Effectiveness of Casirivimab-Imdevimab and Sotrovimab During a SARS-CoV-2 Delta Variant Surge: A Cohort Study and Randomized Comparative Effectiveness Trial.

Importance: The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant. Objective: To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab. Design, Setting, and Participants: This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria. Exposure: For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy. Main Outcomes and Measures: For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound. Results: A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence. Conclusions and Relevance: In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant. Trial Registration: ClinicalTrials.gov Identifier: NCT04790786.

The comparative effectiveness of COVID-19 monoclonal antibodies: A learning health system randomized clinical trial.

BACKGROUND: Monoclonal antibodies (mAb) that neutralize SARS-CoV-2 decrease hospitalization and death compared to placebo in patients with mild to moderate COVID-19; however, comparative effectiveness is unknown. We report the comparative effectiveness of bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab. METHODS: A learning health system platform trial in a U.S. health system enrolled patients meeting mAb Emergency Use Authorization criteria. An electronic health record-embedded application linked local mAb inventory to patient encounters and provided random mAb allocation. Primary outcome was hospital-free days to day 28. Primary analysis was a Bayesian model adjusting for treatment location, age, sex, and time. Inferiority was defined as 99% posterior probability of an odds ratio < 1. Equivalence was defined as 95% posterior probability the odds ratio is within a given bound. FINDINGS: Between March 10 and June 25, 2021, 1935 patients received treatment. Median hospital-free days were 28 (IQR 28, 28) for each mAb. Mortality was 0.8% (1/128), 0.8% (7/885), and 0.7% (6/922) for bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively. Relative to casirivimab-imdevimab (n = 922), median adjusted odds ratios were 0.58 (95% credible interval [CI] 0.30-1.16) and 0.94 (95% CI 0.72-1.24) for bamlanivimab (n = 128) and bamlanivimab-etesevimab (n = 885), respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab. INTERPRETATION: Among patients with mild to moderate COVID-19, bamlanivimab-etesevimab or casirivimab-imdevimab treatment resulted in 86% probability of equivalence. No treatment met prespecified criteria for statistical equivalence. Median hospital-free days to day 28 were 28 (IQR 28, 28) for each mAb. FUNDING AND REGISTRATION: This work received no external funding. The U.S. government provided the reported mAb. This trial is registered at ClinicalTrials.gov, NCT04790786.

Launching a comparative effectiveness adaptive platform trial of monoclonal antibodies for COVID-19 in 21 days.

Outpatient treatments that limit progression to severe coronavirus disease 2019 (COVID-19) are of vital importance to optimise patient outcomes and public health. Monoclonal antibodies (mAb) demonstrated ability to decrease hospitalizations in randomized, clinical trials. However, there are many barriers to mAb treatment such as patient access and clinician education. There are no data comparing efficacy or safety of available mAbs. We sought to rapidly launch an adaptive platform trial with the goals of enhancing access to treatment, regardless of geography and socioeconomic status, and evaluating comparative efficacy and safety of available mAbs. Within 21 days from idea genesis, we allocated mAb treatment to all patients within the context of this clinical trial. Within 2 months, we closed the gap of the likelihood of receiving mAb, conditional on background positivity rate, between Black and White patients (Black patients 0.238; White patients 0.241). We describe trial infrastructure, lessons learned, and future directions for a culture of learning while doing.

Effect of tidal volume in children with acute hypoxemic respiratory failure.

OBJECTIVES: To determine if tidal volume (VT) between 6 and 10 ml/kg body weight using pressure control ventilation affects outcome for children with acute hypoxemic respiratory failure (AHRF) or acute lung injury (ALI). To validate lung injury severity markers such as oxygenation index (OI), PaO2/FiO2 (PF) ratio, and lung injury score (LIS). DESIGN: Retrospective, January 2000-July 2007. SETTING: Tertiary care, 20-bed PICU. PATIENTS: Three hundred and ninety-eight endotracheally intubated and mechanically ventilated children with PF ratio <300. Outcomes were mortality and 28-day ventilator free days. MEASUREMENTS AND MAIN RESULTS: Three hundred and ninety-eight children met study criteria, with 20% mortality. 192 children had ALI. Using >90% pressure control ventilation, 85% of patients achieved VT less than 10 ml/kg. Median VT was not significantly different between survivors and non-survivors during the first 3 days of mechanical ventilation. After controlling for diagnostic category, age, delta P (PIP-PEEP), PEEP, and severity of lung disease, VT was not associated with mortality (P > 0.1), but higher VT at baseline and on day 1 of mechanical ventilation was associated with more ventilator free days (P < 0.05). This was particularly seen in patients with better respiratory system compliance [Crs > 0.5 ml/cmH2O/kg, OR = 0.70 (0.52, 0.95)]. OI, PF ratio, and LIS were all associated with mortality (P < 0.05). CONCLUSIONS: When ventilating children using lung protective strategies with pressure control ventilation, observed VT is between 6 and 10 ml/kg and is not associated with increased mortality. Moreover, higher VT within this range is associated with more ventilator free days, particularly for patients with less severe disease.

Disseminated intravascular coagulation score is associated with mortality for children with shock.

OBJECTIVE: To evaluate the association between disseminated intravascular coagulation (DIC) score and mortality for children with shock. DESIGN: Retrospective. SETTING: Tertiary care, 20-bed pediatric intensive care unit. PATIENTS: A total of 132 children with sepsis or shock admitted from January 2003 to December 2005. MEASUREMENTS AND RESULTS: A total of 132 patients less than 18 years of age with a diagnosis of shock or sepsis were included in the analysis. Of these patients, 90 survived and 42 died (31.8%). Patients ranged from 6 days to 18 years (median 5.8 years), and were a majority male (63%). Variables associated with mortality included peak DIC score within 24 h of ICU admission, age, weight, volume of blood products transfused, inotrope score, pediatric index of mortality (PIM 2) score, 12-h pediatric risk of mortality (PRISM III) score and presence of mechanical ventilation (P < 0.05). Patients with DIC scores >or= 5 (overt DIC) had 50% mortality, compared to 20% for patients with DIC scores < 5. Overall, a one-point rise in DIC score was associated with an increased risk of mortality after adjusting for age, race, gender, hemodynamic instability, and PRISM III score [OR 1.35 (1.02, 1.78)]. Most patients achieve their peak DIC score within 2 h of ICU admission. CONCLUSIONS: This analysis suggests that DIC score, easily calculated early in ICU admission, is associated with mortality for children with sepsis and shock, regardless of initial severity of illness or inotrope use.

Comparison of the pulse oximetric saturation/fraction of inspired oxygen ratio and the PaO2/fraction of inspired oxygen ratio in children.

BACKGROUND: Although diagnostic criteria for acute lung injury (ALI) and ARDS are clear, invasive arterial sampling is required for computation of Pao(2)/fraction of inspired oxygen (Fio(2)) [PF] ratios. The pulse oximetric saturation (Spo(2))/Fio(2) (SF) ratio may be a reliable noninvasive alternative to the PF ratio for identifying children with lung injury. METHODS: We electronically queried blood gas measurements from two tertiary care pediatric ICUs (PICUs). Included in the analysis were corresponding measurements of Spo(2), Pao(2), and Fio(2) charted within 15 min of each other when Spo(2) values were between 80% and 97%. Computed PF and SF ratios were compared to identify threshold values for SF ratios that correspond to PF criteria for ALI (< or = 300) and ARDS (< or = 200). Data from one PICU were used for derivation and validated with measurements from the second PICU. RESULTS: From the 1,298 observations in the derivation data set, SF ratio could be predicted by the regression equation SF = 76 + 0.62 x PF (p < 0.0001, R(2) = 0.61). SF ratios of 263 and 201 corresponded to PF ratios of 300 and 200, respectively. The ALI SF cutoff of 263 had 93% sensitivity and 43% specificity, and the ARDS cutoff of 201 had 84% sensitivity and 78% specificity. Applying these values to the 1,845 observations in the validation data set yielded a sensitivity of 86% and specificity of 47% for ALI and a sensitivity of 68% and specificity of 84% for ARDS. CONCLUSION: SF ratio is a reliable noninvasive marker for PF ratio to identify children with ALI or ARDS.

Perioperative cyclooxygenase 2 inhibition to reduce tumor cell adhesion and metastatic potential of circulating tumor cells in non-small cell lung cancer.

OBJECTIVE: Surgical manipulation of lung cancers may increase circulating tumor cells and contribute to metastatic recurrence after resection. Cyclooxygenase 2 is overexpressed in most non-small cell lung cancer and upregulates the cell adhesion receptor CD44. Our goal was to examine the effects of perioperative cyclooxygenase blockade on the metastatic potential of circulating tumor cells, CD44 expression, and adhesion of cancer cells to extracellular matrix. METHODS: Human non-small cell lung cancer cells (A549) were injected through the lateral tail vein in an in vivo murine model of tumor metastasis with three random treatment groups: no treatment, perioperative selective cyclooxygenase 2 inhibition (celecoxib) only, and continuous celecoxib. Lung metastases were assessed at 6 weeks by a blinded observer. For in vitro experiments, cells were treated with celecoxib, and expression of CD44 was determined by Western blotting. Extracellular matrix adhesion was assessed by Matrigel (BD Labware, Bedford, Mass) assay. RESULTS: In vivo lung metastases were significantly decreased relative to control by both perioperative and continuous celecoxib (P = .0135). There was no significant difference in number of metastases between continuous and perioperative treatment groups. In vitro adhesion to the extracellular matrix was significantly inhibited by celecoxib in a dose-dependent manner (P < .01). A549 cells expressed high levels of CD44, upregulated by interleukin 1beta and downregulated by celecoxib. CONCLUSION: Celecoxib significantly reduced establishment of metastases by circulating tumor cells in a murine model. It also inhibited CD44 expression and extracellular matrix adhesion in vitro. Perioperative modulation of cyclooxygenase 2 may be a novel strategy to minimize metastases from circulating tumor cells during this high-risk period.

Dimethyl celecoxib as a novel non-cyclooxygenase 2 therapy in the treatment of non-small cell lung cancer.

OBJECTIVES: The cyclooxygenase 2 enzyme has become a therapeutic target in cancer treatment. Cyclooxygenase 2 blockade with selective inhibitors increases apoptosis and decreases the metastatic potential of lung cancer cells. Some of the antitumor effects of these inhibitors may occur through both cyclooxygenase 2-dependent and independent pathways. Our goal was to investigate these pathways using celecoxib (selective cyclooxygenase 2 inhibitor) and 2,5-dimethyl celecoxib, a structural analog modified to eliminate cyclooxygenase 2 inhibitory activity, while potentially maintaining antineoplastic properties. METHODS: 2,5-dimethyl celecoxib was synthesized in the Department of Chemistry at the University of Southern California. With the use of non-small cell lung cancer cells (A549), prostaglandin E2 production was quantified by enzyme-linked immunosorbent assay to assess cyclooxygenase 2 activity. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay. Cell migration was performed using transwell inserts that were matrigel coated for invasion experiments. Gelatin zymography was used to assess matrix-metalloproteinase activity. RESULTS: 2,5-dimethyl celecoxib did not inhibit interleukin-1beta-stimulated prostaglandin E2 production, whereas celecoxib did even at low doses. Both celecoxib and 2,5-dimethyl celecoxib decreased tumor cell viability and proliferation with IC50 for celecoxib and 2,5-dimethyl celecoxib of 73 and 53 micromol/L, respectively. Both drugs were also potent inducers of apoptosis, and both inhibited tumor cell migration and invasion. This was associated with down-regulation of matrix metalloproteinase activity. CONCLUSIONS: 2,5-dimethyl celecoxib is a structural analog of celecoxib that lacks cyclooxygenase 2 inhibitory activity but exhibits significant antineoplastic properties comparable to celecoxib. This suggests that the antineoplastic activities of celecoxib are, at least in part, cyclooxygenase independent and that therapeutic strategies can be developed without the side effects of global cyclooxygenase 2 blockade.

Proximal conduit obstruction after Sano modified Norwood procedure.

Sano and colleagues recently described a modification of first stage palliation for hypoplastic left heart syndrome utilizing a right ventricle to pulmonary artery conduit. Preliminary results are favorable, but experience with this technique is limited. We report a case of sudden death due to obstruction of the proximal conduit by fibrointimal hyperplasia. This case of lethal conduit obstruction presented 3 months after initial palliation. Early cardiac catheterization and second stage palliation may be necessary to minimize the risk of such adverse events after the Sano modification.

Evaluation of cyclooxygenase-2 inhibition in an orthotopic murine model of lung cancer for dose-dependent effect.

OBJECTIVES: Cyclooxygenase-2 plays a role in growth, apoptosis, angiogenesis, and metastasis in lung cancer. Inhibition of cyclooxygenase-2 with celecoxib has been shown to inhibit tumor growth. We evaluated the effect of increasing doses of celecoxib in a murine model of human lung cancer. METHODS: Human lung adenocarcinoma cells (A549) were implanted in the left lung upper lobe of mice with severe combined immunodeficiency syndrome. Mice were randomly assigned to 4 groups at implantation (n = 10 per group): control, 125 mg/kg chow, 500 mg/kg chow, 1000 mg/kg chow. After 3 weeks, mice were killed, and a blinded observer measured total tumor volume. The dose effect of celecoxib was examined in vitro by studying cell proliferation, expression of cyclooxygenase-2 (mRNA and protein), and production of prostaglandin E 2 in unstimulated and interleukin 1beta-stimulated cells. RESULTS: All 40 mice survived for 3 weeks with no observed toxicities. Total tumor volume was inhibited in each celecoxib group ( P = .0038, Welch analysis of variance): 206.7 +/- 119.5 mm 3 (control group), 41.4 +/- 54.0 mm 3 (low-dose group), 34.5 +/- 39.3 mm 3 (medium-dose group), and 27.3 +/- 53.6 mm 3 (high-dose group). In vitro celecoxib was effective at inhibiting production of prostaglandin E 2 , even in stimulated cells, although little effect was seen on cyclooxygenase-2 protein levels. Inhibition of proliferation was evident only at doses that exceeded those used in the animal model. CONCLUSION: Inhibition of cyclooxygenase-2 with low-dose celecoxib restricted the growth of lung cancer in this model. This might be mediated by prostaglandin E 2 . Higher doses of celecoxib afforded no additional benefit. Chronic therapy with low-dose cyclooxygenase-2 inhibition has the potential to influence tumor progression in non-small cell lung cancer.

Neochordal repair of the posterior mitral leaflet.

BACKGROUND: Myxomatous mitral valve insufficiency is traditionally repaired by posterior leaflet quadrangular resection and reconstruction. A simplified repair technique without leaflet resection is described, and our initial experience is reviewed. METHODS: Thirty-nine consecutive patients with significant mitral regurgitation underwent repair since January 2000 by placement of expanded polytetrafluoroethylene sutures between the leading (coapting) edge of the posterior leaflet and the corresponding papillary muscle. An annuloplasty ring was placed, and no leaflet tissue was resected. Patient medical records were obtained and retrospectively reviewed. RESULTS: Twenty-five men and 14 women (median age, 61 years; range, 40-88 years) had their mitral valve repaired by a variety of surgical approaches, including robotic (18 patients), right thoracotomy (6 patients), and sternal (15 patients). Three patients have required valve replacement: 1 at the initial operation, 1 because of dehiscence of the annuloplasty ring, and 1 after subsequent rupture of a previously normal native chorda. At follow-up (median, 12 months), 92% (33/36) of the remaining patients had an intact mitral repair with no to mild regurgitation, 8.3% (3/36) of patients had moderate regurgitation, and 92% of all patients (36/39) were in New York Heart Association class I. There were no deaths. CONCLUSIONS: Myxomatous mitral regurgitation due to posterior leaflet insufficiency can be repaired without leaflet resection by placement of neochordae. This repair technique is effective and is readily accomplished by traditional and minimally invasive surgical approaches.

Cyclooxygenase-2 inhibition decreases primary and metastatic tumor burden in a murine model of orthotopic lung adenocarcinoma.

OBJECTIVE: To assess cyclooxygenase-2 inhibition on primary tumor and mediastinal metastases in a murine model of orthotopic lung adenocarcinoma. METHODS: Human lung adenocarcinoma cells (CRL5908, female nonsmoker with cyclooxygenase-2 expression by Western blot) were implanted under direct visualization through the parietal pleura in the upper lobe of the left lung (2 x 10(6) cells/animal) of SCID mice. Mice were randomly assigned to 2 groups, either untreated (n = 62) or celecoxib-treated (n = 60). Celecoxib, a selective cyclooxygenase-2 antagonist, was solubilized in the animals' drink (25 mg/kg per day). Mice were arbitrarily killed at 1, 2, 3, and 4 weeks. A blinded observer assessed primary tumor volume and metastatic disease grossly and histologically. RESULTS: Gross metastatic lymph nodes were present at 3 weeks in none of 15 (0%) treated and 12 of 15 (80.0%) untreated animals (P <.0001). Mean primary tumor volumes at 3 weeks for treated mice were 7.9 +/- 10.0 mm(3) and for untreated mice were 533.1 +/- 453.6 mm(3) (mean +/- SD, P <.0001). Gross metastatic lymph nodes were present at 4 weeks in 3 of 15 (20%) treated and 17 of 17 (100%) untreated animals (P <.0001). Mean primary tumor volumes at 4 weeks for treated mice were 37.1 +/- 46.2 mm(3) and for untreated mice were 809.6 +/- 1226.4 mm(3) (mean +/- SD, P <.0001). Mean blood levels of celecoxib in treated mice were 236.8 +/- 34.2 ng/mL (mean +/- SD). CONCLUSIONS: Cyclooxygenase-2 inhibition results in decreased primary and metastatic tumor burden in a murine model using human lung adenocarcinoma. Cyclooxygenase-2 inhibition has the potential to decrease tumor progression and metastases in patients with lung adenocarcinoma.

Lung cancer and cyclooxygenase-2.

Lung cancer is by far the leading cause of cancer-related death. Overall survival is poor and has not improved substantially over the last half century. It is clear that new approaches are needed and these should include prevention, screening for early detection, and novel treatments based on our understanding of the molecular biology of this disease. Recently attention has been drawn to the role of the cyclooxygenase (COX) enzyme and its involvement in tumorigenesis. Investigations have documented two isoforms, COX-1 and COX-2, encoded by different genes. COX-1 is constitutively expressed in most tissues and appears to be responsible for the production of prostaglandins mediating normal physiologic functions, such as the maintenance of gastric mucosa and regulation of renal blood flow. In contrast, COX-2 is normally undetectable in most tissues, and is induced by cytokines, growth factors, oncogenes, and tumor promoters. A growing body of evidence indicates COX-2 plays a key role in lung cancer, and can serve as a potential marker of prognosis in this disease. Furthermore, the recent availability of COX-2 inhibitor medications offers a unique opportunity to interfere with the development of lung cancer and the progression of metastasis. Because COX-2 inhibitors have been demonstrated to interfere with tumorigenesis, the COX-2 enzyme may be an attractive target for therapeutic and chemoprotective strategies in lung cancer patients.

Intracranial hemorrhage in herpes simplex encephalitis: an unusual presentation.

We describe a 14-month-old patient with atypical presentation of herpes simplex encephalitis. She initially presented with fever, lethargy, seizures, and large hemorrhages in the right parietal lobe, and clinical findings suggestive of a hypercoagulable state. The etiology of coagulation abnormality was not identified, although it was suggested as a possible causative factor in severe bleeding along with acute neuronal lysis as a result of infection. Although large intracerebral hemorrhages are occasionally described with systemic herpes infection, this presentation is unusual beyond the infant period.