Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Inter-rater reliability and prognostic value of baseline Radiographic Assessment of Lung Edema (RALE) scores in observational cohort studies of inpatients with COVID-19.

OBJECTIVES: To reliably quantify the radiographic severity of COVID-19 pneumonia with the Radiographic Assessment of Lung Edema (RALE) score on clinical chest X-rays among inpatients and examine the prognostic value of baseline RALE scores on COVID-19 clinical outcomes. SETTING: Hospitalised patients with COVID-19 in dedicated wards and intensive care units from two different hospital systems. PARTICIPANTS: 425 patients with COVID-19 in a discovery data set and 415 patients in a validation data set. PRIMARY AND SECONDARY OUTCOMES: We measured inter-rater reliability for RALE score annotations by different reviewers and examined for associations of consensus RALE scores with the level of respiratory support, demographics, physiologic variables, applied therapies, plasma host-response biomarkers, SARS-CoV-2 RNA load and clinical outcomes. RESULTS: Inter-rater agreement for RALE scores improved from fair to excellent following reviewer training and feedback (intraclass correlation coefficient of 0.85 vs 0.93, respectively). In the discovery cohort, the required level of respiratory support at the time of CXR acquisition (supplemental oxygen or non-invasive ventilation (n=178); invasive-mechanical ventilation (n=234), extracorporeal membrane oxygenation (n=13)) was significantly associated with RALE scores (median (IQR): 20.0 (14.1-26.7), 26.0 (20.5-34.0) and 44.5 (34.5-48.0), respectively, p<0.0001). Among invasively ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, soluble receptor of advanced glycation end-products and soluble tumour necrosis factor receptor 1 (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted HR 1.04 (1.02-1.07), p=0.002). We replicated the significant associations of RALE scores with baseline disease severity and mortality in the independent validation data set. CONCLUSIONS: With a reproducible method to measure radiographic severity in COVID-19, we found significant associations with clinical and physiologic severity, host inflammation and clinical outcomes. The incorporation of radiographic severity assessments in clinical decision-making may provide important guidance for prognostication and treatment allocation in COVID-19.

Is It All COVID-19? Resident Distress and Reasons for It in 2020.

OBJECTIVE: For resident wellness, it is important to understand and discern the relative contributions of each factor to resident stress. METHODS: After institutional review board approval, a 20-question survey instrument was provided to 90 residents across four specialties (Internal Medicine, Emergency Medicine, General Surgery, and Orthopedic Surgery) at a university-affiliated health system. The survey was completed from October through November 2020 by 63 residents for a 70% participation rate. Qualitative and quantitative analyses were used. RESULTS: The results showed a mean change in status in either direction of 2.66 points on an 11-point scale. Status changes were both positive (less stress) and negative (more stress). Related to the source of change in stress levels, 8 items were seen as predominantly influenced by residency training and 11 factors were predominantly influenced by the pandemic. One item was equally influenced by both. No item was primarily influenced by the sociopolitical climate. For 16 of the 20 items, changes in a negative direction were statistically greater than in a positive direction. CONCLUSIONS: Both positive and negative changes in resident stress status occurred during the pandemic period. Traditional residency stressors remained and because all of the factors were affected by both the pandemic and residency training, efforts to mitigate the negative effects of both need to continue.

Radiographic Assessment of Lung Edema (RALE) Scores are Highly Reproducible and Prognostic of Clinical Outcomes for Inpatients with COVID-19.

INTRODUCTION: Chest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs). METHODS: We performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens. RESULTS: We found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, p<0.0001). Among invasively-ventilated patients, RALE scores were significantly associated with worse respiratory mechanics (plateau and driving pressure) and gas exchange metrics (PaO2/FiO2 and ventilatory ratio), as well as higher plasma levels of IL-6, sRAGE and TNFR1 levels (p<0.05). RALE scores were independently associated with 90-day survival in a multivariate Cox proportional hazards model (adjusted hazard ratio 1.04[1.02-1.07], p=0.002). We validated significant associations of RALE scores with baseline severity and mortality in an independent dataset of 415 COVID-19 inpatients. CONCLUSION: Reproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

An observational study on the use of long acting buprenorphine (Sublocade) and a Tamper resistant PICC for Outpatient IV antibiotic administration in Patients with serious infections and Opioid Use Disorder; The STOP OUD project.

What is STOP OUD?: The STOP OUD project is an observational study on the use of long-acting buprenorphine (Sublocade) and a Tamper resistant PICC clamp for Outpatient IV antibiotic administration in Patients with serious infections and Opioid Use Disorder (STOP OUD). Background: The US opioid crisis is driving up serious infections related to intravenous drug use. These infections require prolonged courses of antibiotics, often resulting in lengthy hospital stays. Extended hospitalizations for monitored parenteral antibiotics for patients with opioid use disorder are challenging for patients, reduce bed capacity, and are associated with significant cost. This observational study reviews the administration of intravenous (IV) antibiotics in a monitored outpatient setting using long-acting injectable buprenorphine (Sublocade, Indivior Inc., North Chesterfield, VA) and a tamper resistant clamp in patients with opioid use disorder . Methods: Long-acting buprenorphine and a tamper resistant clamp were used to treat patients with serious infections and opioid use disorder as outpatients. Results: Hospital days avoided were 30-days per STOP OUD project participant. Eleven of thirteen STOP OUD project participants completed their antibiotic courses as prescribed, there was no evidence of peripherally inserted central catheter (PICC) tampering, and they rated their care as a mean of 4.9/5 (SD 0.4). Institutional savings per STOP OUD patient was $33,000. Outpatient infusion costs were $9,300 for a net savings of $23,700 per STOP OUD project participant. Infections resolved in all participants. Conclusions: The STOP OUD project reduced hospital length of stay for patients with opioid use disorder and serious infections, and had a favorable financial impact.

Biosimilars as a Future, Promising Solution for Financial Toxicity: A Review with Emphasis on Bevacizumab.

A biosimilar is a biochemical product like another already approved biologic agent, known as the reference agent. To be endorsed by the Food and Drug Administration (FDA), biosimilars must demonstrate that they are as safe and effective as their reference item, with no clinical distinction. Humanized monoclonal antibodies (mAb) are revolutionizing the treatment of gastrointestinal and gynecologic malignancies. Bevacizumab, trastuzumab, cetuximab, rituximab, and pegfilgrastim are the most widely used mAb products with oncologic indications. Due to the complexities of the regulatory system, it may take time for anti-cancer biosimilars to play a significant game-changing role. Over the last decade, the use of generics has saved billions of dollars every year, and it is expected that biosimilars will soon prove to be a cost-effective alternative and can play an important role in driving down healthcare costs globally. In this review, we provide a critical appraisal of biosimilars with an emphasis on bevacizumab-awwb (Avastin) and its clinico-pharmacologic characteristics, safety, efficacy, interchangeability, regulatory and oncologic perspectives, and overall clinical perception.