Microvascular Alteration in COVID-19 Documented by Nailfold Capillaroscopy.

COVID-19 is a multisystemic disease that mainly affects and causes dysregulation of the endothelium, causing systemic manifestations. A nailfold video capillaroscopy is a safe, easy, and noninvasive method to evaluate microcirculation alteration. In this review, we analyzed the literature available to date regarding the object of nailfold video capillaroscopy (NVC) use in patients with a SARS-CoV-2 infection, both in the acute phase and after discharge. The scientific evidence pointed out the main alterations in capillary circulation shown by NVC, so reviewing the findings of each article allowed us to define and analyze the future prospects and needs for possibly including NVC within the management of patients with COVID-19, both during and after the acute phase.

Host-Based Treatments for Severe COVID-19.

COVID-19 has been a global health problem since 2020. There are different spectrums of manifestation of this disease, ranging from asymptomatic to extremely severe forms requiring admission to intensive care units and life-support therapies, mainly due to severe pneumonia. The progressive understanding of this disease has allowed researchers and clinicians to implement different therapeutic alternatives, depending on both the severity of clinical involvement and the causative molecular mechanism that has been progressively explored. In this review, we analysed the main therapeutic options available to date based on modulating the host inflammatory response to SARS-CoV-2 infection in patients with severe and critical illness. Although current guidelines are moving toward a personalised treatment approach titrated on the timing of presentation, disease severity, and laboratory parameters, future research is needed to identify additional biomarkers that can anticipate the disease course and guide targeted interventions on an individual basis.

Host-Based Treatments for Severe COVID-19

COVID-19 has been a global health problem since 2020. There are different spectrums of manifestation of this disease, ranging from asymptomatic to extremely severe forms requiring admission to intensive care units and life-support therapies, mainly due to severe pneumonia. The progressive understanding of this disease has allowed researchers and clinicians to implement different therapeutic alternatives, depending on both the severity of clinical involvement and the causative molecular mechanism that has been progressively explored. In this review, we analysed the main therapeutic options available to date based on modulating the host inflammatory response to SARS-CoV-2 infection in patients with severe and critical illness. Although current guidelines are moving toward a personalised treatment approach titrated on the timing of presentation, disease severity, and laboratory parameters, future research is needed to identify additional biomarkers that can anticipate the disease course and guide targeted interventions on an individual basis.

Decreased Gas6 and sAxl Plasma Levels Are Associated with Hair Loss in COVID-19 Survivors.

Post-acute conditions after coronavirus disease 2019 (COVID-19) are quite common, although the underlying pathogenetic mechanisms leading to these conditions are not yet completely understood. In this prospective observational study, we aimed to test the hypothesis that Growth Arrest-Specific 6 (Gas6) and its soluble receptors, Axl (sAxl) and MerTK (sMer), might be implicated. A total of 263 subjects underwent a structured clinical evaluation one year after their hospital discharge for COVID-19, and they consented to donate a blood sample to measure their circulating Gas6, sAxl, and sMer levels. A total of 98 (37.3%) post-COVID-19 subjects complained of at least one residual physical symptom one year after their hospital discharge. Univariate analysis revealed that sAxl was marginally associated with residual symptoms, but at the level of logistic regression analysis, only the diffusing capacity of the lungs for carbon monoxide (DLCO) (OR 0.98, CI 95%: 0.96-0.99; p = 0.007) and the female sex (OR 2.49, CI 95%: 1.45-4.28; p = 0.001) were independently associated with long-lasting symptoms. A total of 69 (26.2%) subjects had hair loss. At the level of univariate analysis, Gas6, sAxl, DLCO, and the female gender were associated with its development. In a logistic regression analysis model, Gas6 (OR 0.96, CI 95%: 0.92-0.99; p = 0.015) and sAxl (OR 0.98, CI 95%; 0.97-1.0; p = 0.014), along with the female sex (OR 6.58, CI 95%: 3.39-12.78; p = 0.0001), were independent predictors of hair loss. Decreased levels of Gas6 and sAxl were associated with a history of hair loss following COVID-19. This was resolved spontaneously in most patients, although 23.7% complained of persistent hair loss one year after hospital discharge.

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

INTRODUCTION: Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multi-center, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. PRIMARY OUTCOME: reduction in 28-day mortality. SECONDARY OUTCOMES: mechanical ventilation-free days at 28 days, need for ICU referral, length of hospitalisation, need for tracheostomy, changes in PaO2:FiO2 ratio, C-reactive protein levels and WHO clinical progression scale at days 3, 7, and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35[10.4%] versus 41[12.1%]; p=0.49), nor in the median mechanical ventilation-free days (23[14] versus 24[16]; p=0.49). ICU referral was necessary in 41[12.2%] versus 45[13.2%]; p=0.68 and tracheostomy in 8[2.4%] versus 9[2.6%]; p=0.82. Survivors in the methylprednisolone group required a longer median hospitalisation (15[11] versus 14[11] days; p=0.005) and experienced an improvement in C-reactive protein levels, but not in PaO2:FiO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified timepoints. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared to conventional dexamethasone in COVID-19 pneumonia.

Severe COVID-19 ARDS Treated by Bronchoalveolar Lavage with Diluted Exogenous Pulmonary Surfactant as Salvage Therapy: In Pursuit of the Holy Grail?

BACKGROUND: Severe pneumonia caused by coronavirus disease 2019 (COVID-19) is characterized by inflammatory lung injury, progressive parenchymal stiffening and consolidation, alveolar and airway collapse, altered vascular permeability, diffuse alveolar damage, and surfactant deficiency. COVID-19 causes both pneumonia and acute respiratory distress syndrome (COVID-19 ARDS). COVID-19 ARDS is characterized by severe refractory hypoxemia and high mortality. Despite extensive research, the treatment of COVID-19 ARDS is far from satisfactory. Some treatments are recommended for exhibiting some clinically positive impacts on COVID-19 patients although there are already several drugs in clinical trials, some of which are already demonstrating promising results in addressing COVID-19. Few studies have demonstrated beneficial effects in non-COVID-19 ARDS treatment of exogenous surfactant, and there is no evidence-based, proven method for the procedure of surfactant administration. AIM: The aim of this work is to underline the key role of ATII cells and reduced surfactant levels in COVID-19 ARDS and to emphasize the rational basis for exogenous surfactant therapy in COVID-19 ARDS, providing insights for future research. METHODS: In this article, we describe and support via the literature the decision to administer large volumes of surfactant to two patients via bronchoalveolar lavage to maximize its distribution in the respiratory tract. RESULTS: In this study, we report on two cases of COVID-19 ARDS in patients who have been successfully treated with diluted surfactants by bronchoalveolar lavage, followed by a low-dose bolus of surfactant. CONCLUSION: Combining the administration of diluted, exogenous pulmonary surfactant via bronchoalveolar lavage along with the standard therapy for SARS-CoV-2-induced ARDS may be a promising way of improving the management of ARDS.

Cytokine Profiles as Potential Prognostic and Therapeutic Markers in SARS-CoV-2-Induced ARDS.

BACKGROUND: Glucocorticoids (GCs) have been shown to reduce mortality and the need for invasive mechanical ventilation (IMV) in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). It has been suggested that serum cytokines levels are markers of disease severity in ARDS, although there is only limited evidence of a relationship between the longitudinal cytokine profile and clinical outcomes in patients with SARS-CoV-2-induced ARDS treated with GC. METHODS: We conducted a single-center observational study to investigate serial plasma cytokine levels in 17 patients supported with non-invasive ventilation (NIV) in order to compare the response in five patients who progressed to IMV versus 12 patients who continued with NIV alone. All patients received methylprednisolone 80 mg/day continuous infusion until clinical improvement. RESULTS: The study groups were comparable at baseline. All patients survived. Although IL-6 was higher in the NIV group at baseline, several cytokines were significantly higher in the IMV group on day 7 (IL-6, IL-8, IL-9, G-CSF, IP-10, MCP-1, MIP-1α) and 14 (IL-6, IL-8, IL-17, G-CSF, MIP-1α, RANTES). No significant differences were observed between groups on day 28. CONCLUSIONS: Patients in the IMV group had higher inflammation levels at intubation than the NIV group, which may indicate a higher resistance to glucocorticoids. Higher GC doses or a longer treatment duration in these patients might have allowed for a better control of inflammation and a better outcome. Further studies are required to define the prognostic value of cytokine patterns, in terms of both GC treatment tailoring and timely initiation of IMV.

Cytokine Profiles as Potential Prognostic and Therapeutic Markers in SARS-CoV-2-Induced ARDS

Background. Glucocorticoids (GCs) have been shown to reduce mortality and the need for invasive mechanical ventilation (IMV) in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS). It has been suggested that serum cytokines levels are markers of disease severity in ARDS, although there is only limited evidence of a relationship between the longitudinal cytokine profile and clinical outcomes in patients with SARS-CoV-2-induced ARDS treated with GC. Methods. We conducted a single-center observational study to investigate serial plasma cytokine levels in 17 patients supported with non-invasive ventilation (NIV) in order to compare the response in five patients who progressed to IMV versus 12 patients who continued with NIV alone. All patients received methylprednisolone 80 mg/day continuous infusion until clinical improvement. Results. The study groups were comparable at baseline. All patients survived. Although IL-6 was higher in the NIV group at baseline, several cytokines were significantly higher in the IMV group on day 7 (IL-6, IL-8, IL-9, G-CSF, IP-10, MCP-1, MIP-1α) and 14 (IL-6, IL-8, IL-17, G-CSF, MIP-1α, RANTES). No significant differences were observed between groups on day 28. Conclusions. Patients in the IMV group had higher inflammation levels at intubation than the NIV group, which may indicate a higher resistance to glucocorticoids. Higher GC doses or a longer treatment duration in these patients might have allowed for a better control of inflammation and a better outcome. Further studies are required to define the prognostic value of cytokine patterns, in terms of both GC treatment tailoring and timely initiation of IMV.

Diagnostic Accuracy of Chest Digital Tomosynthesis in Patients Recovering after COVID-19 Pneumonia.

PURPOSE: To assess the diagnostic accuracy of traditional chest X-ray (CXR) and digital tomosynthesis (DTS) compared to computed tomography (CT) in detecting pulmonary interstitial changes in patients having recovered from severe COVID-19. MATERIALS AND METHODS: This was a retrospective observational study, and received local ethics committee approval. Patients suspected of having COVID-19 pneumonia upon emergency department admission between 1 March and 31 August 2020, and who underwent CXR followed by DTS and CT, were considered. Inclusion criteria were as follows: (1) patients with previous SARS-CoV-2 infection proven by a positive RT-PCR on nasopharyngeal swabs performed upon admission to the hospital, and with complete clinical recovery; (2) a diagnosis of SARS-CoV-2-related ARDS, according to the Berlin criteria, during hospitalization; (3) no recent history of other lung disease; and (4) complete imaging follow-up by CXR, DTS, and CT for at least 6 months and up to one year. Analysis of DTS images was carried out independently by two radiologists with 16 and 10 years of experience in chest imaging, respectively. The following findings were evaluated: (1) ground-glass opacities (GGOs); (2) air-space consolidations with or without air bronchogram; (3) reticulations; and (4) linear consolidation. Indicators of diagnostic performance of RX and digital tomosynthesis were calculated using CT as a reference. All data were analyzed using R statistical software (version 4.0.2, 2020). RESULTS: Out of 44 patients initially included, 25 patients (17 M/8 F), with a mean age of 64 years (standard deviation (SD): 12), met the criteria and were included. The overall average numbers of findings confirmed by CT were GGOs in 11 patients, lung consolidations in 8 patients, 7 lung interstitial reticulations, and linear consolidation in 20 patients. DTS showed a significantly higher diagnostic accuracy compared to CXR in recognizing interstitial lung abnormalities-especially GGOs (p = 0.0412) and linear consolidations (p = 0.0009). The average dose for chest X-ray was 0.10 mSv (0.07-0.32), for DTS was 1.03 mSv (0.74-2.00), and for CT scan was 3 mSv. CONCLUSIONS: According to our results, DTS possesses a high diagnostic accuracy, compared with CXR, in revealing lung fibrotic changes in patients who have recovered from COVID-19 pneumonia.

Different Methods to Improve the Monitoring of Noninvasive Respiratory Support of Patients with Severe Pneumonia/ARDS Due to COVID-19: An Update.

The latest guidelines for the hospital care of patients affected by coronavirus disease 2019 (COVID-19)-related acute respiratory failure have moved towards the widely accepted use of noninvasive respiratory support (NIRS) as opposed to early intubation at the pandemic onset. The establishment of severe COVID-19 pneumonia goes through different pathophysiological phases that partially resemble typical acute respiratory distress syndrome (ARDS) and have been categorized into different clinical-radiological phenotypes. These can variably benefit on the application of external positive end-expiratory pressure (PEEP) during noninvasive mechanical ventilation, mainly due to variable levels of lung recruitment ability and lung compliance during different phases of the disease. A growing body of evidence suggests that intense respiratory effort producing excessive negative pleural pressure swings (Ppl) plays a critical role in the onset and progression of lung and diaphragm damage in patients treated with noninvasive respiratory support. Routine respiratory monitoring is mandatory to avoid the nasty continuation of NIRS in patients who are at higher risk for respiratory deterioration and could benefit from early initiation of invasive mechanical ventilation instead. Here we propose different monitoring methods both in the clinical and experimental settings adapted for this purpose, although further research is required to allow their extensive application in clinical practice. We reviewed the needs and available tools for clinical-physiological monitoring that aims at optimizing the ventilatory management of patients affected by acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

Potential links between COVID-19-associated pulmonary aspergillosis and bronchiectasis as detected by high resolution computed tomography.

PURPOSE: The aim of this observational study was to highlight high resolution CT scan characteristics of COVID-19-associated pulmonary aspergillosis (CAPA) with a focus on the detection of de-novo appeared or evolved bronchiectasis. METHODS: From March 2020 to May 2021, we enrolled 350 consecutive mechanically ventilated ICU patients with COVID-19. Patients with CAPA and at least one chest CT scan performed within 15 days from the diagnosis were included. Two radiologists were asked to identify typical and atypical signs of COVID-19 pneumonia. Bronchiectasis locations were described and a modified Reiff score was calculated, as severity score. A total of 19 CAPA patients (median age 71.0, Interquartile range (IQR) 62.5-75.0; male 16, 84.2%) were included. RESULTS: According to the 2020 ECMM/ISHAM criteria, 18 patients had probable CAPA and one had proven CAPA. The median time between hospital admission and CT scan was 21 days (IQR 14.5-25.0). The incidence of bronchiectasis in the study population was 57.9% (n = 11). Tubular bronchiectasis was detected in 10 patients and were scored as follows: three patients had a score of 1, three patients had a score of score 2, one patient had a score of 5 and four patients had a score of 6. Eight patients had a previous CT scan (performed at hospital admission), among them: 5 patients developed de-novo bronchiectasis, while 2 patients demonstrated a volumetric increase of bronchiectasis. At the 6-months follow-up, the mortality rate for patients with CAPA was >60%. CONCLUSION: the radiologic detection of de-novo appearance or volumetric increase of bronchiectasis in COVID-19 should lead clinicians to search for fungal superinfections.

Radiological-pathological signatures of patients with COVID-19-related pneumomediastinum: is there a role for the Sonic hedgehog and Wnt5a pathways?

Pneumomediastinum is a rare complication of ARDS but is more common during #COVID19. The fibrous hyaline degeneration of the tracheal rings seen in this autoptic series is an original observation that has not been previously described in COVID-19 patients. https://bit.ly/3vxTQde.

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.

Alveolar Epithelial Type II Cells☆

The alveolar epithelium is a thin continuous liquid lining layer primarily composed of two types of epithelial cells, i.e., alveolar type I (ATI) and alveolar type II (ATII) cells. ATI cells have a broad flattened morphology and cover about 95% of the gas exchange surface of the lung. Whilst, ATIIs are small cuboidal cells with characteristic lamellar inclusions and apical microvilli that line the remainder of the alveolus (about 5%). ATII cells make and secrete a pulmonary surfactant, which reduces the surface tension in the alveoli preventing alveolar collapse during respiration and reducing the energy required to inflate the lungs, thereby increasing pulmonary compliance. These cells also transport ions from the apical to the basolateral surface so as to keep the alveoli relatively fluid free and have roles in the innate immune response. Importantly, they are the progenitor cells for the alveolar epithelium in the adult lung. Having a very thin cytoplasm, a limited number of mitochondria and covering a higher surface area, ATI cells are easily damaged during lung injury, after which they are replaced by ATII cells through the alveolar epithelium regeneration process. Despite ATII cells are considered an essential part of this process, numerous interstitial lung diseases are characterized by hyperplastic ATIIs: in fact, they may also contribute to the fibroproliferative reaction by secreting a number of growth factors and proinflammatory molecules.

Interstitial Lung Disease at High Resolution CT after SARS-CoV-2-Related Acute Respiratory Distress Syndrome According to Pulmonary Segmental Anatomy.

BACKGROUND: The purpose of this study was to evaluate High-Resolution CT (HRCT) findings in SARS-CoV-2-related ARDS survivors treated with prolonged low-dose methylprednisolone after hospital discharge. METHODS: A total of 44 consecutive patients (M: 32, F: 12, average age: 64), hospitalised in our department from April to September 2020 for SARS-CoV-2-related ARDS, who had a postdischarge CT scan, were enrolled into this retrospective study. We reviewed the electronic medical charts to collect laboratory, clinical, and demographic data. The CT findings were evaluated and classified according to lung segmental distribution. The imaging findings were correlated with spirometry results and included ground glass opacities (GGOs), consolidations, reticulations, bronchiectasis/bronchiolectasis, linear bands, and loss of pulmonary volume. RESULTS: Alterations in the pulmonary parenchyma were observed in 97.7% of patients at HRCT (median time lapse between ARDS diagnosis and HRCT: 2.8 months, range 0.9 to 6.7). The most common findings were linear bands (84%), followed by GGOs (75%), reticulations (34%), bronchiolectasis (32%), consolidations (30%), bronchiectasis (30%) and volume loss (25%). They had a symmetric distribution, and both lower lobes were the most affected areas. CONCLUSIONS: A reticular pattern with a posterior distribution was observed 3 months after discharge from severe COVID-19 pneumonia, and this differs from previously described postCOVID-19 fibrotic-like changes. We hypothesized that the systematic use of prolonged low-dose of corticosteroid could be the main reason of this different CT scan appearance.

The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung.

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia.

BACKGROUND: In hospitalized patients with coronavirus disease 2019 (COVID-19) pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism. We hypothesize that early prolonged methylprednisolone (MP) treatment could accelerate disease resolution, decreasing the need for intensive care unit (ICU) admission and mortality. METHODS: We conducted a multicenter observational study to explore the association between exposure to prolonged, low-dose MP treatment and need for ICU referral, intubation, or death within 28 days (composite primary end point) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels. RESULTS: Findings are reported as MP (n = 83) vs control (n = 90). The composite primary end point was met by 19 vs 40 (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.24-0.72). Transfer to ICU and invasive MV were necessary in 15 vs 27 (P = .07) and 14 vs 26 (P = .10), respectively. By day 28, the MP group had fewer deaths (6 vs 21; aHR, 0.29; 95% CI, 0.12-0.73) and more days off invasive MV (24.0 ±â€…9.0 vs 17.5 ±â€…12.8; P = .001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the 2 groups (P = .84). CONCLUSION: In patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance. A large randomized controlled trial (RECOVERY trial) has been performed that validates these findings. Clinical trial registration. ClinicalTrials.gov NCT04323592.