Reliable and responsive tools for monitoring disease activity and treatment outcomes in patients with neuropathies are lacking. With the emergence of ultrasensitive blood bioassays, proteins released ...with nerve damage are potentially useful response biomarkers for many neurological disorders, including polyneuropathies. In this review, we provide an overview of the existing literature focusing on potential applications in polyneuropathy clinical care and trials. Whilst several promising candidates have been identified, no studies have investigated if any of these proteins can serve as response biomarkers of longitudinal disease activity, except for neurofilament light (NfL). For NfL, limited evidence exists supporting a role as a response biomarker in Guillain-Barré syndrome, vasculitic neuropathy, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Most evidence exists for NfL as a response biomarker in hereditary transthyretin-related amyloidosis (hATTR). At the present time, the role of NfL is therefore limited to a supporting clinical tool or exploratory endpoint in trials. Future developments will need to focus on the discovery of additional biomarkers for anatomically specific and other forms of nerve damage using high-throughput technologies and highly sensitive analytical platforms in adequality powered studies of appropriate design. For NfL, a better understanding of cut-off values, the relation to clinical symptoms and long-term disability as well as dynamics in serum on and off treatment is needed to further expand and proceed towards implementation.
ICU-acquired weakness is thought to mediate physical impairments in survivors of critical illness, but few studies have investigated this thoroughly. The purpose was to investigate differences in ...post-ICU mortality and physical functioning between patients with and without ICU-acquired weakness at 6 months after ICU discharge.
ICU patients, mechanically ventilated ≥ 2 days, were included in a single-center prospective observational cohort study. ICU-acquired weakness was diagnosed when the average Medical Research Council score was <4 in awake and attentive patients. Post-ICU mortality was recorded until 6 months after ICU discharge; in surviving patients, physical functioning was assessed using the Short-Form Health Survey physical functioning domain. The independent effect of ICU-acquired weakness on post-ICU mortality was analyzed using a multivariable Cox proportional hazards model. The independent effect of ICU-acquired weakness on the physical functioning domain score was analyzed using a multivariable linear regression model.
Of the 156 patients included, 80 had ICU-acquired weakness. Twenty-three patients died in the ICU (20 with ICU-acquired weakness); during 6 months follow-up after ICU discharge another 25 patients died (17 with ICU-acquired weakness). Physical functioning domain scores were available for 96 survivors (39 patients with ICU-acquired weakness). ICU-acquired weakness was independently associated with an increase in post-ICU mortality (hazard ratio 3.6, 95% confidence interval, 1.3 to 9.8; P = 0.01) and with a decrease in physical functioning (β: -16.7 points; 95% confidence interval, -30.2 to -3.1; P = 0.02).
ICU-acquired weakness is independently associated with higher post-ICU mortality and with clinically relevant lower physical functioning in survivors at 6 months after ICU discharge.
Causes of Mortality in ICU-Acquired Weakness van Wagenberg, Linda; Witteveen, Esther; Wieske, Luuk ...
Journal of intensive care medicine,
03/2020, Letnik:
35, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Background:
Intensive care unit–acquired weakness (ICU-AW) is a common complication of critical illness and is associated with increased mortality, longer mechanical ventilation and longer hospital ...stay. Little is known about the causes of mortality in patients with ICU-AW. In this study, we aimed to give an overview of the causes of death in a population diagnosed with ICU-AW during hospital admission.
Methods:
Data from a prospective cohort study in the mixed medical–surgical ICU of the Academic Medical Center in Amsterdam were used. Patients were included when mechanically ventilated for more than 48 hours. Intensive care unit–acquired weakness was defined as a mean medical research council score <4. Baseline data and data on the time of death were collected.
Results:
Fifty-three patients were included. Irreversible shock with multiple organ failure (MOF) was the most common cause of death (28/53 of patients; 26 patients with septic shock and 2 patients with hypovolemic shock). Most common site of sepsis was abdominal (38.5%) and pulmonary (19.2%). On admission to the ICU, 53% had a do-not-resuscitate code. In 74% of the patients, further treatment limitations were implemented during their ICU stay.
Conclusion:
In this cohort of patients with ICU-AW, most patients died of irreversible shock with MOF, caused by sepsis.
Purpose
There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at ...admission (< 24 h) to the intensive care unit.
Methods
From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients. In a subgroup (
n
= 335), blood leukocyte transcriptomes were compared between the sources. Differences in clinical patient profiles and survival were compared in the whole sepsis cohort (
n
= 2019).
Results
The plasma biomarker cohort was categorized into sepsis originating from the respiratory tract (
n
= 334, 53.8%), abdomen (
n
= 159, 25.6%), urinary tract (
n
= 44, 7.1%), cardiovascular (
n
= 41, 6.6%), central nervous system (CNS) (
n
= 18, 2.9%), or skin (
n
= 25, 4%). This analysis revealed stronger inflammatory and cytokine responses, loss of vascular integrity and coagulation activation in abdominal sepsis relative to respiratory. Endothelial cell activation was prominent in urinary, cardiovascular and skin infections, while CNS infection was associated with the least host response aberrations. The leukocyte transcriptional response showed the largest overlap between abdominal and pulmonary infections (76% in common); notable differences between the sources were detected regarding hemostasis, cytokine signaling, innate and adaptive immune, and metabolic transcriptional pathways. After adjustment for confounders, the source of infection remained an independent contributor to 30-day mortality (unadjusted
p
= 0.001, adjusted
p
= 0.028).
Conclusion
Sepsis heterogeneity is partly explained by source-specific host response dysregulations and should be considered when selecting patients for trials testing immune modulatory drugs.
The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated ...with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HCs) before and 7 days after the first and second vaccination. OCR-treated MS patients exhibit a preserved recall response of CD8.sup.+ T central memory cells following first vaccination compared to HCs and a similar CD4.sup.+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2-specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4.sup.+ and CD8.sup.+ T cells. Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients may still benefit from vaccination by inducing a broad CD8.sup.+ T cell response which has been associated with milder disease outcome. The delayed vaccine-induced IgG kinetics in RA-MTX patients indicate an increased risk after the first vaccination, which might require additional shielding or alternative strategies such as treatment interruptions in vulnerable patients.
Axonal damage in chronic inflammatory demyelinating polyneuropathy (CIDP) is the main predictor of poor outcome. We hypothesized that serum neurofilament light chain (sNfL) reflects disease activity ...by detecting ongoing neuro‐axonal damage in CIDP. Three prospective cohorts of CIDP patients were studied: (a) patients starting induction treatment (IT cohort, N = 29) measured at baseline and 6 months after starting treatment; (b) patients on maintenance treatment (MT) starting intravenous immunoglobuline (IVIg) withdrawal (MT cohort, N = 24) measured at baseline and 6 months after IVIg withdrawal or at time of relapse; and (c) patients in long‐term remission without treatment (N = 27). A single molecule array assay was used to measure sNfL. Age‐matched healthy controls (N = 30) and age‐specific reference values were used for comparison. At baseline, sNfL was higher in patients starting IT compared to healthy controls. Ten out of 29 IT (34%) patients have sNfL levels above the 95th percentile of age‐specific cut‐off values. In the MT and remission cohort, elevated sNfL levels were infrequent and not different from healthy controls. sNfL levels were correlated with electrophysiological markers of axonal damage. At follow‐up assessment, patients with active disease (non‐responders and patients who relapsed after IVIg withdrawal) had higher sNfL levels compared with patients with stable disease (responders and patients who were successfully withdrawn from IVIg treatment). sNfL levels were increased in a third of CIDP patients starting IT and reflected axonal damage. sNfL levels might be usable as biomarker of disease activity in a subset of CIDP patients.
To investigate whether patients who develop ICU-acquired weakness have a different pattern of systemic inflammatory markers compared with critically ill patients who do not develop ICU-acquired ...weakness.
Prospective observational cohort study.
Mixed medical-surgical ICU of a tertiary care hospital in the Netherlands.
Newly admitted critically ill patients, greater than or equal to 48 hours on mechanical ventilation with a nonneurologic ICU admission diagnosis, were included.
A panel of systemic inflammatory markers and soluble vascular adhesion molecules were measured in plasma samples of day 0, 2, and 4 after ICU admission. ICU-acquired weakness was diagnosed by manual muscle strength testing as soon as patients were awake and attentive.
Ninety-nine of 204 included patients developed ICU-acquired weakness. Principal component regression analysis, adjusted for confounders, showed that principal component 1, mainly loaded with interleukin-6, interleukin-8, interleukin-10, and fractalkine, was significantly higher in patients who developed ICU-acquired weakness (odds ratio, 1.35 95% CI, 1.18-1.55). Partial least squares-discriminant analysis also showed that these markers were the most important discriminative markers. Mixed-effects models of these markers showed that ICU-acquired weakness was associated with an independent 1.5- to two-fold increase in these markers.
Systemic inflammation is increased in patients who develop ICU-acquired weakness compared with patients who do not develop ICU-acquired weakness in the first 4 days after ICU admission. This finding is consistent when adjusted for confounders, like disease severity. A group consisting of interleukin-6, interleukin-8, interleukin-10, and fractalkine was identified to be the most important.
Background:
Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS).
Objective:
To study serum contactin-1 (sCNTN1) as a novel biomarker for ...disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients.
Methods:
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria.
Results:
Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) (p = 0.017) for progression during follow-up.
Conclusion:
Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.
Background
Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin–angiotensin system (RAS) are responsible for observed differences in ...epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS.
Methods
In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days–18 years), 26 adults (18–65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid.
Results
Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups.
Conclusions
Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.
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