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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global pandemic. Viral entry into host cells is mediated by spike glycoprotein (SGP) interactions with angiotensin-converting enzyme 2 (ACE2) and heparan sulfate glycosaminoglycans on the cell surface. Carbohydrate small molecules were found to bind to the receptor binding domain (RBD) of SGP, which also interacts with ACE2, forming a ternary complex. Moreover, glycans isolated from sea cucumber and red alga species exhibited anti-SARS-CoV-2 activities, presumably by blocking viral entry mediated through SGP-heparan sulfate interactions. Here we report a collection of computational studies conducted as part of a collaborative effort to investigate the effects of marine natural products (NPs) on the wild-type and N501Y mutant SGP RBD. Starting from an X-ray crystal structure of the RBD-ACE2 complex, a model of SGP RBD was built. To investigate the static and dynamic behavior of RBD-NP interactions, blind and site-targeted molecular docking using diverse docking programs (Glide, AutoDock Vina or ClusPro) was carried out, followed by extensive molecular dynamics simulations with two force fields (CHARMM36 or Glycam06) and binding free energy calculations. Predicted conformations of the NPs varied considerably when modeled in water or in complex with RBD. Five NP binding sites on the RBD were studied. NP binding specificities towards SARS-CoV-2 variants were explained and important RBD residues were identified. Statistical analyses of the stability of various protein-NP complexes during molecular dynamics simulations helped to differentiate pseudo-vs. real-binding sites. Our results provide significant insights into the importance of extensive molecular dynamics calculations in order to move beyond the limitations of molecular docking.
ABSTRACT
Purpose: Describe outcomes of patients (pt) with pre-tx COVID-19. Method(s): Multicenter study of SOT/HCT candidates who had a positive (pos) SARS-CoV-2 PCR pre-tx. Result(s): Pre-tx: Of 208 pt, median age was 56 (range 3-76). 87.8% were SOT candidates (40.5% kidney, 40.5% liver, 9.8% lung, 6.9% heart, 2.3% pancreas) and 13.9% were HCT candidates (54.2% allo, 45.8% auto). Pt underwent a median of 2 tests (range 1 - 14). In 41% of pt, > 1 neg PCR was required by the tx center before reactivation. Neg PCR was documented in 67.4% of pt at a median of 41 days (18-68) after pos PCR. Waitlist mortality was 11.0%;deaths were due to COVID-19 in 60% (12/20). Post-tx (all pt): 78 pt underwent tx at a median of 65.5 days (range 17-324) from COVID-19;71/78 have completed 4-weeks of follow-up. 24/78 (30.7%) pt were still PCR pos at time of tx (details below). 54/78 (69.2%) pt underwent routine PCR testing post-tx;62% were tested regularly for 8 weeks. Only 1 pt, who remained asymptomatic, developed recurrent pos PCR on surveillance testing 18 days post-tx. 1 pt had graft loss. There were no deaths at 4 weeks post-tx. Pt transplanted without a negative PCR: 24 pt with COVID-19 did not have neg PCR at time of tx: 9 (37.5%) kidney, 9 (37.5%) liver, 2 (8.3%) SLK, 1 (4.2%) lung, 1 heart (4.2%), 2 auto-HSCT (8.3%), 2 allo-HSCT (8.3%). Of 24 pt who were reactivated at a median of 21 days (range 8 - 38) from COVID-19 diagnosis, 7 underwent tx emergently (5 liver, 1 lung, 1 heart). 20/24 completed 4-weeks of follow-up;all were alive. PCR Cycle thresholds (Ct) increased over time, suggesting a reduction in SARS-CoV-2 viral loads with time elapsed since COVID-19 diagnosis. Conclusion(s): Short-term outcomes of transplantation in SOT/HCT candidates with prior COVID-19 were promising in this small cohort, even with a positive PCR going into transplant. Whether documentation of a negative PCR should be required for all tx candidates with a history of COVID-19 prior to transplantation should be investigated further, particularly among lung tx candidates. For certain tx candidates with COVID-19, relying time-based strategy instead of a test-based strategy may be safe.
ABSTRACT
Purpose: Invasive fungal infection (IFI) complicating Coronavirus disease of 2019 (COVID-19) has been increasingly recognized. IFI is a common opportunistic infection in solid organ transplant (SOT), but association with COVID-19 is unknown. Method(s): This was a retrospective study of all SOT recipients hospitalized with COVID-19 between March 2020 and Oct 2021. IFI was defined based on EORTC/ MSG criteria. Result(s): 107 SOT recipients were hospitalized due to COVID-19. 17 patients were excluded because they were on a systemic antifungal agent on admission. Median age was 62 yrs. 46% were female. 59% (53) were recipients of kidney, 17% (15) of lung, 11% (10) each of heart and liver, and 2% (10) of small bowel. 8% (7) of patients developed IFI within 90 days of COVID-19 (2 proven and 5 probable) (Table): 3 due to yeasts (2 bloodstream and 1 lung), and 4 pulmonary aspergillosis. Median time from COVID-19 diagnosis to IFI was 22 days (1d to 78d). Mechanical ventilation (P = 0.01) and augmented immunosuppression (p = 0.04) were risk factors for IFI;receipt of dexamethasone or IL-6 inhibitor were not risk factors. IFI associated with more prolonged hospital stay (median of 23 days (7-120d) vs 10d (1-80d), respectively). The 90-day mortality after COVID-19 diagnosis was 23% (21), higher for patients with IFI (57% vs 20%;p=0.04). By univariate analysis, the risk factors for death were: use of dexamethasone (p=0.011), IL-6 inhibitor (p=0.001), and IFI (p=0.049);SARS-CoV-2 monoclonal antibody (Mab) was protective (p=0.06). By multivariate analysis, receipt of IL-6 inhibitor (p=0.001) and IFI (p=0.009) were independent risk factors for death;Mab was protective (p=0.02). Overall, 18% (16) patients received systemic antifungals (AF);11% (9) received AFs without any IFI diagnosis and they all received anti-mold agents. Conclusion(s): The incidence of IFI complicating COVID-19 was 8%, and IFI was associated with a higher mortality. The association between receipt of IL-6 inhibitor and death among SOT patients is of concern. Risk and benefit of this agent along with it's side effect should be carefully evaluated in larger trials of SOT and other immunosuppressed COVID-19 patients. (Table Presented).
ABSTRACT
COVID-19 was first discovered in the city of Wuhan. From then onward the virus has spread rapidly infecting thousands of people. The virus is still spreading and attempts are being made to predict and control the growth and spread of this virus. The trend of spread of this virus is highly unpredictable and normal statistical methods of predictions have not provided promising results, thus another approach of predicting the growth of this virus is required. This approach must be able to predict the nonlinear growth of the virus. Thus, an attempt is made to predict the growth of this virus and to show that the normal statistical methods are not able to predict the growth of the virus with high accuracy. The linear predicting algorithms used are Linear Regression, Support Vector Machine, Polynomial Regression and Auto Regressive Integrated Moving Average. The nonlinear predicting algorithm used is Prophet Algorithm for the prediction of exponential growth of spread of the virus. A comprehensive study is done to show how the spread of the virus takes place in different countries. A comparative study is also done to show the differences in performance parameters based on Absolute Mean Error, Mean Squared Error and R-squared (R2) score among different types of predictors. © 2022, The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
ABSTRACT
Background. During the COVID-19 pandemic, >50% of hospitalized patients (pts) received an antimicrobial. ECMO is increasingly used in COVID-19 pts with severe ARDS. ECMO has been used for ARDS due to influenza at our center in prior years. Pts on ECMO are at high risk for infections. We compared the rates of antibiotic (Ab) and antifungal (AF) use in pts on ECMO for COVID-19 vs influenza ARDS. Methods. This was a retrospective review of pts on ECMO for COVID-19 (2020-2021) or influenza (2013-2019). Antimicrobials (Abs and AFs) were categorized as anti-MRSA, anti-pseudomonal β-lactams (AP-BL), carbapenems, and new broader spectrum β-lactams. We calculated total Ab and AF utilization, adjusted for ECMO duration. Results. Seventy-one pts (36 COVID-19 and 35 influenza) were included. COVID-19 pts had longer ECMO duration (median: 25 vs 11 days, p=.03). 100% and 97% of pts with COVID-19 and influenza received ≥1 Ab, respectively, and 42% and 33% an AF, respectively. COVID-19 pts received longer duration of Abs (26 vs 10 days, p< 0.001) and but not AF. COVID-19 group (gp) were more likely to receive anti-MRSA Ab (69% vs 33%, p=.004);otherwise, there were no differences between gps in types of Abs used. When adjusted for ECMO days, COVID-19 gp received higher median number of Abs (1.23 vs 1, p=.06). Specifically, COVID-19 gp received higher median number of anti-MRSA Ab (0.2 vs 0, p=.007) and AP-BL (0.44 vs 0.28, p=.08). There was no difference in Ab-free days between gps, though the proportion of Ab-free days was lower (0.2 vs 0.36) in COVID-19 pts (p=.08). More COVID-19 pts had pathogens recovered from clinical cultures, especially S. aureus and Enterobacterales (Figure). Pathogens recovered from clinical cultures Patients recovered from clinical cultures of patients with COVID-19 and Influenza ARDS requiring ECMO Conclusion. Among pts on ECMO, those with COVID-19 received significantly longer courses of Abs than those with influenza, even after adjusting for longer durations of ECMO. Differences were driven by receipt of anti-MRSA and AP-BLs. Recovery of pathogenic bacteria was greater in COVID-19 pts than influenza pts. Given difficulties in distinguishing pneumonia from airway colonization among ARDS pts on ECMO, development of diagnostic criteria for pt care, rational antimicrobial stewardship and further research are needed.
ABSTRACT
Background. Rescue ECMO has been used worldwide in patients (pts) with ARDS caused by COVID-19. Bacterial super-infections affect 3.5-14.3% of hospitalized pts with COVID-19. Pts requiring ECMO may be at an increased risk of infection due to their severity of illness, gut translocation and ECMO impact on host immunity. Methods. This was a retrospective review of pts requiring ECMO for COVID-19 from April 2020-2021 at a single center. Strict definitions of infections (including ventilator-associated PNA, VAP) were in accordance with CDC criteria. Results. 43 ECMO pts with 1065 ECMO days were evaluated. Median age was 53 yrs (range: 21-62) and median BMI was 36.2 (range: 19.4-75.8). 70% were men and 65% were white. 37 patients (86%) experienced a total of 40 infectious episodes with a median onset from ECMO cannulation to first infection of 10.5d (range: 4-50). Median SOFA and SAPSII scores at time of infection were 12 (6-20) and 63 (30-90), respectively. PNA was the most common infection (78%, with 19% of cases complicated by bacteremia and 3% by empyema) (Fig. 1). The most common organisms isolated were Enterobacterales (37%), S. aureus (25%) and P. aeruginosa (16%) (Fig. 2). Only 2% of all organisms were multi-drug resistant. 3 pts had fungal infections (1 candidemia, 2 aspergillus PNA). Duration of ECMO was significantly longer for infected pts (26d, range: 5-92d) vs (11d, range: 3-24d), p=.01. 95% of infected pts had received steroids vs. 67% of uninfected pts, p=0.09. Treatment success at 1 week was 50%, and 24% and 40% of pts had recurrent infections and persistent/recurrent organisms in clinical cultures, respectively. S. aureus (54%) and Enterobacterales (26%) were associated with persistent or recurrent clinical cultures, requiring prolonged antimicrobial therapy. Mortality rate at 30 days was 65% and was significantly higher for pts with infection than those without (67% vs 33%, p=.02). Conclusion. Super-infection (most commonly PNA) occurred in almost all COVID-19 pts requiring ECMO for >4 days, and was a significant risk factor for death. Recurrent infections among survivors were common, especially when caused by Enterbacterales or S. aureus. Super-infection and mortality rates of ARDS pts on ECMO for COVID-19 were worse than for ARDS pts on ECMO for influenza at our center.