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Patients with pre-existing comorbidities and immunosuppression are at greater risk for SARS-CoV-2 infection and severe manifestations of COVID-19. This also includes cancer patients, who are shown to have a poor prognosis after infection. Here, we describe the case of a 72-year old male patient with B-cell depletion after maintenance treatment with rituximab for non-Hodgkin-lymphoma who had a prolonged COVID-19 course and initial false negative test results. Our case highlights the diagnostic pitfalls in diagnosing COVID-19 in B-cell depleted patients and discuss the role of B-cell depletion in the course and treatment of COVID-19. Furthermore, we investigated peripheral blood monocytes and SARS-CoV-2 specific T cells in our patient. In conclusion, our case report can help physicians to avoid diagnostic pitfalls for COVID-19 in hemato-oncological patients under chemoimmunotherapy and tries to explain the role of B-cell depletion and SARS-CoV-2 specific T cells in this context.

Background Effective antimicrobial treatment is key to reduce mortality associated with bacterial sepsis in patients on intensive care units (ICUs). Dose adjustments are often necessary to account for pathophysiological changes or renal replacement therapy. Extracorporeal membrane oxygenation (ECMO) is increasingly being used for the treatment of respiratory and/or cardiac failure. However, it remains unclear whether dose adjustments are necessary to avoid subtherapeutic drug levels in septic patients on ECMO support. Here, we aimed to evaluate and comparatively assess serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO. Methods Between October 2018 and December 2019, we prospectively enrolled patients on a pneumological ICU in southwest Germany who received antibiotic treatment with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid. All antibiotics were applied using continuous infusion, and therapeutic drug monitoring of serum concentrations (expressed as mg/L) was carried out using high-performance liquid chromatography. Target concentrations were defined as fourfold above the minimal inhibitory concentration (MIC) of susceptible bacterial isolates, according to EUCAST breakpoints. Results The final cohort comprised 105 ICU patients, of whom 30 were treated with ECMO. ECMO patients were significantly younger (mean age: 47.7 vs. 61.2 years; p < 0.001), required renal replacement therapy more frequently (53.3% vs. 32.0%; p = 0.048) and had an elevated ICU mortality (60.0% vs. 22.7%; p < 0.001). Data on antibiotic serum concentrations derived from 112 measurements among ECMO and 186 measurements from non-ECMO patients showed significantly lower median serum concentrations for piperacillin (32.3 vs. 52.9; p = 0.029) and standard-dose meropenem (15.0 vs. 17.8; p = 0.020) in the ECMO group. We found high rates of insufficient antibiotic serum concentrations below the pre-specified MIC target among ECMO patients (piperacillin: 48% vs. 13% in non-ECMO; linezolid: 35% vs. 15% in non-ECMO), whereas no such difference was observed for ceftazidime and meropenem. Conclusions ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.

STRUCTURED ABSTRACTINTRODUCTIONHyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far.RATIONALEIn the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations.RESULTSPGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL-1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN-nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF-α signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found.CONCLUSIONTo conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

Early-onset obesity is known to culminate in type 2 diabetes, arterial hypertension and subsequent cardiovascular disease. The role of sodium (Na+) homeostasis in this process is incompletely understood, yet correlations between Na+ accumulation and hypertension have been observed in adults. We aimed to investigate these associations in adolescents. A cohort of 32 adolescents (13–17 years), comprising 20 obese patients, of whom 11 were hypertensive, as well as 12 age-matched controls, underwent 23Na-MRI of the left lower leg with a standard clinical 3T scanner. Median triceps surae muscle Na+ content in hypertensive obese (11.95 mmol/L [interquartile range 11.62–13.66]) was significantly lower than in normotensive obese (13.63 mmol/L [12.97–17.64]; p = 0.043) or controls (15.37 mmol/L [14.12–16.08]; p = 0.012). No significant differences were found between normotensive obese and controls. Skin Na+ content in hypertensive obese (13.33 mmol/L [11.53–14.22] did not differ to normotensive obese (14.12 mmol/L [13.15–15.83]) or controls (11.48 mmol/L [10.48–12.80]), whereas normotensive obese had higher values compared to controls (p = 0.004). Arterial hypertension in obese adolescents is associated with low muscle Na+ content. These findings suggest an early dysregulation of Na+ homeostasis in cardiometabolic disease. Further research is needed to determine whether this association is causal and how it evolves in the transition to adulthood.

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The SARS-CoV-2 pandemic has highlighted the need for improved technologies to help control the spread of contagious pathogens. While rapid point-of-need testing plays a key role in strategies to rapidly identify and isolate infectious patients, a cornerstone for any disease-control strategy, current test approaches have significant shortcomings related to assay limitations and sample type. Direct quantification of viral shedding in exhaled particles may offer a better rapid testing approach, since SARS-CoV-2 is believed to spread mainly by aerosols. It potentially measures contagiousness directly, the sample is easy to obtain, its production can be standardized between patients, and the limited sample volume lends itself to a fast and sensitive analysis. In view of these benefits, we developed and tested an approach where exhaled particles are efficiently sampled using inertial impaction in a micromachined silicon chip, followed by an in-situ RT-qPCR molecular assay to detect SARS-CoV-2 shedding. We demonstrate that sampling subjects using a one-minute breathing protocol, yields sufficient viral RNA to detect infections with a sensitivity comparable to standard sampling methods. A longitudinal study revealed clear differences in the temporal dynamics of viral load for nasopharyngeal swab, saliva, breath, and antigen tests. Overall, after an infection, the breath-based test is the first to consistently report a negative result, putatively signaling the end of contagiousness and further emphasizing the potential of this tool to help manage the spread of airborne respiratory infections.