Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS: In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS: Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, -1.0; 95% CI, -2.5 to 0; P = 0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, -7.6 to 8.2; nominal P = 0.94). CONCLUSIONS: In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann-La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615.).

Effects of Tocilizumab in COVID-19 patients: a cohort study.

BACKGROUND: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2. METHODS: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020. RESULTS: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10. CONCLUSIONS: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this.

Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.

BACKGROUND: INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest. METHODS: In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316. FINDINGS: Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea. INTERPRETATION: In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study. FUNDING: United Therapeutics Corporation.

Long-term results of mitral valve repair using autologous pericardium annuloplasty.

BACKGROUND AND AIM OF THE STUDY: The use of autologous pericardium for annuloplasty during mitral valve repair is a subject of controversy; hence, the study aim was to evaluate the authors' long-term results using this technique. METHODS: A retrospective review was conducted of 173 consecutive patients (mean age 59.6 +/- 16.3 years; range: 19-92 years) who underwent mitral valve repair complemented by annuloplasty between January 1998 and December 2003. The major causes of mitral regurgitation (MR) were annular dilatation and prolapse of the posterior leaflet. Annuloplasty was performed in all patients using a strip of pericardium treated with 0.6% glutaraldehyde for 10 min. Two rows of continuous horizontal mattress Gore-Tex sutures were used to secure the pericardium to the mitral annulus. Follow up continued for a mean period of 5.25 +/- 1.62 years (range: 1.97 to 9.43 years), and was complete. RESULTS: Three patients (1.7%) died within 30 days of surgery. Subsequently, five patients (2.9%) with MR (with or without mitral stenosis) underwent reoperation at a mean of 3.0 +/- 2.7 years after the initial surgery. At seven years after surgery the actuarial survival rate was 92.5%, and freedom from reoperation 97.1%. Follow up echocardiography was performed in 160 patients. Among these patients, no MR was detected in 34 (21.2%), while 88 (55%) had grade 1 MR, 35 (21.8%) grade 2, and three (1.8%) had grade 3. None of the patients had grade 4 MR. CONCLUSION: The study results indicated that autologous pericardium mitral annuloplasty of the mitral valve provides effective, durable and reproducible repair, and avoids the use of foreign materials.

Tricuspid valve repair using autologous pericardium annuloplasty in adults.

Uncorrected functional tricuspid regurgitation can lead to long-term morbidity and mortality. To evaluate our results using autologous pericardium annuloplasty to treat tricuspid regurgitation, we retrospectively reviewed 59 consecutive adult patients aged 19 years to 83 years (58.7 +/- 15.5 years) who underwent tricuspid valve annuloplasty between 2000 and 2003. Concomitant procedures consisted of mitral valve surgery in 83% of patients, aortic valve surgery in 28%, coronary bypass in 31%, and atrial-septal defect correction in 28%. Annuloplasty was performed using a strip of pericardium treated in glutaraldehyde 0.6% for 10 min. Two rows of continuous horizontal mattress Gore-Tex sutures were used to secure the pericardium to the tricuspid annulus. Follow-up was performed in 100% of the patients, and the mean follow-up was 4.4 +/- 1.2 years (range, 2.4 to 7 years). Postoperative death within 30 days occurred in 1 of 59 patients (1.6%). None of the patients required reoperation related to tricuspid regurgitation or stenosis. The actuarial survival rate was 98.4% at 7 years after operation. Echocardiography was performed in 58 of 58 surviving patients (100%). Up to 7 years postoperatively, tricuspid regurgitation was trace in 67.2% of patients, mild in 31%, and moderate in 1.8%; there was no occurrence of severe regurgitation on follow-up. Our results indicate that autologous pericardium tricuspid annuloplasty is a useful procedure in patients with moderate or severe tricuspid regurgitation. This procedure provides a durable, reproducible annuloplasty of the tricuspid valve.

Alcohol use in donors is a protective factor on recipients' outcome after heart transplantation.

OBJECTIVE: The outcome of heart transplantation is highly influenced by good donor selection. Because a history of alcoholism is prevalent among potential heart donors, we sought to explore the effect of alcohol use in donors on the outcome of heart transplantation in the recipient. METHOD: A total of 437 consecutive patients underwent heart transplantation from January 2002 through September 2005. Patients' files were retrospectively studied. Mean follow-up period was 3.14+/-1.9 years (range, 3 days to 6.5 yrs). The cohort was divided into two subgroups. The alcoholic donor group (ADG) included 98 of 421 patients and the nonalcoholic donor group (NADG) included 323 of 421 patients. Mean age was 35.3+/-11.4 yrs (range, 18-66) for the ADG and 33+/-12.2 yrs (range, 18-62) for the NADG. RESULTS: Mortality among the ADG was 7 of 98 (7.1%) and for NADG was 55 of 323 (17.1%) (P=0.015). The mean interval time between transplant and mortality was, for ADG, 27.7+/-20.6 months (range, 0.07-51) and for NADG, 16.4+/-19.6 months (range, 0.14-73) (P=0.031). Survival rate was significantly higher among the ADG at 72.8+/-1.9 months compared with NADG at 66.2+/-1.5 months (P=0.019). Overall rejection rate was 22 of 421 (5.2%); rejection rate was 17 of 323 (5.2%) in NADG and 5 of 98 (5.1%) in ADG. Rejection free survival was 74.6+/-0.85 with no significant difference between the two groups (P=0.85). CONCLUSION: The chronic alcoholism of donors was found to be a protective factor regarding the outcome after heart transplantation. Significant differences were found in mortality rate and survival after heart transplantation between the ADG and NADG. These data support the fact that it is safe to use donors' hearts regardless of a history of alcoholism.

Pathologic findings in pericardium and native valve tissues after aortic valve-sparing with autologous pericardial leaflet extension.

BACKGROUND AND AIM OF THE STUDY: Aortic valve repair with autologous pericardial leaflet extension is a valuable treatment option for aortic valve disease. The study aim was to examine and describe the histopathologic changes in native and pericardial extension leaflet tissues after this procedure. METHODS: The pathologic findings of nine patients (mean age 26.7 +/- 2.9 years; range: 0-77 years) who underwent aortic valve repair with autologous leaflet extension were analyzed. The initial diagnosis included: bicuspid aortic valve (n = 4), truncus arteriosus (n = 3), ventricular septal defect (n = 1) and subaortic stenosis (n = 1). The pathologic endpoints of the study were fibrosis, calcification and myxomatous changes, based on a scale from 0 to 3. RESULTS: Fibrosis and calcification demonstrated similar grade results in the pericardial and native tissues; no statistical difference was observed (p = 0.261 and p = 0.999, respectively. Myxomatous degeneration was greater in the native tissue (p = 0.012). Among the native tissue group, five patients were graded 1 and three graded 3 for myxomatous degeneration. Among the pericardial tissue patients, six were graded 0, and one each were graded 1, 2, or 3. CONCLUSION: Following aortic valve repair with pericardial leaflet extension, both the pericardial and native valve tissue are susceptible to myxomatous degeneration, fibrosis, and calcification. Among the present patients, myxomatous degeneration was more often present in the native tissue, but there was no difference in calcification or fibrosis between the native and pericardial tissue groups.

Aortic valve-sparing repair with autologous pericardial leaflet extension has a greater early re-operation rate in congenital versus acquired valve disease.

OBJECTIVE: We sought to establish whether there was a difference in outcome after aortic valve repair with autologous pericardial leaflet extension in acquired versus congenital valvular disease. METHODS: One hundred and twenty-eight patients underwent reparative aortic valve surgery at our institution from 1997 through 2005 for acquired or congenital aortic valve disease. The acquired group (43/128) (34%) had a mean age of 56.4+/-20.3 years (range, 7.8-84.6 years) and the congenital group (85/128) (66%) had a mean age of 16.9+/-19.2 years (range, 0.3-82 years). The endpoints of the study were mortality and reoperation rates. RESULTS: Thirty-day mortality was 0/43 (0%) in the congenital group and 1/85 (1.1%) in the acquired group. Late mortality in the acquired group was 3/43 (7%) and 3/84 (3.5%) in the congenital group (neither early nor late proportion of mortality is significantly different between the two groups, according to the nonparametric Binomial test for proportions). There were 13 total reoperations among 11 patients: 1/43 (2.3%) in the acquired group and 10/85 (11.7%) in the congenital group (p=0.07). Two patients from the congenital group were reoperated on twice. The mean interval between original repair and reoperation was 3.6+/-5 years (range, 0-7 years) for acquired and 3.5+/-2.5 years (range, 0-7 years) for the congenital group (Wilcoxon 2-sample test, p=0.7). Total early reoperation rate (<30 days after first surgery) was 11/128 (8.5%); for the congenital group 9/85 (10.5%) and for the acquired group 2/43 (4.6%). Early reoperation rate was significantly higher among the congenital group (p=0.013). The remaining patients are well at mean follow-up of 2.8+/-2.4 years (range 0-7.9). In the acquired group, the mean postoperative aortic regurgitation and stenosis grade by echocardiography was 0.5+/-0.3 (scale, 0-4) and 0.3+/-0.1, respectively. In the congenital group, the follow-up, mean aortic regurgitation and stenosis were 0.9+/-0.8 and 0.5+/-0.3, respectively. CONCLUSIONS: There was no significant difference in early or late mortality and late reoperation rate between the two groups. Early reoperation rate was higher in the congenital versus the acquired aortic valvular disease group. This study supports the fact that the valve-sparing technique is safe and reproducible and repeatable in patients with acquired valve disease.

Aortic valve sparing and restoration with autologous pericardial leaflet extension is an effective alternative in pediatric patients.

We sought to evaluate the durability and efficacy of aortic valve repair with autologous pericardial leaflet extension in children. From 1997 through 2006, 54 patients underwent aortic valve repair with autologous pericardial leaflet extension at a mean age 8.4 +/- 5.3 years (range, 0 to 17 years). Primary endpoints were early and late mortality, freedom of reoperation, and late valve function. Thirty-day and late mortality were one in 54 (1.8%) and two in 53 (3.7%), respectively. There were seven re-operations in six patients, and one patient was re-operated twice. Re-operations were re-repairs in four cases and replacements in three cases. The mean interval between original repair and re-operation was 4.3 +/- 2.5 years. Mean severity grade of post-repair intraoperative aortic regurgitation (AR) was 0.3 (range, grade 0 to 4). At late follow-up, 87.7% of all patients had no AR or only a trace (grade 0-1). Seven patients (12.9%) had mild AR (grade 2-3) and none severe (grade 4); 94.4% had no aortic stenosis or only a trace (grade 0-1), 5.5% had mild (grade 2-3), and none severe. This technique delays potential complications from other approaches to valve pathology and allows a normal growth of the aortic annulus. Although, our data show that this technique has a low mortality and morbidity, more studies are needed to elucidate durability and late outcome.

Aortic valve-sparing repair with autologous pericardial leaflet extension has low long-term mortality and reoperation rates in children and adults.

OBJECTIVES: We sought to establish whether there was a difference in outcome after aortic valve repair with autologous pericardial leaflet extension in pediatric and adult populations. METHODS: In our study, 128 patients (pediatric and adult) underwent valvular pericardial extension repair at our institution from 1997 through 2006. The patients were divided into either the pediatric group (< or =18 years of age; n = 54/128, 42%), with a mean age of 8.4 +/- 5.4 (range, 0-17 years), or the adult group (n = 74/128, 58%), with a mean age of 48.9 +/- 19.7 (range, 19-85 years). The endpoints of the study were mortality and reoperation rates. RESULTS: Thirty-day mortality for the adult group was 0, and for the pediatric group it was 1/54 (1.8%), with no statistical difference (P = .1) between the groups. Late mortality for the pediatric group was 2/54 (3.7%) and in the adult group was 2/74 (2.7%). There was no statistical difference (P = .12) between the groups. In the pediatric group, there were 6 total reoperations (6/54) in 5 patients, with one patient undergoing reoperation twice. From these 6 cases, 3 were re-repair and 3 had aortic valve replacement; the mean interval between original repair and reoperation was 4.3 +/- 2.5 years (range, 0.1-7.7 years). In the adult group, there were 5 total reoperations (5/74). From these 5 cases, 3 had aortic valve replacement and 2 re-repair; the mean interval between original repair and reoperation was 3.5 +/- 3 years (range, 0.1-7 years). There was no statistical difference in the reoperation rate between the 2 groups (P= .38). At late follow-up, 82% of all patients in the adult group had no aortic regurgitation or only a trace (grades 0 and 1) and 78% of all patients in the pediatric group had no aortic regurgitation or only a trace (grades 0 and 1). There was no statistical difference in either aortic regurgitation (P = .06) or aortic stenosis (P = .28) between the 2 groups. CONCLUSIONS: Aortic valve repair with autologous pericardial leaflet extension has low mortality and morbidity rates, as well as good mid-term durability in both the pediatric and the adult groups.