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

PURPOSE: 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: 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: 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.

A 33-Year-Old Man With Acute Hemoptysis.

CASE PRESENTATION: 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.

The incidence of propofol infusion syndrome in critically-ill patients.

PURPOSE: 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: 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: 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.

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

OBJECTIVES: 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: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: 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: 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.

Idiopathic pulmonary fibrosis: Current and future treatment.

OBJECTIVES: 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: 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: 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.

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

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: 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: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: 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.

Idiopathic pulmonary fibrosis: Molecular mechanisms and potential treatment approaches.

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.

Imaging of suspected pulmonary embolism and deep venous thrombosis in obese patients.

Obesity is a growing problem around the world, and radiology departments frequently encounter difficulties related to large patient size. Diagnosis and management of suspected venous thromboembolism, in particular deep venous thrombosis (DVT) and pulmonary embolism (PE), are challenging even in some lean patients, and can become even more complicated in the setting of obesity. Many obstacles must be overcome to obtain imaging examinations in obese patients with suspected PE and/or DVT, and to ensure that these examinations are of sufficient quality to diagnose or exclude thromboembolic disease, or to establish an alternative diagnosis. Equipment limitations and technical issues both need to be acknowledged and addressed. Table weight limits and scanner sizes that readily accommodate obese and even morbidly obese patients are not in place at many clinical sites. There are also issues with image quality, which can be substantially compromised. We discuss current understanding of the effects of patient size on imaging in general and, more specifically, on the imaging modalities used for the diagnosis and treatment of DVT and PE. Emphasis will be placed on the technical parameters and protocol nuances, including contrast dosing, which are necessary to refine and optimize images for the diagnosis of DVT and PE in obese patients, while remaining cognizant of radiation exposure. More research is necessary to develop consistent high-level evidence regarding protocols to guide radiologists, and to help them effectively utilize emerging technology.

Intensity of Vasopressor Therapy for Septic Shock and the Risk of In-Hospital Death.

CONTEXT: Given the high mortality of 30%-60% associated with septic shock, distinguishing which patients do or do not have a reasonable chance of surviving with aggressive treatment could help clinicians and families make informed decisions. OBJECTIVES: To determine if intensity of vasopressor therapy accurately predicts in-hospital death. METHODS: This observational cohort study analyzed in-hospital mortality as a function of intensity of vasopressor therapy in a consecutive series of adults with septic shock treated over a four-year period. Receiver operating characteristic curve analysis assessed the overall strength of the intensity-mortality relationship. RESULTS: A total of 808 patients with septic shock experienced an in-hospital death rate of 41.0% (331/808; 95% CI, 38.5%-44.5%). The greater the peak number of vasopressors required, the higher the death rate, which reached 92.3% (12/13; 95% CI, 79.4%-100.0%) when three different pressors were being infused at full dose. The receiver operating characteristic curve analysis revealed that number of simultaneous vasopressors and vasopressor dose load performed equally well in predicting death or survival. CONCLUSION: When a standard full dose of a vasopressor fails to normalize blood pressure in a patient with septic shock, escalation begins to yield diminishing returns as the dose and multiplicity of agents approach practical upper limits. Although it is not possible to specify a precise cutoff for limiting vs. intensifying therapy, a mortality of 80% or higher-characterized by two or more concurrent vasopressors at full dose-should prompt shared decision making with the patient's family.

Possible hepatotoxicity associated with intravenous acetaminophen in a 36-year-old female patient.

We present a case of a 36-year-old female who came into the emergency department with right-side abdominal pain. She went to the operating room for a diagnostic laparoscopy and appendectomy. She received intravenous (IV) acetaminophen every six hours both preoperatively and postoperatively for pain control. The patient's aspartate aminotransferase and alanine aminotransferase levels were elevated and peaked at 4,833 and 6,600 IU/L, respectively, from baselines of 14 and 15, respectively, while she was receiving 16 doses of IV acetaminophen. The patient was transferred to a regional liver transplant center for evaluation for a transplant. She was treated with IV N-acetylcysteine and discharged with a normal liver-function test without a transplant. This case report supports the possibility of hepatotoxicity associated with IV acetaminophen.

Eosinophilic pneumonia associated with azacitidine in a patient with myelodysplastic syndrome.

Eosinophilic pneumonia is characterized by cough, lung infiltrates on imaging, and by the presence of eosinophils in the alveoli and pulmonary interstitium. Azacitidine, a pyramidine nucleoside analog of cytidine, is FDA approved for the treatment of various myelodysplastic syndromes. We present a case of a 76-year-old man with recently diagnosed myelodysplastic syndrome, who developed eosinophilic pneumonia after initiating therapy with azacitidine. There was clinical and radiographic improvement with cessation of the drug and treatment with prednisone. Diagnosis of drug-induced eosinophilic pneumonia is established by having a temporal relationship between onset of symptoms and initiation of therapy, bronchoalveolar lavage or lung biopsy evidence of pulmonary eosinophilia, no other explanation for the disease, and improvement upon cessation of the offending agent. Our case illustrates the need for a high index of suspicion to identify adverse pulmonary reactions associated with newly developed medications.

Written disclosure therapy for patients with chronic lung disease undergoing pulmonary rehabilitation.

PURPOSE: Chronic lung diseases are typically associated with impaired quality of life, stress, and anxiety. Written disclosure therapy (WDT) reduces stress in patients with a variety of chronic illnesses. We sought to determine whether WDT benefits patients with chronic lung disease. METHODS: A prospective, randomized, controlled trial was performed to evaluate the effect of using WDT in patients (N = 66) participating in a pulmonary rehabilitation program. Patients were randomly assigned to write about a particularly traumatic life event (WDT group) or to write about an emotionally neutral subject (control group). Exercise capacity, dyspnea and quality of life, and values of spirometry were recorded at baseline, at the end of the program, and at 6 months. RESULTS: The 6-minute walk distance (6MWD) significantly improved in both groups at 2 months, from 278 to 327 m in WDT and from 269 to 314 m in control groups (P < .01 in both groups). There was no difference in improvement in 6MWD between groups (P = .88). At 6 months, the gains made in 6MWD were no longer present. Dyspnea severity, as well as most of the other domains of the Chronic Respiratory Disease Questionnaire and the St. George's Respiratory Questionnaire, showed improvement within each group, but not between WDT and control groups. CONCLUSION: WDT did not add any additional benefit in patients with chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis when included as a component of pulmonary rehabilitation. These results are in contrast to previously seen benefits in patients with asthma.

Pharmacological treatment options for bronchiectasis: focus on antimicrobial and anti-inflammatory agents.

Patients with bronchiectasis experience tenacious mucus, recurrent infectious exacerbations, and progressive worsening of symptoms and obstruction over time. Treatment is aimed at trying to break the cycle of infection and progressive airway destruction. Antibacterial treatment is targeted towards likely organisms or tailored to the results of sputum culture. Inhaled antibacterial therapy may offer the advantage of increased local concentration of medication, while minimizing systemic adverse effects; however, to date, studies have been equivocal in this disorder. Macrolides, in addition to their antibacterial properties, have unique anti-inflammatory properties, which may make them useful in this disorder. Other mucoactive and anti-inflammatory agents, such as inhaled corticosteroids, mannitol and hypertonic saline, may also prove useful in this disease, but further studies are needed.

Bronchiectasis: new findings in the pathogenesis and treatment of this disease.

PURPOSE OF REVIEW: Bronchiectasis is an under-appreciated cause of chronic lung disease in the USA. We highlight developments in diagnosis and treatment of this debilitating disease. RECENT FINDINGS: A possible link between gastroesophageal reflux and development of nontuberculous mycobacterial lung disease was highlighted. Reflux is more common in patients with nontuberculous mycobacterial lung disease, and among those with established bronchiectasis more extensive disease was observed in those patients who also had reflux. Long-term mortality in bronchiectasis was significantly associated with age, lower body mass index, dyspnea, lack of vaccination, hypoxemia, hypercapnia, and other functional parameters. In a large, randomized clinical trial, addition of inhaled tobramycin to ciprofloxacin for acute exacerbations of Pseudomonas infection produced microbiologic improvement correlating with clinical outcomes but not overall improvement. A review noted that five macrolide trials reported reduced sputum volume, improved lung function, and better symptom control. Finally, articles suggested benefit from inhaled hyperosmolar agents (e.g. hypertonic saline and inhaled mannitol). SUMMARY: The possible link between gastroesophageal reflux and nontuberculous mycobacterial lung disease, and the microbiology and resistance patterns of bacteria observed in these patients were clarified. A large study of inhaled tobramycin for exacerbations was inconclusive, but macrolide therapy and hyperosmolar agents hold promise.

Radiology-Pathology Conference: pulmonary hyalinizing granuloma associated with lupus-like anticoagulant and Morvan's Syndrome.

Pulmonary hyalinizing granulomata are rare, noninfectious, fibrosing lesions of the lung, which can mimic metastatic disease radiographically. Their etiology is unknown, but they may be caused by an exaggerated immune response. We report the radiology, long clinical course, and pathology of a patient with pulmonary hyalinizing granuloma who presented with initially asymptomatic pulmonary nodules. Over a 10-year period, the patient developed multiple insidious autoimmune phenomena, including lupus anticoagulant, neuromyotonia, demyelinating sensorimotor polyneuropathy, and eventually, Morvan's syndrome. Such an association has not been previously published to our knowledge.

The effect of pulmonary rehabilitation on healthcare utilization in chronic obstructive pulmonary disease: The Northeast Pulmonary Rehabilitation Consortium.

Although pulmonary rehabilitation results in improvement in multiple outcome areas, relatively few studies in the United States have evaluated its effect on healthcare utilization. This study compared aspects of healthcare utilization during the year before to the year after outpatient pulmonary rehabilitation in patients with chronic obstructive pulmonary disease referred to 11 hospital-based centers in Connecticut and New York. Utilization data from 128 of 132 patients who originally gave informed consent were evaluated; their mean age was 69 years and their forced expiratory volume in 1 second was 44% of predicted. Forty-five percent had 1 or more hospitalizations in the year before beginning pulmonary rehabilitation. In the year after pulmonary rehabilitation, there were 0.25 fewer total hospitalizations (P = .017) and 2.18 fewer hospital days (P = .015) per patient and 271 fewer hospital days for the group. Hospitalizations for respiratory reasons also decreased significantly. Most of the reduction in hospital utilization was due to a decrease in intensive care unit days. The number of physician visits decreased by 2.4 in the year after pulmonary rehabilitation (P < .0001); most of this reduction was due to decreased visits to primary care providers. The estimated costs/charges for the aspects of healthcare utilization that we studied decreased by a mean of 4,694 dollars and a median of 390 dollars (P = .0002). This study suggests that pulmonary rehabilitation leads to a reduction in healthcare utilization.

Results of an 8-week, outpatient pulmonary rehabilitation program on patients with and without chronic obstructive pulmonary disease.

PURPOSE: To determine whether there is any difference in the effect of pulmonary rehabilitation (PR) on outcomes in patients with and without chronic obstructive pulmonary disease (COPD). METHODS: Retrospective analysis of medical records of all patients enrolling in PR over a 5-year period. RESULTS: A total of 422 patients enrolled in a multidisciplinary PR program from August 1999 to April 2004. Three hundred nine patients had COPD and 113 patients had diagnoses other than COPD. Three hundred seventy-nine patients completed the program. PR was conducted according to currently accepted guidelines. Measurements included the 6-minute walk distance (6MW) performed at the beginning and end of the program and quality of life as determined by the Chronic Respiratory Questionnaire (CRQ) at the beginning and end of the program. Both groups had significant improvements in the 6MW and all domains of the CRQ following PR. There was no significant difference in any of these outcomes between the 2 groups. The baseline forced expiratory volume in 1 second (FEV1) was not correlated with improvement in the 6MW in either group. CONCLUSIONS: There is no significant difference in improvement in exercise tolerance or quality of life following PR in COPD versus non-COPD patients. Baseline lung function does not predict improvement in exercise tolerance. PR is effective for patients with disability due to any chronic respiratory disease and not just COPD.

Rapid pleurodesis for malignant pleural effusions.

STUDY OBJECTIVE: To determine the feasibility of rapid pleurodesis in patients with malignant pleural effusions in order to reduce hospital length of stay in patients with a limited life expectancy. DESIGN: Prospective case series. SETTING: Two university hospital programs. PATIENTS: Thirty-eight patients with symptomatic pleural effusions associated with malignancy. INTERVENTIONS: A 14F catheter was inserted percutaneously into the pleural space after radiographic confirmation of free fluid by lateral decubitus views. Following radiographic confirmation of complete fluid evacuation, a sclerosing agent (ie, talc slurry or bleomycin) was instilled into the pleural space. This was accomplished within 2 h of chest tube insertion, unless the tube was inserted in the evening or if the lung was trapped. After clamping the tube for 90 min, the pleural space was drained for 2 h, after which the chest tube was removed. The intervention was scored as "successful" if no radiographic evidence of fluid reaccumulation was noted at 4 weeks. A "partial successful" score indicated reaccumulation of fluid that did not produce symptoms and did not require repeat pleural drainage of any sort. All other outcomes were scored as "unsuccessful." MEASUREMENTS AND RESULTS: Forty chest tubes were inserted into 38 patients. Four procedures revealed the presence of a trapped lung and did not result in any attempt at pleurodesis. Five patients who received pleurodesis died in less than 1 month and therefore were not evaluable. Two patients had technical problems with the chest tube and were not evaluable. Of the remaining 29 procedures, drainage procedures with pleurodesis were performed in 27 patients, a complete response was seen in 14 patients (48%), a partial response was seen in 9 patients (31%), and 6 patients (21%) did not respond to pleurodesis. Chemical pleurodesis was completed as an outpatient procedure in only two patients. In one of these, the outcome was unsuccessful. In the remainder, insertion of the chest tube in the evening or additional medical problems necessitated hospital admission, but the entire procedure was completed within 24 h. CONCLUSIONS: Chemical pleurodesis can be accomplished with good results in < 24 h in the majority of patients with malignant pleural effusions.