Modelling upper respiratory viral load dynamics of SARS-CoV-2

Relationships between viral load, severity of illness, and transmissibility of virus are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with the control of the viral load. Neutralising antibodies correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralising antibodies. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.

Prevalence, characteristics, and predictors of Long COVID among diagnosed cases of COVID-19

Background: Long COVID or long-term complication after COVID-19 has the ability to affect health and quality of life. Knowledge about the burden and predictors could aid in their prevention and management. Most of the studies are from high-income countries and focus on severe cases. We did this study to estimate the prevalence and identify the characteristics and predictors of Long COVID among our patients. Methodology: We recruited adult (≥18 years) patients who were diagnosed as Reverse Transcription Polymerase Chain Reaction (RTPCR) confirmed SARS-COV-2 infection and were either hospitalized or tested on outpatient basis. Eligible participants were followed up telephonically after four weeks of diagnosis of SARS-COV-2 infection to collect data on sociodemographic, clinical history, vaccination history, Cycle threshold (Ct) values during diagnosis and other variables. Characteristic of Long COVID were elicited, and multivariable logistic regression was done to find the predictors of Long COVID. Results: We have analyzed 487 individual data with a median follow-up of 44 days (Inter quartile range (IQR): 39,47). Overall, Long COVID was reported by 29.2% (95% Confidence interval (CI): 25.3%,33.4%) participants. Prevalence of Long COVID among patients with mild/moderate disease (n = 415) was 23.4% (95% CI: 19.5%,27.7%) as compared to 62.5% (95% CI: 50.7%,73%) in severe/critical cases(n=72). The most common Long COVID symptom was fatigue (64.8%) followed by cough (32.4%). Statistically significant predictors of Long COVID were - Pre-existing medical conditions (Adjusted Odds ratio (aOR)=2.00, 95% CI: 1.16,3.44), having a more significant number of symptoms during acute phase of COVID-19 disease (aOR=11.24, 95% CI: 4.00,31.51), two doses of COVID-19 vaccination (aOR=2.32, 95% CI: 1.17,4.58), the severity of illness (aOR=5.71, 95% CI: 3.00,10.89) and being admitted to hospital (Odds ratio (OR)=3.89, 95% CI: 2.49,6.08). Conclusion: A considerable proportion of COVID-19 cases reported Long COVID symptoms. More research is needed in Long COVID to objectively assess the symptoms and find the biological and radiological markers.

Longitudinal assessment of disability amongst patients of bipolar and unipolar depressive disorders presenting to a tertiary care center in North India

Objectives: To assess and compare the changes in disability scores associated with Bipolar Depression (BD) and Unipolar Depression (UD) over 1 year. Methods: A longitudinal study was taken up in adults diagnosed with unipolar or bipolar depressive disorder with current depressive episode. Diagnosis was made according to Schedule for Clinical Assessment in Neuropsychiatry. Severity scoring was done using Hamilton’s Depression (HAM-D) rating scale and Hamilton’s Anxiety (HAM-A) rating scale. Disability was assessed using Indian Disability Evaluation and Assessment Scale (IDEAS) and London handicap Scale (LHS) at baseline, 6 and 12 months. Results: Sixty participants were recruited (42 UD and 18 BD). No significant differences were seen in socio-demographic parameters, except higher education levels and males being overrepresented in UD. Significant differences at baseline were seen in HAM-D ( p = .001) and HAM-A ( p = .003) scores. The extent of disability was seen to correlate with severity of illness only in case of BD at baseline. No significant differences were seen in the IDEAS scores at baseline. IDEAS score improved at each follow-up assessment ( p < .001). LHS showed significant improvement over time in UD ( p < .001), but not BD ( p = .076). Percentage individuals meeting cut-off for benchmark disability (>40%) were comparable at baseline but were significantly more in the BD at 12-months ( p = .049). Conclusion and implications: Disability in psychiatry occurs equally amongst unipolar and bipolar depressive disorders and tends to improve over time, although the level of improvement may differ. It may not always correspond to severity of illness. These factors should be considered while certifying disability.

Prevalence of Inherited Procoagulant States in Cerebral Venous Thrombosis and its Correlation with Severity and Outcome

Background Cerebral venous thrombosis (CVT) is one of the important causes of stroke in young adults. It is caused by complete or partial thrombotic occlusion of the cerebral venous sinuses or cortical veins. There are many risk factors associated with this condition, out of which common ones are oral contraceptives use, genetic, or acquired thrombophilias, infections, malignancy, pregnancy, and puerperium. We aimed to study the prevalence of inherited procoagulant states in patients with CVT and correlate these states with the severity and outcome. Materials and Methods It was a prospective observational study of 2 years duration in which 75 patients, 18 to 50 years old, with confirmed CVT were included. The baseline data, imaging findings were recorded for all the patients. After 3 months of the onset of CVT, anticoagulants were stopped and a procoagulant test was done for all patients. Severity was assessed by Glasgow Coma Score (GCS) at the onset of illness. Functional assessments were done using the modified Rankin Scale (mRS) at presentation, at 7 days, 6 weeks, and 3 months. Results In the present study, any procoagulant state was seen in 9 out of 75 patients with CVT that accounted for 12% of the total population. There was no significant correlation between the presence of procoagulant states and severity of illness as assessed by GCS at presentation. The presence of any thrombophilia did not affect the final outcome at 7 days, 6 weeks or 3 months (p = 0.532, p = 0.944 and p = 0.965 respectively) as assessed by modified Rankin Scale (mRS). Conclusion Inherited procoagulant states are an important risk factor for CVT. The presence of an inherited procoagulant state does not have any correlation with the disease severity and outcome.

Differentiating septic children with and without acute respiratory distress syndrome using proteomics

Both sepsis and acute respiratory distress syndrome (ARDS) rely on imprecise clinical definitions leading to heterogeneity, which has contributed to negative trials. Because circulating protein/DNA complexes have been implicated in sepsis and ARDS, we aimed to develop a proteomic signature of DNA-bound proteins to discriminate between septic children with and without ARDS. We performed a prospective case-control study in twelve septic children with ARDS matched to 12 septic children without ARDS on age, severity of illness score, and source of infection. We performed co-immunoprecipitation and downstream proteomics in plasma collected ≤ 24 hours of intensive care unit admission. Expression profiles were generated, and a random forest classifier was used on differentially expressed proteins to develop a signature which discriminated ARDS. The classifier was tested in six independent blinded samples. Neutrophil and nucleosome proteins were over-represented in ARDS, including two S100A proteins, superoxide dismutase (SOD), and three histones. Random forest produced a 10-protein signature which accurately discriminated between septic children with and without ARDS. This classifier perfectly assigned six independent blinded samples as having ARDS or not. We validated higher expression of the most informative discriminating protein, galectin-3-binding protein, in children with ARDS. Our methodology has applicability to isolation of DNA-bound proteins from plasma. Our results support the premise of a molecular definition of ARDS, and give preliminary insight into why some septic children, but not others, develop ARDS.

Investigating the cognitive capacity constraints of an ICU care team using a systems engineering approach

Background ICU operational conditions may contribute to cognitive overload and negatively impact on clinical decision making. We aimed to develop a quantitative model to investigate the association between the operational conditions and the quantity of medication orders as a measurable indicator of the multidisciplinary care team’s cognitive capacity. Methods The temporal data of patients at one medical ICU (MICU) of Mayo Clinic in Rochester, MN between February 2016 to March 2018 was used. This dataset includes a total of 4822 unique patients admitted to the MICU and a total of 6240 MICU admissions. Guided by the Systems Engineering Initiative for Patient Safety model, quantifiable measures attainable from electronic medical records were identified and a conceptual framework of distributed cognition in ICU was developed. Univariate piecewise Poisson regression models were built to investigate the relationship between system-level workload indicators, including patient census and patient characteristics (severity of illness, new admission, and mortality risk) and the quantity of medication orders, as the output of the care team’s decision making. Results Comparing the coefficients of different line segments obtained from the regression models using a generalized F-test, we identified that, when the ICU was more than 50% occupied (patient census > 18), the number of medication orders per patient per hour was significantly reduced (average = 0.74; standard deviation (SD) = 0.56 vs. average = 0.65; SD = 0.48; p < 0.001). The reduction was more pronounced (average = 0.81; SD = 0.59 vs. average = 0.63; SD = 0.47; p < 0.001), and the breakpoint shifted to a lower patient census (16 patients) when at a higher presence of severely-ill patients requiring invasive mechanical ventilation during their stay, which might be encountered in an ICU treating patients with COVID-19. Conclusions Our model suggests that ICU operational factors, such as admission rates and patient severity of illness may impact the critical care team’s cognitive function and result in changes in the production of medication orders. The results of this analysis heighten the importance of increasing situational awareness of the care team to detect and react to changing circumstances in the ICU that may contribute to cognitive overload.

Impact of Ursodeoxycholic Acid in Critically Ill Patients With Sepsis: A Retrospective Study

Background: Using ursodeoxycholic acid (UDCA) in critically ill patients as adjunctive therapy for sepsis/septic shock in neonates and children is controversial, while it has not been extensively investigated in adults. This study aims to assess the effect of UDCA use on the early resolution of sepsis/septic shock in critically ill adult patients. Method: A retrospective study of critically ill adult patients in the intensive care unit (ICU) admitted with sepsis/septic shock at King Abdulaziz Medical City. Based on their usage of UDCA, patients were categorized into two groups. A total of 88 patients were included for analysis after matching, based on severity of illness scores within 24-hours of ICU admission. The primary outcome was to assess the effect of UDCA on the severity and resolution of shock at day three of ICU admission. The secondary outcomes were 30-day in-hospital mortality, mechanical ventilation (MV) duration, and ICU length of stay (LOS). Results: Out of the 88 patients matched, 44 patients (50%) received UDCA during the study period. Using UDCA was neither associated with improvement in Sequential Organ Failure Assessment (SOFA) score ( p-value: 0.32), inotropes/vasopressors requirement ( p-value: 0.79), Glasgow Coma Scale (GCS) ( p-value: 0.59) nor total bilirubin levels ( p-value: 0.79) at day three compared with the control. There was a significant association between using UDCA and improvement in PaO2/FiO2 ratio ( p-value: 0.01) and early extubation at day three ( p-value: 0.04). Conclusion: Using UDCA in critically ill patients with sepsis/septic shock was not associated with improvement in shock severity and resolution. However, patients who received UDCA were more likely to be extubated and not require MV on day three of ICU admission.

Persistence of live virus in critically ill patients infected with SARS-COV-2: a prospective observational study

Background Research on the duration of infectivity of ICU patients with COVID-19 has been sparse. Tests based on Reverse Transcriptase polymerase chain reaction (RT-PCR) detect both live virus and non-infectious viral RNA. We aimed to determine the duration of infectiousness based on viral culture of nasopharyngeal samples of patients with COVID-19. Methods Prospective observational study in adult intensive care units with a diagnosis of COVID-19 Pneumonia. Patients had repeated nasopharyngeal sampling performed after day 10 of ICU admission. Culture positive rate (based on viral culture on Vero cells in a level 4 lab) and Cycle threshold from RT-PCR were measured. Results Nine patients of the 108 samples (8.3%, 95% CI 3.9–15.2%) grew live virus at a median of 13 days (interquartile range 11–19) after their initial positive test. 74.1% of patients were RT-PCR positive but culture negative, and the remaining (17.6%) were RT-PCR and culture negative. Cycle threshold showed excellent ability to predict the presence of live virus, with a Ct < 25 with an AUC of 0.90 (95% CI 0.83–0.97, p < 0.001). The specificity of a Ct > 25 to predict negative viral culture was 100% (95% CI 70–100%). Conclusion 8.3% of our ICU patients with COVID-19 grew live virus at a median of 13 days post-initial positive RT-PCR test. Severity of illness, use of mechanical ventilation, and time between tests did not predict the presence of live virus. Cycle threshold of > 25 had the best ability to determine the lack of live virus in these patents.

Scoring Systems for Organ Dysfunction and Multiple Organ Dysfunction: The PODIUM Consensus Conference

CONTEXT Multiple scores exist to characterize organ dysfunction in children. OBJECTIVE To review the literature on multiple organ dysfunction (MOD) scoring systems to estimate severity of illness and to characterize the performance characteristics of currently used scoring tools and clinical assessments for organ dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020. STUDY SELECTION Studies were included if they evaluated critically ill children with MOD, evaluated the performance characteristics of scoring tools for MOD, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. DATA EXTRACTION Data were abstracted into a standard data extraction form by a task force member. RESULTS Of 1152 unique abstracts screened, 156 full text studies were assessed including a total of 54 eligible studies. The most commonly reported scores were the Pediatric Logistic Organ Dysfunction Score (PELOD), pediatric Sequential Organ Failure Assessment score (pSOFA), Pediatric Index of Mortality (PIM), PRISM, and counts of organ dysfunction using the International Pediatric Sepsis Definition Consensus Conference. Cut-offs for specific organ dysfunction criteria, diagnostic elements included, and use of counts versus weighting varied substantially. LIMITATIONS While scores demonstrated an increase in mortality associated with the severity and number of organ dysfunctions, the performance ranged widely. CONCLUSIONS The multitude of scores on organ dysfunction to assess severity of illness indicates a need for unified and data-driven organ dysfunction criteria, derived and validated in large, heterogenous international databases of critically ill children.

Vitamin D Deficiency among Children with Sepsis in a Tertiary Care Center in Eastern Nepal

INTRODUCTION: Vitamin D deficiency (VDD) is exceedingly predominant in children leading to dysregulation of the immune system and inflammation. Data on the prevalence of VDD in children with sepsis and its association with sepsis severity are limited from our part of the world. The primary aim of this study was to identify the burden of VDD in children with sepsis. MATERIAL AND METHODS: One hundred and five children (< 15 years) with sepsis were enrolled from April 15, 2017 to April 14, 2018 from a tertiary care center in Eastern Nepal. Demographic data including BMI, sequential organ failure assessment (SOFA) scores were recorded at the time of admission. Plasma 25-hydroxy vitamin D [25(OH)D] levels were measured by chemiluminescence immunoassay technique (CLIA) (MAGLUMI 25-OH Vitamin D; CLIA) within 24 hours of admission. Vitamin D concentrations of <20 ng/mL (50 nmol/L) were considered as deficient. RESULTS: Of the 105 children enrolled, the majority 74 (70.55%) had vitamin D deficiency. Vitamin D was deficient in 77, 65, and 66% of children in 1-5, 5-10, and 10-15 years of age group respectively. Vitamin D deficiency was maximum (80%) in underweight children. In the VDD group, 60% had severe sepsis, whereas only 32% had severe sepsis in vitamin D sufficient group with significant statistical association with sepsis severity and vitamin D deficiency. CONCLUSION: A high burden of VDD is present in children with sepsis which was found to be associated with greater severity of illness.