The clinical characteristics, management, and outcome of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) after solid organ transplant (SOT) ...remain unknown. We report our preliminary experience with 18 SOT (kidney 44.4%, liver 33.3%, and heart 22.2%) recipients diagnosed with COVID‐19 by March 23, 2020 at a tertiary‐care center at Madrid. Median age at diagnosis was 71.0 ± 12.8 years, and the median interval since transplantation was 9.3 years. Fever (83.3%) and radiographic abnormalities in form of unilateral or bilateral/multifocal consolidations (72.2%) were the most common presentations. Lopinavir/ritonavir (usually associated with hydroxychloroquine) was used in 50.0% of patients and had to be prematurely discontinued in 2 of them. Other antiviral regimens included hydroxychloroquine monotherapy (27.8%) and interferon‐β (16.7%). As of April 4, the case‐fatality rate was 27.8% (5/18). After a median follow‐up of 18 days from symptom onset, 30.8% (4/13) of survivors developed progressive respiratory failure, 7.7% (1/13) showed stable clinical condition or improvement, and 61.5% (8/13) had been discharged home. C‐reactive protein levels at various points were significantly higher among recipients who experienced unfavorable outcome. In conclusion, this frontline report suggests that SARS‐CoV‐2 infection has a severe course in SOT recipients.
In the present experience with 18 transplant recipients diagnosed with COVID‐19 by March 23, 2020 at their institution in Madrid, the authors found a case fatality rate of 27.8%, with 30.8% of survivors developing progressive respiratory failure or acute respiratory distress syndrome.
The replication kinetics of nonpathogenic anelloviruses belonging to the Alphatorquevirus genus (such as torque teno virus) might reflect the overall state of posttransplant immunosuppression. We ...analyzed 221 kidney transplant (KT) recipients in whom plasma alphatorquevirus DNA load was quantified by real‐time polymerase chain reaction at baseline and regularly through the first 12 posttransplant months. Study outcomes included posttransplant infection and a composite of opportunistic infection and/or de novo malignancy (immunosuppression‐related adverse event iRAE). Alphatorquevirus DNA loads at month 1 were higher among patients who subsequently developed posttransplant infection (P = .023) or iRAE (P = .009). Likewise, those with iRAE beyond months 3 and 6 also exhibited higher peak viral loads over the preceding periods. Areas under the curve for log10 alphatorquevirus DNAemia estimated by months 1 or 6 were significantly higher in patients experiencing study outcomes. Alphatorquevirus DNA loads above 3.15 and 4.56 log10 copies/mL at month 1 predicted the occurrence of posttransplant infection (adjusted hazard ratio aHR: 2.88; 95% confidence interval CI: 1.13‐7.36; P = .027) and iRAE (aHR: 5.17; 95% CI: 2.01‐13.33; P = .001). In conclusion, posttransplant monitoring of plasma alphatorquevirus DNA kinetics may be useful to identify KT recipients at increased risk of immunosuppression‐related complications.
In this single‐center prospective cohort study, the kinetics of plasma alphatorquevirus (highly prevalent, nonpathogenic anelloviruses) DNA levels were found to be associated with the occurrence of overall infection and immunosuppression‐related adverse events in kidney transplant recipients, suggesting a potential role as a surrogate marker of the overall amount of posttransplant immunosuppression.
Coronavirus disease 2019 (COVID‐19) can lead to a massive cytokine release. The use of the anti‐interleukin‐6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this ...hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID‐19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6‐point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6‐point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon‐β (adjusted odds ratio aOR: 0.23; 95% confidence interval CI: 0.06‐0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06‐0.99; P = .048) were negatively associated with clinical improvement by day 7. All‐cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C‐reactive protein levels dropped by day 2. There were no TCZ‐attributable adverse events. In this observational single‐center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID‐19 pneumonia.
Highlights
COVID‐19 can lead to a hyperinflammatory state that mirrors the cytokine release syndrome.
The off‐labeluse of the anti‐interleukin‐6 receptor monoclonal antibody tocilizumab has been proposed to abrogate this deleterious inflammatory response, although the supporting evidence is scarce.
In the present single‐centre study comprising 88 consecutive patients with COVID‐19 pneumonia that received at least one dose of intravenous tocilizumab between March 16 and 27, 2020, the rates of clinical improvement (defined by discharge to home and/or a decrease of = 2 points on a six‐point ordinal scale) were 44.3% (39/88) and 73.9% (65/88) by days 7 and 14, respectively.
The previous or concomitant use of interferon‐β and baseline serum lactate dehydrogenase levels >450 U/L were negatively associated with clinical improvement by day 7. All‐cause mortality was 6.8%, with no tocilizumab‐attributable adverse events.
Monitoring for cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) may be useful for individualizing valganciclovir (VGCV) prophylaxis after kidney transplantation (KT). We performed a ...commercial ELISA‐based interferon (IFN)‐γ release assay (QTF‐CMV) from posttransplant months 2‐5 (362 points) in 120 CMV‐seropositive KT recipients that received antithymocyte globulin as induction therapy and VGCV prophylaxis (median of 92 days). Forty‐seven patients (39.3%) had CMV infection after discontinuation of prophylaxis. The QTF‐CMV assay was reactive, nonreactive, and indeterminate in 264 (72.9%), 90 (24.9%), and 8 points (2.2%). The QTF‐CMV assay at prophylaxis discontinuation exhibited suboptimal accuracy for predicting protective CMV‐CMI (sensitivity: 77.4%; specificity: 34.3%; positive predictive value PPV: 64.1%; negative predictive value NPV: 50.0%), with no differences in 1‐year CMV infection rates between patients with negative (nonreactive or indeterminate) or reactive results (45.8% vs 36.1%; P = .244). Specificity and PPV to predict protective CMV‐CMI improved by elevating the IFN‐γ cutoff value to 1.13 IU/mL (65.7% and 71.4%) and 7.0 IU/mL (85.7% and 76.2%), although NPVs decreased. The QTF‐CMV assay as per manufacturer's interpretative criteria performed poorly to predict protection from CMV infection following discontinuation of VGCV prophylaxis among ATG‐treated CMV‐seropositive KT recipients. This performance is slightly improved by modifying the IFN‐γ positivity threshold.
This study of CMV‐seropositive kidney transplant recipients who received induction therapy with antithymocyte globulin demonstrates that monitoring of cell‐mediated immunity with a commercial ELISA‐based interferon‐γ release assay performed poorly to predict protection from CMV infection following discontinuation of valganciclovir prophylaxis. See Kumar and Humar’s editorial on page 1961.
To investigate risk factors for invasive aspergillosis (IA) after kidney transplantation (KT), we conducted a systematic search in PubMed and EMBASE to identify studies published until June 2020. We ...included case‐control or cohort design studies comprising KT recipients with a diagnosis of IA, defined according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria, and assessed risk factors for the development of IA. Random‐effect models meta‐analysis served to pool data. We identified eleven case‐control studies (319 IA cases and 835 controls). There was an increased risk of IA among recipients with underlying chronic lung diseases (odds ratio OR = 7.26; 95% confidence interval CI = 1.05‐50.06) and among those with diabetic nephropathy (OR = 1.65; 95% CI = 1.10‐2.48). Requiring posttransplant hemodialysis (OR = 3.69; 95% CI = 2.13‐6.37) or surgical reintervention (OR = 6.28; 95% CI = 1.67‐23.66) were also associated with an increased risk. Moreover, a positive link was identified between IA and posttransplant bacterial infection (OR = 7.51; 95% CI = 4.37‐12.91), respiratory tract viral infection (OR = 7.75; 95% CI = 1.60‐37.57), cytomegalovirus infection or disease (OR = 2.67; 95% CI = 1.12‐6.32), and acute graft rejection (OR = 3.01; 95% CI = 1.78‐5.09). In contrast, receiving a kidney from a living donor was associated with a reduced risk (OR = 0.65; 95% CI = 0.46‐0.93). KT recipients that accumulate several of these conditions should be closely monitored and a low threshold of suspicion for IA should be maintained. Future studies should explore the benefit of mold‐active prophylaxis to this subgroup of KT recipients at highest risk.
The authors identify several risk factors associated with the development of invasive aspergillosis in kidney transplant recipients.
Heart transplant recipients (HTr) have a higher probability of suffer from severe coronavirus disease-2019 (COVID-19) in comparison to general population, but their risk has changed over the course ...of the pandemic in relation to various factors. We conducted a prospective study including all HTr at risk of COVID-19 in a tertiary center between February 2020 and October 2022. The aim was to analyze how the prognosis (incidence of pneumonia and mortality) of COVID-19 in HTr has evolved over time, contextualizing variants, vaccination, and other treatments.
Of 308 HTr included, 124 got the infection (39.2%). COVID and non-COVID HTr had similar baseline characteristics. COVID-19 patients with pneumonia had a poorer prognosis than those with less severe presentations, with a higher rate of hospitalization (93.3 vs. 14.1%, p < .001) and death (41.0 vs. 1.2%, p < .001). Multivariate analysis identified age ≥60 years (odds ratio OR 3.65, 95% confidence interval CI 1.16-11.49, p = .027), and chronic kidney disease ≥3a (OR 4.95, 95% CI 1.39-17.54, p = .014) as predictors of pneumonia. Two-dose vaccination (OR 0.20, CI 95% 0.05-0.72, p = .02) and early remdesivir administration (OR 0.17, CI 0.03-0.90, p = .037) were protective factors. Over the course of the pandemic considering three periods in the follow-up (prevaccination February-December 2020, postvaccination January-December 2021, and post early remdesivir indication January-October 2022), we observed a reduction in pneumonia incidence from 62% to 19% (p < .001); and mortality (from 23% to 4%, p < .001).
The prognosis of COVID-19 in HTr has improved over time, likely due to vaccination and early administration of remdesivir.
A potential benefit of immunomodulatory agents such as tocilizumab (TCZ) has been reported in patients with coronavirus disease 2019 (COVID‐19) and severe pulmonary involvement. However, this therapy ...has been scarcely studied in kidney transplant (KT) recipients. Herein, we describe the clinical course and outcome of 10 KT patients with severe COVID‐19 that were treated with TCZ. Mean age of the study group was 54 ± 10 years (70% females), and 30% of the cases were within 6 months from transplant. Mycophenolate mofetil was discontinued in all cases upon admission, whereas baseline steroids were maintained and tacrolimus dose was reduced. Initial treatment included hydroxychloroquine, antibiotics, and prophylactic anticoagulation. Before treatment with TCZ, 3 patients were receiving high‐flow oxygen, 4 patients low‐flow oxygen and 1 case non‐invasive ventilation. All patients received a single dose of intravenous TCZ within a mean time of 7 ± 4 days since admission. During a median follow‐up of 16 days (IQR: 10‐29), 7 patients (70%) gradually improved and were finally discharged while three cases (30%) did not exhibited clinical improvement and ultimately died. In conclusion, although treatment with TCZ could be associated with improved clinical outcomes in a subset of KT recipients with COVID‐19, further studies are warranted before drawing firm conclusions.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in ...the general population, scarce information is available regarding coronavirus disease 2019 (COVID‐19)‐associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID‐19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)‐β‐d‐glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.
The best method for monitoring cytomegalovirus (CMV)‐specific cell‐mediated immunity (CMV‐CMI) among high‐risk kidney transplant (KT) recipients remains uncertain. We assessed CMV‐CMI by ...intracellular cytokine staining (ICS) by flow cytometry and a commercial interferon (IFN)‐γ release assay (QuantiFERON®‐CMV QTF‐CMV) at posttransplant months 3, 4, and 5 in 53 CMV‐seropositive KT recipients that had received induction therapy with antithymocyte globulin (ATG) and a 3‐month course of valganciclovir prophylaxis. The discriminative capacity (areas under receiver operating characteristics curve auROCs) and diagnostic accuracy to predict immune protection against CMV infection from the discontinuation of prophylaxis to month 12 were compared between both methods. There was significant although moderate correlations between CMV‐specific IFN‐γ‐producing CD8+ T‐cell counts enumerated by ICS and IFN‐γ levels by QTF‐CMV at months 3 (rho: 0.493; p = 0.005) and 4 (rho: 0.440; p = 0.077). The auROCs for CMV‐specific CD4+ and CD8+ T‐cells by ICS were nonsignificantly higher than that of QTF‐CMV (0.696 and 0.733 vs. 0.678; p = 0.900 and 0.692, respectively). The optimal cut‐off of ≥0.395 CMV‐specific CD8+ T‐cells yielded a sensitivity of 86.4%, specificity of 54.6%, positive predictive value of 79.2% and negative predictive value of 66.7% to predict protection. The corresponding estimates for QTF‐CMV (IFN‐γ levels ≥0.2 IU/mL) were 78.9%, 37.5%, 75.0%, and 42.9%, respectively. The enumeration of CMV‐specific IFN‐γ‐producing CD8+ T‐cells at the time of cessation of prophylaxis performed slightly better than the QTF‐CMV assay to predict immune protection in seropositive KT recipients previously treated with ATG.
Whether immunosuppression impairs severe acute respiratory syndrome coronavirus 2‐specific T cell–mediated immunity (SARS‐CoV‐2‐CMI) after liver transplantation (LT) remains unknown. We included 31 ...LT recipients in whom SARS‐CoV‐2‐CMI was assessed by intracellular cytokine staining (ICS) and interferon (IFN)‐γ FluoroSpot assay after a median of 103 days from COVID‐19 diagnosis. Serum SARS‐CoV‐2 IgG antibodies were measured by ELISA. A control group of nontransplant immunocompetent patients were matched (1:1 ratio) by age and time from diagnosis. Post‐transplant SARS‐CoV‐2‐CMI was detected by ICS in 90.3% (28/31) of recipients, with higher proportions for IFN‐γ‐producing CD4+ than CD8+ responses (93.5% versus 83.9%). Positive spike‐specific and nucleoprotein‐specific responses were found by FluoroSpot in 86.7% (26/30) of recipients each, whereas membrane protein‐specific response was present in 83.3% (25/30). An inverse correlation was observed between the number of spike‐specific IFN‐γ‐producing SFUs and time from diagnosis (Spearman's rho: −0.418; p value = .024). Two recipients (6.5%) failed to mount either T cell–mediated or IgG responses. There were no significant differences between LT recipients and nontransplant patients in the magnitude of responses by FluoroSpot to any of the antigens. Most LT recipients mount detectable—but declining over time—SARS‐CoV‐2‐CMI after a median of 3 months from COVID‐19, with no meaningful differences with immunocompetent patients.
This single‐center study shows that, after a median of 103 days from diagnosis, the majority of liver transplant recipients recovered from COVID‐19 exhibit SARS‐CoV‐2‐specific cell‐mediated immunity detectable by two different methods that was comparable to nonimmunocompromised control patients.
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