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Background: Information on the clinical characteristics and pathophysiological mechanisms underlying post-COVID-19 fatigue are scarce. The main objective of this study was to evaluate sex-specific humoral and T-cell responses associated with post-COVID-19 fatigue in a sample of individuals treated as outpatients. Methods: At a median time of 279 (179;325) days after the acute infection, a total of 281 individuals (45.9% men) aged 18-87 years old were included in the analysis. The participants were examined at the University Hospital of Augsburg, Southern Germany. Fatigue was assessed using the Fatigue Assessment Scale (FAS). Levels of anti-SARS-CoV2-spike IgG antibodies were measured by an enzyme-linked immunosorbent assay (ELISA), and for exploration of the SARS-CoV2-specific T-cell response, ex vivo ELISpot/FLUOROspot assays were conducted using an interferon-γ (IFN-γ) and interleukin-2 (IL-2) SARS-CoV-iSpot kit. Results: Women more significantly suffered from post-COVID-19 fatigue in comparison to men (47.4% versus 25.6%, p=0.0002). Females but not males with fatigue showed a significantly lower number of T-cells producing IFN-γ, IL-2 or both IL-2 and IFNγ in comparison with females without fatigue. In both sexes, serum levels of anti-SARS-CoV2-spike IgG antibodies did not differ significantly between participants with or without fatigue. Conclusions: Development of fatigue after acute COVID-19 disease might be associated with SARS-CoV-2-specific T-cell responses in women, but not men after a mild infection course treated outpatient. [ABSTRACT FROM AUTHOR]

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines. [ABSTRACT FROM AUTHOR]

We conducted a prospectively randomised clinical trial to investigate the role of adjuvant outpatient immunochemotherapy administered postoperatively in high-risk patients with renal cell carcinoma. In total, 203 renal carcinoma patients' status post radical tumour nephrectomy were stratified into three risk groups: patients with tumour extending into renal vein/vena cava or invading beyond Gerota's fascia (pT3b/c pN0 or pT4pN0), patients with locoregional lymph node infiltration (pN+), and patients after complete resection of tumour relapse or solitary metastasis (R0). Patients were randomised to undergo either (A) 8 weeks of outpatient subcutaneous interleukin-2 (sc-rIL-2), subcutaneous interferon-alpha2a (sc-rIFN-alpha2a), and intravenous 5-fluorouracil (iv-5-FU) according to the standard Atzpodien regimen (Atzpodien et al, 2004) or (B) observation. Two-, 5-, and 8-year survival rates were 81, 58, and 58% in the treatment arm, and 91, 76, and 66% in the observation arm (log rank P=0.0278), with a median follow-up of 4.3 years. Two, 5-, and 8-year relapse-free survival rates were calculated at 54, 42, and 39% in the treatment arm, and at 62, 49, and 49% in the observation arm (log rank P=0.2398). Stage-adapted subanalyses revealed no survival advantages of treatment over observation, as well. Our results established that there was no relapse-free survival benefit and the overall survival was inferior with an adjuvant 8-week-outpatient sc-rIL-2/sc-rIFN-alpha2a/iv-5-FU-based immunochemotherapy compared to observation in high-risk renal cell carcinoma patients following radical tumour nephrectomy. [ABSTRACT FROM AUTHOR]

The prognosis for patients with metastatic renal cell carcinoma (RCC) remains unsatisfactory to date. Combined immunochemotherapy (ICT) strives for a synergistic effect avoiding a substantial increase of therapy-related adverse events. The combination therapy regimes consisting of either interferon-alpha-2a/vinblastine (IFN-alpha2a/VBL) or interferon-alpha-2a/interleukin-2/5-fluorouracil (IFN-alpha2a/IL-2/5-FU) demonstrated objective remission rates, surpassing the results obtained with the administration of single immunotherapeutic agents. Despite the data from a recently published study, the role of these two therapy combinations did not seem clearly defined. Therefore, we compared the impact of IFN-alpha2a/VBL and IFN-alpha2a/IL-2/5-FU on remission and survival as well as the safety profile in a retrospective study in patients with metastatic RCC. In a retrospective single-center study, 105 patients with metastatic RCC having received treatment between 1992 and 2002 with either s.c. IFN-alpha2a/ i.v. VBL ( n=70, group 1) or s.c. IFN-alpha2a/ s.c. IL-2/ i.v. 5-FU ( n=35, group 2) were evaluated. At a median follow-up of 17 months, remission and survival rates as well as the toxicity profiles of the respective groups were documented and compared. The median age throughout the entire patient population was 61 years. Patients in the IFN-alpha2a/VBL group reached a median overall survival of 20 months compared to 17 months for the patients in the IFN-alpha2a/IL-2/5-FU population ( p=0.850). The objective response rate in the first patient group reached 25.7%, whereas the tumor remission rate of group 2 amounted to 22.9% ( p=0.680). Patients showing an objective response reached a significantly higher survival rate than patients without response reaction (median survival was 36 vs 10 months, p=0.0001). The incidence of each therapy-induced adverse event was higher throughout the second treatment group. These differences were significant with respect to flu-like symptoms (85.7 vs 57.1%, p=0.003), grade 3/4 elevations of liver enzymes (14.3 vs 1.4%, p=0.007), nausea/vomiting (74.3 vs 50%, p=0.017), the severity of erythemas (74.3 vs 10%, p<0.001), and patients with lung edema (17.1 vs 2.9%, p=0.009). Eight patients discontinued the ICT, two of whom died of a myocardial infarction.Despite an overall limited prognosis, patients showing a tumor remission seem to benefit from ICT in terms of overall survival. While both treatment options offer comparable remission and survival rates, the IFN-alpha2a/VBL regimen induces fewer adverse events than the treatment with IFN-alpha2a/IL-2/5-FU. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration (FDA) approved Zinbryta, an interleukin-2 receptor blocking antibody (daclizumab; Biogen and AbbVie) for the treatment of adults with relapsing forms of multiple sclerosis (MS) in May, 2016. It was also approved by the European Union in July, 2016. Zinbryta is a long-acting, self-administered monthly injection that was branded as a new MS drug for patients who needed a "new option for treatment." It blocks interleukin-2 receptor alpha (CD25) and modulates T-cell expansion. The drug was withdrawn from the market in March, 2018 following 12 reports from Germany (9), United States (2), and Spain (1) following the development of "inflammatory encephalitis and meningoencephalitis" in patients on Zinbryta. Although cases of hepatotoxicity made news with Zinbryta earlier along this drug's postmarketing journey in the treatment of patients with MS, the European Medicines Agency (EMA) ordered a review of the risks of hepatotoxicity with Zinbryta use June, 2017; this analysis will focus on the pharmacovigilance data concerning the central nervous system (CNS) complications. The details of the CNS complications have been elucidated by EMA. Every drug failure provides an opportunity for learning, but it is also noteworthy that no FDA-approved MS drug in modern times has met with such an untimely, sudden, and inglorious exit. This should serve as a cautionary tale for all clinicians who use "newer MS drugs" that have mushroomed in recent memory following a flurry of recent FDA approvals. [ABSTRACT FROM AUTHOR]