High Flow Nasal Oxygen in frail COVID-19 patients hospitalized in intermediate care units and non-eligible to invasive mechanical ventilation

Background in COVID-19 patients, older age (sixty or older), comorbidities, and frailty are associated with a higher risk for mortality and invasive mechanical ventilation (IMV) failure. It therefore seems appropriate to suggest limitations of care to older and vulnerable patients with severe COVID-19 pneumonia and a poor expected outcome, who would not benefit from invasive treatment. HFNO (high flow nasal oxygen) is a non-invasive respiratory support device already used in de novo acute respiratory failure. The main objective of this study was to evaluate the survival of patients treated with HFNO outside the ICU (intensive care unit) for a severe COVID-19 pneumonia, otherwise presenting limitations of care making them non-eligible for IMV. Secondary objectives were the description of our cohort and the identification of prognostic factors for HFNO failure. Methods we conducted a retrospective cohort study. We included all patients with limitations of care making them non-eligible for IMV and treated with HFNO for a severe COVID-19 pneumonia, hospitalized in a COVID-19 unit of the pulmonology department of Lyon Sud University Hospital, France, from March 2020 to March 2021. Primary outcome was the description of the vital status at day-30 after HFNO initiation, using the WHO (World Health Organization) 7-points ordinal scale. Results fifty-six patients were included. Median age was 83 years [76.3-87.0], mean duration for HFNO was 7.5 days, 53% had a CFS score (Clinical Frailty Scale) >4. At day-30, 73% of patients were deceased, one patient (2%) was undergoing HFNO, 9% of patients were discharged from hospital. HFNO failure occurred in 66% of patients. Clinical signs of respiratory failure before HFNO initiation (respiratory rate >30/min, retractions, and abdominal paradoxical breathing pattern) were associated with mortality (p=.001). Conclusions we suggest that HFNO is an option in non-ICU skilled units for older and frail patients with a severe COVID-19 pneumonia, otherwise non-suitable for intensive care and mechanical ventilation. Observation of clinical signs of respiratory failure before HFNO initiation was associated with mortality.Background

B-cell malignancies and COVID-19: a narrative review.

BACKGROUND: COVID-19 has been extensively characterized in immunocompetent hosts and to a lesser extent in immunocompromised populations. Among the latter, patients treated for B-cell malignancies have immunosuppression generated by B-cell lymphodepletion/aplasia resulting in an increased susceptibility to respiratory virus infections and poor response to vaccination. The consequence is that these patients are likely to develop severe or critical COVID-19. OBJECTIVES: To examine the overall impact of COVID-19 in patients treated for a B-cell malignancy or receiving chimeric antigen receptor T (CAR-T) immunotherapy administered in case of relapsed or refractory disease. SOURCES: We searched in the MEDLINE database to identify relevant studies, trials, reviews, or meta-analyses focusing on SARS-CoV-2 vaccination or COVID-19 management in patients treated for a B-cell malignancy or recipients of CAR-T cell therapy up to 8 July 2022. CONTENT: The epidemiology and outcomes of COVID-19 in patients with B-cell malignancy and CAR-T cell recipients are summarized. Vaccine efficacy in these subgroups is compiled. Considering the successive surges of variants of concern, we propose a critical appraisal of treatment strategies by discussing the use of neutralizing monoclonal antibodies, convalescent plasma therapy, direct-acting antiviral drugs, corticosteroids, and immunomodulators. IMPLICATIONS: For patients with B-cell malignancy, preventive vaccination against SARS-CoV-2 remains essential and the management of COVID-19 includes control of viral replication because of protracted SARS-CoV-2 shedding. Passive immunotherapy (monoclonal neutralizing antibody therapy and convalescent plasma therapy) and direct-active antivirals, such as remdesivir and nirmatrelvir/ritonavir are the best currently available treatments. Real-world data and subgroup analyses in larger trials are warranted to assess COVID-19 therapeutics in B-cell depleted populations.

A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients.

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients' age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.

The burden of SARS-CoV-2 in patients receiving chimeric antigen receptor T cell immunotherapy: everything to lose.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell immunotherapy has revolutionized the prognosis of refractory or relapsed B-cell malignancies. CAR-T cell recipients have immunosuppression generated by B-cell aplasia, leading to a higher susceptibility to respiratory virus infections and poor response to vaccination. AREAS COVERED: This review focuses on the challenge posed by B-cell targeted immunotherapies: managing long-lasting B-cell impairment during the successive surges of a deadly viral pandemic. We restricted this report to data regarding vaccine efficacy in CAR-T cell recipients, outcomes after developing COVID-19 and specificities of treatment management. We searched in MEDLINE database to identify relevant studies until 31 March 2022. EXPERT OPINION: Among available observational studies, the pooled mortality rate reached 40% in CAR-T cell recipients infected by SARS-CoV-2. Additionally, vaccine responses seem to be widely impaired in recipients (seroconversion 20%, T-cell response 50%). In this setting of B-cell depletion, passive immunotherapy is the backbone of treatment. Convalescent plasma therapy has proven to be a highly effective curative treatment with rare adverse events. Neutralizing monoclonal antibodies could be used as pre-exposure prophylaxis or early treatment but their neutralizing activity is constantly challenged by new variants. In order to reduce viral replication, direct-acting antiviral drugs should be considered.

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.

Undernourished patients do not have increased risk of severe COVID-19 outcomes.

Background: Undernutrition has been previously identified as a deleterious factor in acute infections. In covid-19 infection, obesity is a risk-factor of severe evolution, but initial undernutrition has not been evaluated yet. Methods: We retrospectively analyzed correlation between nutritional status at admission and severe outcomes (intensive care unit admission, invasive mechanical ventilation requirement and death) of patients hospitalized for confirmed covid-19 infection. Results: Risk of intensive care unit admission and invasive mechanical ventilation requirement was not significantly different between undernutrition and normoweight sub-groups, but increased in excessive weight sub-group (ODDR (IC 95%) 1.048 (1.011-1.086), p = 0.011). Risk of death was the same in all sub-groups. Conclusion: Undernutrition didn't appear as a factor of severe outcomes in covid-19 infection.

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

A retrospective comparison of COVID-19 and seasonal influenza mortality and outcomes in the ICUs of a French university hospital.

BACKGROUND: SARS-Cov-2 (COVID-19) has become a major worldwide health concern since its appearance in China at the end of 2019. OBJECTIVE: To evaluate the intrinsic mortality and burden of COVID-19 and seasonal influenza pneumonia in ICUs in the city of Lyon, France. DESIGN: A retrospective study. SETTING: Six ICUs in a single institution in Lyon, France. PATIENTS: Consecutive patients admitted to an ICU with SARS-CoV-2 pneumonia from 27 February to 4 April 2020 (COVID-19 group) and seasonal influenza pneumonia from 1 November 2015 to 30 April 2019 (influenza group). A total of 350 patients were included in the COVID-19 group (18 refused to consent) and 325 in the influenza group (one refused to consent). Diagnosis was confirmed by RT-PCR. Follow-up was completed on 1 April 2021. MAIN OUTCOMES AND MEASURES: Differences in 90-day adjusted-mortality between the COVID-19 and influenza groups were evaluated using a multivariable Cox proportional hazards model. RESULTS: COVID-19 patients were younger, mostly men and had a higher median BMI, and comorbidities, including immunosuppressive condition or respiratory history were less frequent. In univariate analysis, no significant differences were observed between the two groups regarding in-ICU mortality, 30, 60 and 90-day mortality. After Cox modelling adjusted on age, sex, BMI, cancer, sepsis-related organ failure assessment (SOFA) score, simplified acute physiology score SAPS II score, chronic obstructive pulmonary disease and myocardial infarction, the probability of death associated with COVID-19 was significantly higher in comparison to seasonal influenza [hazard ratio 1.57, 95% CI (1.14 to 2.17); P = 0.006]. The clinical course and morbidity profile of both groups was markedly different; COVID-19 patients had less severe illness at admission (SAPS II score, 37 [28 to 48] vs. 48 [39 to 61], P < 0.001 and SOFA score, 4 [2 to 8] vs. 8 [5 to 11], P < 0.001), but the disease was more severe considering ICU length of stay, duration of mechanical ventilation, PEEP level and prone positioning requirement. CONCLUSION: After ICU admission, COVID-19 was associated with an increased risk of death compared with seasonal influenza. Patient characteristics, clinical course and morbidity profile of these diseases is markedly different.

Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.

BACKGROUND: Patients with severe COVID-19 have emerged as a population at high risk of invasive fungal infections (IFIs). However, to our knowledge, the prevalence of IFIs has not yet been assessed in large populations of mechanically ventilated patients. We aimed to identify the prevalence, risk factors, and mortality associated with IFIs in mechanically ventilated patients with COVID-19 under intensive care. METHODS: We performed a national, multicentre, observational cohort study in 18 French intensive care units (ICUs). We retrospectively and prospectively enrolled adult patients (aged ≥18 years) with RT-PCR-confirmed SARS-CoV-2 infection and requiring mechanical ventilation for acute respiratory distress syndrome, with all demographic and clinical and biological follow-up data anonymised and collected from electronic case report forms. Patients were systematically screened for respiratory fungal microorganisms once or twice a week during the period of mechanical ventilation up to ICU discharge. The primary outcome was the prevalence of IFIs in all eligible participants with a minimum of three microbiological samples screened during ICU admission, with proven or probable (pr/pb) COVID-19-associated pulmonary aspergillosis (CAPA) classified according to the recent ECMM/ISHAM definitions. Secondary outcomes were risk factors of pr/pb CAPA, ICU mortality between the pr/pb CAPA and non-pr/pb CAPA groups, and associations of pr/pb CAPA and related variables with ICU mortality, identified by regression models. The MYCOVID study is registered with ClinicalTrials.gov, NCT04368221. FINDINGS: Between Feb 29 and July 9, 2020, we enrolled 565 mechanically ventilated patients with COVID-19. 509 patients with at least three screening samples were analysed (mean age 59·4 years [SD 12·5], 400 [79%] men). 128 (25%) patients had 138 episodes of pr/pb or possible IFIs. 76 (15%) patients fulfilled the criteria for pr/pb CAPA. According to multivariate analysis, age older than 62 years (odds ratio [OR] 2·34 [95% CI 1·39-3·92], p=0·0013), treatment with dexamethasone and anti-IL-6 (OR 2·71 [1·12-6·56], p=0·027), and long duration of mechanical ventilation (>14 days; OR 2·16 [1·14-4·09], p=0·019) were independently associated with pr/pb CAPA. 38 (7%) patients had one or more other pr/pb IFIs: 32 (6%) had candidaemia, six (1%) had invasive mucormycosis, and one (<1%) had invasive fusariosis. Multivariate analysis of associations with death, adjusted for candidaemia, for the 509 patients identified three significant factors: age older than 62 years (hazard ratio [HR] 1·71 [95% CI 1·26-2·32], p=0·0005), solid organ transplantation (HR 2·46 [1·53-3·95], p=0·0002), and pr/pb CAPA (HR 1·45 [95% CI 1·03-2·03], p=0·033). At time of ICU discharge, survival curves showed that overall ICU mortality was significantly higher in patients with pr/pb CAPA than in those without, at 61·8% (95% CI 50·0-72·8) versus 32·1% (27·7-36·7; p<0·0001). INTERPRETATION: This study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19. FUNDING: Pfizer.

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study.

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.

Open-label randomized controlled trial of ultra-low tidal ventilation without extracorporeal circulation in patients with COVID-19 pneumonia and moderate to severe ARDS: study protocol for the VT4COVID trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a severe complication of COVID-19 pneumonia, with a mortality rate amounting to 34-50% in moderate and severe ARDS, and is associated with prolonged duration of invasive mechanical ventilation. Such as in non-COVID ARDS, harmful mechanical ventilation settings might be associated with worse outcomes. Reducing the tidal volume down to 4 mL kg-1 of predicted body weight (PBW) to provide ultra-low tidal volume ventilation (ULTV) is an appealing technique to minimize ventilator-inducted lung injury. Furthermore, in the context of a worldwide pandemic, it does not require any additional material and consumables and may be applied in low- to middle-income countries. We hypothesized that ULTV without extracorporeal circulation is a credible option to reduce COVID-19-related ARDS mortality and duration of mechanical ventilation. METHODS: The VT4COVID study is a randomized, multi-centric prospective open-labeled, controlled superiority trial. Adult patients admitted in the intensive care unit with COVID-19-related mild to severe ARDS defined by a PaO2/FiO2 ratio ≤ 150 mmHg under invasive mechanical ventilation for less than 48 h, and consent to participate to the study will be eligible. Patients will be randomized into two balanced parallels groups, at a 1:1 ratio. The control group will be ventilated with protective ventilation settings (tidal volume 6 mL kg-1 PBW), and the intervention group will be ventilated with ULTV (tidal volume 4 mL kg-1 PBW). The primary outcome is a composite score based on 90-day all-cause mortality as a prioritized criterion and the number of ventilator-free days at day 60 after inclusion. The randomization list will be stratified by site of recruitment and generated using random blocks of sizes 4 and 6. Data will be analyzed using intention-to-treat principles. DISCUSSION: The purpose of this manuscript is to provide primary publication of study protocol to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. Enrollment of patients in the study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov NCT04349618 . Registered on April 16, 2020.

An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-ß-1a and hydroxychloroquine in hospitalized patients with COVID-19.

OBJECTIVES: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-ß-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support. METHODS: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely. RESULTS: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-ß-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-ß-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. CONCLUSION: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.

BMI and pneumonia outcomes in critically ill covid-19 patients: An international multicenter study.

OBJECTIVE: Previous studies have unveiled a relationship between the severity of coronavirus disease 2019 (COVID-19) pneumonia and obesity. The aims of this multicenter retrospective cohort study were to disentangle the association of BMI and associated metabolic risk factors (diabetes, hypertension, hyperlipidemia, and current smoking status) in critically ill patients with COVID-19. METHODS: Patients admitted to intensive care units for COVID-19 in 21 centers (in Europe, Israel, and the United States) were enrolled in this study between February 19, 2020, and May 19, 2020. Primary and secondary outcomes were the need for invasive mechanical ventilation (IMV) and 28-day mortality, respectively. RESULTS: A total of 1,461 patients were enrolled; the median (interquartile range) age was 64 years (40.9-72.0); 73.2% of patients were male; the median BMI was 28.1 kg/m2 (25.4-32.3); a total of 1,080 patients (73.9%) required IMV; and the 28-day mortality estimate was 36.1% (95% CI: 33.0-39.5). An adjusted mixed logistic regression model showed a significant linear relationship between BMI and IMV: odds ratio = 1.27 (95% CI: 1.12-1.45) per 5 kg/m2 . An adjusted Cox proportional hazards regression model showed a significant association between BMI and mortality, which was increased only in obesity class III (≥40; hazard ratio = 1.68 [95% CI: 1.06-2.64]). CONCLUSIONS: In critically ill COVID-19 patients, a linear association between BMI and the need for IMV, independent of other metabolic risk factors, and a nonlinear association between BMI and mortality risk were observed.

Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19).

Occurrence of putative invasive pulmonary aspergillosis was screened in 153 consecutive adult intensive care unit (ICU) patients with respiratory samples addressed for mycological diagnosis during a 6-week period at the emergence of coronavirus disease 2019 (COVID-19) pandemic. Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) was observed for 106 patients (69.3%). Nineteen of them (17.9%) with positive Aspergillus results were considered as having putative invasive pulmonary aspergillosis. These observations underline the risk of pulmonary aspergillosis in COVID-19 patients, even in patients not previously known to be immunosuppressed, advocating active search for Aspergillus infection and prompt antifungal treatment. Standardized surveillance protocols and updated definitions for ICU putative invasive pulmonary aspergillosis are needed. LAY ABSTRACT: Adult ICU patients with respiratory samples addressed for mycological diagnosis were screened during the emergence of COVID-19 pandemic. Positive SARS-CoV-2 PCR was observed for 106 patients, nineteen of them (17.9%) having aspergillosis. This underlines the risk of aspergillosis in COVID-19 patients.