COVID-19 in kidney transplant recipients.

There is minimal information on coronavirus disease 2019 (COVID-19) in immunocompromised individuals. We have studied 10 patients treated at 12 adult care hospitals. Ten kidney transplant recipients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by polymerase chain reaction, and 9 were admitted. The median age was 57 (interquartile range [IQR] 47-67), 60% were male, 40% Caucasian, and 30% Black/African American. Median time from transplant to COVID-19 testing was 2822 days (IQR 1272-4592). The most common symptom was fever, followed by cough, myalgia, chills, and fatigue. The most common chest X-ray and computed tomography abnormality was multifocal patchy opacities. Three patients had no abnormal findings. Leukopenia was seen in 20% of patients, and allograft function was stable in 50% of patients. Nine patients were on tacrolimus and a mycophenolic antimetabolite, and 70% were on prednisone. Hospitalized patients had their antimetabolite agent stopped. All hospitalized patients received hydroxychloroquine and azithromycin. Three patients died (30%), and 5 (50%) developed acute kidney injury. Kidney transplant recipients infected with COVID-19 should be monitored closely in the setting of lowered immunosuppression. Most individuals required hospitalization and presenting symptoms were similar to those of nontransplant individuals.

Pediatric solid organ transplant recipients demonstrate robust cell-mediated and humoral responses to three doses of mRNA SARS-CoV-2 vaccine.

Pediatric solid organ transplant recipients (pSOTR) often demonstrate suboptimal vaccine responses and are not included in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy trials. This population has shown variable humoral immunity following SARS-CoV-2 vaccination, and no studies have assessed cell-mediated responses after SARS-CoV-2 vaccination in pSOTR. SARS-CoV-2-specific interferon-gamma release assay (IGRA), immunoglobulin G (IgG), and receptor-binding domain (RBD)-angiotensin-converting enzyme 2 (ACE2) blocking antibody (Ab) were measured in pSOTR aged 5-17 years after 2-3 doses of SARS-CoV-2 mRNA vaccine. In all, 33 subjects were included, with 25 tested after the second dose of mRNA vaccine (V2) and 21 tested after the third dose of mRNA vaccine (V3). Of the 19 subjects who had IgG testing after V3, 100.0% (19/19) had a positive IgG response. Of the 17 subjects who had IGRA testing after V3, 94.1% (16/17) had a positive IGRA response. RBD-ACE2 blocking antibody increased significantly from V2 to V3 (p = .007). Subjects <1 year from transplant demonstrated a significantly larger increase in RBD-ACE2 blocking Ab from V2 to V3 than did those >1 year from transplant (p = .05). SARS-CoV-2 vaccination induces humoral and cell-mediated responses in the majority of pSOTR, with improved quantitative humoral response after three doses.

Successful liver transplantation in patients with active SARS-CoV-2 infection.

The Coronavirus Disease 2019 (COVID-19) pandemic has substantially impacted solid organ transplantation, including temporary inactivation of waitlist candidates with COVID-19 infection. We report two cases of liver transplantation (LT) in individuals with asymptomatic COVID-19 infection. The first patient is a 68-year-old female with decompensated cirrhosis complicated by worsening frailty and sarcopenia. The second patient is a 22-year-old female with acute liver failure likely secondary to drug/toxin exposure. Both patients were treated with COVID-19-directed therapies and neither patient developed symptomatic disease. These cases demonstrate that LT can be safely performed in select patients with asymptomatic COVID-19 infection at the time of transplant.

Incidence and severity of SARS-CoV-2 infections in liver and kidney transplant recipients in the post-vaccination era: Real-life data from Denmark.

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been associated with a high risk of adverse outcomes in solid organ transplant (SOT) recipients in the pre-vaccination era. In this retrospective cohort study, we examined the incidence and severity of COVID-19 in kidney and liver transplant recipients in Denmark in the post-vaccination era, from December 27, 2020, to December 27, 2021. We included 1428 SOT recipients with 143 cases of first-positive SARS-CoV-2 PCR test. The cumulative incidence of first-positive SARS-CoV-2 PCR test 1 year after initiation of vaccination was 10.4% (95% CI: 8.8-12.0), and the incidence was higher in kidney than in liver transplant recipients (11.6% [95% CI: 9.4-13.8] vs. 7.4% [95% CI: 5.1-9.8], p = .009). After the first-positive SARS-CoV-2 PCR test, the hospitalization rate was 31.5% (95% CI: 23.9-39.1), and 30-day all-cause mortality was 3.7% (95% CI: 0.5-6.8). Hospitalization was lower in vaccinated than in unvaccinated SOT recipients (26.4% [95% CI: 18.1-34.6] vs. 48.5% [95% CI: 31.4-65.5], p = .011), as was mortality (1.8% [95% CI: 0.0-4.3] vs. 9.1% [95% CI: 0.0-18.9], p = .047). In conclusion, SOT recipients remain at high risk of adverse outcomes after SARS-CoV-2 infections, with a lower risk observed in vaccinated than in unvaccinated SOT recipients.

Outcomes following SARS-CoV-2 infection in individuals with and without solid organ transplantation-A Danish nationwide cohort study.

The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization and death, and the effects of SARS-CoV-2 vaccines in solid organ transplant recipients (SOTRs) is still debated. We performed a nationwide, population-based, matched cohort study, including all Danish SOTRs (n = 5184) and a matched cohort from the general population (n = 41 472). Cox regression analyses were used to calculate incidence rate ratios (IRRs). SOTRs had a slightly increased risk of SARS-CoV-2 infection and were vaccinated earlier than the general population. The overall risk of hospital contact with COVID-19, severe COVID-19, need for assisted respiration, and hospitalization followed by death was substantially higher in SOTRs (IRR: 32.8 95%CI [29.0-37.0], 9.2 [6.7-12.7], 12.5 [7.6-20.8], 12.4 [7.9-12.7]). The risk of hospitalization and death after SARS-CoV-2 infection decreased substantially in SOTRs after the emergence of the Omicron variant (IRR: 0.45 [0.37-0.56], 0.17 [0.09-0.30]). Three vaccinations reduced the risk of SARS-CoV-2 infection only marginally compared to two vaccinations, but SOTRs with three vaccinations had a lower risk of death (IRR: 022 [0.16-0.35]). We conclude that SOTRs have a risk of SARS-CoV-2 infection comparable to the general population, but substantially increased the risk of hospitalization and death following SARS-CoV-2 infection. A third vaccination only reduces the risk of SARS-CoV2 infection marginally, but SOTRs vaccinated 3 times have reduced mortality.

Effectiveness of first, second, and third COVID-19 vaccine doses in solid organ transplant recipients: A population-based cohort study from Canada.

Limited data exists on the effectiveness of a third COVID-19 vaccine dose in solid organ transplant recipients. We conducted a population-based cohort study using linked healthcare databases from Ontario, Canada to answer this question. We included solid organ transplant recipients (n = 12,842) as of December 14, 2020, with follow-up until November 28, 2021. We used an extended Cox proportional hazards model with vaccination status, including BNT162b2, mRNA-1273, and ChAdOx1 vaccines, modeled as a time-dependent exposure. Individuals started in the unvaccinated category (reference) and could contribute person-time to first, second, and third doses. Over a median follow-up of 349 days, 12.7% (n = 1632) remained unvaccinated, 54.1% (n = 6953) received 3 doses, and 488 (3.8%) tested positive for SARS-CoV-2 (of which 260 [53.3%] had a clinically important outcome [i.e., hospitalization or death]). Adjusted vaccine effectiveness against infection was 31% (95% CI: 2, 51%), 46% (95% CI: 21, 63%), and 72% (95% CI: 43, 86%) for one, two, and three doses. Vaccine effectiveness against clinically important outcomes was 38% (95% CI: 4, 61%), 54% (95% CI: 23, 73%), and 67% (95% CI: 11, 87%). Vaccine effectiveness in solid organ transplant recipients is lower than the general population, however, vaccine effectiveness improved following a third dose.

Quantifying excess deaths among solid organ transplant recipients in the COVID-19 era.

Estimating the total coronavirus disease 2019 (COVID-19) mortality burden of solid organ transplant recipients (SOTRs), both directly through COVID-19 infection and indirectly through other impacts on the healthcare system and society, is critical for understanding the disease's impact on the SOTR population. Using SRTR data, we modeled expected mortality risk per month pre-COVID (January 2015-February 2020) for kidney/liver/heart/lung SOTRs, and compared monthly COVID-era deaths (March 2020-March 2021) to expected rates, overall and among subgroups. Deaths above expected rates were designated "excess deaths." Between March 2020 and March 2021, there were 3739/827/265/252 excess deaths among kidney/liver/heart/lung SOTRs, respectively, representing a 41.2%/27.4%/18.5%/15.0% increase above expected deaths. 93.0% of excess deaths occurred in patients age≥50. The observed:expected ratio was highest among Hispanic SOTRs (1.82) and lowest among White SOTRs (1.20); 56.0% of excess deaths occurred among Black or Hispanic SOTRs. 64.7% of excess deaths occurred among patients who had survived ≥5 years post-transplant. Excess deaths peaked in January 2021; geographic distribution of excess deaths broadly mirrored COVID-19 incidence. COVID-19 likely caused over 5000 excess deaths among SOTRs in the US in a 13-month period, representing 1 in 75 SOTRs and a substantial proportion of all deaths among SOTRs during this time. SOTRs will remain at elevated mortality risk until the COVID-19 pandemic can be controlled.

Survey of current transplant center practices regarding COVID-19 vaccine mandates in the United States.

An electronic survey canvassing current policies of transplant centers regarding a COVID-19 vaccine mandate for transplant candidates and living donors was distributed to clinicians at US solid organ transplant centers performing transplants from October 14, 2021-November 15, 2021. Responses were received from staff at 141 unique transplant centers. These respondents represented 56.4% of US transplant centers, and responding centers performed 78.5% of kidney transplants and 82.4% of liver transplants in the year prior to survey administration. Only 35.7% of centers reported implementing a vaccine mandate, while 60.7% reported that vaccination was not required. A minority (42%) of responding centers with a vaccine mandate for transplant candidates also mandated vaccination for living organ donors. Centers with a vaccine mandate most frequently cited clinical evidence supporting the efficacy of pre-transplant vaccination (82%) and stewardship obligations to ensure organs were transplanted into the lowest risk patients (64%). Centers without a vaccine mandate cited a variety of reasons including administrative, equity, and legal considerations for their decision. Transplant centers in the United States exhibit significant heterogeneity in COVID-19 vaccination mandate policies for transplant candidates. While all centers encourage vaccination, most centers have not mandated COVID-19 vaccination for candidates and living donors, citing administrative opposition, legal prohibitions, and concern about equity in access to transplants.

A third dose of SARS-CoV-2 vaccine increases neutralizing antibodies against variants of concern in solid organ transplant recipients.

Vaccine-induced SARS-CoV-2 antibody responses are attenuated in solid organ transplant recipients (SOTRs) and breakthrough infections are more common. Additional SARS-CoV-2 vaccine doses increase anti-spike IgG in some SOTRs, but it is uncertain whether neutralization of variants of concern (VOCs) is enhanced. We tested 47 SOTRs for clinical and research anti-spike IgG, pseudoneutralization (ACE2 blocking), and live-virus neutralization (nAb) against VOCs before and after a third SARS-CoV-2 vaccine dose (70% mRNA, 30% Ad26.COV2.S) with comparison to 15 healthy controls after two mRNA vaccine doses. We used correlation analysis to compare anti-spike IgG assays and focused on thresholds associated with neutralization. A third SARS-CoV-2 vaccine dose increased median total anti-spike (1.6-fold), pseudoneutralization against VOCs (2.5-fold vs. Delta), and neutralizing antibodies (1.4-fold against Delta). However, neutralization activity was significantly lower than healthy controls (p < .001); 32% of SOTRs had zero detectable nAb against Delta after third vaccination compared to 100% for controls. Correlation with nAb was seen at anti-spike IgG >4 Log10 (AU/ml) on the Euroimmun ELISA and >4 Log10 (AU/ml) on the MSD research assay. These findings highlight benefits of a third vaccine dose for some SOTRs and the need for alternative strategies to improve protection in a significant subset of this population.

Insufficient response to mRNA SARS-CoV-2 vaccine and high incidence of severe COVID-19 in kidney transplant recipients during pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination may fail to sufficiently protect transplant recipients against coronavirus disease 2019 (COVID-19). We retrospectively evaluated COVID-19 in kidney transplant recipients (n = 226) after BNT162b2 mRNA vaccine administration. The control group consisted of unvaccinated patients (n = 194) during the previous pandemic wave. We measured anti-spike protein immunoglobulin G (IgG) levels and cellular responses, using enzyme-linked immunosorbent spot assay, in a prospective cohort after vaccination (n = 31) and recovery from COVID-19 (n = 19). COVID-19 was diagnosed in 37 (16%) vaccinated and 43 (22%) unvaccinated patients. COVID-19 severity was similar in both groups, with patients exhibiting a comparable need for hospitalization (41% vs. 40%, p = 1.000) and mortality (14% vs. 9%, p = .726). Short posttransplant periods were associated with COVID-19 after vaccination (p < .001). Only 5 (16%) patients achieved positive SARS-CoV-2 IgG after vaccination, and 17 (89%, p < .001) recovered from COVID-19 (median IgG levels, 0.6 vs. 52.5 AU/ml, p < .001). A cellular response following vaccination was present in the majority (n = 22, 71%), with an increase in interleukin 2 secreting T cells (p < .001). Despite detectable T cell immunity after mRNA vaccination, kidney transplant recipients remained at a high risk of severe COVID-19. Humoral responses induced by vaccination were significantly lower than that after COVID-19.

Intensity of mycophenolate mofetil treatment is associated with an impaired immune response to SARS-CoV-2 vaccination in kidney transplant recipients.

Kidney transplant recipients (KTRs) are extremely vulnerable to SARS-CoV-2 infection and show an impaired immune response to SARS-CoV-2 vaccination. We analyzed factors related to vaccination efficiency in KTRs. In a multicenter prospective observational study (NCT04743947), IgG antibodies levels against SARS-CoV-2 spike S1 subunit and their neutralization capacity after SARS-CoV-2 vaccination were analyzed in 225 KTRs and compared to 176 controls. After the vaccination, 56 (24.9%) KTRs became seropositive of whom 68% had neutralizing antibodies. This immune response was significantly lower compared to controls (239 [78-519] BAU/ml versus 1826 [560-3180] BAU/ml for KTRs and controls, p < .0001). The strongest predictor for an impaired response was mycophenolate mofetil (MMF) treatment. Multivariate regression analysis revealed that MMF-free regimen was highly associated with seroconversion (OR 13.25, 95% CI 3.22-54.6; p < .001). In contrast, other immunosuppressive drugs had no significant influence. 187 out of 225 KTRs were treated with MMF of whom 26 (13.9%) developed antibodies. 23 of these seropositive KTRs had a daily MMF dose ≤1 g. Furthermore, higher trough MMF concentrations correlated with lower antibody titers (R -0.354, p < .001) supporting a dose-dependent unfavorable effect of MMF. Our data indicate that MMF dose modification could lead to an improved immune response.

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.