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Low dose vs high dose tocilizumab in COVID-19 patients with hypoxemic respiratory failure

Chung, Juri; Brosnahan, Shari B; Islam, Shahidul; Altshuler, Diana; Spiegler, Peter; Li, Wai Kin; Wang, Wai Man; Chen, Xian Jie Cindy
PURPOSE/OBJECTIVE:Tocilizumab has been shown to decrease mortality when used concomitantly with steroids in COVID-19 with 8 mg/kg (max 800 mg) being the standard dose. Our study sought to assess whether a low dose (400 mg) shows similar benefit compared to a high dose for COVID patients concurrently on the same median dose of steroids. MATERIALS/METHODS/METHODS:A retrospective, multihospital observational study of COVID-19 patients who received tocilizumab in conjunction with steroids between March 2020 and August 2021 was conducted. RESULTS:A total of 407 patients were analyzed with low dose group being significantly more ill at baseline as a higher percentage of patients received vasopressors, were admitted to the ICU and on mechanical ventilation. In the propensity-matched analysis, both groups receiving a median dexamethasone equivalent dose of 10 mg showed no difference in 28-day mortality (p = 0.613). The high dose group had a higher rate of fungal and viral infections. CONCLUSION/CONCLUSIONS:Compared to low dose tocilizumab, the high dose did not provide additional efficacy and mortality benefit but resulted in higher fungal and viral infections. This study illustrates that low dose tocilizumab can be an alternative to high dose during a drug shortage of tocilizumab without compensating for efficacy and safety, conserving resources for more patients.
PMCID:10084735
PMID: 37043893
ISSN: 1557-8615
CID: 5464172

A 33-Year-Old Man With Acute Hemoptysis [Case Report]

Meier, Erin; Katz, Douglas S; Spiegler, Peter
A 33-year-old man with a medical history of childhood exercise-induced asthma presented to the ED with 2 days of hemoptysis. He described the hemoptysis as bright red blood with clots, approximately 100 cm3 in total. He denied prior hemoptysis, pulmonary infections, or exposure to TB. Years ago he had an episode of gross hematuria, but a urologic workup was unrevealing.
PMID: 36628679
ISSN: 1931-3543
CID: 5434372

LOW-DOSE VERSUS HIGH-DOSE TOCILIZUMAB IN COVID-19 PATIENTS WITH HYPOXIC RESPIRATORY FAILURE [Meeting Abstract]

Wang, W M; Chen, X J; Chung, J; Kin, Li W; Islam, S; Altshuler, D; Spiegler, P; Brosnahan, S
INTRODUCTION: Tocilizumab has been shown to decrease mortality when used concomitantly with steroids in COVID-19. Tocilizumab dose of 8 mg/kg (max: 800 mg), stemmed from the RECOVERY trial, has been the standard dose for COVID. Due to a drug shortage of tocilizumab, our study seeks to assess whether low dose (400 mg) shows similar benefit compared to high dose for COVID patients concurrently on same median dose of steroids.
METHOD(S): This was a retrospective observational study of COVID-19 patients who received tocilizumab in conjunction with steroids. Between March 2020 and August 2021, adult patients with positive COVID-19 PCR, hypoxic respiratory failure defined as FiO2>70%, and received a dose of tocilizumab in conjunction with steroids were included. Patients were excluded if they have died within 24 hours of treatment initiation. Primary outcome was 28-day mortality and secondary outcomes included biomarker improvement and relative risk of infection. Propensity matched analysis between groups was performed.
RESULT(S): A total of 407 patients met the study criteria and were analyzed. The low dose and high dose tocilizumab group had 222 and 185 patients respectively. Gender and age were similar between groups and all patients received steroids. The low dose group was significantly more ill at baseline as a higher percentage of patients received vasopressors, were admitted to the ICU and on mechanical ventilation. In the propensity-matched analysis of 56 patients in each group, with a median dose of steroid of 10 mg in both groups showed no difference in 28 day mortality (HR 0.82 [95% CI: 0.41-1.67]; p=0.6138). A greater decrease to normalization of CRP (p< 0.0001) and downtrend of ferritin (p=0.503) was observed in the high dose group at day 14. The high dose group trended a higher rate of fungal and viral infections.
CONCLUSION(S): Compared to low dose tocilizumab, high dose did not provide additional efficacy and mortality benefit but resulted in uptrend of fungal and viral infections. While a greater decrease in CRP was seen in the high dose group, it did not translate into lower mortality. This study illustrates that low dose tocilizumab can be an alternative to high dose during a drug shortage of tocilizumab without compensating for efficacy and safety, conserving resources for more patients
EMBASE:640005728
ISSN: 1530-0293
CID: 5513732

A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation

Lonze, Bonnie E; Spiegler, Peter; Wesson, Russell N; Alachkar, Nada; Petkova, Eva; Weldon, Elaina P; Dieter, Rebecca A; Li, Yi; Quinn, Max; Mattoo, Aprajita; Soomro, Irfana; Cohen, Steven M; Leung, Sherry; Deterville, Cecilia L; Landrum, B Mark; Ali, Muhammad Imran; Cohen, David J; Singer, Andrew L; Sen, Ayan; Chong, Edward; Hochman, Judith S; Troxel, Andrea B; Montgomery, Robert A
OBJECTIVES/OBJECTIVE:We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN/METHODS:Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING/METHODS:Five U.S. medical centers. PATIENTS/METHODS:Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS/METHODS:Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival ,frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS:Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.
PMID: 35583232
ISSN: 1530-0293
CID: 5249242

The incidence of propofol infusion syndrome in critically-ill patients

Li, Wai Kin; Chen, Xian Jie Cindy; Altshuler, Diana; Islam, Shahidul; Spiegler, Peter; Emerson, Liane; Bender, Michael
PURPOSE/OBJECTIVE:PRIS is a potentially fatal syndrome characterized by various clinical symptoms and abnormalities. Experts suggest that propofol treatment duration ≥48 h or dose ≥83 μg/kg/min is associated with developing PRIS. We hypothesized PRIS might be underdiagnosed due to the overlap of PRIS clinical manifestations with critical illnesses. MATERIALS AND METHODS/METHODS:Multihospital, retrospective study of adult patients who received continuous propofol infusion ≥48 h or dose ≥60μg/kg/min for >24 h since admission were assessed for the development of PRIS. RESULTS:The incidence of PRIS was 2.9% with a PRIS-associated mortality rate of 36.8%. In PRIS patients, propofol was administered at a median dose of 36.4 μg/kg/min and over a median duration of 147.0 h. The development of PRIS was observed at a median of 125.0 h post-propofol initiation and a cumulative dose of 276.5 mg/kg. The development of metabolic acidosis (78.9%), cardiac dysfunction (52.6%), hypertriglyceridemia (100%), and rhabdomyolysis (26.3%) were observed in our PRIS patients. CONCLUSION/CONCLUSIONS:PRIS can often be overlooked and underdiagnosed. It is important to monitor for early signs of PRIS in patients who are on prolonged propofol infusion. Prompt recognition and interventions can minimize the dangers resulting from PRIS.
PMID: 35724444
ISSN: 1557-8615
CID: 5281852

Reply: Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk [Comment]

Chen, Xian Jie Cindy; Altshuler, Diana; Spiegler, Peter; Brosnahan, Shari B
PMID: 34330173
ISSN: 1542-6270
CID: 5176832

Idiopathic pulmonary fibrosis: Current and future treatment

Glass, Daniel S; Grossfeld, David; Renna, Heather A; Agarwala, Priya; Spiegler, Peter; DeLeon, Joshua; Reiss, Allison B
OBJECTIVES/OBJECTIVE:Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3-5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development. DATA SOURCE/METHODS:The data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management. RESULTS:Etiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy. CONCLUSION/CONCLUSIONS:Clearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well-being.
PMID: 35001525
ISSN: 1752-699x
CID: 5175912

Prevalence of propofol infusion syndrome in critically ill patients [Meeting Abstract]

Li, W K; Chen, X J; Altshuler, D; Islam, S; Emerson, L; Spiegler, P; Bender, M
INTRODUCTION: Propofol has been widely used in the ICU for sedation and refractory status epilepticus. PRIS is a serious and potentially fatal condition that is characterized by a spectrum of clinical symptoms and abnormalities. Literature suggests that a longer duration of propofol >= 48 hours or a dose >= 83 mcg/kg/min is associated with a higher risk of PRIS. Many of the critically ill patients in our health system required a larger dose of propofol and prolonged duration of infusion for sedation in the ICU, especially during Covid-19. Delayed treatment of PRIS can lead to death. It is very likely that patients who develop PRIS may often go unrecognized as the manifestations of PRIS can overlap with common ICU conditions. The current prevalence of PRIS is unknown, however, a prospective study has reported a prevalence of 1.1% in critically ill patients.
METHOD(S): Patients were identified by querying the NYU Langone Health COVID clinical data mart from March 2020 till February 2021. The inclusion criteria included patients receiving propofol infusion for >= 48 hours or receiving a dose >= 60 mcg/kg/min for more than 24 hours. Pregnant patients, children, and patients with rhabdomyolysis prior to the start of infusion were excluded. PRIS was defined by the development of metabolic acidosis and cardiac dysfunction with 2 or more minor criteria (rhabdomyolysis, hypertriglyceridemia, renal failure, and hepatic transaminitis) or developing 3 or more minor criteria.
RESULT(S): 424 patients were included in our study. Of the 424 patients, 21 patients were found to have developed PRIS. The occurrence of PRIS was observed at the median infusion rate of 36.1 mcg/kg/min and a median duration of infusion of 147 hours. The prevalence of PRIS was found to be 4.9%.
CONCLUSION(S): The prevalence of PRIS in our study was found to be 4.9%. The occurrence of PRIS was observed at the median infusion rate of 36.1 mcg/kg/min suggesting that PRIS can be developed at a lower rate of infusion than previously reported. We suggest that patients - especially those receiving a duration >= 48 hours and a higher dose of 60 mcg/kg/min - should be monitored for signs and symptoms of PRIS during propofol infusion as it may be underrecognized because PRIS is characterized by multiple clinical manifestations that overlap with critical illness
EMBASE:637188824
ISSN: 1530-0293
CID: 5158262

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk

Brosnahan, Shari B; Chen, Xian Jie Cindy; Chung, Juri; Altshuler, Diana; Islam, Shahidul; Thomas, Sarun V; Winner, Megan D; Greco, Allison A; Divers, Jasmin; Spiegler, Peter; Sterman, Daniel H; Parnia, Sam
BACKGROUND:Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES/OBJECTIVE:The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS:A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS:= 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE/UNASSIGNED:Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.
PMID: 34180274
ISSN: 1542-6270
CID: 4926192

Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches

Glass, Daniel S; Grossfeld, David; Renna, Heather A; Agarwala, Priya; Spiegler, Peter; Kasselman, Lora J; Glass, Amy D; DeLeon, Joshua; Reiss, Allison B
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease with high mortality that commonly occurs in middle-aged and older adults. IPF, characterized by a decline in lung function, often manifests as exertional dyspnea and cough. Symptoms result from a fibrotic process driven by alveolar epithelial cells that leads to increased migration, proliferation, and differentiation of lung fibroblasts. Ultimately, the differentiation of fibroblasts into myofibroblasts, which synthesize excessive amounts of extracellular matrix proteins, destroys the lung architecture. However, the factors that induce the fibrotic process are unclear. Diagnosis can be a difficult process; the gold standard for diagnosis is the multidisciplinary conference. Practical biomarkers are needed to improve diagnostic and prognostic accuracy. High-resolution computed tomography typically shows interstitial pneumonia with basal and peripheral honeycombing. Gas exchange and diffusion capacity are impaired. Treatments are limited, although the anti-fibrotic drugs pirfenidone and nintedanib can slow the progression of the disease. Lung transplantation is often contraindicated because of age and comorbidities, but it improves survival when successful. The incidence and prevalence of IPF has been increasing and there is an urgent need for improved therapies. This review covers the detailed cellular and molecular mechanisms underlying IPF progression as well as current treatments and cutting-edge research into new therapeutic targets.
PMID: 32487481
ISSN: 2212-5353
CID: 4468982