Recombinant human interleukin-7 reverses T cell exhaustion ex vivo in critically ill COVID-19 patients

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

Feasibility of non-invasive respiratory drive and breathing pattern evaluation using CPAP in COVID-19 patients.

PURPOSE: Increased respiratory drive and respiratory effort are major features of acute hypoxemic respiratory failure (AHRF) and might help to predict the need for intubation. We aimed to explore the feasibility of a non-invasive respiratory drive evaluation and describe how these parameters may help to predict the need for intubation. MATERIALS AND METHODS: We conducted a prospective observational study. All consecutive patients with COVID-19-related AHRF requiring high-flow nasal cannula (HFNC) were screened for inclusion. Physiologic data (including: occlusion pressure (P0.1), tidal volume (Vt), inspiratory time (Ti), peak and mean inspiratory flow (Vt/Ti)) were collected during a short continuous positive airway pressure (CPAP) session. Measurements were repeated once, 12-24 h later. RESULTS: Measurements were completed in 31 patients after the screening of 45 patients (70%). P0.1 was high (4.4 [2.7-5.1]), but it was not significantly higher in patients who were intubated. The Vt (p = .006), Vt/Ti (p = .019), minute ventilation (p = .006), and Ti/Ttot (p = .003) were higher among intubated patients compared to non-intubated patients. Intubated patients had a significant increase in their diaphragm thickening fraction, Vt, and Vt/Ti over time. CONCLUSIONS: Non-invasive assessment of respiratory drive was feasible in patients with AHRF and showed an increased P0.1, although it was not predictive of intubation.

Lung ultrasound score as a tool to monitor disease progression and detect ventilator-associated pneumonia during COVID-19-associated ARDS.

BACKGROUND: Lung ultrasound can accurately detect pandemic coronavirus disease (COVID-19) pulmonary lesions. A lung ultrasound score (LUS) was developed to improve reproducibility of the technique. OBJECTIVES: To evaluate the clinical value of LUS monitoring to guide COVID-19-associated acute respiratory distress syndrome (ARDS) management. METHODS: We conducted a single center, prospective observational study, including all patients admitted with COVID-19-associated ARDS between March and April 2020. A systematic daily LUS evaluation was performed. RESULTS: Thirty-three consecutive patients were included. LUS was significantly and negatively correlated to PaO2/FIO2. LUS increased significantly over time in non-survivors compared to survivors. LUS increased in 83% of ventilatory associated pneumonia (VAP) episodes, when compared to the previous LUS evaluation. LUS was not significantly higher in patients presenting post-extubation respiratory failure. CONCLUSIONS: In conclusion, our study demonstrates that LUS variations are correlated to disease severity and progression, and LUS monitoring could contribute to the early diagnosis of VAPs.

The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

Lung ultrasound score to monitor COVID-19 pneumonia progression in patients with ARDS.

COVID-19 pneumonia typically begins with subpleural ground glass opacities with progressive extension on computerized tomography studies. Lung ultrasound is well suited to this interstitial, subpleural involvement, and it is now broadly used in intensive care units (ICUs). The extension and severity of lung infiltrates can be described numerically with a reproducible and validated lung ultrasound score (LUSS). We hypothesized that LUSS might be useful as a tool to non-invasively monitor the evolution of COVID-19 pneumonia at the bedside. LUSS monitoring was rapidly implemented in the management of our COVID-19 patients with RT-PCR-documented COVID-19. The LUSS was evaluated repeatedly at the bedside. We present a graphic description of the course of LUSS during COVID-19 in 10 consecutive patients admitted in our intensive care unit with moderate to severe ARDS between March 15 and 30th. LUSS appeared to be closely related to the disease progression. In successfully extubated patients, LUSS decreased and was lower than at the time of intubation. LUSS increased inexorably in a patient who died from refractory hypoxemia. LUSS helped with the diagnosis of ventilator-associated pneumonia (VAP), showing an increased score and the presence of new lung consolidations in all 5 patients with VAPs. There was also a good agreement between CT-scans and LUSS as for the presence of lung consolidations. In conclusion, our early experience suggests that LUSS monitoring accurately reflect disease progression and indicates potential usefulness for the management of COVID-19 patients with ARDS. It might help with early VAP diagnosis, mechanical ventilation weaning management, and potentially reduce the need for X-ray and CT exams. LUSS evaluation is easy to use and readily available in ICUs throughout the world, and might be a safe, cheap and simple tool to optimize critically ill COVID-19 patients care during the pandemic.