired bacterial meningitis in adults. NEnglJMed 354(1):44–53 3. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW et al (2016) Community-acquired bacterial meningitis in adults in Additional file 1 Suplementary material. the Netherlands, 2006–14: a prospective cohort study. Lancet Infect Dis 16(3):339–347 4. Lucas MJ, Brouwer MC, van de Beek D (2016) Neurological sequelae of Abbreviations bacterial meningitis. J Infect 73(1):18–27 COGBAT: Cognitive basic assessment test set; CSF: Cerebrospinal fluid; IQR: 5. Buchholz G, Koedel U, Pfister HW, Kastenbauer S, Klein M (2016) Dramatic Interquartile range; LPS: Lipopolysaccharide; LTA: Lipoteichoic acid; MIF: reduction of mortality in pneumococcal meningitis. Crit Care 20(1):312 Macrophage migration inhibitory factor; MOI: Multiplicity of infection; PBMC: 6. Hasbun R, Rosenthal N, Balada-Llasat JM, Chung J, Duff S, Bozzette S et al Peripheral blood mononuclear cell; RPMI: Roswell Park Memorial Institute; UV: (2017) Epidemiology of meningitis and encephalitis in the United States, Ultraviolet; VTS: Vienna test system; WB: Whole blood; WMO: Dutch medical 2011–2014. Clin Infect Dis 65(3):359–363 research involving human subjects. 7. Glimaker M, Brink M, Naucler P, Sjolin J (2016) Betamethasone and dexa- methasone in adult community-acquired bacterial meningitis: a quality Author contributions registry study from 1995 to 2014. Clin Microbiol Infect 22(9):814e1-e7 ATK carried out the experiments, analyzed data and wrote the manuscript. MT 8. Thornorethardottir A, Erlendsdottir H, Sigurethardottir B, Harethardottir H, and BS contributed to analyzing of the neuropsychological data. AvdE, MCB Reynisson IK, Gottfreethsson M et al (2014) Bacterial meningitis in adults and DvdB contributed to the design and cohort collection of this study. MVS in Iceland, 1995–2010. Scand J Infect Dis 46(5):354–360 contributed to the design of the experimental data. MCB and DvdB advised 9. Kragsbjerg P, Kallman J, Olcen P (1994) Pneumococcal meningitis in on the first version of the manuscript. All authors read, revised and approved adults. ScandJInfectDis 26(6):659–666 the final manuscript. 10. Kastenbauer S, Pfister HW (2003) Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases. Funding Brain 126(Pt 5):1015–1025 This work was supported by grants from the European Research Council 11. Larsen F, Brandt CT, Larsen L, Klastrup V, Wiese L, Helweg-Larsen J et al (ERC Starting Grant [proposal/contract 281156]), Netherlands Organization (2019) Risk factors and prognosis of seizures in adults with community- for Health Research and Development (ZonMw; NWO-Vici Grant [Proposal/ acquired bacterial meningitis in Denmark: observational cohort studies. Contract 91819627]), both to D. van de Beek. The Netherlands Reference Labo- BMJ Open 9(7):e030263 ratory for Bacterial Meningitis is supported by the National Institute of Public 12. Zoons E, Weisfelt M, de Gans J, Spanjaard L, Koelman JH, Reitsma JB et al Health and the Environmental Protection, Bilthoven. The funders had no role (2008) Seizures in adults with bacterial meningitis. Neurology 70(22 Pt in the design of the study, collection, analysis, and interpretation of data or in 2):2109–2115 writing the manuscript. 13. Hoogman M, van de Beek D, Weisfelt M, de Gans J, Schmand B (2007) Cognitive outcome in adults after bacterial meningitis. JNeurolNeuro- Ethics approval and consent to participate surgPsychiatry 78(10):1092–1096 The study was conducted according to the principles of the Declaration of 14. van de Beek D, Schmand B, de Gans J, Weisfelt M, Vaessen H, Dankert Helsinki (version of 2013, Fortaleza, Brazil) and to the Dutch Medical Research J et al (2002) Cognitive impairment in adults with good recovery after Involving Human Subjects Act ( WMO). All studies were performed with bacterial meningitis. JInfectDis 186(7):1047–1052 approval of the local ethics committee and informed consent was obtained 15. Kloek AT, Brouwer MC, Schmand B, Tanck MWT, van de Beek D (2020) for all patients and controls. Long-term neurological and cognitive outcome, and quality of life in adults after pneumococcal meningitis. Clin Microbiol Infect Competing interest 16. Weisfelt M, Hoogman M, van de Beek D, de Gans J, Dreschler WA, The authors declare that they have no competing interests. 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Kouris A, Pistiki A, Katoulis A, Georgitsi M, Giatrakou S, Papadavid E et al (2005) ISO-1 binding to the tautomerase active site of MIF inhibits its pro- (2014) Proinflammatory cytokine responses in patients with psoriasis. Eur inflammatory activity and increases survival in severe sepsis. J Biol Chem Cytokine Netw 25(4):63–68 280(44):36541–36544 29. Weisfelt M, van de Beek D, Hoogman M, Hardeman C, de Gans J, Publisher’s Note Schmand B (2006) Cognitive outcome in adults with moderate disability Springer Nature remains neutral with regard to jurisdictional claims in pub- after pneumococcal meningitis. JInfect 52(6):433–439 lished maps and institutional affiliations. 30. Oikonomidi A, Tautvydaite D, Gholamrezaee MM, Henry H, Bacher M, Popp J (2017) Macrophage migration inhibitory factor is associated with Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Individual responsiveness of macrophage migration inhibitory factor predicts long-term cognitive impairment after bacterial meningitis

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10.1186/s40478-020-01100-7
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Abstract

Background: Patients with pneumococcal meningitis are at risk for death and neurological sequelae including cog- nitive impairment. Functional genetic polymorphisms of macrophage migration inhibitory factor (MIF) alleles have shown to predict mortality of pneumococcal meningitis. Methods: We investigated whether MIF concentrations during the acute phase of disease were predictive for death in a nationwide prospective cohort study. Subsequently, we studied whether individual ex vivo MIF response years after meningitis was associated with the development of cognitive impairment. Results: We found that in the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were pre- dictive for mortality (p = 0.009). Cognitive impairment, examined 1–5 years after meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared to 1 of 63 (2%) in controls, and was consistently associ- ated with individual variability in MIF production by peripheral blood mononuclear cells after ex vivo stimulation with various infectious stimuli. Conclusions: Our study confirms the role of MIF in poor disease outcome of pneumococcal meningitis. Inter-indi- vidual differences in MIF production were associated with long-term cognitive impairment years after pneumococ- cal meningitis. The present study provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. Keywords: Macrophage migration inhibitory factor, Bacterial meningitis, Pneumococcal meningitis, Cognitive impairment Background associated with mortality ranging from 6 to 24% and a Acute bacterial meningitis is a life-threatening disease substantial morbidity ranging from 23–29% [3–8]. Com- that ranks among the top 10 infectious causes of death mon neurological sequelae after pneumococcal men- [1]. Streptococcus pneumoniae is the most common cause ingitis are focal cerebral deficits (11–36%), hearing loss of bacterial meningitis, accounting for 75% of cases in (22–69%) and, seizures (4–31%) [4, 9–12]. developed countries [2, 3]. Pneumococcal meningitis is Cognitive impairment occurs in 14–32% after pneumo- coccal meningitis and even in those with apparent good clinical outcome [13–15]. A long-term follow up of adults *Correspondence: d.vandebeek@amsterdamumc.nl with bacterial meningitis included in a randomized con- Department of Neurology, Amsterdam UMC, University of Amsterdam, trolled study on the adjunctive dexamethasone therapy, Amsterdam Neuroscience, Meibergdreef 9, 1105 AZ Amsterdam, The showed no difference in neuropsychological outcome Netherlands Full list of author information is available at the end of the article between dexamethasone- and placebo treated patients © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kloek et al. acta neuropathol commun (2021) 9:4 Page 2 of 10 [16]. However, in a cross-sectional study, we recently at −  70 or −  80 degrees  ºC. Patients in this study were described that pneumococcal meningitis patients treated included in the MeninGene study as well, a nation-wide with dexamethasone had less frequent cognitive impair- Dutch prospective cohort study analyzing genetic risk ment compared to patients not treated with dexametha- factors in bacterial meningitis, described elsewhere [3]. sone [15]. Clinical data and outcome were prospectively collected Macrophage migration inhibitory factor (MIF) plays by the attending physicians, mostly neurologists, in an an important role in our innate immune system as a pro- online database. Outcome was scored at discharge by inflammatory cytokine and a neuro-endocrine mediator the Glasgow Outcome Scale (GOS) score, a score rang- [17, 18]. MIF is expressed by cells of the immune system ing from 1 to 5, a score of 1 indicating death, 2 is persis- but also by cells of the central nervous system and vari- tent vegetative state, 3 is severe disability, 4 is moderate ous other organs [19]. It stimulates cytokine production disability (capable of living independently but unable to of macrophages and enhances Toll-like receptor 4 expres- return to work or school) and, 5 is mild or no disabil- sion on macrophage surface increasing phagocytosis and ity (able to return to work or school) [23]. Patients were inhibiting apoptosis [17]. It also acts as an endogenous included during the acute phase of the illness and pro- counter-regulator of glucocorticoid immunosuppressive vided written informed consent for participation for both action [18]. MIF has been implicated as playing a causa- the MeninGene and the serial sampling study. tive role in many disease states, including sepsis, pneu- monia, diabetes, rheumatoid arthritis, inflammatory Patient cohort and controls of recall study bowel disease, cancer, and inflammatory skin disease Participants in the recall study had been included in the [20]. MIF also has been associated with the develop- MeninGene study between October 2011 and March ment of cognitive impairment, mainly in Alzheimer’s dis- 2015. Patients in this study were older than 16  years of ease [20]. We previously have identified MIF as genetic age and had a community-acquired acute bacterial men- marker of patient’s outcome in community-acquired ingitis confirmed by CSF cultures, or a positive CSF PCR bacterial meningitis [21]. In a prospective, nationwide in combination with typical CSF abnormalities. On the cohort of patients with pneumococcal meningitis, we informed consent form of the MeninGene study, the showed high-expression MIF alleles were associated with patient was asked whether they allowed the research- disease severity and death [21]. In patients with pneumo- ers to approach them for follow-up studies on long-term coccal meningitis MIF cerebrospinal fluid (CSF) values neurological sequelae. Patients eligible for the current were increased and high CSF MIF levels are associated follow-up study provided this consent and had been with systemic complications and death [21, 22]. admitted with pneumococcal meningitis 1–5 years prior Here, we further define the role of MIF on outcome in the follow-up study. The control group consisted of the pneumococcal meningitis. We investigated associations partners or other proxies of the patients. Before partici- between serial MIF blood levels and outcome in the acute pation patients and controls were questioned about their illness. Furthermore, we evaluated the long-term cog- medical history, medication use, and ongoing illness. If nitive outcome of these patients and determined asso- patients had ongoing infections or felt ill they could not ciations between the inter-individual variability of MIF participate in the study. Patients who gave permission to concentrations after ex vivo stimulatory experiments and participate in this follow-up study were recalled to the cognitive impairment. Academic Medical Center for a blood withdrawal and neuropsychological examination. Methods Serial blood sampling in bacterial meningitis patients Whole blood and PBMC stimulation experiments Patients with bacterial meningitis admitted between In the Recall study blood from patients and controls April 2014 and January 2017 in one of our 12 participat- was collected in heparin tubes. To isolate peripheral ing centers in the Netherlands were included. Inclusion blood mononuclear cells (PBMCs) the whole blood was criteria were a clinical suspicion on bacterial meningi- 1:1 diluted with Dulbecco’s phosphate-buffered saline tis and one of the following CSF characteristics: pleio- (D-PBS) and thereafter centrifuged with Ficoll . Isolated cytosis > 1000 cells per 3  mm , glucose < 1.9  mmol/L, PBMCs were washed three times with D-PBS before protein > 2.20  g/L or a positive Gram stain. Bacterial diluted in Roswell Park Memorial Institute (RPMI) meningitis needed to be confirmed with either a posi - medium. Whole blood and isolated PBMCs were stim- tive CSF culture of positive blood culture. Blood samples ulated at 37  ºC with RPMI, lipopolysaccharide (LPS) were withdrawn on day 0, 1, 2 and 7 of admission and 10  ng/ml, lipoteichoic acid (LTA) 1000  ng/ml and ultra- 3  months after discharge. Blood samples were immedi- violet (UV) killed S. pneumoniae strains D39 (serotype 2) ately processed in the participating hospitals and stored multiplicity of infection (MOI) 10 and 6303 (serotype 3) K loek et al. acta neuropathol commun (2021) 9:4 Page 3 of 10 MOI 5. After 24  h stimulated samples were centrifuged causative pathogen in 38 of these 54 (70%) episodes. for 10 min at 400 × G and supernatant was collected and On admission, 20 of 54 (41%) presented with the classic stored at − 80 ºC until further use. triad of fever, neck stiffness and decreased conscious - ness (defined as Glasgow coma scale score of < 14) and 12 of 54 (22%) were comatose. Twelve of 54 patients Cytokine measurements (22%) died. Human MIF, IL-6 and IL-10 levels in the blood sam- To investigate whether MIF concentrations were asso- ples of the serial sampling and the stimulation experi- ciated with outcome we obtained serial blood samples. ments were measured with the Luminex technology by Plasma samples were obtained on day 0 from 30 of 56 using an assay of Bio-Techne. Measurements were done (54%) available episodes, on day 1 from 47 of 55 (85%) according manufacturing protocol. The lower and upper episodes, day 2 from 50 of 52 (96%) episodes, on day 7 limit of detection  for MIF were respectively 219  pg/ml from 37 of 56 (66%) episodes, and of patients alive after and 55,600 pg/ml. 3  months from 32 of 42 (76%) available episodes. MIF concentration during early admission (day 0) did not Neuropsychological examination differ with the convalescent samples that were taken Cognitive functioning was tested with the Cognitive 3  months after discharge (Fig.  1a). On the contrary, for Basic Assessment Test set (COGBAT) of the Vienna Test IL-6 concentrations, a clear increase was observed in the System (VTS), Schuhfried, Mödling, Austria. Details of early phase of disease. In line with previous results on this test set are previous described [15]. All VTS COG- high-expression MIF alleles and cerebrospinal fluid con - BAT normative test scores were expressed as z-scores centrations [21], higher plasma concentrations of MIF on corrected for age and education with the control group admission were associated with mortality (median MIF as a reference. The value of the z-score represents the blood level of survivors 8,244  pg/ml [IQR 7463–11,465] distance between the patient score and the mean con- vs deceased patients 14,623  pg/ml [IQR 12,949–18,020], trol group score, in units of the standard deviation. p = 0.009; Fig.  1b). In the following days the same trend The z-score is negative when the patient score is below was visible but the larger spread of measurements led the mean control group score and positive when above. to a non-significant difference. Limiting the analysis to To compare differences in MIF concentration between the 38 pneumococcal meningitis patients showed simi- groups with worse versus good scores on cognitive lar results, with higher plasma concentration of MIF on performance, the groups were divided in < − 1 SD (z admission being associated with mortality (p = 0.039). score < − 1, worse scores) versus ≥ − 1 SD (z score ≥ − 1, Subsequently, we investigated whether variability of MIF good scores). concentration after ex  vivo stimulation was associated with cognitive impairment after pneumococcal meningitis Statistical analyses in a long-term follow up study. Patient enrollment in this Data was analyzed by using IBM SPSS statistics (version study have been described elsewhere [15]. For this study 24). Differences in MIF concentration between groups we included 79 patients, 1–5  years after pneumococcal were calculated with the t test or Mann Whitney U test meningitis, and 63 controls. Gender and age were simi- depending respectively on a normal or skewed distribu- lar between patients and controls (Table  2). As described tion. If not normal distributed, MIF concentrations in previously, multivariate analysis of covariance showed sig- the stimulation experiments were converted to a normal nificant differences in overall test scores of neuropsycho - distribution with a log transformation. The Friedman test logical testing between patients and controls (p = 0.008) was used to compare paired samples in all groups (> 2) [15]. Of the cognitive domains, alertness (p = 0.01) and and the Wilcoxon signed rank test was used to compare cognitive flexibility (p = 0.03) were most affected [15]. two related samples. All tests were two-tailed and p val- Of the patients who underwent neuropsychological ues of < 0.05 were considered as statistical significant. evaluation, whole blood or fresh isolated PBMCs were Statistical analyses to examine difference in cognitive stimulated with RPMI (negative control), LTA, LPS, functioning between patients and controls are described and two different UV-killed S. pneumoniae strains: in a previous study [15]. D39, and ATCC 6303. As a major component of the membrane (cell wall) of all Gram positive bacteria, LTA Results is important for bacterial survival, growth, and patho- From April 2014 to December 2017 54 patients com- genicity. LPS is a major component of the outer mem- prising 56 bacterial meningitis episodes were included brane of Gram negative bacteria and plays a key role in in our multicenter prospective serial sampling study host–pathogen interactions with the innate immune (Table 1). Of these 54 patients, 35 (65%) were male and system. the median age was 62  years. S. pneumoniae was the Kloek et al. acta neuropathol commun (2021) 9:4 Page 4 of 10 Table 1 Clinical characteristics of  the  54 patients with  bacterial meningitis and  38 patients with  pneumococcal meningitis in the serial sampling study Characteristics Patients (n = 54) Pneumococcal n/N (%) meningitis patients (n = 38) n/N (%) Male 35/54 (65%) 22/38 (58%) Age in years, mean (SD) 54 (21) 61 (18) Symptoms and predisposing conditions Duration of symptoms < 24 h 22/52 (42%) 19/38 (50%) Sinusitis/otitis media 16/53 (30%) 13/37 (35%) Pneumonia 3/48 (6%) 2/32 (6%) Immunocompromised state 10/53 (19%) 31/38 (82%) Clinical characteristics on admission Classic triad 20/49 (41%) 19/34 (56%) Coma 12/54 (22%) 11/38 (29%) Focal neurologic deficits 12/53 (23%) 10/37 (27%) Causing pathogen S. pneumoniae 38/54 (70%) 100% N. meningitidis 5/54 (9%) – Other 11/54 (21%) – Laboratory characteristics on admission** C-reactive protein (mg/L) 141 (54–267) 141 (59–293) Blood leukocyte count (× 10^9 cells/L) 18.3 (11.9–23.8) 18.3 (11.9–26.6) CSF leukocyte count (× 10^6 cells/L) 2874 (685–7877) 2462 (511–6170) Standard dose of dexamethasone therapy 43/49 (88%) 32/33 (97%) Clinical course/complications Circulatory shock 6/47 (13%) 6/33 (18%) Intensive care admission 23/52 (44%) 21/35 (60%) Cerebral infarction 6/47 (13%) 6/32 (19%) Outcome at discharge GOS 1 12/54 (22%) 11/38 (29%) GOS 3 5/54 (9%) 4/38 (11%) GOS 4 7/54 (13%) 4/38 (11%) GOS 5 30/54 (56%) 19/38 (50%) Mortality at 3 months 14/54 (26%) 13/38 (34%) ** CRP, blood leukocyte count, CSF leukocyte count were known in respectively all, 53 of 54 (pneumococcal 37 of 38) and 50 of 54 (pneumococcal 34 of 38) patients, data are median (interquartile range) IL-6 and IL-10 concentration were increased 24  h Discussion after ex vivo stimulation with LTA, LPS and both pneu- Our study confirms the role of MIF in poor disease mococcal strains, as compared to the negative con- outcome in the acute phase of pneumococcal men- trol samples with RPMI (Additional file  1: Fig.  1b and ingitis. Our findings are in line with a previous study c). MIF concentration was not increased after whole that described high-expression MIF alleles to be asso- blood and PBMC stimulation with LTA, LPS or pneu- ciated with disease severity and death in patients mococci, compared to negative control samples with with pneumococcal meningitis. We found that higher RPMI (Additional file  1: Fig.  1a). However, in whole plasma MIF concentrations during the early phase of blood stimulation experiments patients showed higher disease were predictive for mortality in bacterial men- MIF responses than control subjects for all stimuli ingitis. Our findings are consistent with the harmful (respectively p = 0.031, p = 0.004, p = 0.018, p = 0.042, consequences of robust pro-inflammatory cytokine Fig. 2). Whole blood stimulation showed no differences responses on brain edema and neuronal damage in the in MIF response between patients and control subjects, course of bacterial meningitis [1]. MIF has also shown but MIF concentrations after PBMC stimulation were to be markedly and persistently upregulated and to higher in patients with a worse performance on the be  associated with  increased disease severity and early most affected cognitive domain alertness (Fig. 3 ). death in patients with sepsis [24, 25]. Administration K loek et al. acta neuropathol commun (2021) 9:4 Page 5 of 10 ab c 20000 250 100000 150 0 0 Survived Died *0.009 Fig. 1 Cytokine concentrations at day 0, 1, 2 and 7 of admission and 3 months after admission. A Scatter plot of cytokine concentration in pg/ml of 56 bacterial meningitis episodes. Black lines are medians with interquartile ranges, a MIF, b IL-6, c IL-10. B MIF concentration in pg/ml at day 0, 1, 2 and 7 of admission of survivors versus deceased patients. White bars: survivors, black bars: patients that died during admission. Bars are presented as medians with interquartile ranges (lines in grey) of recombinant MIF protein in a murine sepsis model is currently unknown. In a prospective cohort study, increased mortality following LPS administration [26]. baseline data, including clinical characteristics, and cyto- Several experimental sepsis studies in mice showed biochemical parameters of blood and cerebrospinal fluid that the neutralization of MIF reduced pro-inflamma - between patients with or without cognitive impairment tory cytokine production and organ injury, and thereby after meningitis were similar [14]. In patients with clini- increased the survival rate [21, 27, 28]. Therefore, MIF cal pre-dementia disease stage, MIF has been associ- modulation is an interesting adjunctive therapy to ated with biomarkers of Alzheimer’s disease pathology improve outcome of pneumococcal meningitis. and predicted cognitive impairment [30]. MIF cerebro- Our study shows that individuals with an increased spinal fluid (CSF) levels in even moderately cognitively pro-inflammatory response consisting of a higher MIF impaired subjects were higher compared to participants expression after PBMC stimulation, are at risk for worse with normal cognition [30]. Experimental studies showed cognitive functioning. Previous studies showed that that MIF deficient mice had reduced astrocyte activation pneumococcal meningitis patients were at risk to develop and tau hyperphosphorylation in Alzheimer’s disease cognitive impairment [13–16, 29]. The pathophysiology models [31]. of cognitive impairment after pneumococcal meningitis Day 0 Day 1 Day 2 Day 7 3 months Day 0 Day 1 Day 2 Day 7 3 months Day 0 Day 0 Day 1 Day 1 Day 2 Day 2 Day 7 Day 7 Day 0 Day 1 Day 2 Day 7 3 months MIF concentration MIF concentration pg/ml IL-6 concentration IL-10 concentration Kloek et al. acta neuropathol commun (2021) 9:4 Page 6 of 10 Table 2 Clinical characteristics of the 80 patients with pneumococcal meningitis and 69 controls in the follow up study Characteristics Patients (n = 80) Controls (n = 69) n/N (%) n/N (%) Male 39/80 (49%) 35/69 (51%) Age in years* 63 (56–69) 65 (54–68) Predisposing conditions before admission Duration of symptoms < 24 h 35/79 (44%) Sinusitis/otitis media 44/79 (55%) Pneumonia 10/78 (13%) Immunocompromised state 16/80 (20%) Clinical characteristics on admission Classic triad 35/76 (44%) Coma 4/80 (5%) Focal neurologic deficits 18/79 (23%) Laboratory characteristics on admission* Blood leukocyte count (× 10^9 cells/L) 17.5 (13.3–23.6) CSF leukocyte count (× 10^6 cells/L) 3492 (1298–7805) Standard dose of dexamethasone therapy 69/80 (86%) Clinical course/complications Seizures 12/76 (15%) Circulatory shock 1/73 (1%) Intensive care admission 26/77 (33%) Cerebral infarction 7/69 (9%) Outcome at discharge GOS 3 2/80 (3%) GOS 4 17/80 (21%) GOS 5 61/80 (76%) Years from discharge to testing* 2.5 (1.1—4.6) Median (IQR 25–75) High MIF responsiveness may persist for a long time showing increased MIF production is associated with after the acute disease. Blood MIF levels on admis- Alzheimer disease and mild cognitive impairment sug- sion were not different than those among survivors gesting that MIF is involved in the neuro-inflammatory 3 months after infection, although we did not test MIF process occurring in cognitive decline [36, 37]. One levels in control subjects. However, even years after study has shown MIF can bind to the  amyloid protein, the disease, patients had higher MIF responsiveness on possibly leading to accumulation of amyloid-beta in infectious stimuli compared to controls. A study with Alzheimer disease [38]. patients suffering from sepsis showed consistent results Our study has several limitations. The most impor - with higher ex  vivo MIF release by PBMCs in patients tant limitation is selection bias. First, we did not versus healthy control subjects [32]. Furthermore, sample all patients in the acute phase of disease. Sam- murine models of sepsis have shown low-grade brain ples from early time points were missed because of inflammation persists after recovering from sepsis, sug - informed consent procedures. At later time points gesting a severe infection is able to induce in microglia some patients had died. These two factors led to selec - a primed-like state [33, 34]. The persistent brain inflam - tion bias leading to underrepresentation of the most mation was associated with increased levels of amyloid- severely ill patients. This might have caused an under - beta peptide and long-term cognitive deficits in sepsis estimation of the predictive effect of MIF concentra - survivors [33]. Likewise in patient studies it is known tions. Second, all patients in our prospective study that severe sepsis in the older population is indepen- underwent lumbar puncture. Since lumbar punc- dently associated with substantial and persistent new ture in some cases cannot be done in the most severe cognitive impairments [35]. Although with this study patients, this may also have led to an underestimation we cannot prove  a causal relationship, we hypothesize of the rate of unfavorable outcome and death in our that prolonged MIF upregulation contributes to the cohort. Third, the patients in the follow up study were cognitive impairments of survivors of pneumococcal a selected group of patients with relatively good con- meningitis. This hypothesis is strengthened by studies dition after disease, which could have underestimated K loek et al. acta neuropathol commun (2021) 9:4 Page 7 of 10 a b RPMI LTA * p= 0.031 40000 * p= 0.004 cd S. pneumoniae 6303 S. pneumoniae D39 * p= 0.018 80000 * p= 0.042 Fig. 2 MIF concentration after 24 h whole blood stimulation of patients versus controls. Bars are boxplot with medians and interquartile ranges a after RPMI stimulation of WB of patients 19,459 pg/ml [IQR 15,880–26755] versus that of controls 16,182 pg/ml [IQR 13,334–23006], p = 0.031; b after LTA stimulation of WB of patients 12,461 pg/ml [IQR 10,649–16253] versus that of controls 9932 pg/ml [IQR 7718–12592], p = 0.009; c after S. pneumoniae 6303 stimulation of WB of patients 22,042 pg/ml [IQR 16,505–33155] versus that of controls 18,588 pg/ml [IQR 14,974–23099], p = 0.018; d after S. pneumoniae D39 stimulation of WB of patients 22,889 pg/ml [IQR 16,057–31820] versus that of controls 18,805 pg/ml [IQR 16,063–22865], p = 0.042. See Additional file 1: Figs. 2.1 and 2.2 for IL-6 and IL-10 concentrations after 24 h WB stimulation of patients versus controls (no significant differences) the rate of cognitive impairment, decreasing the study subpopulations for our ex  vivo stimulation experi- power to detect meaningful associations between indi- ments. Stimulation of specific cell population would vidual MIF responsiveness and cognitive impairment. likely have increased our study power, providing more Another limitation is that we did not use specific cell specific information [39]. Interestingly, stimulation Patients Controls Patients Controls Patients Controls Patients Controls MIF (pg/ml) MIF (pg/ml) MIF (pg/ml) MIF (pg/ml) Kloek et al. acta neuropathol commun (2021) 9:4 Page 8 of 10 ab LTA stimulated samples LPS stimulated samples 50000 30000 * p= 0.033 * p= 0.017 0 0 Cognitive testing Cognitive testing cd S. pneumoniae D39 stimulated S. pneumoniae 6303 stimulated samples samples * p= 0.024 * p= 0.025 Cognitive testing Cognitive testing Fig. 3 MIF concentration after 24 h PBMC stimulation versus performance on cognitive testing. MIF concentration in pg/ml after 24 h PBMC stimulation in groups with good performance on cognitive testing (test score ≥ − 1SD) and worse performance on cognitive testing (test score < − 1 SD). a After stimulation with LTA. b After stimulation with LPS. c After stimulation with S. pneumoniae 6306. d After stimulation with S. pneumoniae D39. Grey lines are medians and interquartile ranges. See Additional file 1: Figs. 3.1 and 3.2 for IL-6 and IL-10 concentrations after 24 h PBMC stimulation in groups divided on performance on cognitive testing (no significant differences) ≥ ≥ -1 SD < -1 SD ≥≥ -1 SD < -1 SD ≥ ≥ -1 SD < -1 SD ≥ ≥ -1 SD < -1 SD MIF pg/ml MIF pg/ml MIF pg/ml MIF pg/ml K loek et al. acta neuropathol commun (2021) 9:4 Page 9 of 10 University of Amsterdam, Nieuwe Achtergracht 129 B, 1001 NK Amsterdam, experiments showed consistent results for all stimuli The Netherlands. Department of Epidemiology and Data Science, Amster- which may suggest that our results are robust—at least dam UMC, University of Amsterdam, Amsterdam Public Health, Meibergdreef between different stimuli. 9, 1105 AZ Amsterdam, The Netherlands. Department of Medical Microbiol- ogy and Infection Prevention, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity, Meibergdreef 9, 1105 AZ Amsterdam, Conclusions The Netherlands. Department of Medical Microbiology and Infection Our study shows that high MIF concentrations in the Prevention, The Netherlands Reference Laboratory for Bacterial Meningitis, Amsterdam Infection and Immunity, Meibergdreef 9, 1105 AZ Amsterdam, early phase of acute bacterial meningitis predict poor The Netherlands. Department of Neurology, Amsterdam UMC, University outcome of disease. Furthermore, we found associa- of Amsterdam, Amsterdam Neuroscience, PO Box 22660, 1100DD Amsterdam, tions between high MIF levels and occurrence of cogni- The Netherlands. tive impairment, suggesting MIF contributes to cognitive Received: 3 November 2020 Accepted: 6 December 2020 impairments in pneumococcal meningitis. Both results suggest MIF modulating therapy could be an interest- ing new target to influence outcome of pneumococcal meningitis. References 1. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E (2016) Community-acquired bacterial meningitis. Nat Rev Dis Primers Supplementary Information 2:16074 The online version contains supplementary material available at https ://doi. 2. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community- org/10.1186/s4047 8-020-01100 -7. acquired bacterial meningitis in adults. NEnglJMed 354(1):44–53 3. 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