Longitudinal outcomes of COVID-19 in solid organ transplant recipients from 2020 to 2023.

Data regarding coronavirus disease 2019 (COVID-19) outcomes in solid organ transplant recipients (SOTr) across severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) waves, including the impact of different measures, are lacking. This cohort study, conducted from March 2020 to May 2023 in Toronto, Canada, aimed to analyze COVID-19 outcomes in 1975 SOTr across various SARS-CoV-2 waves and assess the impact of preventive and treatment measures. The primary outcome was severe COVID-19, defined as requiring supplemental oxygen, with secondary outcomes including hospitalization, length of stay, intensive care unit (ICU) admission, and 30-day and 1-year all-cause mortality. SARS-CoV-2 waves were categorized as Wildtype/Alpha/Delta (318 cases, 16.1%), Omicron BA.1 (268, 26.2%), Omicron BA.2 (268, 13.6%), Omicron BA.5 (561, 28.4%), Omicron BQ.1.1 (188, 9.5%), and Omicron XBB.1.5 (123, 6.2%). Severe COVID-19 rate was highest during the Wildtype/Alpha/Delta wave (44.6%), and lower in Omicron waves (5.7%-16.1%). Lung transplantation was associated with severe COVID-19 (OR: 4.62, 95% CI: 2.71-7.89), along with rituximab treatment (OR: 4.24, 95% CI: 1.04-17.3), long-term corticosteroid use (OR: 3.11, 95% CI: 1.46-6.62), older age (OR: 1.51, 95% CI: 1.30-1.76), chronic lung disease (OR: 2.11, 95% CI: 1.36-3.30), chronic kidney disease (OR: 2.18, 95% CI: 1.17-4.07), and diabetes (OR: 1.97, 95% CI: 1.37-2.83). Early treatment and ≥3 vaccine doses were associated with reduced severity (OR: 0.29, 95% CI: 0.19-0.46, and 0.35, 95% CI: 0.21-0.60, respectively). Tixagevimab/cilgavimab and bivalent boosters did not show a significant impact. The study concludes that COVID-19 severity decreased across different variants in SOTr. Lung transplantation was associated with worse outcomes and may benefit more from preventive and early therapeutic interventions.

COVID-19 Reinfection Has Better Outcomes Than the First Infection in Solid Organ Transplant Recipients.

BACKGROUND: Solid organ transplant recipients face an increased risk of severe coronavirus disease 2019 (COVID-19) and are vulnerable to repeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. In nonimmunocompromised individuals, SARS-CoV-2 reinfections are milder likely because of cross-protective immunity. We sought to determine whether SARS-CoV-2 reinfection exhibits milder manifestations than primary infection in transplant recipients. METHODS: Using a large, prospective cohort of adult transplant patients with COVID-19, we identified patients with SARS-CoV-2 reinfections. We performed a 1:1 nearest neighbor propensity score matching to control potential confounders, including the COVID-19 variant. We compared outcomes including oxygen requirement, hospitalization, and intensive care unit admission within 30 d after diagnosis between patients with reinfection and those with the first episode of COVID-19. RESULTS: Between 2020 and 2023, 103 reinfections were identified in a cohort of 1869 transplant recipients infected with SARS-CoV-2 (incidence of 2.7% per year). These included 50 kidney (48.5%), 27 lung (26.2%), 7 heart (6.8%), 6 liver (5.8%), and 13 multiorgan (12.6%) transplants. The median age was 54.5 y (interquartile range [IQR], 40.5-65.5) and the median time from transplant to first infection was 6.6 y (IQR, 2.8-11.2). The time between the primary COVID-19 and reinfection was 326 d (IQR, 226-434). Three doses or more of SARS-CoV-2 vaccine are received by 87.4% of patients. After propensity score matching, reinfections were associated with significantly lower hospitalization (5.8% versus 19.4%; risk ratio, 0.3; 95% CI, 0.12-0.71) and oxygen requirement (3.9% versus 13.6%; risk ratio, 0.29; 95% CI, 0.10-0.84). In a within-patient analysis only in the reinfection group, the second infection was milder than the first (3.9% required oxygen versus 19.4%, P < 0.0001), and severe first COVID-19 was the only predictor of severe reinfection. CONCLUSIONS: Transplant recipients with COVID-19 reinfection present better outcomes than those with the first infection, providing clinical evidence for the development of cross-protective immunity.

Short-course early outpatient remdesivir prevents severe disease due to COVID-19 in organ transplant recipients during the omicron BA.2 wave.

Solid organ transplant recipients (SOTr) remain at risk of severe COVID-19. Several previous early therapies are no longer effective against new circulating variants. We performed a prospective cohort study in outpatient adult SOTr during the omicron BA.2 wave (April-May 2022), to determine the effectiveness of 3 doses of remdesivir given within 7 days of symptoms onset. Patients were followed for at least 30 days. The primary outcome was hospitalization. Of 210 SOTr that had COVID-19, we included 192. The median age was 54.5 years and 61.5% were men. The most common transplants were kidney (41.7%), lung (19.3%), liver (18.8%), and heart (6.3%). Most patients (90.1%) had previously received ≥3 COVID-19 vaccine doses. Fifteen (7.8%) were hospitalized, 5(2.6%) required supplemental oxygen, 3(1.6%) ICU admission, and 2(1%) mechanical ventilation with 2(1%) deaths. Age, the number of comorbidities, prednisone chronic treatment, and lung transplant were risk factors for hospitalization. Early remdesivir significantly decreased the hospitalization rate: adjusted hazard ratio 0.12 (95% CI: 0.03-0.57). The adjusted number needed to treat to prevent one hospitalization was 15.2 (95% CI: 13.6-31.4). No patient that received early remdesivir needed ICU admission or died. In a cohort of SOTr with COVID-19 infection, administration of 3-dose early remdesivir independently reduced the disease severity.

Impact of Vaccination and Early Monoclonal Antibody Therapy on Coronavirus Disease 2019 Outcomes in Organ Transplant Recipients During the Omicron Wave.

BACKGROUND: Solid organ transplant (SOT) recipients are at high risk for complications from coronavirus disease 2019 (COVID-19) and vaccine breakthrough infections are common. We determined the effectiveness of ≥3 doses of mRNA vaccine and early monoclonal antibody therapy in reducing disease severity against the Omicron (B.1.1.529) variant. METHODS: Prospective cohort study of consecutive SOT recipients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection referred to our transplant center who were followed for at least 30 days. The primary outcome was supplemental oxygen requirement. Effectiveness of sotrovimab and ≥3 vaccine doses was estimated using adjusted risk ratios (RR). RESULTS: Three hundred adult organ transplant recipients were included. Seventy-one patients (24.1%) were hospitalized, 44 (14.9%) required supplemental oxygen, 19 (6.5%) were admitted to the intensive care unit (ICU), 15 (5.1%) required mechanical ventilation (MV), and 13 (4.4%) died. On multivariate analysis, age and multiple comorbidities were risk factors for oxygen requirement. Both receipt of ≥3 vaccine doses prior to SARS-CoV-2 infection and receipt of sotrovimab in the first 7 days of symptom onset was associated with a reduction in the need for supplemental oxygen (RR 0.30 [95% confidence interval {CI}: .17 to .54] and RR 0.24 (95% CI: .1 to .59), respectively]. For sotrovimab, the number needed to treat (NNT) to prevent one patient requiring oxygen was 6.64 (95% CI: 4.56-13.66). Both sotrovimab use and having received ≥3 vaccine doses were also associated with a shorter hospitalization length of stay. CONCLUSIONS: In a cohort of SOT recipients with Omicron variant COVID-19 infection, prior receipt of ≥3 mRNA vaccine doses and early monoclonal antibody therapy were independently associated with significantly reduced disease severity.

Prospective observational study and serosurvey of SARS-CoV-2 infection in asymptomatic healthcare workers at a Canadian tertiary care center.

Health care workers (HCWs) are at higher risk for SARS-CoV-2 infection and may play a role in transmitting the infection to vulnerable patients and members of the community. This is particularly worrisome in the context of asymptomatic infection. We performed a cross-sectional study looking at asymptomatic SARS-CoV-2 infection in HCWs. We screened asymptomatic HCWs for SARS-CoV-2 via PCR. Complementary viral genome sequencing was performed on positive swab specimens. A seroprevalence analysis was also performed using multiple assays. Asymptomatic health care worker cohorts had a combined swab positivity rate of 29/5776 (0.50%, 95%CI 0.32-0.75) relative to a comparative cohort of symptomatic HCWs, where 54/1597 (3.4%) tested positive for SARS-CoV-2 (ratio of symptomatic to asymptomatic 6.8:1). SARS-CoV-2 seroprevalence among 996 asymptomatic HCWs with no prior known exposure to SARS-CoV-2 was 1.4-3.4%, depending on assay. A novel in-house Coronavirus protein microarray showed differing SARS-CoV-2 protein reactivities and helped define likely true positives vs. suspected false positives. Our study demonstrates the utility of routine screening of asymptomatic HCWs, which may help to identify a significant proportion of infections.

Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.

Prevention of viral transmission during lung transplantation with hepatitis C-viraemic donors: an open-label, single-centre, pilot trial.

BACKGROUND: A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation. METHODS: We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044. FINDINGS: From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV-positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16·76-24·75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20-12 000] vs 4390 IU/mL [1170-112 000] at day 7; p=0·048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV-positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV-negative donors. The most common grade 3-4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment. INTERPRETATION: Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor-recipient transmission. FUNDING: Canadian Institutes of Health Research.

Improving our mechanistic understanding of the indirect effects of CMV infection in transplant recipients.

Cytomegalovirus (CMV) is an immunomodulatory virus that indirectly increases the risk for bacterial, fungal, and viral infections. However, the pathogenesis of this phenomenon is poorly understood. We determined whether inflammatory responses to different Toll-like receptor (TLR) ligands are blunted during CMV infection in solid-organ transplant (SOT) patients. Peripheral blood mononuclear cells from 38 SOT patients with and without CMV were incubated in the presence of various viral, fungal, and bacterial TLR ligands. Cytokines were measured in the supernatant by multiplex enzyme-linked immunosorbent assay. Patients had blunted cytokine responses to bacterial, fungal, and viral ligands during CMV infection when compared to the absence of CMV infection. This was independent of viral load, clinical presentation of CMV infection or immunosuppression, supporting the clinical observation in SOT recipients that CMV infection increases susceptibility to bacterial, fungal, and other viral infections. Moreover, in the absence of CMV infection, patients with subsequent CMV infection had lower cytokines in response to TLR ligands compared to those without subsequent CMV infection, suggesting that inherent differences in patients not directly related to CMV also contribute to this increased susceptibility. In summary, these data provide novel ex vivo evidence to support indirect effects of CMV.