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Although vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been successful, there are no good treatments for those who are actively infected. While SARS-CoV-2 primarily infects the respiratory tract, clinical evidence indicates that cells from sensory organs and the brain are also susceptible to infection. While many patients suffer from diverse neurological symptoms, the viruss neuronal entry remains mysterious. To discover host factors involved in SARS-CoV-2 viral entry, we performed CRISPR activation (CRISPRa) screens targeting all 6000+ human membrane proteins in cells with and without overexpression of ACE2 using Spike-pseudotyped lentiviruses. This unbiased gain-of-function screening identified both novel and previously validated host factors. Notably, newly found host factors have high expression in neuronal and immune cells, including potassium channel KCNA6, protease LGMN, and MHC-II component HLA-DPB1. We validated these factors using replication-competent SARS-CoV-2 infection assays. Notably, the overexpression of KCNA6 led to a marked increase in infection even in cells with undetectable levels of ACE2 expression. Analysis of human olfactory epithelium scRNA-seq data revealed that OLIG2+/TUJ1+ cells--previously identified as sites of infection in COVID-19 autopsy studies-- have high KCNA6 expression and minimal levels of ACE2. The presence of KCNA6 may thus explain sensory/neuronal aspects of COVID-19 symptoms. Further, we demonstrate that FDA-approved compound dalfampridine, an inhibitor of KCNA-family potassium channels, suppresses viral entry in a dosage-dependent manner. Finally, we identified common prescription drugs likely to modulate the top identified host factors, and performed a retrospective analysis of insurance claims of ~8 million patients. This large cohort study revealed a statistically significant association between top drug classes, particularly those targeting potassium channels, and COVID-19 severity. Taken together, the potassium channel KCNA6 facilitates neuronal entry of SARS-CoV-2 and is a promising target for drug repurposing and development.
ABSTRACT
ImportanceCOVID-19 has severely impacted older populations and strained healthcare resources, with many patients requiring long periods of hospitalization. Reducing the hospital length of stay (LOS) reduces patient and hospital burden. Given that adverse drug reactions are known to prolong LOS, unmanaged pharmacogenomic risk and drug interactions among COVID-19 patients may be a risk factor for longer hospital stays. ObjectiveThe objective of this study was to determine if pharmacogenomic and drug interaction risks were associated with longer lengths of stay among high-risk patients hospitalized with COVID-19. DesignRetrospective cohort study of medical and pharmacy claims SettingAdministrative database from a large U.S. health insurance company ParticipantsMedicare Advantage members with a first COVID-19 hospitalization between January 2020 and June 2020, who did not die during the stay. Exposures(1) Pharmacogenetic interaction probability (PIP) of [≤]25% (low), 26%-50% (moderate), or >50% (high), which indicate the likelihood that one or more clinically actionable gene-drug or gene-drug-drug interactions would be identified with testing; (2) drug-drug interaction (DDI) severity of minimal, minor, moderate, major, or contraindicated, which indicate the severity of an interaction between two or more active medications. Main Outcomes and MeasuresThe primary outcome was hospital length of stay. Results were stratified by hierarchical condition categories (HCC) counts and chronic conditions. ResultsA total of 6,025 patients hospitalized with COVID-19 were included in the study. Patients with moderate or high PIP were hospitalized for 9% (CI: 4%-15%; p < 0.001) and 16% longer (CI: 8%-24%; p < 0.001), respectively, compared to those with low PIP, whereas RAF score was not associated with LOS. High PIP was significantly associated with 12%-22% longer lengths of stay compared to low PIP in patients with hypertension, hyperlipidemia, diabetes, or COPD. Finally, among patients with 2 or 3 HCCs, a 10% longer length of stay was observed among patients with moderate or more severe DDI compared to minimal or minor DDI. Conclusions and RelevanceProactively mitigating pharmacogenomic risk has the potential to reduce length of stay in patients hospitalized with COVID-19 especially those with COPD, diabetes, hyperlipidemia, and hypertension. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the impact of unmanaged pharmacogenomic risk among patients hospitalized with COVID-19? FindingsAmong 6,025 patients hospitalized with COVID-19, those with greater unmanaged pharmacogenomic risk for adverse drug reactions had longer hospital stays than those with lower risk, both within the entire cohort and within groups matched by number and type of chronic conditions. MeaningPreemptive pharmacogenomic testing may shorten hospital stay by reducing adverse drug reactions among seriously ill patients and more broadly improve patient risk classification, care utilization predictions, and health system performance.
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ObjectiveClinical sequelae have not been well characterized during the post-acute phase of SARS-CoV-2 among adults 18 to 65 years old, and this study sought to fill that gap by evaluating excess risk and relative hazards for developing incident clinical sequelae during the post-acute phase. DesignRetrospective cohort study including three propensity-matched groups. SettingThis study merged three data sources from a large United States health plan: a large national administrative claims database, an outpatient lab testing database, and an inpatient hospital admissions database. ParticipantsIndividuals 18 to 65 years old with continuous health plan enrollment from January 2019 to date of SARS-CoV-2 diagnosis. Three comparator groups were identified and propensity-score matched to individuals infected with SARS-CoV-2: a 2020 comparator group, a historical 2019 comparator group and a historical comparator group with viral lower respiratory tract illness (vLRTI). Main outcome measuresOver 50 clinical sequelae during the post-acute phase (index date + 21 days) were ascertained using ICD-10 codes. Excess risk due to SARS-CoV-2 during the 4 months following the acute phase of illness and hazard ratios with 95% Bonferroni-corrected confidence intervals were calculated. ResultsThis study found 14% of adults [≤]65 years of age who were infected with SARS-CoV-2 (n=193113) had at least one new clinical sequelae that required medical attention during the post-acute phase of illness. When considering risk for specific sequelae attributable to SARS-Cov-2 infection during the post-acute phase, clinical outcomes including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety and fatigue were significantly elevated compared to the three propensity-matched comparator groups (2020, 2019, vLRTI). Significant risk differences due to SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people and hazard ratios ranged from 1.24 to 25.65 when compared to the 2020 comparator group. ConclusionsOur results confirm excess risk for developing clinical sequelae due to SARS-CoV-2 during the post-acute phase, including specific types of sequelae less commonly seen among other viral illnesses. Although individuals who were older, had pre-existing conditions, and were hospitalized due to COVID-19 were at greatest excess risk, younger adults ([≤]50 years), adults who did not have pre-existing conditions or adults who were not hospitalized due to COVID-19 were still at elevated risk for developing new clinical sequelae. The elevated risk for incident sequelae during the post-acute phase is relevant for healthcare planning. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSSmall observational studies and case reports of hospitalized patients have shown some COVID-19 survivors suffer from short- and long-term sequelae. Few studies have characterized the excess risk of clinical sequelae attributable to SARS-CoV-2 during the post-acute phase among adults [≤]65 years of age in a large generalizable sample. What this study addsThis study found 14% of individuals [≤]65 years of age who were infected with SARS-CoV-2 (n=193113) had a diagnosis of at least one new sequelae that required medical attention during the post-acute phase of illness. Elevated risk for specific clinical sequelae during the post-acute phase of illness was noted across a range of organ systems including cardiovascular, neurologic, kidney, respiratory, and mental health complications. The risk for incident sequelae increases with age, pre-existing conditions, and hospitalization for COVID-19; however, even among adults [≤] 50 years of age and individuals without pre-existing conditions or hospitalization due to COVID-19, risk for some clinical sequelae is still elevated. These results indicate where additional diagnostic follow-up, rehabilitation, and symptom management may be warranted among younger adults with milder infection.
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BackgroundWhether angiotensin-converting enzyme (ACE) Inhibitors and angiotensin receptor blockers (ARBs) mitigate or exacerbate SARS-CoV-2 infection remains uncertain. In a national study, we evaluated the association of ACE inhibitors and ARB with coronavirus disease-19 (COVID-19) hospitalization and mortality among individuals with hypertension. MethodsAmong Medicare Advantage and commercially insured individuals, we identified 2,263 people with hypertension, receiving [≥]1 antihypertensive agents, and who had a positive outpatient SARS-CoV-2 test (outpatient cohort). In a propensity score-matched analysis, we determined the association of ACE inhibitors and ARBs with the risk of hospitalization for COVID-19. In a second study of 7,933 individuals with hypertension who were hospitalized with COVID-19 (inpatient cohort), we tested the association of these medications with in-hospital mortality. We stratified all our assessments by insurance groups. ResultsAmong individuals in the outpatient and inpatient cohorts, 31.9% and 29.8%, respectively, used ACE inhibitors and 32.3% and 28.1% used ARBs. In the outpatient study, over a median 30.0 (19.0 - 40.0) days after testing positive, 12.7% were hospitalized for COVID-19. In propensity score-matched analyses, neither ACE inhibitors (HR, 0.77 [0.53, 1.13], P = 0.18), nor ARBs (HR, 0.88 [0.61, 1.26], P = 0.48), were significantly associated with risk of hospitalization. In analyses stratified by insurance group, ACE inhibitors, but not ARBs, were associated with a significant lower risk of hospitalization in the Medicare group (HR, 0.61 [0.41, 0.93], P = 0.02), but not the commercially insured group (HR: 2.14 [0.82, 5.60], P = 0.12; P-interaction 0.09). In the inpatient study, 14.2% died, 59.5% survived to discharge, and 26.3% had an ongoing hospitalization. In propensity score-matched analyses, neither use of ACE inhibitor (0.97 [0.81, 1.16]; P = 0.74) nor ARB (1.15 [0.95, 1.38]; P = 0.15) was associated with risk of in-hospital mortality, in total or in the stratified analyses. ConclusionsThe use of ACE inhibitors and ARBs was not associated with the risk of hospitalization or mortality among those infected with SARS-CoV-2. However, there was a nearly 40% lower risk of hospitalization with the use of ACE inhibitors in the Medicare population. This finding merits a clinical trial to evaluate the potential role of ACE inhibitors in reducing the risk of hospitalization among older individuals, who are at an elevated risk of adverse outcomes with the infection.
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OBJECTIVE@#To evaluate the curative effect of percutaneous vertebroplasty (PVP) for senile osteoporotic vertebral compressive fractures with posterior vertebral defect and spinal canal compromise. @*METHODS@#A total of 50 patients with osteoporotic vertebral compressive fractures (50 vertebrae) underwent PVP from July, 2010 to October, 2013. Subsequent visual analogue scale (VAS) rating, analgesic utilization and mobility were recorded before and after the surgery. @*RESULTS@#A total of 42 patients were followed up completely. The median VAS, analgesic administration score and patients' mobility score was significantly decreased at the 2nd hour, the 3rd day, the 1st month, the 3rd month, the 6th month and the 1st year after the surgery compared with those at the pre-operation (P<0.01). Five recurrence fractures were observed after PVP. @*CONCLUSION@#PVP is safe and effective and it is worthy for clinical popularization and application.
