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.

Three-month follow-up after severe COVID-19 infection: are chest CT results associated with respiratory outcomes and respiratory recovery in COVID-19 patients?

BACKGROUND: CT Severity Score (CT-SS) can be used to assess the extent of severe coronavirus disease 19 (COVID-19) pneumonia. Follow-up CT-SS in patients surviving COVID-19-associated hyperinflammation and its correlation with respiratory parameters remains unknown. This study aims to assess the association between CT-SS and respiratory outcomes, both in hospital and at three months after hospitalization. METHODS: Patients from the COVID-19 High-intensity Immunosuppression in Cytokine storm Syndrome (CHIC) study surviving hospitalization due to COVID-19 associated hyperinflammation were invited for follow-up assessment at three months after hospitalization. Results of CT-SS three months after hospitalization were compared with CT-SS at hospital admission. CT-SS at admission and at 3-months were correlated with respiratory status during hospitalization and with patient reported outcomes as well as pulmonary- and exercise function tests at 3-months after hospitalization. RESULTS: A total of 113 patients were included. Mean CT-SS decreased by 40.4% (SD 27.6) in three months (P < 0.001). CT-SS during hospitalization was higher in patients requiring more oxygen (P < 0.001). CT-SS at 3-months was higher in patients with more dyspnoea (CT-SS 8.31 (3.98) in patients with modified Medical Council Dyspnoea scale (mMRC) 0-2 vs. 11.03 (4.47) in those with mMRC 3-4). CT-SS at 3-months was also higher in patients with a more impaired pulmonary function (7.4 (3.6) in patients with diffusing capacity for carbon monoxide (DLCO) > 80%pred vs. 14.3 (3.2) in those with DLCO < 40%pred, P = 0.002). CONCLUSION: Patients surviving hospitalization for COVID-19-associated hyperinflammation with higher CT-SS have worse respiratory outcome, both in-hospital and at 3-months after hospitalization. Strict monitoring of patients with high CT-SS is therefore warranted.

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.

Changes in problematic activities of daily living in persons with COPD during 1 year of usual care.

INTRODUCTION: Persons with chronic obstructive pulmonary disease (COPD) are often limited in performing their activities of daily living (ADLs). However, it remains unknown whether and to what extent problematic ADLs change over time and whether exacerbation-related hospitalisations affect problematic ADLs. Therefore, we investigated self-reported problematic ADLs of persons with COPD during 1 year of usual care (i.e. without a specific experimental intervention). METHODS: Stable persons with moderate to very severe COPD (n = 137) were included in this longitudinal study (registered in the Dutch Trial Register [NTR 3941]). Participants were visited at home at baseline and after 1 year. Participants with an exacerbation-related hospitalisation during follow-up were visited additionally within 2 weeks after hospital discharge. During all visits, participants' personalised problematic ADLs were assessed using the Canadian Occupational Performance Measure (COPM), and perceived performance and satisfaction of important problematic ADLs were rated on a 10-point scale. RESULTS: In total, 90% of the participants reported at least one new important problematic ADL after 1 year. In the subgroup of participants with an exacerbation-related hospitalisation (n = 31), 92% of the participants reported new problematic ADLs 2 weeks after discharge and 90% reported new problematic ADLs again after 1 year. Only the satisfaction score of problematic ADLs as mentioned during baseline improved after 1-year follow-up in all participants (p = .002) and in participants without an exacerbation-related hospitalisation (n = 106; p = .014). CONCLUSION: Problematic ADLs changed during 1 year of usual care, which underlines the need for regular assessment of problematic ADLs and referral to treatment options like monodisciplinary occupational therapy and/or a comprehensive pulmonary rehabilitation programme.

Patient versus proxy-reported problematic activities of daily life in patients with COPD.

BACKGROUND AND OBJECTIVE: Loved ones (proxies) of patients with COPD are confronted with the patients' limitations in activities of daily living (ADLs). However, it remains unknown whether proxies are able to correctly estimate the problematic ADLs of the patient. Therefore, we aimed to investigate the level of agreement between patient-reported and proxy-reported problematic ADLs of the patient. METHODS: Stable outpatients with moderate to very severe COPD (n = 194) and their resident proxies (n = 194) were included in this cross-sectional study. Patients' problematic ADLs were assessed in the domains 'self-care', 'mobility', 'productivity' and 'leisure' using the Canadian Occupational Performance Measure (COPM) in both patients and resident proxies. Furthermore, the perceived performance and satisfaction for important problematic ADLs were rated on a 10-point scale. RESULTS: In total, 830 problematic ADLs were reported by patients, and 735 by proxies. Agreement in reporting problematic ADLs within a domain was poor (productivity and leisure; κ; = 0.20 and 0.16, respectively) to fair (self-care and mobility; κ = 0.32 and 0.22, respectively). Similar performance and satisfaction scores, for equally reported problematic ADLs, were given by 24.0% and 17.6% of the pairs, respectively. CONCLUSION: Proxies were often not able to identify the patients' most important problematic ADLs. Moreover, when patient and proxy agreed about the presence of a specific problematic ADL, the perception of the performance and the satisfaction with that performance differed within most pairs. This emphasizes the importance of involving proxies, besides patients alone, in identifying patients' problematic ADLs.

Knowledge gaps in patients with COPD and their proxies.

BACKGROUND: Although proxies of patients with chronic obstructive pulmonary disease (COPD) need health-related knowledge to support patients in managing their disease, their current level of knowledge remains unknown. We aimed to compare health-related knowledge (generic and COPD-related knowledge) between patients with COPD and their resident proxies. METHODS: In this cross-sectional study, we included stable patients with moderate to very severe COPD and their resident proxies (n = 194 couples). Thirty-four statements about generic health and COPD-related topics were assessed in patients and proxies separately. Statements could be answered by 'true', 'false', or 'do not know'. This study is approved by the Medical Research Ethics Committees United (MEC-U), the Netherlands (NL42721.060.12/M12-1280). RESULTS: Patients answered on average 17% of the statements incorrect, and 19% with 'do not know'. The same figure (19%) for the incorrect and unknown statements was shown by proxies. Patients who attended pulmonary rehabilitation previously answered more statements correct (about three) compared to patients who did not attend pulmonary rehabilitation. More correct answers were reported by: younger patients, patients with a higher level of education, patients who previously participated in pulmonary rehabilitation, patients with better cognitive functioning, and patients with a COPD diagnosis longer ago. CONCLUSIONS: Proxies of patients with COPD as well as patients themselves answer about two third of 34 knowledge statements about COPD correct. So, both patients and proxies seem to have an incomplete knowledge about COPD and general health. Therefore, education about general health and COPD should be offered to all subgroups of patients with COPD and their proxies. TRIAL REGISTRATION: This study is registered in the Dutch Trial Register ( NTR3941 ). Registered 19 April 2013.

Uniportal video-assisted thoracoscopic surgery for lobectomy: the learning curve.

OBJECTIVES: Prior reported learning curves for uniportal video-assisted thoracoscopic lobectomy were predominantly based on surgery duration, while reports on complications are limited. Therefore, our study assessed the learning curve based on both technique-related complications and surgery duration. METHODS: We retrospectively collected data from patients who had undergone uniportal video-assisted thoracoscopic lobectomy between 2015 and 2020. Exclusion criteria were concomitant procedures other than ipsilateral wedge resection, discontinued procedures, or lost to follow-up (less than 30 days). Learning curves were constructed per surgeon who performed over 20 procedures using non-risk adjusted cumulative sum (CUSUM) analysis for technique-related complications and cumulative sum analysis for surgery duration. Based on the literature, an acceptable complication rate was set at 30%, an unacceptable complication rate at 45%, and a mean surgery duration of 145 min. RESULTS: Learning curves were constructed for three thoracic surgeons and one fellow who performed 324 uniportal video-assisted thoracoscopic lobectomies in total. Each surgeon was experienced in multiportal video-assisted thoracoscopic lobectomy, the fellow was familiar with basic multiportal video-assisted thoracoscopic procedures. Cumulative sum charts of three surgeons reached a statistically significant technique-related complication rate below 30% between 50 and 96 procedures. Regarding surgery duration, typical learning curves were observed for three surgeons with a transition point between 14 and 26 procedures. CONCLUSIONS: Learning of uniportal video-assisted thoracoscopic surgery for lobectomy is safe without unacceptable complication rates and has a declining surgery duration over time for thoracic surgeons with experience in multiportal video-assisted thoracoscopic lobectomies. However, it remains unknown when the different stages of mastery are completed.

A No-Chest-Drain Policy After Video-assisted Thoracoscopic Surgery Wedge Resection in Selected Patients: Our 12-Year Experience.

BACKGROUND: Postoperative pleural drainage omission after video-assisted thoracoscopic surgery (VATS) for wedge resections may facilitate faster recovery. This retrospective cohort study presents our 12-year experience with omitting thoracic drainage in patients who underwent a VATS wedge resection, aiming to assess its safety and efficacy. METHODS: Records from consecutive patients who underwent a VATS wedge resection at our hospital between February 2008 and October 2020 were retrospectively reviewed and assessed for eligibility. Patient and surgical characteristics as well as postoperative data were collected and compared between patients who received a chest drain (CD) or received no chest drain (NCD) after surgery. Univariable and multivariable analyses were performed to determine whether drain placement was associated with complications (primary outcome), and major complications requiring pleural drainage or length of hospital stay (secondary outcomes). RESULTS: Data of 348 patients were analyzed. The drainless group (n = 98) and drain group (n = 237) were significantly different in the following baseline and surgical characteristics: sex, pulmonary function, interstitial lung disease, final pathology, number of wedges, and surgical approach. No significant differences were detected in postoperative complications (NCD 8.2%, CD 14.8%; P = .10), major complications (NCD 5.1%, CD 5.1%; P > .99), or complications requiring pleural drainage (NCD 5.1%, CD 3.8%; P = .56). The drainless group did show a significantly shorter hospitalization (NCD 2 ± 2, CD 3 ± 2 days; P < .001). Multivariable analyses revealed that drain placement was not significantly correlated with postoperative complications. In contrast, prolonged hospitalization was significantly influenced by drain placement. CONCLUSIONS: Our findings suggest that a no-chest-drain policy after VATS wedge resections can safely fast-track rehabilitation for selected patients.

Risk of Pneumothorax Requiring Pleural Drainage after Drainless VATS Pulmonary Wedge Resection: A Systematic Review and Meta-Analysis.

OBJECTIVE: Omitting pleural drainage after video-assisted thoracic surgery (VATS) for pulmonary wedge resections has been shown to be a safe approach to enhance recovery. However, major concerns remain regarding the risk of postoperative pneumothoraces requiring surgical interventions. Therefore, our objective was to provide conclusive evidence whether chest tube omission after VATS wedge resection is safe and does not increase the risk of pneumothoraces requiring pleural drainage. METHODS: Five scientific databases were searched. Studies comparing patients with (CT group) and without chest tube drainage (NCT group) after VATS wedge resection were evaluated. Outcomes included radiographically diagnosed pneumothoraces and pneumothoraces requiring pleural drainage, postoperative complications, hospitalization, and pain scores. RESULTS: Overall, 9 studies (3 randomized controlled trials) were included (N = 928). Meta-analysis showed significantly more radiographically diagnosed pneumothoraces in the NCT group (risk ratio [RR] = 2.58, 95% confidence interval [CI]: 1.56 to 4.29, P < 0.001; I2 = 0%). However, no significant differences were found in postoperative pneumothoraces requiring pleural drainage (RR = 1.72, 95% CI: 0.63 to 4.74, P = 0.29; I2 = 0%) or complications (RR = 0.77, 95% CI: 0.39 to 1.52, P = 0.46; I2 = 0%). Furthermore, the NCT group showed significantly shorter hospitalization (mean difference = -1.26, 95% CI: -1.56 to -0.95, P < 0.001) with high heterogeneity (I2 = 58%, P = 0.02), and lower pain scores on postoperative day 1 (standard mean difference [SMD] = -0.98, 95% CI: -1.71 to -0.25, P = 0.009; I2 = 92%) and postoperative day 2 (SMD = -1.28, 95% CI: -2.55 to -0.01, P = 0.05; I2 = 96%) compared with the CT group. CONCLUSIONS: VATS wedge resection without routine chest tube placement is suggested as a safe and less invasive approach in selected patients that does not increase the risk of a pneumothorax requiring pleural drainage.

Surgical mediastinal lymph node staging for non-small-cell lung carcinoma.

BACKGROUND: The current preferred approach for surgical mediastinal staging of non-small-cell lung carcinoma is video-assisted mediastinoscopy. An alternative technique in which lymph nodes are resected instead of biopsied is video-assisted mediastinoscopic lymphadenectomy (VAMLA) that is suggested to be superior in detecting N2 disease. Yet, evidence is conflicting and furthermore limited by sample size. The objective was to compare mediastinal staging through VAMLA and video-assisted mediastinoscopy. METHODS: A single-center cohort study was conducted. All consecutive patients that underwent surgical mediastinal staging of non-small-cell lung carcinoma by VAMLA (2011 to 2018) were compared to historic video-assisted mediastinoscopy controls (2007 to 2011). Patients with negative surgical mediastinal staging underwent subsequent anatomical resection with systematic regional lymphadenectomy. Primary outcome was the sensitivity and negative predictive value for detecting N2 disease. RESULTS: Two-hundred-sixty-nine video-assisted mediastinoscopic lymphadenectomies and 118 video-assisted mediastinoscopies were performed. The prevalence of N2 disease was 20% and 26% respectively in the VAMLA and video-assisted mediastinoscopy group, while the rate of unforeseen pN2 resulting from lymph node dissection during anatomical resection was 4% and 11%, respectively. Invasive staging using VAMLA demonstrated superior sensitivity of 0.82 and a negative predictive value of 0.96 when compared to video-assisted mediastinoscopy (0.62 and 0.89, respectively), offering a 64% decrease in risk of unforeseen pN2 following anatomical resection. However, VAMLA is also associated with a 75% risk increase on complications (P=0.36). CONCLUSIONS: We conclude that performing invasive mediastinal lymph node assessment for staging of non-small-cell lung carcinoma, VAMLA should be the preferred technique with superior sensitivity and negative predictive value in detecting N2 disease. Though, VAMLA is also associated with an increased risk of complications.

Minimally Invasive Approach to Esophageal Perforation after Endoscopic Ultrasound-Guided Fine-Needle Aspiration: A Report of 2 Cases.

Esophageal perforation after endoscopic ultrasound-guided fine-needle aspiration for mediastinal staging is a rare but severe complication. We report 2 cases of patients with esophageal perforation who were treated using video-assisted thoracoscopic surgery in combination with esophageal stenting. Through these cases, the feasibility of minimally invasive thoracic surgery was evaluated.

Chest tube drainage versus video-assisted thoracoscopic surgery for a first episode of primary spontaneous pneumothorax: a systematic review and meta-analysis.

Primary spontaneous pneumothorax affects up to 28 patients per 100 000 population yearly and is commonly resolved by chest tube drainage. However, drainage is also known to be associated with ipsilateral recurrence rates ranging from 25% to 43%. Preventive video-assisted thoracoscopic surgery (VATS) may be an effective alternative to diminish these recurrence rates and its associated morbidity. The aim of this study was to compare the efficacy of chest tube drainage and VATS as first line treatments of an initial episode of primary spontaneous pneumothorax. The MEDLINE, EMBASE, CENTRAL and Clinicaltrials.gov databases were searched through 16 September 2018. Data regarding the ipsilateral recurrence rate and the length of hospitalization were extracted and submitted to meta-analysis using the random-effects model and the I2 test for heterogeneity. Two randomized controlled trials and 2 observational studies were included, enrolling a total of 479 patients. Pairwise analysis demonstrated significantly reduced ipsilateral recurrence rates [odds ratio 0.15, 95% confidence interval (CI) 0.07-0.33; P < 0.00001] and length of hospitalization (standardized mean difference -2.19, 95% CI -4.34 to -0.04; P = 0.046) in favour of VATS. However, a significant level of heterogeneity was detected for the length of hospitalization (I2 = 97%; P < 0.00001). Subgroup analysis that stratified study design found no statistical differences regarding recurrence rate. In conclusion, VATS can be an effective and attractive alternative to standard chest tube drainage, with reduced ipsilateral recurrence rates and length of hospitalization. However, given the low quality of the majority of included studies, more well-designed randomized controlled trials are necessary to strengthen the current evidence.

[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.