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Objectives: Besides in-centre ECMO care, the certificated ECMO centre of the University Hospital Regensburg (UKR) offers out-of-centre ECMO initiation with mobile equipment. During the pandemic situation, this treatment was especially meant for patients with critical cardiopulmonary failure in remote hospitals who present themselves as too unstable for interhospital transfer. We evaluated if treatment with outof-centre ECMO initiation could benefit patients;outcome, by comparing this group with a group of COVID-19 patients who received ECMO therapy at the UKR by in-hospital initiation. Method(s): Retrospective single-centre study including 169 patients who received ECMO due to COVID-19- induced cardiopulmonary failure between March 2020 till March 2022. Patients;population was separated into two groups according to the location of ECMO initiation, out-of-centre or in-centre, and into two subgroups by the used ECMO mode, venovenous (VV) or venoarterial (VA). We compared demographics, treatment duration, adverse events and patient;s outcome. The primary endpoint of the investigation was patients;survival to hospital discharge rate or death on ECMO or after ECMO explant. Result(s): Regarding the total study population, 98 (58.0%) of the 169 patients could be discharged from the UKR. Before initiation of ECMO therapy and with regard to complications during the course of intensive care, such as renal failure requiring dialysis or bleeding, there were no relevant differences between the two groups and subgroups. The out-of-centre group showed a significantly higher survival rate with 70 (63.6%) survivors out of 110 externally cannulated patients. Conclusion(s): In the study population, external ECMO cannulation was beneficial in terms of survival, although the reasons did not show significant differences between the groups. A possible approach for the good overall survival of the study groups in international comparison could be the existing centre expertise. (Figure Presented).
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Introduction: Post-sternotomy chest pain (CP) has been widely reported in literature. The etiologies include myocardial infarction, pulmonary embolism, hypersensitivity reactions to foreign material, wound infection, sternal instability and dehiscence, neuropathic pain due to intercoastal nerve damage or sternal wire fracture leading to migration. Here, we report a rare case of a young patient who presented with chronic chest pain after an atrial septal defect (ASD) repair. Case: A 28-year-old male with past medical history significant for an ASD (secundum) repair with autologous pericardial patch, hyperlipidemia, COVID-19 infection, known first degree AV block, and early repolarization changes, presented for a follow-up office visit three years after his ASD repair with complaints of typical anginal symptoms. Diagnosis: Vitals, physical exam, troponin, D-dimer and inflammatory markers were unremarkable. Chest x-ray (Figure 1A) showed sternal wires in place and no fractures of wires. EKG (Figure 1B) was unchanged. Echocardiogram showed LVEF 50% and no wall motion abnormalities. He underwent a coronary CTA which identified intermittent compression on the mid-RCA from the third bottom stainless steel sternal wire (Figure 1C), warranting removal. Treatment: He underwent explantation of all sternal wires and selective right coronary angiography (Figure 1D) was performed, which revealed intact and patent RCA without any complications. He continues to follow-up in our clinic without any CP. Conclusion(s): Chronic CP after any cardiac surgery remains a diagnostic dilemma and a source of anxiety for patients. We recommend comprehensive discussions with patients prior to surgery about these probable complications to alleviate the anxiety. Lastly, from research thus far, removal of sternal wires is a safe, simple, and effective procedure that should be offered to patients with persistent post-sternotomy CP after exclusion of serious complications.
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SESSION TITLE: Pulmonary Issues in Transplantation Case Report Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Fibrotic interstitial lung disease (fILD) can be idiopathic or associated with several underlying conditions and in response to various types of injury. Post COVID-19 fILD is an increasingly recognized clinical entity with the potential for a large burden of morbidity and mortality.[1] We present a series of 6 patients with progressive pulmonary fibrosis as sequela of COVID-19 requiring lung transplantation. CASE PRESENTATION: Four of the 6 patients had known underlying chronic ILD prior to COVID-19 infection (2 with idiopathic pulmonary fibrosis [IPF] and 1 each with scleroderma and rheumatoid arthritis associated ILD). The other 2 patients had no prior history of lung disease and asymptomatic before infection. One of these had a strong family history of IPF. The presentations involved signs of progressive respiratory failure after the initial lung injury from COVID-19. 4 patients were hospitalized during their acute COVID-19 illness and had varying treatments including steroids, antibiotics, anti-virals, convalescent plasma, Tocilizumab, and non-invasive positive pressure ventilation. At the time of transplant evaluation, CT imaging showed prominent interstitial thickening, honeycombing consistent with fibrotic processes for all our patients;PFT revealed severe restrictive ventilatory defect with reduced diffusion capacity ranging 24%-53%;3 patients required venous-venous extracorporeal membrane oxygenation (ECMO) as a bridge to transplantation for 14 and 93 days. The remainder required 6-10 L of supplemental oxygenation at rest. Two patients underwent initial transplant evaluation while in respiratory failure.5 patients received bilateral lung transplantation and one single left lung transplantation.Duration of time between initial COVID-19 induced lung injury and transplantation ranged from 3-13 months, with a median 6-7 months.Lung explant pathology showed advanced usual interstitial pneumonia in all. Superimposed diffuse alveolar damage was noted in 3 cases. Post-transplant to discharge ranged 10-31 days and at 2 months follow-up, all patients were liberated of oxygen needs. All subjects remain alive at a median 11-12 months, with no evidence of allograft dysfunction. DISCUSSION: Since the emergence of SARS-COV2 in 2019, histopathological fibrotic anomalies have been found to be present in up to one-third of those who recover from ARDS due to COVID-19 [2] and their incidence increases as duration of ARDS increases [3]. Further work is required to understand the pathogenesis of the fibrotic process following acute COVID-19. CONCLUSIONS: We highlight this syndrome with our case series of 6 patients who showed progressive fibrotic disease after COVID-19. Patients with pre-exiting ILD appear to be particularly at risk but this entity may occur in those without pre-existing ILD. Lung transplantation offers a viable treatment option for selected patients with an otherwise poor prognosis. Reference #1: 1.Bharat, A., Querrey, M., Markov, N. S., Kim, S., Kurihara, C., Garza-Castillon, R., Manerikar, A., Shilatifard, A., Tomic, R., Politanska, Y., Abdala-Valencia, H., Yeldandi, A. V., Lomasney, J. W., Misharin, A. V., & Budinger, G. (2020). Lung transplantation for pulmonary fibrosis secondary to severe COVID-19. medRxiv : the preprint server for health sciences, 2020.10.26.20218636. https://doi.org/10.1101/2020.10.26.20218636 Reference #2: 2. Rai DK, Sharma P, Kumar R. Post covid 19 pulmonary fibrosis. Is it real threat?. Indian J Tuberc. 2021;68(3):330-333. doi:10.1016/j.ijtb.2020.11.003 Reference #3: 3. Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, Curtis HJ, Mehrkar A, Evans D, Inglesby P, Cockburn J, McDonald HI, MacKenna B, Tomlinson L, Douglas IJ, Rentsch CT, Mathur R, Wong AYS, Grieve R, Harrison D, Forbes H, Schultze A, Croker R, Parry J, Hester F, Harper S, Perera R, Evans SJW, Smeeth L, Goldacre B. Factors associated with C VID-19-related death using OpenSAFELY. Nature. 2020 Aug;584(7821):430-436. doi: 10.1038/s41586-020-2521-4. Epub 2020 Jul 8. PMID: 32640463;PMCID: PMC7611074. DISCLOSURES: no disclosure on file for Philip Camp;research relationship with United Therapeutics Please note: 2016- ongoing by Reda Girgis, value=Grant/Research research relationship with Pfizer Please note: 2014-2020 by Reda Girgis, value=Grant/Research Speaker/Speaker's Bureau relationship with Boehringher Ingelheim Please note: 2016-ongoing by Reda Girgis, value=Honoraria Speaker/Speaker's Bureau relationship with Genentech Please note: 2016-ongoing by Reda Girgis, value=Honoraria No relevant relationships by Ryan Hadley No relevant relationships by Sheila Krishnan No relevant relationships by Sheetal Maragiri No relevant relationships by Edward Murphy No relevant relationships by Jay Patel No relevant relationships by Keval Ray No relevant relationships by Gayathri Sathiyamoorthy No relevant relationships by Neel Shah No relevant relationships by Subhan Toor
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Purpose: We report the clinical outcomes of an Adult Respiratory ECMO (VV-ECMO) program that was rapidly established in a community hospital within a 4-week period. The program was launched in response to increasing patients presenting with acute respiratory failure due to COVID-19. Method(s): Our institution supported urgent preparedness to add VVECMO therapy to our established, nurse-run Adult VA-ECMO program. ICU nurses were trained to run VV-ECMO through interdisciplinary collaboration with neonatal-pediatric ECMO nurses, cardiac perfusionists, providers (NP, PA), respiratory therapists, and physicians. Retrospective data of VV-ECMO therapy was collected between November 2020 and June 2022. Result(s): 29 patients with ARDS due to COVID-19 received VV-ECMO. Of the 29 patients were 23 males and 6 females, of median age 48 (31-59) years and median body mass index (BMI) 31.4 kg/m2 (20.5-49.2). The mean duration of VV-ECMO was 970 hours (44.1 days) and the longest run time was 2752 hours (114.6 days). Patient survival rate to VV-ECMO explant was 66%. Patient survival to discharge with a return to pre-ECMO functional capacity was 55%, defined as supplemental oxygen requirements less than 3L nasal cannula and rehabilitating to activities of daily living. Conclusion(s): In the setting of the COVID-19 pandemic, an Adult VV-ECMO program was rapidly developed and executed in an advanced community hospital system. Our VV-ECMO program results are comparable to programs at major academic centers, with survival rates on par with statistics reported by the ELSO registry. Additionally, our outcomes demonstrate that a nurse-run VV-ECMO program can be both feasible and successful.
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Background and aims: Transforming growth factor beta (TGF-beta) signalling is a key driver of liver fibrosis. In primary sclerosing cholangitis (PSC), integrins over-expressed on injured cholangiocytes (alpha-v/beta-6) and myofibroblasts (alpha-v/beta-1) regulate TGFbeta activity. PLN-74809 is an oral, once-daily, dual-selective inhibitor of integrins alpha-v/beta-6 and alpha-v/beta-1 in development for the treatment of PSC and idiopathic pulmonary fibrosis. It has shown favourable tolerability in over 280 healthy participants, reduced TGF-beta signalling and achieved high target engagement in human lungs. Pre-clinical evaluation of antifibrotic activity resulting from dual integrin inhibition was performed to support clinical evaluation. Method: PLN-74809 was administered orally for 6 weeks in BALBc. Mdr2-/- mice with established fibrosis. A tool alpha-v/beta-6 and alpha-v/beta-1 inhibitor compound, PLN-75068, was tested therapeutically in a diet-induced mouse model of biliary fibrosis using 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC). Hepatic collagen was quantified by hydroxyproline (OHP) and collagen proportionate area (CPA) and TGF-beta signalling by phosphorylated SMAD3 (pSMAD3) levels. An ex vivo study evaluated the effects of 2-day treatment with PLN-74809 on the expression of profibrotic genes, COL1A1 and COL1A2, in precision-cut liver slices (PCLivS) from tissue explants of participants with biliary fibrosis (n = 2 PSC;n = 2 primary biliary cholangitis [PBC]). A review of available blinded safety data from the enrolling Phase 2a study in participants with PSC was performed (NCT04480840). Results: PLN-74809 dose-dependently reduced OHP (up to ∼30%, p < 0.05), CPA (up to ∼50%, p < 0.05) and pSMAD3 (up to ∼40%, p < 0.001) in the BALBc.Mdr2-/- mouse model, as well as COL1A1 and COL1A2 gene expression (up to ∼30%, p = 0.0789) in PCLivS from tissue explants of participants with PSC and PBC. PLN-75068 reduced OHP (up to ∼20%, p < 0.05) in DDC-injured mice in a dose-dependent manner. PLN-74809waswell tolerated in participants with PSC. Most adverse events (AEs)were mild;nonewere severe. The most common AE was mild headache. One participant experienced serious AEs at least 20 days after the last dose of study drug, deemed not related by the investigator. One participant prematurely discontinued due to COVID-19. PLN-74809 pharmacokinetics in participants with PSC were consistent with those of healthy participants. Conclusion: Pharmacological inhibition of integrins alpha-v/beta-6 and alpha-v/beta-1 demonstrated antifibrotic activity in two models of biliary fibrosis and in PCLivS from participants with PSC or PBC. Available safety findings from participants with PSC enrolled in the ongoing Phase 2a INTEGRIS-PSC study, continue to support the favourable tolerability profile of PLN-74809.
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Sublineages of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Omicron variants continue to amass mutations in the spike (S) glycoprotein, which leads to immune evasion and rapid spread of the virus across the human population. Here we demonstrate the susceptibility of the Omicron variant BA.1 (B.1.1.529.1) to four repurposable drugs, Methylene blue (MB), Mycophenolic acid (MPA), Posaconazole (POS), and Niclosamide (Niclo) in post-exposure treatments of primary human airway cell cultures. MB, MPA, POS, and Niclo are known to block infection of human nasal and bronchial airway epithelial explant cultures (HAEEC) with the Wuhan strain, and four variants of concern (VoC), Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28), Delta (B.1.617.2) (Weiss et al., 2021, Murer et al., 2022). Our results here not only reinforce the broad anti-coronavirus effects of MB, MPA, POS and Niclo, but also demonstrate that the Omicron variant BA.1 (B.1.1.529.1) sheds infectious virus from HAEEC over at least 15 d, and maintains both intracellular and extracellular viral genomic RNA without overt toxicity, suggesting viral persistence. The data emphasize the potential of repurposable drugs against COVID-19.
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There is global interest in both the beneficial and detrimental health effects of ultraviolet-C (UVC) radiation in the wavelength range 200-230 nm (known as Far-UVC). Technology using Far-UVC is proposed as a highly effective control measure for reducing the transmission of COVID-19. Far-UVC, and other wavelengths of UVC, are well-known to efficiently inactivate pathogens in air and on surfaces. Although studies have shown irradiation of skin with 254 nm UV results in DNA damage in the epidermal basal layer, irradiation with Far-UVC (222 nm) shows minimal DNA damage and only in the granular layer, which is comprised of non-proliferating keratinocytes. Therefore, accumulation of these DNA photoproducts would not be expected to be associated with cancer risk. It has also been shown that even high doses of Far-UVC exposure to human skin do not induce erythema. However, the effects of Far-UVC on the immune system are, to the best of our knowledge, unknown. It is well-reported that both ultraviolet B (UVB 280-315 nm) and ultraviolet-A (UVA 315-400 nm) have effects on cutaneous Langerhans cells (LC), inducing migration from the epidermis to the draining lymph nodes, thereby suppressing skin immune function. Here we present data generated in a range of skin types (Fitzpatrick II-V) demonstrating little or no impact of Far-UVC on the cutaneous immune system, as assessed by Langerhans cell migration, at doses of up to 3,000 mJ/cm2 (US daily limit is 450 mJ/cm2). These results support the safety of filtered Far-UVC use, which could have a transformative effect on public health, allowing effective virus inactivation and reduction of transmission independent of human behavior. Conflict of interest disclosure: the authors state no conflict of interest. However, MJC and RPH are directors of Ten Bio Ltd, a company focused on developing human skin explant models.
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Background: A promising approach to tackle the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) could be small interfering (si)RNAs. However, it is unclear so far, which viral replication steps can be efficiently inhibited with siRNAs. Here we report the first-ever in-depth analysis of RNAi-accessible SARS-CoV-2 replication steps. Methods: siRNAs were designed against four genomic regions of SARS-CoV-2. Initial screening of siRNA activity was performed with a dual luciferase reporter assay. Efficacy of siRNAs to terminate various viral replication steps was analyzed by infecting VeroE6 cells with wildtype SARS-CoV-2 or a GFP expressing recombinant SARS-CoV-2 and monitoring viral spread in real-time by time-lapse fluorescence microscopy. Positive and negative sense viral RNA transcripts were distinctly quantified via sense specific cDNA synthesis and reverse-transcriptase quantitative PCR. Finally, the antiviral activity of the siRNAs was primarily evaluated in a highly relevant model, SARS-CoV-2 infected human lung explants. Results: When applied in a prophylactic fashion, siRNAs were able to target genomic RNA (gRNA) of SARS-CoV-2 after cell entry, terminating replication before start of transcription, thereby preventing cytopathic effects. Surprisingly, siRNAs were not active against intermediate negative sense transcripts formed during replication. Targeting sequences that are commonly shared by all viral transcripts indeed allowed a simultaneous suppression of gRNA and subgenomic (sg)RNAs by a single siRNA. However, siRNAs that targeted ORF1 which is solely part of gRNA, presented an enhanced antiviral activity. We show that the reason for this was that siRNAs that targeted the common regions of transcripts were outcompeted by the highly abundant sgRNAs. Based on these findings, we developed a chemically stabilized siRNA, which targets a highly conserved region of ORF1, and which inhibited SARS-CoV-2 replication by >90% ex vivo in explants of the human lung. Conclusion: Our work strongly encourages the development of siRNA-based therapies for COVID-19 and suggests that early therapy start, or prophylactic application, together with targeting ORF1, might be key for high antiviral efficacy.
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Background: Lung transplantation has been performed as a life-saving treatment in a small number of post-acute COVID- 19 patients who develop severe pulmonary insufficiency. We report a detailed clinicopathologic analysis of 7 such patients that underwent bilateral orthotopic lung transplantation at our institution. Design: The time interval between initial diagnosis of Covid-19 infection and lung transplantation, other clinical findings, and imaging features of the 7 patients were reviewed. The pathologic findings in the 14 explants were assessed and histologic abnormalities were classified into parenchymal, airway and vascular changes. The extent (1+-to 4+ based on # of slides with the abnormality) and severity (mild, moderate, marked) of histologic abnormalities were recorded. Results: Patients ranged in age from 34 to 55 years old and were transplanted at 10.4 to 24 weeks after initial diagnosis of Covid- 19 (median 16 weeks). Six of these patients had been previously treated with ECMO for 82-145 days. Other clinical and imaging features are summarized in Table 1. All 14 explants showed diffuse marked interstitial fibrosis with a nonspecific interstitial pneumonia (NSIP) pattern. Other pathologic changes included extensive alveolar hemosiderosis (n=7 patients);prominent peribronchial metaplasia (n=7);focal multinucleated giant cells in either the parenchyma, vascular wall or peribronchiolar location (n=6);focal thrombosis involving medium to large vessels (n=4) and lung cysts associated with delicate calcifications and multinucleated giant cells (n=1). No diffuse alveolar damage changes (DAD) or vasculitis were identified. Conclusions: Lung explants from patients with post-acute COVID-19 syndrome show severe NSIP pattern of fibrosis and other pathologic changes that do not resemble the extensive fibrotic changes resulting from organizing phase of DAD or the extensive vascular changes seen in patients dying during the acute or subacute phases of COVID-19 infection. Further studies with lung biopsies are needed to understand the mechanism of fibrosis in post-acute COVID-19 syndrome and identify individuals who are likely to develop severe pulmonary fibrosis requiring lung transplantation.
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Introduction: The COVID-19 pandemic has changed the lives of many in the past year. As of writing this article, the virus has claimed over half a million American lives and has infected millions more. It has affected many people regardless of age, gender, race, religion, or medical history. We have noticed a unique sequence of events in urology patients with a prior history of inflatable penis prothesis implantation who have gotten critically ill from the SARS-CoV-2 virus. Objective: We report our experience with patients with an inflatable penile prothesis who suffered respiratory failure due to the SARS-CoV-2 virus and findings that would help limit the risk of implant infection and/or erosion if prolonged urethral catherization is needed. Methods: We have encountered 3 patients with a very similar history in the past year. They were all men aged 57-72 years old who had a functioning inflatable penile prothesis (IPP) for many years (3-13) and were intubated for a prolonged period of time (2-4 weeks) after suffering respiratory distress from the SARS-CoV-2 virus. During this time, they all had a prolonged urethral Foley catherization for urinary drainage while in the ICU. They were all subsequently found to have urethral erosion of a penile implant cylinder which was not present prior to hospitalization. Their charts were reviewed. Results: Two patients underwent explantation of their IPP during their hospital stay and one presented to our outpatient office 2 months after discharge with the complaint of urethral cylinder erosion and underwent subsequent explantation. Conclusions: Urethral catheterization is commonly used in the intensive care unit and spinal cord injury patients due to their convenience and efficacy. The friction and inflammation created by prolonged transurethral catheterization can be disastrous for IPPs by increasing the likelihood of infection and/or device erosion. In fact, Steidle and Mulcahy found that five out of their nine patients (55%) with IPPs who had an indwelling or intermittent transurethral catheterization were eventually found to have erosion of their IPP. In addition, indwelling transurethral catheters also confer a higher risk of urinary tract infection. Han et al. found that suprapubic tube placement conferred a statistically significantly lower risk of urinary tract infection when compared to indwelling transurethral catheterization for over five days at an odds ratio of 0.142 (95% CI 0.073-0.0276). Another alternative to bladder drainage in the intubated IPP patient is clean intermittent catherization (CIC), however this poses a unique challenge in the intubated COVID positive patient as it repeatedly exposes healthcare staff the virus-carrying patient. When compared to indwelling transurethral catherization, suprapubic tube placement has been shown to confer a lower risk of urinary tract infection and IPP infection/erosion. This can primarily be explained by its ability to drain the bladder without creating inflammation and friction in the urethra. Therefore, we propose that any team caring for a patient with an IPP and a planned, prolonged indwelling transurethral catheterization consult urology services to have a suprapubic tube temporarily placed. This will ensure that the risk of urinary tract infection and/or IPP erosion is kept as low as possible. Disclosure: Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Boston Scientific, Neotract
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Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV-229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counter selection and challenge with the ß-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantation) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS-CoV-2 and variants-of-concern (alpha, beta, gamma, delta) from HAEEC in either pre- or post exposure regimens at clinically relevant concentrations. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral concentrations of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence synergy modelling. Neither MB, nor MPA, nor POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.
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On human lung parenchymal explants, chloroquine concentration clinically achievable in the lung (100 µM) inhibited the lipopolysaccharide-induced release of TNF-É (by 76%), IL-6 (by 68%), CCL2 (by 72%), and CCL3 (by 67%). Besides its antiviral activity, chloroquine might also mitigate the cytokine storm associated with severe pneumonia caused by coronaviruses.