Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin‐6 (IL‐6) release. The IL‐6‐receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID‐19) . In this pandemic, kidney transplant (KT) recipients are a high‐risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID‐19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL‐6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D‐dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C‐reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004‐1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID‐19 but randomized trials are needed.

SARS‐CoV‐2 infection has produced high mortality in kidney transplant (KT) recipients, especially in the elderly. Until December 2020, 1011 KT with COVID‐19 have been prospectively included in the Spanish Registry and followed until recovery or death. In multivariable analysis, age, pneumonia, and KT performed ≤6 months before COVID‐19 were predictors of death, whereas gastrointestinal symptoms were protective. Survival analysis showed significant increasing mortality risk in four subgroups according to recipient age and time after KT (age <65 years and posttransplant time >6 months, age <65 and time ≤6, age ≥65 and time >6 and age ≥65 and time ≤6): mortality rates were, respectively, 11.3%, 24.5%, 35.4%, and 54.5% (p < .001). Patients were significantly younger, presented less pneumonia, and received less frequently specific anti‐COVID‐19 treatment in the second wave (July–December) than in the first one (March–June). Overall mortality was lower in the second wave (15.1 vs. 27.4%, p < .001) but similar in critical patients (66.7% vs. 58.1%, p = .29). The interaction between age and time post‐KT should be considered when selecting recipients for transplantation in the COVID‐19 pandemic. Advanced age and a recent KT should foster strict protective measures, including vaccination.

Background. Coronavirus infectious disease 2019 (COVID-19) pandemic has posed at risk the kidney transplant (KT) population. We describe clinical pictures, risk factors for death, and chances to recovery in a large cohort of KT recipients with COVID-19. Methods. Inclusion in a Spanish prospectively filled registry was allowed for KT cases with confirmed COVID-19. Outcomes were assessed as in-hospital mortality or recovery. Results. The study population comprised of 414 patients. Fever, respiratory symptoms, and dyspnea were the most frequent COVID-19-related symptoms, and 81.4% of them had pneumonia. More than one-third of patients showed digestive symptoms at diagnosis, combinations of nausea, vomiting, and diarrhea. Most patients were hospitalized, 12.1% in intensive care units, and 17.6% needed ventilator support. Treatment for COVID-19 included frequently hydroxychloroquine, azithromycin, high-dose steroids, lopinavir/ritonavir, and tocilizumab. After a mean follow-up of 44 days, the fatality rate was 26.3%. Pneumonia without gastrointestinal symptoms was associated with a 36.3% mortality (respiratory phenotype), and gastrointestinal symptoms without pneumonia with a 5.3% mortality (gastrointestinal phenotype). The mixed pneumonia and gastrointestinal phenotype showed an intermediate mortality of 19.5% (mixed phenotype). Multivariate Cox regression analysis showed that age and pneumonia were independently associated with death, whereas the gastrointestinal phenotype was associated with recovery. Conclusions. COVID-19 is frequent among the KT population. Advanced age and pneumonia are the main clinical features associated with a high-mortality rate. Gastrointestinal disease is associated with a more benign course and lower mortality.

Patient 2 commenced pembrolizumab 200 mg every 3 wk in November 2016; his PSA was 0.43 mg/l and scans revealed bilateral pelvic nodes, a large pelvic mass (53 mm), and a complex fistula between the rectum and bladder. He received 11 pembrolizumab courses with no immunological toxicity and experienced a partial response. However, pembrolizumab was stopped because of fistula worsening requiring intravenous antibiotics and surgical intervention. He made a full recovery and remains disease-free 40 mo after starting pembrolizumab (Fig. 1F,G). Tumour NGS had indicated an MSH6 mutation (Y214*), high MutLoad, and high MSINGS score, with MSH6 loss but incomplete MSH2 loss on IHC, as well as PD-L1 positivity (1%). IHC showed high TILs; most of these cells were CD4 + FOXP3 and Tregs (CD4 + FOXP3 + ; Fig. 1H). We previously showed that a small but important subset of mCRPC tumours have evidence of MMRd by IHC and this is associated with high MutLoad and MSI-NGS. However, only some MMRd cancers present with high T-cell infiltration, PD-L1 protein expression, and elevated T-cell-associated transcripts [2]. The rearrangement identified for patient 1 was associated with immune evasion and PD-L1 overexpression in mouse models using an N-terminal binding antibody [4]. This could explain his PD-L1 negativity (since the antibodies routinely used target the C-terminus) and extraordinary response to pembrolizumab in an otherwise immune "cold" tumour. Patient 2, besides MMRd, presented with a highly inflamed cancer, mainly represented by Tregs and CD4 + FOXP3 cells. Interestingly, in mCRPC models, ICIs reprogram CD4 + cells towards a Th1 rather than Th17 lineage in nodal disease, possibly explaining this responsiveness [5]. In conclusion, elucidation of the mCRPC subset benefiting from ICIs requires multiple orthogonal assays, including genomic analyses, IHC, and tumour microenvironment studies.

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