Higher Clinical Severity Research Articles

Clinical Characterization and Prediction of Clinical Severity of SARS-CoV-2 Infection Among US Adults Using Data From the US National COVID Cohort Collaborative

The National COVID Cohort Collaborative (N3C) is a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative COVID-19 cohort to date. This multicenter data set can support robust evidence-based development of predictive and diagnostic tools and inform clinical care and policy. To evaluate COVID-19 severity and risk factors over time and assess the use of machine learning to predict clinical severity. In a retrospective cohort study of 1 926 526 US adults with SARS-CoV-2 infection (polymerase chain reaction >99% or antigen <1%) and adult patients without SARS-CoV-2 infection who served as controls from 34 medical centers nationwide between January 1, 2020, and December 7, 2020, patients were stratified using a World Health Organization COVID-19 severity scale and demographic characteristics. Differences between groups over time were evaluated using multivariable logistic regression. Random forest and XGBoost models were used to predict severe clinical course (death, discharge to hospice, invasive ventilatory support, or extracorporeal membrane oxygenation). Patient demographic characteristics and COVID-19 severity using the World Health Organization COVID-19 severity scale and differences between groups over time using multivariable logistic regression. The cohort included 174 568 adults who tested positive for SARS-CoV-2 (mean [SD] age, 44.4 [18.6] years; 53.2% female) and 1 133 848 adult controls who tested negative for SARS-CoV-2 (mean [SD] age, 49.5 [19.2] years; 57.1% female). Of the 174 568 adults with SARS-CoV-2, 32 472 (18.6%) were hospitalized, and 6565 (20.2%) of those had a severe clinical course (invasive ventilatory support, extracorporeal membrane oxygenation, death, or discharge to hospice). Of the hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March to April 2020 to 8.6% in September to October 2020 (P = .002 for monthly trend). Using 64 inputs available on the first hospital day, this study predicted a severe clinical course using random forest and XGBoost models (area under the receiver operating curve = 0.87 for both) that were stable over time. The factor most strongly associated with clinical severity was pH; this result was consistent across machine learning methods. In a separate multivariable logistic regression model built for inference, age (odds ratio [OR], 1.03 per year; 95% CI, 1.03-1.04), male sex (OR, 1.60; 95% CI, 1.51-1.69), liver disease (OR, 1.20; 95% CI, 1.08-1.34), dementia (OR, 1.26; 95% CI, 1.13-1.41), African American (OR, 1.12; 95% CI, 1.05-1.20) and Asian (OR, 1.33; 95% CI, 1.12-1.57) race, and obesity (OR, 1.36; 95% CI, 1.27-1.46) were independently associated with higher clinical severity. This cohort study found that COVID-19 mortality decreased over time during 2020 and that patient demographic characteristics and comorbidities were associated with higher clinical severity. The machine learning models accurately predicted ultimate clinical severity using commonly collected clinical data from the first 24 hours of a hospital admission.

A reappraisal of the presence of small or large fiber neuropathy in patients with erythromelalgia

ObjectiveTo assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). MethodsThirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). ResultsWhile 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. ConclusionPeripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. SignificanceThe association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype.

Association of serum uric acid with clinical and radiological severity of knee osteoarthritis in non-gouty patients

BackgroundA growing body of evidence suggested that uric acid (UA) may contribute in the pathways underlying osteoarthritis (OA) pathogenesis; however, studies that investigated the relationship between UA and OA emerged inconclusive results. The purpose of the study was to explore the association of serum uric acid (sUA) levels with clinical severity, radiological severity of knee osteoarthritis (KOA) based on Kellgren-Lawrence (KL) grading system, and MRI changes in non-gouty patients.ResultsWOMAC scores: pain, stiffness, function, and total score are significantly higher in H-sUA group than L-sUA group (p = 0.004, p = 0.019, p = 0.018, p = 0.008 respectively). Joint space width (JSW) is significantly narrower in H-sUA group than L-sUA group (p = 0.013). H-sUA group had more frequent KL grade 4 (p < 0.001), osteophytes grade 4 (p < 0.001), focal bone erosion (p < 0.001), bone marrow lesions (p = 0.023), and synovitis (p = 0.011) than L-sUA group. Female KOA patients in H-sUA group had significantly higher pain, stiffness, and function and total WOMAC scores than L-sUA group (p = 0.003, p = 0.015, p = 0.008, p = 0.004), more frequently had KL grade 4 and osteophytes grade 4 (p = 0.003, p < 0.001), significantly narrower JSW (p = 0.016), more frequently show focal bone erosion (p = 0.002), bone marrow lesions (p = 0.019), and synovitis (p = 0.004) than L-sUA group. In regression analysis, female sex (p = 0.035), duration of KOA (p = 0.031), and sUA level (p = 0.025) were associated with KL severity. For female patients with KOA, KL severity is associated with duration of KOA (p = 0.045) and sUA (p = 0.009).ConclusionHigher sUA level is associated with higher clinical severity, higher radiographic KL grades, and more frequent MRI findings in patients with primary KOA patients. Our results also indicated that sUA level was significantly associated with KOA severity in female patients, but not in male patients. More studies are warranted to explore whether the two conditions exist simultaneously or there is a direct causal relationship between the two conditions.

The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19: An Observational Study

The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19: An Observational Study

Premature Atrial Contractions and Their Association with Stroke Features and Outcome

BackgroundFrequent premature atrial contractions (PACs) are associated with atrial fibrillation, stroke, and mortality. However, the cut-off value for PAC counts that could identify patients with different stroke features is unclear, and the association of PACs to outcome is not determined. MethodsThe study retrospectively included patients with acute ischemic stroke who had underwent both a 24 h Holter recording and a brain MRI in Taipei Veterans General Hospital from January 2015 to May 2016. Patients were categorized into four groups according to their PAC frequencies on 24 h Holter recording. We compared the clinical severity, neuroimage features, stroke subtypes, and functional outcome among the four groups of patients. ResultsAmong the 278 patients, the lower, middle, and upper quartiles of the PAC counts were 23, 74, and 459.5, respectively. In contrast to the 1st quartile of patients, the 3rd (PAC 75-459/24 h) and the 4th (PAC ≥460/24 h) quartiles of patients had higher NIH Stroke Scale (NIHSS) at admission (p = 0.014 and p = 0.002, respectively). The frequencies of cryptogenic stroke were not different among the 4 quartiles of the patients, but cryptogenic stroke patients with ≥ 75PACs/24hours had higher stroke severity compared to those with PACs < 75counts/24 h (NIHSS 9.1 vs. 5.2, p = 0.043). There was an increased trend in infarcts of multiple vascular territories and in mortality at 1 year among the four groups of patients with increased PAC frequency (p = 0.045 and p = 0.002, respectively). The 4th PAC quartile was associated with poor functional outcome (modified Rankin Scale ≥ 4) at 3 months in univariate analysis (OR: 5.66, CI: 2.69–11.91, p < 0.001), but was not an independent predictor after controlling for initial stroke severity. ConclusionsPACs ≥ 75 counts/24 h was associated with higher clinical severity in patients with acute ischemic stroke.

Emerging Resistance of Gram Negative Pathogens in Community-Acquired Pneumonia.

In recent decades, there has been a growing interest about the role of gram negative bacteria in community-acquired pneumonia (CAP), especially Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. The prevalence of these pathogens differs largely according to the local ecology and the geographical location. Identifying gram negative bacteria, and in particular resistant gram negative bacteria, is of paramount importance in patients with CAP because these pathogens are associated with higher clinical severity and unfavorable outcomes. The use of individualized risk factors to predict each pathogen is a helpful strategy that needs to be locally validated. However, it should be taken into account that most of the risk factors identified in the literature are heterogeneously defined or lack consistency. New diagnostic techniques, such as molecular testing, are promising methods for early detection of these gram negative pathogens. The increasing mechanisms of resistance to antibiotics of these pathogens have limited our therapeutic approach. This narrative review focuses on the epidemiology, risk factors, diagnosis, and therapeutic options for the most relevant gram negative bacteria that cause CAP.

S21. CORRELATES AND TRANSITION RATE OF CHILDREN AND ADOLESCENTS WITH ATTENUATED PSYCHOTIC SYMPTOMS: FINDINGS FROM A LONGITUDINAL STUDY

BackgroundThe identification of people at high risk of developing psychosis is one of the most promising strategies to improve outcomes. However, in children and adolescents research on the high risk state and attenuated psychotic symptoms is still in its infancy and the clinical validity of at risk criteria appears understudied in this population (Tor et al. 2018). Thus, in this longitudinal cohort study, we aimed to: (1) characterize the clinical profile of APS adolescents, adolescents suffering from early onset psychosis (EOP) and adolescents with psychiatric disorders other than APS and EOP (non-APS) and (2) to calculate the cumulative transition rate to psychosis at follow-ups and investigate predictors of conversion to psychosis.MethodsHelp-seeking adolescents (aged 12–18 years) consecutively admitted to Child and Adolescent Neuropsychiatric inpatient and outpatient units of the IRCCS Mondino Foundation (Pavia, Italy) were recruited. The Comprehensive Assessment of At-Risk Mental State (CAARMS) was used in order to evaluate the presence of attenuated or full-blown psychotic symptoms. The final sample consisted of 31 EOP, 110 APS and 102 non-APS adolescents. At baseline patients underwent an extensive clinical and, in a subset, also neuropsychological assessment using standardized semi-structured interviews and instruments. All APS patients recruited until March 2019 were followed up for a median period of 33 months (range 4–81 months) and baseline measures were repeated (every 12 months). Transition to psychosis was defined according to the CAARMS criteria.ResultsAt baseline, APS status was associated with poor socio-occupational functioning, especially social functioning (p<0.0001), as well as clinical severity (p<0.0001) as assessed by clinicians. APS adolescents reported a higher level of suicidality compared to non-APS (p=0.0003). The APS group displayed a higher number of comorbid disorders compared to the EOP and non-APS (p<0.0001) and was related to a wide range of disorders. APS and non-APS adolescents did not significantly differ in any of the neuropsychological test administered, although a worsening trend was observed between the two groups with lower scores in APS adolescents. The cumulative proportion of psychosis transition in the APS group was 13%, 17%, 24.2% and 26.8% at 1,2,3 and 4-year follow-ups, respectively. A high percentage of APS patients received at least one psychotropic medication (62.1%) during the follow-up period, especially antipsychotics (43.7%). Baseline lower global and social functioning (p=0.0092), higher clinical severity (p<0.0001), negative symptoms, lower Total IQ (p=0.02) and Processing Speed Index (p=0.03) were associated with transitioning to psychosis at follow-ups.DiscussionOur findings support the validity and clinical relevance of the identification of APS in children and adolescents. Indeed, in our sample APS adolescents suffer from a variety of comorbidities and non-psychotic symptoms, present higher suicidality and are markedly impaired compared to non-psychotic adolescents not fulfilling APS criteria. Moreover, they show a cumulative transition risk to psychosis of 26.8% at 4 years that, although being lower than that found in adult samples, is still comparable to that of other conditions in preventive medicine.

Contributing Factors to the Clinical and Economic Burden of Patients with Laboratory-Confirmed Carbapenem-Nonsusceptible Gram-Negative Urinary Tract Infections.

PurposeWe explored patient- and hospital-level predictor variables for worse clinical and economic outcomes in carbapenem-nonsusceptible urinary tract infections (UTIs).Patients and MethodsWe used electronic data (January 2013–September 2015; 78 US hospitals) from a large multicenter clinical database. Nonduplicate gram-negative isolates were considered carbapenem-nonsusceptible if they had resistant/intermediate susceptibility. Potential predictors of outcomes (mortality, 30-day readmissions, length of stay [LOS], hospital total cost, and net gain/loss per case) were examined using generalized linear mixed models. Significant predictors were identified based on statistical significance and model goodness-of-fit criteria.ResultsA total of 1439 carbapenem-nonsusceptible urine cases were identified. The mortality rate was 5.5%; the hospital readmission rate was 25.0%. Mean (standard deviation [SD]) LOS, total cost, and loss per case were 12 (14) days, $21,502 ($37,172), and $5828 ($26,540), respectively. Hospital-onset (vs community-onset) infection significantly impacted all outcomes: mortality (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.19–4.11; P=.01), 30-day readmissions (OR, 2.35; 95% CI, 1.49–3.71; P<.001), LOS (25.7 vs 10.2 days; P<.001), hospital total cost ($67,810 vs $22,141; P<.001), and loss per case (–$28,054 vs –$10,809; P<.001). Mechanical ventilation/intensive care unit status, neoplasms, and other underlying diseases were also common predictors for worse outcomes overall; polymicrobial infection was significantly associated with worse economic outcomes. Other key predictors were >1 prior hospitalization for 30-day readmissions, high Acute Laboratory Risk of Mortality Score for mortality, LOS, cost, and hospital teaching status for cost.ConclusionHospital-onset infections, polymicrobial infections, higher clinical severity, and underlying diseases are key predictors for worsened overall burden of carbapenem-nonsusceptible gram-negative UTIs.

Contributing Factors to the Clinical and Economic Burden of Patients with Laboratory-Confirmed Carbapenem-Nonsusceptible Gram-Negative Respiratory Infections.

PurposeThis study examined patient- and hospital-level predictor variables that contribute to worse clinical and economic outcomes in patients with carbapenem-nonsusceptible respiratory infections.Patients and MethodsElectronic data (January 2013 to September 2015) were from 78 US hospitals. Nonduplicate, gram-negative respiratory isolates were considered carbapenem-nonsusceptible if they tested resistant/intermediate to imipenem, meropenem, doripenem, or ertapenem. Potential predictors of outcomes (in-hospital mortality, 30-day readmission, length of stay [LOS], hospital total cost, and net gain/loss per patient) were examined using univariate analysis and generalized linear mixed models. Statistical significance and model goodness-of-fit criteria were used to identify significant predictors.ResultsA total of 1488 carbapenem-nonsusceptible respiratory patients were identified. Overall, the mortality rate was 13.7%, 30-day readmission rate was 20.6%, mean LOS was 20 days, mean total cost was $54,158, and mean net loss was $139 per patient. Our models showed that hospital-onset infection, higher clinical severity, mechanical ventilation/intensive care unit status, polymicrobial infection, and underlying diseases were all significant predictors for mortality, LOS, and total cost. Hospital-onset infections were also associated with a significantly greater net loss (P≤.01), and underlying disease significantly impacted readmissions (P=.03). The number of prior admissions, hospital characteristics, and payer type were also found to significantly impact measured outcomes.ConclusionCarbapenem-nonsusceptible respiratory infections are associated with a considerable clinical and economic burden. The impact of hospital-onset infections on both clinical and economic outcomes highlights the continued need for action on this modifiable risk factor through antimicrobial stewardship and optimal therapy, thereby reducing the burden in this patient population.

Soluble vascular endothelial-cadherin in CSF after subarachnoid hemorrhage.

To determine if CSF and plasma levels of soluble vascular endothelial (sVE)-cadherin are associated with functional outcome after subarachnoid hemorrhage (SAH) and to investigate sVE-cadherin effects on microglia. Serial CSF and plasma were collected from prospectively enrolled patients with nontraumatic SAH from a ruptured aneurysm in the anterior circulation and who required an external ventricular drain for clinical indications. Patients with normal-pressure hydrocephalus without SAH served as controls. For prospective assessment of long-term outcomes at 3 and 6 months after SAH, modified Rankin Scale scores (mRS) were obtained and dichotomized into good (mRS ≤ 2) vs poor (mRS > 2) outcome groups. For SAH severity, Hunt and Hess grade was assessed. Association of CSF sVE-cadherin levels with long-term outcomes, HH grade, and CSF tumor necrosis factor (TNF)-α levels were evaluated. sVE-cadherin effects on microglia were also studied. sVE-cadherin levels in CSF, but not in plasma, were higher in patients with SAH and were associated with higher clinical severity and higher CSF TNF-α levels. Patients with SAH with higher CSF sVE-cadherin levels over time were more likely to develop worse functional outcome at 3 months after SAH. Incubation of cultured microglia with sVE-cadherin resulted in increased inducible nitric oxide synthase, interleukin-1β, reactive oxygen species, cell soma size, and metabolic activity, consistent with microglia activation. Microinjection of sVE-cadherin fragments into mouse brain results in an increased number of microglia surrounding the injection site, compared to injection of denatured vascular endothelial-cadherin fragments. These results support the existence of a novel pathway by which sVE-cadherin, released from injured endothelium after SAH, can shift microglia into a more proinflammatory phenotype and contribute to neuroinflammation and poor outcome in SAH.

Interaction of atrial fibrillation and antithrombotics on outcome in intracerebral hemorrhage.

To analyze the clinical differences between patients with primary intracerebral hemorrhage (ICH) with and without atrial fibrillation (AF) and assess whether the effect of the antithrombotic pretreatment on outcome is modified by the presence of AF. In this prospective observational study, researchers from 2 university hospitals included 1,106 consecutive patients with ICH. Clinical characteristics were described and stratified by presence of AF. In-hospital and 3-month mortality and 3-month disability were analyzed, considering antithrombotic pretreatment (none, antiplatelets, or oral anticoagulants) and AF (yes/no). AF was present in 21.9% of primary ICH cases. Patients with AF-ICH were older, with more vascular risk factors, more antithrombotic pretreatment, higher clinical severity, higher hematoma volume, and higher in-hospital and 3-month mortality. Do-not-resuscitate orders were applied more frequently in AF-ICH cases. After 2 different adjustment models, mortality remained significantly higher in patients with AF-ICH. However, after introducing previous antithrombotic treatment in the model, the adjusted odds ratio for 3-month mortality was 1.45 (95% confidence interval 0.74-2.85, p = 0.284) for patients with AF-ICH compared with non-AF cases. AF modified the effect of antithrombotic pretreatment on in-hospital (p int = 0.077) and 3-month mortality (p int = 0.008). Among patients without AF, antithrombotic pretreatment increased mortality; no effect was observed in patients with AF-ICH. Patients with AF and ICH had increased mortality; however, AF had no independent effect on mortality after adjustment for antithrombotic pretreatment. Conversely, antithrombotic pretreatment had a deleterious effect on outcome in patients with ICH without AF, but no detectable effect in patients with AF with ICH.

A variant of the castor zinc finger 1 (CASZ1) gene is differentially associated with the clinical classification of chronic venous disease

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27–1.34, P = 1 × 10−98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD.

Reduced synchronized brain activity in schizophrenia during viewing of comedy movies

Previous evaluation of brain function in schizophrenia has focused on standard experimental tasks, with cerebral response to natural stimuli less clear. This study employed inter-subject correlation (ISC) analysis to investigate the neural basis of humor processing during free viewing of comedy movies in patients with schizophrenia. We recruited 29 patients diagnosed with schizophrenia and 29 healthy, age- and sex-matched controls. Each participant underwent fMRI scanning during two viewings of three comedy movie clips. The ISC map from each participant pair within each population group and each movie viewing was separately derived. The significance of ISC within a group and between two groups were assessed by bootstrapping. The ISC map from each patient pair were also correlated with the product of Positive and Negative Syndrome Scale (PANSS) rating between the same participant pair in schizophrenia patients. Schizophrenia patients showed significant ISC in bilateral lateraloccipital, bilateral superior frontal, left supramarginal, and right lateralorbiofrontal cortices. Compared with the controls, the schizophrenia group exhibited significantly lower ISC in the left superior temporal sulcus, bilateral supramarginal, and bilateral inferiorparietal cortices. Higher clinical severity (higher total PANSS rating) was associated with lower ISC in the middle frontal and middle temporal regions, and also higher ISC in the visual cortex, inferior temporal gyrus, and anterior cingulate. The findings indicated that patients with schizophrenia are characterized by lower ISC in a frontal parietal network while viewing comedy film clips, which implicated a deficit in the cognitive component of humor processing. The lower synchronization in parts of the frontal parietal network also correlated with symptom severity.

Transdiagnostic variations in impulsivity and compulsivity in obsessive-compulsive disorder and gambling disorder correlate with effective connectivity in cortical-striatal-thalamic-cortical circuits

Individual differences in impulsivity and compulsivity is thought to underlie vulnerability to a broad range of disorders and are closely tied to cortical-striatal-thalamic-cortical function. However, whether impulsivity and compulsivity in clinical disorders is continuous with the healthy population and explains cortical-striatal-thalamic-cortical dysfunction across different disorders remains unclear. Here, we characterized the relationship between cortical-striatal-thalamic-cortical effective connectivity, estimated using dynamic causal modelling of resting-state functional magnetic resonance imaging data, and dimensional phenotypes of impulsivity and compulsivity in two symptomatically distinct but phenotypically related disorders, obsessive-compulsive disorder and gambling disorder. 487 online participants provided data for modelling of dimensional phenotypes. These data were combined with 34 obsessive-compulsive disorder patients, 22 gambling disorder patients, and 39 healthy controls, who underwent functional magnetic resonance imaging. Three core dimensions were identified: disinhibition, impulsivity, and compulsivity. Patients’ scores on these dimensions were continuously distributed with the healthy participants, supporting a continuum model of psychopathology. Across all participants, higher disinhibition correlated with lower bottom-up connectivity in the dorsal circuit and greater bottom-up connectivity in the ventral circuit, and higher compulsivity correlated with lower bottom-up connectivity in the dorsal circuit. In patients, higher clinical severity was also linked to lower bottom-up connectivity in the dorsal circuit, but these findings were independent of phenotypic variation, demonstrating convergence towards behaviourally and clinically relevant changes in brain dynamics. Effective connectivity did not differ as a function of traditional diagnostic labels and only weak associations were observed for functional connectivity measures. Together, our results demonstrate that cortical-striatal-thalamic-cortical dysfunction across obsessive-compulsive disorder and gambling disorder may be better characterized by dimensional phenotypes than diagnostic comparisons, supporting investigation of quantitative liability phenotypes.

Thyroid Function and Autoimmune Indications in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Objective: Previous studies have shown that functional abnormalities of the thyroid are associated with the pathogenesis of several neurological diseases. However, their relationship in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis remains to be defined. Methods: Forty-three patients with anti-NMDAR encephalitis were examined for thyroid function and autoimmune indications, in comparison with 225 healthy controls (CTL). Patients were further classified into 2 subgroups based on their free tri-iodothyronine (fT3) levels. Moreover, fT3 levels were also investigated after at least three months of follow-up. The clinical characteristics of the patients and CTL were described in detail. Results: Serum levels of fT3 and thyroid-stimulating hormone (TSH) were found to be relatively lower in patients with anti-NMDAR encephalitis than in CTL (both p < 0.001). Low T3 syndrome also occurred more frequently in anti- NMDAR encephalitis (25.6 vs. 0.4%, p < 0.001). However, no statistical differences were detected between patients and CTL in terms of the positive rate of thyroid antibodies and other types of thyroid dysfunction. Patients with low T3 levels tended to have a longer hospital stay (p = 0.006), a higher rate of abnormal brain magnetic resonance imaging (MRI) findings (p = 0.033), a higher frequency of consciousness declination (p = 0.029), and a higher modified Rankin scale (mRS) score during hospitalization. Low fT3 levels were also associated with abnormal MRI findings, a decline in consciousness, and the mRS score on admission. In addition, fT3 seemed to gradually return to normal levels upon improvement of the mRS score (r = –0.649, p = 0.002). Conclusions: Low T3 syndrome often copresents in anti-NMDAR encephalitis and indicates a longer hospitalization, abnormal MRI findings, consciousness declination, and a higher clinical severity. However, fT3 levels do not seem to influence the prognosis of anti-NMDAR encephalitis.

2356 The nasopharyngeal microbiome is perturbed and associated with increased clinical severity during acute respiratory viral infection

OBJECTIVES/SPECIFIC AIMS: We sought to investigate the role of the host microbiome during severe, acute respiratory infection (ARI) to understand the drivers of both acute clinical pathogenesis. METHODS/STUDY POPULATION: Nasopharyngeal swabs comprised of mixed cell populations at the active site of infection were collected from 192 hospitalized pediatric patients with ARI. We combined comprehensive respiratory virus detection and virus genome sequencing with 16S rRNA gene sequencing to evaluate the microbial content of the airway during ARI. This data was coupled with 11 clinical parameters, which were compiled to create a clinical severity score. The microbiome profiles were assessed to determine if clinical severity of infection, and/or specific virus was associated with increased clinical severity. RESULTS/ANTICIPATED RESULTS: We identified 8 major microbiome profiles classified by dominant bacterial genus, Moraxella, Corynebacterium, Staphylococcus, Haemophilus, Streptococcus, Alloiococcus, Schlegelella, and Diverse. Increased clinical severity was significantly associated with microbiome profiles dominated by Haemophilus, Streptococcus, and Schlegelella, whereas Corynebacterium and Alloiococcus were more prevalent in children with less severe disease. Independent of the microbial community, more than 60% of patients with the highest clinical severity were infected with either respiratory syncytial virus or rhinovirus. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that individually and in combination, both virus and microbial composition may drive clinical severity during acute respiratory viral infections. It is still unclear how the complex interplay between virus, bacterial community, and the host response influence long-term respiratory impacts, such as the development of asthma. Nonetheless, during ARIs therapeutic interventions such as antibiotics and probiotics may be warranted in a subset of patients that are identified to have both a virus and microbiome profile that is associated with increased pathogenesis to limit both acute and long-term phenotypes.

Systematic model of peripheral inflammation after subarachnoid hemorrhage.

To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models. This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: <24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously. Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity. Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Adult-onset Hydroa Vacciniforme: A Rare Occurrence or a Lymphoma Premonition?

Sir, Hydroa vacciniforme (HV) is a photodermatosis affecting children and adolescents, with papulovesicular eruptions and varioliform scars on face and other photoexposed parts.[1] Classically, the presentation is during childhood, though very rarely late onset cases have been described.[2] A subset of cutaneous T cell lymphoma, designated as HV-like lymphoma (HVLL) has also been described, which closely mimics HV.[3] A 42-year-old male patient, farmer by occupation, reported to dermatology outpatient department with history of severe burning sensation and swelling limited to face and scalp on sun exposure. This was followed by painful skin eruptions, which further progressed to become fluid filled within 3 to 5 days, followed by brown coloured scab formation and eventually depressed scars. The patient has been experiencing similar recurrent episodes since last 8 years, from February to August every year. The patient reported mild malaise and lethargy during vesicular phase of illness, but no other symptoms like fever or chills, burning in eyes, arthralgia, weight loss, easy fatiguability, bruising tendency, abdominal discomfort, or features suggestive of lymphoproliferative etiology. There was no family history of similar illness and patient denied intake of any photosensitizing drug. On cutaneous examination, few erythematous papulovesicles 0.2 cm to 0.4 cm in size with overlying crust were noted on right cheek [Figure 1]. Both cheeks and scalp also showed multiple brown to black-colored scabs, 0.5 cm to 1.2 cm in size [Figure 2]. Multiple well-defined, depressed, and varioliform scars ranging from 0.2 cm to 1.5 cm [Figure 1] were present on forehead, cheeks, nose, and scalp. No cervical, axillary or inguinal lymphadenopathy, and hepatosplenomegaly was noted. Cytological smears and blood samples were negative for human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV). Urine samples showed no fluorescence on Wood's lamp examination and urinary and fecal porphyrin levels were within normal limits. The hemogram, peripheral blood smear, ultrasonography of abdomen and lymph nodes revealed no abnormality. A provisional diagnosis of discoid lupus erythematosus (DLE), adult-onset HV, and HVLL was arrived at and a lesional skin biopsy was obtained. Biopsy revealed intracellular edema, basal cell vacoulization, and areas of necrosis in epidermis along with mixed neutrophilic and lymphocytic dermal infiltrate [Figure 3]. There were no atypical lymphocytes or viral inclusion bodies. The immunohistochemical (IHC) studies were negative for T-cell lymphoma (CD8 and CD56). These findings were consistent with the primary diagnosis of HV. Immunofluoresence for antinuclear antibody (ANA) was negative.Figure 1: Erythematous papulovesicles and multiple depressed varioliform scars of varying size on right cheekFigure 2: Brown-colored scabs with multiple varioliform scars on left cheekFigure 3: Hematoxylin and eosin (H and E) stain of biopsy from papulovesicle showing epidermal edema, basal and suprabasal cell vacuolization and keratinocyte necrosis (depicted by black arrow) (×10)The patient was advised strict photoprotection and oral hydroxychloroquine (400 mg/day) with beta-carotene supplements. On follow-up visits at 3 and 6 weeks, patient was experiencing lesser number of episodes with decreased clinical severity. The original description of HV has been credited to Bazin, though it was confused with erythropoietic protoporphyria in those reports.[4] The disease typically affects children and adolescents as a phototoxic rash and remits by early adulthood. Typically exacerbations are noted in spring to summer season due to higher proportion of UVA rays reaching earth during this time of year. HV is sometimes confused with HVLL due to similarities in clinical presentation and age group affected. However, HVLL is typically associated with EBV infection, higher clinical severity and disfigurement, involvement of non-photoexposed parts, e.g., scalp and trunk, as well as systemic complications.[5] Unlike HV, HVLL lesions are not induced by sun exposure and do not tend to resolve with age. Involvement of scalp in our patient did not correlate with HV because dense scalp hair normally provides considerable photoprotection, hence creating a suspicion of HVLL. This; however, could possibly be due to the occupation of patient which mandates prolonged sun exposure in open spaces, hence increasing the dose of photoexposure and clinical severity. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Readmission for Acute Exacerbation within 30 Days of Discharge Is Associated with a Subsequent Progressive Increase in Mortality Risk in COPD Patients: A Long-Term Observational Study.

Background and ObjectiveTwenty per cent of chronic obstructive pulmonary disease (COPD) patients are readmitted for acute exacerbation (AECOPD) within 30 days of discharge. The prognostic significance of early readmission is not fully understood. The objective of our study was to estimate the mortality risk associated with readmission for acute exacerbation within 30 days of discharge in COPD patients.MethodsThe cohort (n = 378) was divided into patients readmitted (n = 68) and not readmitted (n = 310) within 30 days of discharge. Clinical, laboratory, microbiological, and severity data were evaluated at admission and during hospital stay, and mortality data were recorded at four time points during follow-up: 30 days, 6 months, 1 year and 3 years.ResultsPatients readmitted within 30 days had poorer lung function, worse dyspnea perception and higher clinical severity. Two or more prior AECOPD (HR, 2.47; 95% CI, 1.51–4.05) was the only variable independently associated with 30-day readmission. The mortality risk during the follow-up period showed a progressive increase in patients readmitted within 30 days in comparison to patients not readmitted; moreover, 30-day readmission was an independent risk factor for mortality at 1 year (HR, 2.48; 95% CI, 1.10–5.59). In patients readmitted within 30 days, the estimated absolute increase in the mortality risk was 4% at 30 days (number needed to harm NNH, 25), 17% at 6-months (NNH, 6), 19% at 1-year (NNH, 6) and 24% at 3 years (NNH, 5).ConclusionIn conclusion a readmission for AECOPD within 30 days is associated with a progressive increased long-term risk of death.

Comparison of age-specific hospitalization during pandemic and seasonal influenza periods from 2009 to 2012 in Taiwan: a nationwide population-based study

BackgroundDetermining the age-specific hospitalization burden associated with seasonal influenza and the (H1N1) 2009 pandemic is important for the development of effective vaccine strategies and clinical management. The aim of this study was to investigate age-specific differences in hospitalization rates during the pandemic and seasonal periods.MethodsUsing the Taiwan National Health Insurance Research Database (NHIRD), we identified hospitalized patients with a principle discharge diagnosis of influenza-related infection (ICD-9-CM 487) between 2009 and 2012.ResultsBased on the time distribution of influenza-related hospitalizations and previously reported epidemic periods, the first and second waves of the (H1N1) 2009 pandemic (p1 is known as 2009.07-2010.01, and p2 is known as 2010.12-2011.03) and three seasonal periods (s1 is known as 2010.03-2010.11, s2 is known as 2011.10-2012.03, and s3 is known as 2012.04-2012.10) were found. During these five periods, children younger than 7 years of age consistently had the highest hospitalization rate of the studied age groups. In individuals younger than 50 years of age, the seasonal periods were associated with a significantly lower risk of hospitalization than that of p1 (Relative risk (RR) range = 0.18–0.85); however, they had a significantly higher hospitalization risk for adults over 50 years of age (RR = 1.51–3.22). Individuals over 50 years of age also had a higher intensive care unit admission rate and case fatality ratio than individuals under than 50 years of age during the seasonal periods and especially during the pandemic periods.ConclusionsIn both pandemic and seasonal periods, the highest hospitalization rate was observed for children younger than 7 years of age. Adults over 50 years of age had a higher hospitalization risk during the seasonal periods and a higher clinical severity during the pandemic periods. Those results emphasize that the importance of influenza-related prevention strategies in the younger and older age groups, either seasonal or pandemic periods.