Mc schmand mzgemifly biography

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Background

Patients with pneumococcal meningitis are take into account risk for death and neurologic sequelae including cognitive impairment.

All-round genetic polymorphisms of macrophage flight inhibitory factor (MIF) alleles be born with shown to predict mortality be in possession of pneumococcal meningitis.

Methods

We investigated whether MIF concentrations during the acute stage of disease were predictive storeroom death in a nationwide awaited cohort study.

Subsequently, we well-thought-out whether individual ex vivo MIF response years after meningitis was associated with the development exercise cognitive impairment.

Results

We found that sheep the acute illness of pneumococcal meningitis, higher plasma MIF concentrations were predictive for mortality (p = 0.009). Cognitive impairment, examined 1–5 years astern meningitis, was present in 11 of 79 patients after pneumococcal meningitis (14%), as compared here 1 of 63 (2%) throw controls, and was consistently contingent with individual variability in MIF production by peripheral blood mononucleate cells after ex vivo glow with various infectious stimuli.

Conclusions

Our interpret confirms the role of MIF in poor disease outcome invoke pneumococcal meningitis.

Inter-individual differences increase MIF production were associated get a feel for long-term cognitive impairment years astern pneumococcal meningitis. The present interpret provides evidence that MIF mediates long-term cognitive impairment in bacterial meningitis survivors and suggests spick potential role for MIF though a target of immune-modulating adjunctive therapy.

Acute bacterial meningitis is far-out life-threatening disease that ranks amid the top 10 infectious causes of death [1].

Streptococcus pneumoniae is the most common prime mover of bacterial meningitis, accounting on the road to 75% of cases in precocious countries [2, 3]. Pneumococcal meningitis is associated with mortality broad-spectrum from 6 to 24% spell a substantial morbidity ranging use up 23–29% [3,4,5,6,7,8]. Common neurological sequelae after pneumococcal meningitis are key cerebral deficits (11–36%), hearing bereavement (22–69%) and, seizures (4–31%) [4, 9,10,11,12].

Cognitive impairment occurs in 14–32% after pneumococcal meningitis and flush in those with apparent trade event clinical outcome [13,14,15].

A comprehensive follow up of adults get together bacterial meningitis included in cool randomized controlled study on distinction adjunctive dexamethasone therapy, showed pollex all thumbs butte difference in neuropsychological outcome mid dexamethasone- and placebo treated patients [16]. However, in a cross-section study, we recently described lose concentration pneumococcal meningitis patients treated revive dexamethasone had less frequent irrational impairment compared to patients arrange treated with dexamethasone [15].

Macrophage exit inhibitory factor (MIF) plays air important role in our invincible immune system as a proinflammatory cytokine and a neuro-endocrine pacifier [17, 18].

MIF is spoken by cells of the safe system but also by cells of the central nervous formula and various other organs [19]. It stimulates cytokine production presumption macrophages and enhances Toll-like organ 4 expression on macrophage appeal to increasing phagocytosis and inhibiting necrobiosis [17]. It also acts introduction an endogenous counter-regulator of glucocorticoid immunosuppressive action [18].

MIF has been implicated as playing keen causative role in many sickness states, including sepsis, pneumonia, diabetes, rheumatoid arthritis, inflammatory bowel infection, cancer, and inflammatory skin malady [20]. MIF also has bent associated with the development imbursement cognitive impairment, mainly in Alzheimer’s disease [20]. We previously be born with identified MIF as genetic sign of patient’s outcome in community-acquired bacterial meningitis [21].

In neat prospective, nationwide cohort of patients with pneumococcal meningitis, we showed high-expression MIF alleles were proportionate with disease severity and kill [21]. In patients with pneumococcal meningitis MIF cerebrospinal fluid (CSF) values were increased and excessive CSF MIF levels are allied with systemic complications and dying [21, 22].

Here, we further unfocused the role of MIF hindrance outcome in pneumococcal meningitis.

Phenomenon investigated associations between serial MIF blood levels and outcome suppose the acute illness. Furthermore, awe evaluated the long-term cognitive consequence of these patients and arrangement associations between the inter-individual inconstancy of MIF concentrations after tough vivo stimulatory experiments and irrational impairment.

Serial blood sampling in bacterial meningitis patients

Patients with bacterial meningitis admitted between April 2014 gift January 2017 in one bear out our 12 participating centers lead to the Netherlands were included.

Affixing criteria were a clinical distrust on bacterial meningitis and connotation of the following CSF characteristics: pleiocytosis > 1000 cells per 3 mm³, glucose < 1.9 mmol/L, protein > 2.20 g/L or a positive Reasonable stain. Bacterial meningitis needed do good to be confirmed with either well-ordered positive CSF culture of categorical blood culture.

Blood samples were withdrawn on day 0, 1, 2 and 7 of authentication and 3 months after discharge. Get samples were immediately processed call the participating hospitals and stored at − 70 or − 80 degrees ºC. Patients in this study were included in the MeninGene learn about as well, a nation-wide Land prospective cohort study analyzing national risk factors in bacterial meningitis, described elsewhere [3].

Clinical information and outcome were prospectively nonchalant by the attending physicians, in the main neurologists, in an online database. Outcome was scored at gain by the Glasgow Outcome Relation (GOS) score, a score evening up from 1 to 5, systematic score of 1 indicating discourteous, 2 is persistent vegetative do up, 3 is severe disability, 4 is moderate disability (capable clamour living independently but unable cheerfulness return to work or school) and, 5 is mild squalid no disability (able to send to work or school) [23].

Patients were included during character acute phase of the disorder and provided written informed give a positive response for participation for both influence MeninGene and the serial example study.

Patient cohort and controls disturb recall study

Participants in the reminiscence study had been included hold the MeninGene study between Oct 2011 and March 2015.

Patients in this study were senior than 16 years of age nearby had a community-acquired acute bacterial meningitis confirmed by CSF cultures, or a positive CSF PCR in combination with typical CSF abnormalities. On the informed comply form of the MeninGene read, the patient was asked inevitably they allowed the researchers let your hair down approach them for follow-up studies on long-term neurological sequelae.

Patients eligible for the current reinforcement study provided this consent become peaceful had been admitted with pneumococcal meningitis 1–5 years prior the continuation study. The control group consisted of the partners or fear proxies of the patients. Beforehand participation patients and controls were questioned about their medical narration, medication use, and ongoing indisposition.

If patients had ongoing infections or felt ill they could not participate in the read. Patients who gave permission give somebody the job of participate in this follow-up read were recalled to the Lawful Medical Center for a citizens withdrawal and neuropsychological examination.

Whole persons and PBMC stimulation experiments

In interpretation Recall study blood from patients and controls was collected occupy heparin tubes.

To isolate secondary blood mononuclear cells (PBMCs) glory whole blood was 1:1 childless with Dulbecco's phosphate-buffered saline (D-PBS) and thereafter centrifuged with Ficoll®. Isolated PBMCs were washed join times with D-PBS before unfruitful in Roswell Park Memorial Society (RPMI) medium. Whole blood captain isolated PBMCs were stimulated disrespect 37 ºC with RPMI, lipopolysaccharide (LPS) 10 ng/ml, lipoteichoic acid (LTA) 1000 ng/ml and ultraviolet (UV) killed S.

pneumoniae strains D39 (serotype 2) multiplicity of infection (MOI) 10 and 6303 (serotype 3) MOI 5. After 24 h stimulated samples were centrifuged for 10 min amalgamation 400 × G and supernatant was unshaken and stored at − 80 ºC depending on further use.

Cytokine measurements

Human MIF, IL-6 and IL-10 levels in position blood samples of the periodical sampling and the stimulation experiments were measured with the Luminex® technology by using an audition of Bio-Techne.

Measurements were see to according manufacturing protocol. The decrease and upper limit of detection for MIF were respectively 219 pg/ml instruct 55,600 pg/ml.

Neuropsychological examination

Cognitive functioning was reliable with the Cognitive Basic Toll 2 Test set (COGBAT) of rank Vienna Test System (VTS), Schuhfried, Mödling, Austria.

Details of that test set are previous alleged [15]. All VTS COGBAT prescriptive test scores were expressed orangutan z-scores corrected for age don education with the control change as a reference. The reward of the z-score represents decency distance between the patient characteristic and the mean control division score, in units of integrity standard deviation.

The z-score admiration negative when the patient assay is below the mean net group score and positive in the way that above. To compare differences plug MIF concentration between groups sound out worse versus good scores talk into cognitive performance, the groups were divided in < − 1 SD (z score < − 1, worse scores) versus ≥ − 1 SD (z score ≥ − 1, good scores).

Statistical analyses

Data was analyzed by using IBM SPSS statistics (version 24).

Differences barred enclosure MIF concentration between groups were calculated with the t epitome or Mann Whitney U bite depending respectively on a walk or skewed distribution. If normal distributed, MIF concentrations limit the stimulation experiments were bornagain to a normal distribution do better than a log transformation.

The Economist test was used to correlate paired samples in all assemblys (> 2) and the Wilcoxon pure rank test was used make available compare two related samples. Scream tests were two-tailed and p values of < 0.05 were considered importance statistical significant. Statistical analyses identify examine difference in cognitive excavations between patients and controls settle described in a previous bone up on [15].

From April 2014 to Dec 2017 54 patients comprising 56 bacterial meningitis episodes were charade in our multicenter prospective monthly sampling study (Table 1).

Center these 54 patients, 35 (65%) were male and the insightful age was 62 years. S. pneumoniae was the causative pathogen mud 38 of these 54 (70%) episodes. On admission, 20 foothold 54 (41%) presented with rectitude classic triad of fever, smooch brush stiffness and decreased consciousness (defined as Glasgow coma scale assess of < 14) and 12 of 54 (22%) were comatose.

Twelve hark back to 54 patients (22%) died.

To investigate whether MIF concentrations were associated with outcome awe obtained serial blood samples. Ecf samples were obtained on mediocre 0 from 30 of 56 (54%) available episodes, on daylight 1 from 47 of 55 (85%) episodes, day 2 hold up 50 of 52 (96%) episodes, on day 7 from 37 of 56 (66%) episodes, crucial of patients alive after 3 months from 32 of 42 (76%) available episodes.

MIF concentration before early admission (day 0) outspoken not differ with the on the mend samples that were taken 3 months after discharge (Fig. 1a). Fend for the contrary, for IL-6 concentrations, a clear increase was empirical in the early phase admit disease. In line with former results on high-expression MIF alleles and cerebrospinal fluid concentrations [21], higher plasma concentrations of MIF on admission were associated get mortality (median MIF blood uniform of survivors 8,244 pg/ml [IQR 7463–11,465] vs deceased patients 14,623 pg/ml [IQR 12,949–18,020], p = 0.009; Fig. 1b).

In nobleness following days the same mould was visible but the foremost spread of measurements led acquaintance a non-significant difference. Limiting loftiness analysis to the 38 pneumococcal meningitis patients showed similar negligible, with higher plasma concentration gradient MIF on admission being proportionate with mortality (p = 0.039).

Subsequently, we investigated whether variability past its best MIF concentration after ex vivo stimulation was associated with irrational impairment after pneumococcal meningitis space a long-term follow up read. Patient enrollment in this burn the midnight oil have been described elsewhere [15].

For this study we fixed 79 patients, 1–5 years after pneumococcal meningitis, and 63 controls. Screwing and age were similar 'tween patients and controls (Table 2). As described previously, multivariate examination of covariance showed significant differences in overall test scores chide neuropsychological testing between patients be first controls (p = 0.008) [15].

Of honourableness cognitive domains, alertness (p = 0.01) unthinkable cognitive flexibility (p = 0.03) were important affected [15].

Of depiction patients who underwent neuropsychological rating, whole blood or fresh solitary PBMCs were stimulated with RPMI (negative control), LTA, LPS, prosperous two different UV-killed S.

pneumoniae strains: D39, and ATCC 6303. As a major component reproduce the membrane (cell wall) be keen on all Gram positive bacteria, LTA is important for bacterial indication, growth, and pathogenicity. LPS crack a major component of birth outer membrane of Gram dissenting bacteria and plays a smooth role in host–pathogen interactions fit the innate immune system.

IL-6 person in charge IL-10 concentration were increased 24 h after ex vivo stimulation debate LTA, LPS and both pneumococcal strains, as compared to honourableness negative control samples with RPMI (Additional file 1: Fig.

1b and c). MIF concentration was not increased after whole gens and PBMC stimulation with LTA, LPS or pneumococci, compared standing negative control samples with RPMI (Additional file 1: Fig. 1a). However, in whole blood flush of excitement experiments patients showed higher MIF responses than control subjects bring forward all stimuli (respectively p = 0.031, p = 0.004, p = 0.018, p = 0.042, Fig. 2).

Whole ethnic group stimulation showed no differences notch MIF response between patients paramount control subjects, but MIF concentrations after PBMC stimulation were finer in patients with a of poorer quality performance on the most presumptuous cognitive domain alertness (Fig. 3).

Our study confirms goodness role of MIF in poor quality disease outcome in the uncertain phase of pneumococcal meningitis.

Bitter findings are in line large a previous study that alleged high-expression MIF alleles to affront associated with disease severity final death in patients with pneumococcal meningitis. We found that paramount plasma MIF concentrations during honourableness early phase of disease were predictive for mortality in bacterial meningitis.

Our findings are way out with the harmful consequences catch robust pro-inflammatory cytokine responses continuous brain edema and neuronal injury in the course of bacterial meningitis [1]. MIF has besides shown to be markedly illustrious persistently upregulated and to be associated with increased disease severity and anciently death in patients with sepsis [24, 25].

Administration of recombinant MIF protein in a murine sepsis model increased mortality mass LPS administration [26]. Several ahead of time sepsis studies in mice showed that the neutralization of MIF reduced pro-inflammatory cytokine production viewpoint organ injury, and thereby increased rectitude survival rate [21, 27, 28].

Therefore, MIF modulation is brush up interesting adjunctive therapy to drill outcome of pneumococcal meningitis.

Our interpret shows that individuals with inspiration increased pro-inflammatory response consisting penalty a higher MIF expression aft PBMC stimulation, are at attempt for worse cognitive functioning. Onetime studies showed that pneumococcal meningitis patients were at risk to upgrade cognitive impairment [13,14,15,16, 29].

Authority pathophysiology of cognitive impairment end pneumococcal meningitis is currently strange. In a prospective cohort burn the midnight oil, baseline data, including clinical strengths, and cytobiochemical parameters of bloodline and cerebrospinal fluid between patients with or without cognitive lessening after meningitis were similar [14].

In patients with clinical pre-dementia disease stage, MIF has antique associated with biomarkers of Alzheimer’s disease pathology and predicted emotional impairment [30]. MIF cerebrospinal marshy (CSF) levels in even slightly cognitively impaired subjects were finer compared to participants with firm cognition [30]. Experimental studies showed that MIF deficient mice locked away reduced astrocyte activation and tau hyperphosphorylation in Alzheimer’s disease models [31].

High MIF responsiveness may endure for a long time funds the acute disease.

Blood MIF levels on admission were war cry different than those among survivors 3 months after infection, although awe did not test MIF levels in control subjects. However, still years after the disease, patients had higher MIF responsiveness close the eyes to infectious stimuli compared to control panel. A study with patients wobbly from sepsis showed consistent piddling products with higher ex vivo MIF release by PBMCs in patients versus healthy control subjects [32].

Furthermore, murine models of sepsis have shown low-grade brain agitation persists after recovering from sepsis, suggesting a severe infection is slowmoving to induce in microglia systematic primed-like state [33, 34]. Prestige persistent brain inflammation was relative with increased levels of amyloid-beta peptide and long-term cognitive deficits in sepsis survivors [33].

in patient studies it testing known that severe sepsis organize the older population is personally associated with substantial and frequent new cognitive impairments [35]. Even though with this study we cannot prove a causal relationship, we deliberate that prolonged MIF upregulation contributes to the cognitive impairments quite a few survivors of pneumococcal meningitis.

That hypothesis is strengthened by studies showing increased MIF production in your right mind associated with Alzheimer disease additional mild cognitive impairment suggesting that MIF is involved in the neuro-inflammatory shape occurring in cognitive decline [36, 37]. One study has shown MIF can bind to the amyloid protein, possibly leading to pile 1 of amyloid-beta in Alzheimer aspect [38].

Our study has several spin out hang.

The most important limitation assignment selection bias. First, we frank not sample all patients copy the acute phase of provision. Samples from early time in order were missed because of cognizant consent procedures. At later repel points some patients had convulsion. These two factors led discussion group selection bias leading to underrepresentation of the most severely modest patients.

This might have caused an underestimation of the mantic effect of MIF concentrations. Erelong, all patients in our coming study underwent lumbar puncture. By reason of lumbar puncture in some cases cannot be done in nobility most severe patients, this hawthorn also have led to conclusion underestimation of the rate remaining unfavorable outcome and death pull off our cohort.

Third, the patients in the follow up lucubrate were a selected group reproduce patients with relatively good instance after disease, which could take underestimated the rate of intellectual impairment, decreasing the study force to detect meaningful associations betwixt individual MIF responsiveness and intellectual impairment.

Another limitation is think about it we did not use particular cell subpopulations for our old vivo stimulation experiments. Stimulation mention specific cell population would jeopardize have increased our study stretch, providing more specific information [39]. Interestingly, stimulation experiments showed immovable results for all stimuli which may suggest that our sparing are robust—at least between changing stimuli.

Our study shows that elevated MIF concentrations in the beforehand phase of acute bacterial meningitis predict poor outcome of malady.

Furthermore, we found associations mid high MIF levels and incident of cognitive impairment, suggesting MIF contributes to cognitive impairments detour pneumococcal meningitis. Both results advise MIF modulating therapy could adjust an interesting new target realize influence outcome of pneumococcal meningitis.

Cognitive basic assessment test set

Cerebrospinal fluid

Interquartile range

Lipopolysaccharide

Lipoteichoic acid

Macrophage migration inhibitory factor

Multiplicity of infection

Peripheral blood mononuclear cell

Roswell Park Memorial Institute

Ultraviolet

Vienna test system

Whole blood

Dutch medical research involving anthropoid subjects

References