Electrophysiological correlates of dentate nucleus deep brain stimulation for post-stroke motor recovery.

While ipsilesional cortical electroencephalography has been associated with post-stroke recovery mechanisms and outcomes, the role of cerebellum and its interaction with the ipsilesional cortex is still largely unknown. We have previously shown that post-stroke motor control relies on increased cortico-cerebellar coherence (CCC) in the low beta band to maintain motor task accuracy and to compensate for decreased excitability of the ipsilesional cortex. We now extend our work to investigate corticocerebellar network changes associated with chronic stimulation of the dentato-thalamo-cortical pathway aimed at promoting post-stroke motor rehabilitation. We investigated the excitability of ipsilesional cortex, dentate (DN), and their interaction as a function of treatment outcome measures. Relative to baseline, ten human participants (two women) at the end of 4-8 months of DN deep brain stimulation (DBS) showed 1) significantly improved motor control indexed by computerized motor tasks; 2) significant increase in ipsilesional premotor cortex event-related desynchronization that correlated with improvements in motor function; and 3) significant decrease in CCC, including causal interactions between the DN and ipsilesional cortex, which also correlated with motor function improvements. Furthermore, we show that the functional state of the DN in the post-stroke state and its connectivity with ipsilesional cortex were predictive of motor outcomes associated with DN-DBS. The findings suggest that as participants recovered, the ipsilesional cortex became more involved in motor control, with less demand on the cerebellum to support task planning and execution. Our data provide unique mechanistic insights into the functional state of cortico-cerebellar-cortical network after stroke and its modulation by DN-DBS.Significance Statement The study aims to understand the brain mechanisms underlying the effects of cerebellar dentate deep brain stimulation (DN-DBS), a novel upcoming therapy for chronic stroke. We provide evidence that functional improvements as a result of DN-DBS therapy were accompanied by significant improvements in task behavior and ipsilesional cortex excitability. More importantly.

The role of dorsolateral striatum in the effects of deep cerebellar stimulation-mediated motor recovery following ischemic stroke in rodents.

Despite great advances in acute care and rehabilitation, stroke remains the leading cause of motor impairment in the industrialized world. We have developed a deep brain stimulation (DBS)-based approach for post-stroke rehabilitation that has shown reproducible effects in rodent models and has been recently translated to humans. Mechanisms underlying the rehabilitative effects of this novel therapy have been largely focused on the ipsilesional cortex, including cortical reorganization, synaptogenesis, neurogenesis and greater expression of markers of long-term potentiation. The role of subcortical structures on its therapeutic benefits, particularly the striatum, remain unclear. In this study, we compared the motor rehabilitative effects of deep cerebellar stimulation in two rodent models of cerebral ischemia: a) cortical ischemia; and b) combined striatal and cortical ischemia. All animals underwent the same procedures, including implantation of the electrodes and tethered connections for stimulation. Both experimental groups received four weeks of continuous lateral cerebellar nucleus (LCN) DBS and each was paired with a no stimulation, sham, group. Fine motor function was indexed using the pasta matrix task. Brain tissue was harvested for histology and immunohistochemical analyses. In the cortical-only ischemia, the average pasta matrix performance of both sham and stimulated groups reduced from 19 to 24 pieces to 7-8 pieces following the stroke induction. At the end of the four-week treatment, the performance of stimulated group was significantly greater than that of sham group (14 pieces vs 7 pieces, p < 0.0001). Similarly, in the combined cortical and striatal ischemia, the performance of both sham and stimulated groups reduced from 29 to 30 pieces to 7-11 pieces following the stroke induction. However, at the end of the four-week treatment, the performance of stimulated group was not significantly greater than that of sham group (15 pieces vs 11 pieces, p = 0.452). In the post-mortem analysis, the number of cells expressing CaMKIIα at the perilesional cortical and striatum of the LCN DBS treated animals receiving cortical-only stroke elevated but not those receiving cortical+striatal stroke. The current findings suggested that the observed, LCN DBS-enhanced motor recovery and perilesional plasticity may involve striatal mechanisms.

Loss of Efficacy in Ventral Intermediate Nucleus Stimulation for Essential Tremor.

OBJECTIVE: The primary aim of this study is to report long-term outcomes associated with deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) performed at our institution. We further aimed to elicit the factors associated with loss of efficacy and to discuss the need for exploring and establishing reliable rescue targets. METHODS: To study long-term outcomes, we performed a retrospective chart review and extracted tremor scores of 43 patients who underwent VIM DBS lead implantation for essential tremor at our center. We further evaluated factors that could influence outcomes over time, including demographics, body mass index, duration of follow-up, degree of parenchymal atrophy indexed by the global cortical atrophy scale, and third ventricular width. RESULTS: In this cohort, tremor scores on the latest follow-up (median 52.7 months) were noted to be worse than initial postoperative scores in 56% of DBS leads. Furthermore, 14% of leads were associated with clinically significant loss of benefit. Factors including the length of time since the lead implantation, age at the time of surgery, sex, body mass index, preoperative atrophy, and third ventricular width were not predictive of long-term outcomes. CONCLUSIONS: Our study identified a substantial subgroup of VIM-DBS patient who experienced a gradual decline in treatment efficacy over time. We propose that this phenomenon can be attributed primarily to habituation and disease progression. Furthermore, we discuss the need to establish reliable and effective rescue targets for this subpopulation of patients, with ventral-oralis complex and dentate nucleus emerging as potential candidates.

A novel restrainer device for acquistion of brain images in awake rats.

Functional neuroimaging methods like fMRI and PET are vital in neuroscience research, but require that subjects remain still throughout the scan. In animal research, anesthetic agents are typically applied to facilitate the acquisition of high-quality data with minimal motion artifact. However, anesthesia can have profound effects on brain metabolism, selectively altering dynamic neural networks and confounding the acquired data. To overcome the challenge, we have developed a novel head fixation device designed to support awake rat brain imaging. A validation experiment demonstrated that the device effectively minimizes animal motion throughout the scan, with mean absolute displacement and mean relative displacement of 0.0256 (SD: 0.001) and 0.009 (SD: 0.002), across eight evaluated subjects throughout fMRI image acquisition (total scanning time per subject: 31 min, 12 s). Furthermore, the awake scans did not induce discernable stress to the animals, with stable physiological parameters throughout the scan (Mean HR: 344, Mean RR: 56, Mean SpO2: 94 %) and unaltered serum corticosterone levels (p = 0.159). In conclusion, the device presented in this paper offers an effective and safe method of acquiring functional brain images in rats, allowing researchers to minimize the confounding effects of anesthetic use.

Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission.

Immune-mediated inflammatory diseases (IMIDs) are typically characterised by relapsing and remitting flares of inflammation. However, the unpredictability of disease flares impedes their study. Addressing this critical knowledge gap, we use the experimental medicine approach of immunomodulatory drug withdrawal in rheumatoid arthritis (RA) remission to synchronise flare processes allowing detailed characterisation. Exploratory mass cytometry analyses reveal three circulating cellular subsets heralding the onset of arthritis flare - CD45RO+PD1hi CD4+ and CD8+ T cells, and CD27+CD86+CD21- B cells - further characterised by single-cell sequencing. Distinct lymphocyte subsets including cytotoxic and exhausted CD4+ memory T cells, memory CD8+CXCR5+ T cells, and IGHA1+ plasma cells are primed for activation in flare patients. Regulatory memory CD4+ T cells (Treg cells) increase at flare onset, but with dysfunctional regulatory marker expression compared to drug-free remission. Significant clonal expansion is observed in T cells, but not B cells, after drug cessation; this is widespread throughout memory CD8+ T cell subsets but limited to the granzyme-expressing cytotoxic subset within CD4+ memory T cells. Based on our observations, we suggest a model of immune dysregulation for understanding RA flare, with potential for further translational research towards novel avenues for its treatment and prevention.

Evaluation of spatial precision and accuracy of cone-beam CT using an in vitro phantom model.

OBJECTIVE: High accuracy and precision are essential in stereotactic neurosurgery, as targeting errors can significantly affect clinical outcomes. Image registration is a vital step in stereotaxis, and understanding the error associated with different image registration methods is important to inform the choice of equipment and techniques in stereotactic neurosurgery. The authors aimed to quantify the test-retest reliability and stereotactic accuracy of cone-beam CT (CBCT) compared with the current clinical gold-standard technique (i.e., CT). METHODS: Two anthropomorphic phantom models with 40 independent unique steel spheres were developed to compare CBCT frame and stereotactic space registration with the clinical gold standard (CT). The cartesian coordinates of each sphere were compared between the imaging modalities for test-retest reliability and overall accuracy. RESULTS: Both imaging modalities showed similar levels of fiducial deviation from the expected geometry. The equivalence test demonstrated mean differences between CT and CBCT registration of -0.082 mm (90% CI -0.27 to 0.11), -0.045 mm (90% CI -0.43 to 0.34), and -0.041 mm (90% CI -0.064 to 0.018) for coordinates in the x-, y-, and z-axes, respectively. The mean euclidean distance difference between the two modalities was 0.28 mm (90% CI 0.27-0.29). CONCLUSIONS: Accuracy and precision were comparable between CBCT and CT image registrations. These findings suggest that CBCT registration can be used as a clinically equivalent substitute to gold-standard CT acquisition.

Paired DBS and TMS Reveals Dentato-Cortical Facilitation Underlying Upper Extremity Movement in Chronic Stroke Survivors.

BACKGROUND: Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement. However, there is a lack of understanding of physiologic influence of DTC in humans, largely due to difficulty in accessing the dentate nucleus. OBJECTIVE: Characterize DTC physiology using dentate nucleus deep brain stimulation (DBS) combined with transcranial magnetic stimulation (TMS) in stroke. METHODS: Nine chronic stroke survivors with moderate-to-severe UE impairment (Fugl-Meyer 13-38) underwent a paired DBS-TMS experiment before receiving experimental dentate nucleus DBS in our first-in-human phase I trial (Baker et al., 2023, Nature Medicine). Conditioning DBS pulses were given to dentate nucleus 1 to 10 ms prior to supra-threshold TMS pulses given to ipsilesional motor cortex. Effects were assessed on motor evoked potentials (MEPs). Size of DBS-conditioned MEPs was expressed relative to TMS MEPs, where values >1 indicate facilitation. RESULTS: Dentate nucleus DBS led to facilitation of MEPs at short-latency intervals (3.5 and 5 ms, P = .049 and .021, respectively), a phenomenon we have termed dentato-cortical facilitation (DCF). Higher DCF was observed among patients with more severe UE impairment. Diffusion tensor imaging revealed microstructure of thalamo-cortical portion of DTC was related to higher corticomotor excitability. CONCLUSIONS: Our in vivo investigation reveals for the first time in humans the intrinsic excitatory properties of DTC, which can serve as a novel therapeutic target for post-stroke motor recovery.

Myogenic and cortical evoked potentials vary as a function of stimulus pulse geometry delivered in the subthalamic nucleus of Parkinson's disease patients.

Introduction: The therapeutic efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) may be limited for some patients by the presence of stimulation-related side effects. Such effects are most often attributed to electrical current spread beyond the target region. Prior computational modeling studies have suggested that changing the degree of asymmetry of the individual phases of the biphasic, stimulus pulse may allow for more selective activation of neural elements in the target region. To the extent that different neural elements contribute to the therapeutic vs. side-effect inducing effects of DBS, such improved selectivity may provide a new parameter for optimizing DBS to increase the therapeutic window. Methods: We investigated the effect of six different pulse geometries on cortical and myogenic evoked potentials in eight patients with PD whose leads were temporarily externalized following STN DBS implant surgery. DBS-cortical evoked potentials were quantified using peak to peak measurements and wavelets and myogenic potentials were quantified using RMS. Results: We found that the slope of the recruitment curves differed significantly as a function of pulse geometry for both the cortical- and myogenic responses. Notably, this effect was observed most frequently when stimulation was delivered using a monopolar, as opposed to a bipolar, configuration. Discussion: Manipulating pulse geometry results in differential physiological effects at both the cortical and neuromuscular level. Exploiting these differences may help to expand DBS' therapeutic window and support the potential for incorporating pulse geometry as an additional parameter for optimizing therapeutic benefit.

Cerebellar deep brain stimulation for chronic post-stroke motor rehabilitation: a phase I trial.

Upper-extremity impairment after stroke remains a major therapeutic challenge and a target of neuromodulation treatment efforts. In this open-label, non-randomized phase I trial, we applied deep brain stimulation to the cerebellar dentate nucleus combined with renewed physical rehabilitation to promote functional reorganization of ipsilesional cortex in 12 individuals with persistent (1-3 years), moderate-to-severe upper-extremity impairment. No serious perioperative or stimulation-related adverse events were encountered, with participants demonstrating a seven-point median improvement on the Upper-Extremity Fugl-Meyer Assessment. All individuals who enrolled with partial preservation of distal motor function exceeded minimal clinically important difference regardless of time since stroke, with a median improvement of 15 Upper-Extremity Fugl-Meyer Assessment points. These robust functional gains were directly correlated with cortical reorganization evidenced by increased ipsilesional metabolism. Our findings support the safety and feasibility of deep brain stimulation to the cerebellar dentate nucleus as a promising tool for modulation of late-stage neuroplasticity for functional recovery and the need for larger clinical trials. ClinicalTrials.gov registration: NCT02835443 .

Number of days required to measure sedentary time and physical activity using accelerometery in rheumatoid arthritis: a reliability study.

This study aimed to determine the minimum number of days required to reliably estimate free-living sedentary time, light-intensity physical activity (LPA) and moderate-intensity physical activity (MPA) using accelerometer data in people with Rheumatoid Arthritis (RA), according to Disease Activity Score-28-C-reactive protein (DAS-28-CRP). Secondary analysis of two existing RA cohorts with controlled (cohort 1) and active (cohort 2) disease was undertaken. People with RA were classified as being in remission (DAS-28-CRP < 2.4, n = 9), or with low (DAS-28-CRP ≥ 2.4-≤ 3.2, n = 15), moderate (DAS-28-CRP > 3.2-≤ 5.1, n = 41) or high (DAS-28-CRP > 5.1, n = 16) disease activity. Participants wore an ActiGraph accelerometer on their right hip for 7 days during waking hours. Validated RA-specific cut-points were applied to accelerometer data to estimate free-living sedentary time, LPA and MPA (%/day). Single-day intraclass correlation coefficients (ICC) were calculated and used in the Spearman Brown prophecy formula to determine the number of monitoring days required to achieve measurement reliability (ICC ≥ 0.80) for each group. The remission group required ≥ 4 monitoring days to achieve an ICC ≥ 0.80 for sedentary time and LPA, with low, moderate and high disease activity groups requiring ≥ 3 monitoring days to reliably estimate these behaviours. The monitoring days required for MPA were more variable across disease activity groups (remission = ≥ 3 days; low = ≥ 2 days; moderate = ≥ 3 days; high = ≥ 5 days). We conclude at least 4 monitoring days will reliably estimate sedentary time and LPA in RA, across the whole spectrum of disease activity. However, to reliably estimate behaviours across the movement continuum (sedentary time, LPA, MPA), at least 5 monitoring days are required.

Intracranial Bleeding in Deep Brain Stimulation Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Deep brain stimulation (DBS) is a neurosurgical treatment used for the treatment of movement disorders. Surgical and perioperative complications, although infrequent, can result in clinically significant neurological impairment. OBJECTIVES: In this study, we evaluated the incidence and risk factors of intracranial bleeding in DBS surgery. METHOD: Medline, EMBASE, and Cochrane were screened in line with PRISMA 2020 guidelines to capture studies reporting on the incidence of hemorrhagic events in DBS. After removing duplicates, the search yielded 1,510 papers. Abstracts were evaluated by two independent reviewers for relevance. A total of 386 abstracts progressed to the full-text screen and were assessed against eligibility criteria. A total of 151 studies met the criteria and were included in the analysis. Any disagreement between the reviewers was resolved by consensus. Relevant data points were extracted and analyzed in OpenMeta [Analyst] software. RESULTS: The incidence of intracranial bleeding was 2.5% (95% CI: 2.2-2.8%) per each patient and 1.4% (95% CI: 1.2-1.6%) per each implanted lead. There was no statistically significant difference across implantation targets and clinical indications. Patients who developed an intracranial bleed were on average 5 years older (95% CI: 1.26-13.19), but no difference was observed between the genders (p = 0.891). A nonsignificant trend was observed for a higher risk of bleeding in patients with hypertension (OR: 2.99, 95% CI: 0.97-9.19) (p = 0.056). The use of microelectrode recording did not affect the rate of bleeding (p = 0.79). CONCLUSIONS: In this review, we find that the rate of bleeding per each implanted lead was 1.4% and that older patients had a higher risk of hemorrhage.

The impact of pulse timing on cortical and subthalamic nucleus deep brain stimulation evoked potentials.

The impact of pulse timing is an important factor in our understanding of how to effectively modulate the basal ganglia thalamocortical (BGTC) circuit. Single pulse low-frequency DBS-evoked potentials generated through electrical stimulation of the subthalamic nucleus (STN) provide insight into circuit activation, but how the long-latency components change as a function of pulse timing is not well-understood. We investigated how timing between stimulation pulses delivered in the STN region influence the neural activity in the STN and cortex. DBS leads implanted in the STN of five patients with Parkinson's disease were temporarily externalized, allowing for the delivery of paired pulses with inter-pulse intervals (IPIs) ranging from 0.2 to 10 ms. Neural activation was measured through local field potential (LFP) recordings from the DBS lead and scalp EEG. DBS-evoked potentials were computed using contacts positioned in dorsolateral STN as determined through co-registered post-operative imaging. We quantified the degree to which distinct IPIs influenced the amplitude of evoked responses across frequencies and time using the wavelet transform and power spectral density curves. The beta frequency content of the DBS evoked responses in the STN and scalp EEG increased as a function of pulse-interval timing. Pulse intervals <1.0 ms apart were associated with minimal to no change in the evoked response. IPIs from 1.5 to 3.0 ms yielded a significant increase in the evoked response, while those >4 ms produced modest, but non-significant growth. Beta frequency activity in the scalp EEG and STN LFP response was maximal when IPIs were between 1.5 and 4.0 ms. These results demonstrate that long-latency components of DBS-evoked responses are pre-dominantly in the beta frequency range and that pulse interval timing impacts the level of BGTC circuit activation.

Neurostimulation for Functional Recovery After Traumatic Brain Injury: Current Evidence and Future Directions for Invasive Surgical Approaches.

We aim to provide a comprehensive review of the current scientific evidence supporting the use of invasive neurostimulation in the treatment of deficits associated with traumatic brain injury (TBI), as well as to identify future directions for research and highlight important questions that remain unaddressed. Neurostimulation is a treatment modality with expanding applications in modern medical practice. Targeted electrical stimulation of specific brain regions has been shown to increase synaptogenesis and enhance structural reorganization of neuronal networks. This underlying therapeutic effect might be of high value for patients suffering from TBI because it could modulate neuronal connectivity and function of areas that are partially or completely spared after injury. The current published literature exploring the application of invasive neurostimulation for the treatment of functional deficits associated with TBI is scarce but promising. Rodent models have shown that targeted stimulation of the hippocampus or connecting structures can result in significant cognitive recovery, while stimulation of the motor cortex and deep cerebellar nuclei is associated with motor improvements. Data from clinical studies are extremely limited; single-patient reports and case series found neurostimulation to be effective in relieving motor symptoms, improving visuospatial memory, and supporting emotional adjustment. Looking forward, it will be important to identify stimulation targets and paradigms that can maximize improvement over multiple functional domains. It will also be important to corroborate the observed behavioral improvements with histological, electrophysiological, and radiological evidence. Finally, the impact of biological variables such as sex and age on the treatment outcomes needs to be explored.

Changes in somatosensory evoked potentials elicited by lateral cerebellar nucleus deep brain stimulation in the naïve rodent.

Deep brain stimulation (DBS) of the deep cerebellar nuclei has been shown to enhance perilesional cortical excitability and promote motor rehabilitation in preclinical models of cortical ischemia and is currently being evaluated in patients with chronic, post-stroke deficits. Understanding the effects of cerebellar DBS on contralateral sensorimotor cortex may be key to developing approaches to optimize stimulation delivery and treatment outcomes. Using the naïve rat model, we characterized the effects of DBS of the lateral cerebellar nucleus (LCN) on somatosensory evoked potentials (SSEPs) and evaluated their potential use as a surrogate index of cortical excitability. SSEPs were recorded concurrently with continuous 30 Hz or 100 Hz LCN DBS and compared to the DBS OFF condition. Ratios of SSEP peak to peak amplitude during 100 Hz LCN DBS to DBS OFF at longer latency peaks were significantly>1, suggesting that cortical excitability was enhanced as a result of LCN DBS. Although changes in SSEP peak to peak amplitudes were observed, they were modest in relation to previously reported effects on motor cortical excitability. Overall, our findings suggest that LCN output influences thalamocortical somatosensory pathways, however further work is need to better understand the potential role of SSEPs in optimizing therapy.

Deep cerebellar stimulation enhances cognitive recovery after prefrontal traumatic brain injury in rodent.

Functional outcome following traumatic brain injury (TBI) varies greatly, with approximately half of those who survive suffering long-term motor and cognitive deficits despite contemporary rehabilitation efforts. We have previously shown that deep brain stimulation (DBS) of the lateral cerebellar nucleus (LCN) enhances rehabilitation of motor deficits that result from brain injury. The objective of the present study was to evaluate the efficacy of LCN DBS on recovery from rodent TBI that uniquely models the injury location, chronicity and resultant cognitive symptoms observed in most human TBI patients. We used controlled cortical impact (CCI) to produce an injury that targeted the medial prefrontal cortex (mPFC-CCI) bilaterally, resulting in cognitive deficits. Unilateral LCN DBS electrode implantation was performed 6 weeks post-injury. Electrical stimulation started at week eight post-injury and continued for an additional 4 weeks. Cognition was evaluated using baited Y-maze, novel object recognition task and Barnes maze. Post-mortem analyses, including Western Blot and immunohistochemistry, were conducted to elucidate the cellular and molecular mechanisms of recovery. We found that mPFC-CCI produced significant cognitive deficits compared to pre-injury and naïve animals. Moreover, LCN DBS treatment significantly enhanced the long-term memory process and executive functions of applying strategy. Analyses of post-mortem tissues showed significantly greater expression of CaMKIIα, BDNF and p75NTR across perilesional cortex and higher expression of postsynaptic formations in LCN DBS-treated animals compared to untreated. Overall, these data suggest that LCN DBS is an effective treatment of cognitive deficits that result from TBI, possibly by activation of ascending, glutamatergic projections to thalamus and subsequent upregulation of thalamocortical activity that engages neuroplastic mechanisms for facilitation of functional re-organization. These results support a role for cerebellar output neuromodulation as a novel therapeutic approach to enhance rehabilitation for patients with chronic, post-TBI cognitive deficits that are unresponsive to traditional rehabilitative efforts.

Outcomes following SARS-CoV-2 infection in patients with primary and secondary immunodeficiency in the UK.

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to the hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir, and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count, and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Clinical frailty, and not features of acute infection, is associated with late mortality in COVID-19: a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess mortality after hospital discharge. Identification of patients at increased risk of death following hospital discharge is needed to guide clinical monitoring and early intervention. Herein, we aimed to identify predictors of early vs. late mortality in COVID-19 patients. METHODS: A total of 471 patients with polymerase chain reaction-confirmed COVID-19 were followed up for 9 months [median (inter-quartile range) of follow-up time: 271 (14) days] after hospital admission. COVID-19-related signs and symptoms, laboratory features, co-morbidities, Coronavirus Clinical Characterisation Consortium (4C) mortality and Clinical Frailty Scale (CFS) scores were analysed by logistic regression for association with early (28 day) vs. late mortality. Receiver operating characteristic (ROC) analysis was used to determine the discriminative value of 4C and CFS scores for early vs. late mortality. RESULTS: A total of 120 patients died within 28 days from hospital admission. Of the remaining 351 patients, 41 died within the next 8 months. Respiratory failure, systemic inflammation, and renal impairment were associated with early mortality, while active cancer and dementia were associated with late mortality, after adjustment for age and sex. 4C mortality score and CFS were associated with both early [odds ratio (OR) (95% confidence interval-CI): 4C: 1.34 (1.25-1.45); CFS: 1.49 (1.33-1.66)] and late [OR (95% CI): 4C: 1.23 (1.12-1.36); CFS: 2.04 (1.62-2.56)] mortality. After adjustment for CFS, the association between 4C and late mortality was lost. By ROC analysis, 4C mortality score was superior to CFS for 28 day mortality [area under the curve (AUC) (95% CI): 0.779 (0.732-0.825) vs. 0.723 (0.673-0.773), respectively; P = 0.039]. In contrast, CFS had higher predictive value for late mortality compared with 4C mortality score [AUC (95% CI): 0.830 (0.776-0.883) vs. 0.724 (0.650-0.798), respectively; P = 0.007]. CONCLUSIONS: In our cohort, late mortality in COVID-19 patients is more strongly associated with premorbid clinical frailty than with severity of the acute infection phase.