Single dose tocilizumab for COVID-19 associated cytokine storm syndrome: Less is more.

AIMS: We aim to evaluate the clinical pharmacokinetics of a single dose interleukin-6 (IL-6) antibody tocilizumab (TCZ) in methylprednisolone (MP)-treated COVID-19 patients with cytokine storm syndrome (CSS). METHODS: MP pre-treated patients with COVID-19-associated CSS, defined as at least two elevations of C-reactive protein (CRP) >100 mg/L, ferritin >900 µg/L or D-dimers >1500 µg/L, received intravenous TCZ (8 mg/kg, max. 800 mg) upon clinical deterioration. A nonlinear-mixed effects model was developed based on TCZ serum concentrations and dosing information. Population pharmacokinetic parameters were estimated and concentration-time profiles were plotted against individual predicted values. Fixed dose simulations were subsequently performed based on the final model. RESULTS: In total 40 patients (mean [SD] age: 62 [12] years, 20% female, body weight: 87 [17] kg) with COVID-19 induced CSS were evaluated on pharmacokinetics and laboratory parameters. A biphasic elimination of TCZ serum concentration was described by a homogeneous population pharmacokinetic model. Serum TCZ concentrations above the 1 µg/L target saturation threshold were covered for 16 days in all evaluated patients treated with a single dose of 8 mg/kg. In a simulation with TCZ 400 mg fixed dose, this condition of full IL-6 receptor occupancy at minimum serum concentration was also met. CONCLUSIONS: A single dose (8 mg/kg, max. 800 mg) is sufficient to cover a period of 16 days of IL-6-mediated hyperinflammation in COVID-19-induced CSS in MP-treated patients. Based on body weight PK simulations, a fixed-dose tocilizumab of 400 mg should be considered to prevent overtreatment, future drug shortage and unnecessary drug expenditure.

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study.

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Tocilizumab in Severe COVID-19 Pneumonia and Concomitant Cytokine Release Syndrome.

Younger patients with COVID-19 may experience an exaggerated immune response to SARS-CoV-2 infection and develop cytokine release syndrome (CRS), which may be life threatening. There is no proven antiviral therapy for COVID-19 so far, but profound immunosuppression has recently been suggested as a treatment for COVID-19-associated CRS. We present a case of life-threatening CRS caused by COVID-19 infection with a favourable response to immunosuppressive therapy with tocilizumab (TCZ). The rapid clinical and biochemical improvement following TCZ administration suggests that treatment with immunotherapy can be life-saving in selected patients with COVID-19-induced CRS. LEARNING POINTS: Cytokine release syndrome may cause sudden and potentially life-threatening clinical deterioration in COVID-19 pneumonia, particularly in younger patients.Immunosuppressive therapy may provide important additional therapeutic benefit in these patients.Tocilizumab, a specific IL-6 inhibitor, led to dramatic clinical improvement in a young patient with severe COVID-19-associated cytokine release syndrome.

Inhaled mannitol for non-cystic fibrosis bronchiectasis: a randomised, controlled trial.

RATIONALE: Bronchiectasis is characterised by excessive production of mucus and pulmonary exacerbations. Inhaled osmotic agents may enhance mucociliary clearance, but few long-term clinical trials have been conducted. OBJECTIVES: To determine the impact of inhaled mannitol on exacerbation rates in patients with non-cystic fibrosis (CF) bronchiectasis. Secondary endpoints included time to first exacerbation, duration of exacerbations, antibiotic use for exacerbations and quality of life (QOL) (St George's Respiratory Questionnaire, SGRQ). METHODS: Patients with non-CF bronchiectasis and a history of chronic excess production of sputum and ≥2 pulmonary exacerbations in the previous 12 months were randomised (1:1) to 52 weeks treatment with inhaled mannitol 400 mg or low-dose mannitol control twice a day. Patients were 18-85 years of age, baseline FEV1 ≥40% and ≤85% predicted and a baseline SGRQ score ≥30. MAIN RESULTS: 461 patients (233 in the mannitol and 228 in the control arm) were treated. Baseline demographics were similar in the two arms. The exacerbation rate was not significantly reduced on mannitol (rate ratio 0.92, p=0.31). However, time to first exacerbation was increased on mannitol (HR 0.78, p=0.022). SGRQ score was improved on mannitol compared with low-dose mannitol control (-2.4 units, p=0.046). Adverse events were similar between groups. CONCLUSIONS: Mannitol 400 mg inhaled twice daily for 12 months in patients with clinically significant bronchiectasis did not significantly reduce exacerbation rates. There were statistically significant improvements in time to first exacerbation and QOL. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION NUMBER: NCT00669331.

Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial.

IMPORTANCE: Macrolide antibiotics have been shown beneficial in cystic fibrosis (CF) and diffuse panbronchiolitis, and earlier findings also suggest a benefit in non-CF bronchiectasis. OBJECTIVE: To determine the efficacy of macrolide maintenance treatment for adults with non-CF bronchiectasis. DESIGN, SETTING, AND PARTICIPANTS: The BAT (Bronchiectasis and Long-term Azithromycin Treatment) study, a randomized, double-blind, placebo-controlled trial conducted between April 2008 and September 2010 in 14 hospitals in The Netherlands among 83 outpatients with non-CF bronchiectasis and 3 or more lower respiratory tract infections in the preceding year. INTERVENTIONS: Azithromycin (250 mg daily) or placebo for 12 months. MAIN OUTCOME MEASURES: Number of infectious exacerbations during 12 months of treatment. Secondary end points included lung function, sputum bacteriology, inflammatory markers, adverse effects, symptom scores, and quality of life. RESULTS: Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0-1), compared with 2 (IQR, 1-3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16-0.51]). In a mixed-model analysis, change in forced expiratory volume in the first second of expiration (percent of predicted) over time differed between groups (F1,78.8 = 4.085, P = .047), with an increase of 1.03% per 3 months in the azithromycin group and a decrease of 0.10% per 3 months in the placebo group. Gastrointestinal adverse effects occurred in 40% of patients in the azithromycin group and in 5% in the placebo group (relative risk, 7.44 [95% CI, 0.97-56.88] for abdominal pain and 8.36 [95% CI, 1.10-63.15] for diarrhea) but without need for discontinuation of study treatment. A macrolide resistance rate of 88% was noted in azithromycin-treated individuals, compared with 26% in the placebo group. CONCLUSIONS AND RELEVANCE: Among adults with non-CF bronchiectasis, the daily use of azithromycin for 12 months compared with placebo resulted in a lower rate of infectious exacerbations. This could result in better quality of life and might influence survival, although effects on antibiotic resistance need to be considered. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00415350.

[A man with persisting dyspnea]. / Een man met aanhoudende dyspneu.

A 67-year-old male was diagnosed with pulmonary embolism and treated with anticoagulants. Half a year later CT of the chest showed growth of the embolism and that pleural fluid and pleural noduli had appeared. A 18FDG-PET-CT showed uptake in these abnormalities and in several bones. Bone biopsy showed a leiomyosarcoma. The patient was diagnosed with metastasized pulmonary artery sarcoma.

Complete video-assisted thoracoscopic surgery lobectomy and its learning curve. A single center study introducing the technique in The Netherlands.

Data regarding the benefits for the complete video-assisted thoracic surgery (c-VATS) lobectomy over the open lobectomy are numerous. This article describes the experience of introducing this technique in a training hospital, the first reported cohort in The Netherlands. From March 2006 to November 2008, all patients operated on for proven or suspected lung cancer were analyzed. Prospective data from these patients were evaluated. A subgroup analysis for the c-VATS lobectomy is presented. A total of 184 operations were performed on 172 patients. In 122 (66.3%) of the operations the resection ended in a lobectomy of which 70 were done by complete thoracoscopic procedure. For the c-VATS lobectomy the mean operating time was 179 min, with a mean blood loss of 444 ml. The median hospital stay was four days. Complications were present in 10% of c-VATS lobectomies. No mortality was seen in the c-VATS group. After thorough evaluation and training, c-VATS lobectomy is a safe procedure that can be performed in a relatively low volume hospital. It has exceptional short-term benefits. For training purposes all operations must start thoracoscopically. All patients must be operated according the intention to treat method.

Analytical and clinical performance of three natriuretic peptide tests in the emergency room.

BACKGROUND: The aim of the present study was to investigate the analytical and diagnostic utility of B-type natriuretic peptide (BNP) and the N-terminus of this prohormone, N-terminal pro-BNP (NT-pro-BNP) testing in the emergency department to identify acute congestive heart failure (CHF). METHODS: A blood sample taken from patients presenting to the emergency department with acute dyspnoea (n=80) was analyzed for natriuretic peptides using three different assays [Triage BNP (Biosite), Centaur BNP (Bayer) and Elecsys NT-pro-BNP (Roche)]. A cardiologist and a pulmonologist, blinded to the actual natriuretic peptide levels, reviewed all test results (including echocardiography, etc.) retrospectively and made a diagnosis of dyspnoea due to CHF or not. RESULTS: Analytical testing showed good correlation and coefficients of variation of less than 10% for all three assays. Cardiac-related dyspnoea was found in 40 patients (50%). NT-proBNP and BNP values were significantly elevated in these patients. For identifying patients with CHF, BNP and NT-proBNP scored equally well (area under the receiver operating characteristic curve of 0.78, 0.77 and 0.78 for the Biosite, Roche and Bayer assays, respectively). CONCLUSIONS: In general, the different assays tested for BNP and NT-pro-BNP correlate very well in patients with suspected CHF and may aid in the risk stratification process in emergency departments. However, the value must always be interpreted in conjunction with other clinical information. It should also be considered that renal impairment can affect the results.