Observational study on off-label use of tocilizumab in patients with severe COVID-19.

BACKGROUND: In December 2019 a novel coronavirus designated SARS-CoV-2 was identified, and the disease COVID-19 has caused many deaths. SARS-CoV-2 infection has been associated with the development of cytokine storm (including interleukin 6 (IL-6)), which can cause lung damage and lack of oxygen. Tocilizumab (TCZ) inhibits ligand binding to the IL-6 receptor and may be a potential treatment for the hyperinflammation symptoms of COVID-19. However, data regarding the efficacy of TCZ in COVID-19 are lacking. The rapid spread of the pandemic in France, especially in the Paris region, constrained us to the off-label use of TCZ in patients with severe clinical conditions. METHODS: A single-centre observational cohort study of 44 patients infected with COVID-19 was carried out between 6 April and 21 April 2020 in Groupe Hospitalier Intercommunal Le Raincy-Montfermeil (GHILRM). Twenty-two patients diagnosed with COVID-19 were treated with TCZ and were compared with 22 patients not treated with TCZ matched for age, gender and length of hospital stay for COVID-19. Respiratory rate and oxygen supplementation as well as laboratory parameters (such as C-reactive protein (CRP), aspartate aminotransferase and alanine aminotransferase) were collected at baseline and during 14 days of follow-up. Our primary objective was to assess the efficacy of TCZ on respiratory clinical conditions. FINDINGS: The average respiratory rate was lower in the TCZ group than in the control group (21.5 vs 25.5 breaths/min at day 14, 95% CI -7.5 to -0.4; p=0.03). Treated patients tended to be intubated less during the course of the disease (2/22 vs 6/22, 95% CI -0.4 to 0.1; p=0.12). In each group, 10 patients no longer required oxygen therapy. We found a significant decrease in CRP in treated patients on day 7 (p=0.04). TCZ caused cytolysis in more than half (14/22) of the patients but without clinical impact. INTERPRETATION: There was a significant difference in the respiratory rate on day 14 of follow-up, with a greater decrease observed in the treated group. Fewer patients required mechanical ventilation in the TCZ group, especially among patients with more extensive CT lung damage, than in the control group. The same number of patients were weaned off oxygen on day 14 in the two groups, while the patients in the TCZ group had more severe impairment at inclusion. We consider that TCZ showed significant control of the biological inflammatory syndrome, suggesting that it may limit the effect of the cytokine storm. Our study seems to indicate the efficacy of TCZ, particularly in patients with severe initial pulmonary impairment. Selecting the best candidates and the best timing for TCZ therapy needs to be determined in randomised clinical trials.

Liver function test abnormalities are associated with a poorer prognosis in Covid-19 patients: Results of a French cohort.

AIM: To assess the impact of liver function test (LFT) abnormalities on the prognosis of patients with coronavirus disease 2019 (COVID-19) in a French cohort of hospitalized patients. PATIENTS AND METHOD: From March 13 to April 22, 2020, we collected on a computerized and anonymized database, medical records, laboratory data and clinical outcomes of patients hospitalized for confirmed cases of COVID-19 infection (RT-PCR and/or CT-scan). Patients were followed up until April 22, 2020 or until death or discharge. We have considered for statistical analysis, LFT abnormalities with levels greater than two times the upper limit of normal. Composite endpoint included admission to ICU, mechanical ventilation, severe radiologic injury and death to define disease severity. RESULTS: Among 281 patients (median age 60 years) with COVID-19, 102 (36.3%) had abnormal LFT. Hypertension (45.6%) and diabetes (29.5%) were the main comorbidities. 20.2% were taken liver-toxic drugs at the admission and 27.4% were given drugs known to induce hepatic cytolysis during hospitalization. Patients with elevated levels of ALT or AST were significantly more severe with a higher rate of admission to ICU (40.0% vs 6.0%, p< 0.0001), and global mortality (26.7% vs 12.1%, p= 0.03). In multivariate analysis, obesity and cytolytic profil were associated with the composite endpoint (respectively 2.37 [1.21; 4.64], p= 0.01 and OR 6.20, 95% confidence interval [1.84, 20.95], p-value 0.003) CONCLUSION: Most of liver injuries are mild and transient during COVID-19. LFT abnormalities are associated with a poorer prognosis and could be a relevant biomarker for early detection of severe infection.

Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices.

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial. Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices. Design, Setting, and Participants: Uncontrolled single-center cohort study including 20 patients with end-stage tracheal lesions or with proximal lung tumors requiring a pneumonectomy. The study was conducted in Paris, France, from October 2009 through February 2017; final follow-up for all patients occurred on November 2, 2017. Exposures: Radical resection of the lesions was performed using standard surgical techniques. After resection, airway reconstruction was performed using a human cryopreserved (-80°C) aortic allograft, which was not matched by the ABO and leukocyte antigen systems. To prevent airway collapse, a custom-made stent was inserted into the allograft. In patients with proximal lung tumors, the lung-sparing intervention of bronchial transplantation was used. Main Outcomes and Measures: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity. Results: Twenty patients were included in the study (mean age, 54.9 years; age range, 24-79 years; 13 men [65%]). Thirteen patients underwent tracheal (n = 5), bronchial (n = 7), or carinal (n = 1) transplantation. Airway transplantation was not performed in 7 patients for the following reasons: medical contraindication (n = 1), unavoidable pneumonectomy (n = 1), exploratory thoracotomy only (n = 2), and a lobectomy or bilobectomy was possible (n = 3). Among the 20 patients initially included, the overall 90-day mortality rate was 5% (1 patient underwent a carinal transplantation and died). No mortality at 90 days was observed among patients who underwent tracheal or bronchial reconstruction. Among the 13 patients who underwent airway transplantation, major 90-day morbidity events occurred in 4 (30.8%) and included laryngeal edema, acute lung edema, acute respiratory distress syndrome, and atrial fibrillation. There was no adverse event directly related to the surgical technique. Stent removal was performed at a postoperative mean of 18.2 months. At a median follow-up of 3 years 11 months, 10 of the 13 patients (76.9%) were alive. Of these 10 patients, 8 (80%) breathed normally through newly formed airways after stent removal. Regeneration of epithelium and de novo generation of cartilage were observed within aortic matrices from recipient cells. Conclusions and Relevance: In this uncontrolled study, airway bioengineering using stented aortic matrices demonstrated feasibility for complex tracheal and bronchial reconstruction. Further research is needed to assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT01331863.

A simple algorithm for the identification of clinical COPD phenotypes.

This study aimed to identify simple rules for allocating chronic obstructive pulmonary disease (COPD) patients to clinical phenotypes identified by cluster analyses.Data from 2409 COPD patients of French/Belgian COPD cohorts were analysed using cluster analysis resulting in the identification of subgroups, for which clinical relevance was determined by comparing 3-year all-cause mortality. Classification and regression trees (CARTs) were used to develop an algorithm for allocating patients to these subgroups. This algorithm was tested in 3651 patients from the COPD Cohorts Collaborative International Assessment (3CIA) initiative.Cluster analysis identified five subgroups of COPD patients with different clinical characteristics (especially regarding severity of respiratory disease and the presence of cardiovascular comorbidities and diabetes). The CART-based algorithm indicated that the variables relevant for patient grouping differed markedly between patients with isolated respiratory disease (FEV1, dyspnoea grade) and those with multi-morbidity (dyspnoea grade, age, FEV1 and body mass index). Application of this algorithm to the 3CIA cohorts confirmed that it identified subgroups of patients with different clinical characteristics, mortality rates (median, from 4% to 27%) and age at death (median, from 68 to 76 years).A simple algorithm, integrating respiratory characteristics and comorbidities, allowed the identification of clinically relevant COPD phenotypes.

Impact of distance from surgery department on the outcome of patients followed for non-small-cell lung cancer in the respiratory department of nonacademic hospitals: Results of the KBP-2010-study.

OBJECTIVE: Increased postoperative mortality in low volume centers has contributed to merge and space thoracic surgical centers. Some studies have showed that the likelihood of receiving surgery was lower in lung cancer patients living far from a thoracic surgery center. Our objective was thus to determine whether surgery and survival rates in patients with non-small-cell lung cancer (NSCLC) were influenced by the distance between the respiratory and thoracic surgery departments. METHODS: KBP-2010-CPHG is a prospective multicenter epidemiological study including 6083 patients followed in 104 nonacademic hospitals for primary NSCLC diagnosed in 2010. Distance between respiratory and thoracic surgery departments were obtained retrospectively. Predictive factors for surgery and mortality were identified by logistic regression and Cox hazard model. RESULTS: Twenty-three percent of hospitals had a thoracic surgery department; otherwise, mean distance between the hospital and the surgery center was 65km. Nineteen percent of patients underwent surgery. Distance was neither an independent factor for surgery (odds-ratios [95% CI]: 0.971 [0.74-1.274], 0.883 [0.662-1.178], and 1.015 [0.783-1.317] for 1-34, 35-79, and ≥80km vs. 0km) nor for mortality (hazard-ratios [95% CI]: 1.020 [0.935-1.111], 1.003 [0.915-1.099], and 1.006 [0.927-1.091]) (P>0.05). DISCUSSION: This result supports the French national strategy which merges surgery departments and should reassure patients (and physicians) who could be afraid to be lately addressed to surgery or loose chance when being followed far from the thoracic surgical center.

Prevalence and incidence of interstitial lung diseases in a multi-ethnic county of Greater Paris.

The objective of the study was to estimate the prevalence and incidence of interstitial lung diseases (ILDs) in Seine-Saint-Denis, a multi-ethnic county of Greater Paris, France.Patients with ILDs were identified between January and December 2012 by using several sources; all potentially involved medical specialists from public and private hospitals, community-based pulmonologists and general practitioners, and the Social Security system. Diagnoses were validated centrally by an expert multidisciplinary discussion.1170 ILD cases were reported (crude overall prevalence: 97.9/105 and incidence: 19.4/105/year). In the 848 reviewed cases, the most prevalent diagnoses were sarcoidosis (42.6%), connective tissue diseases associated ILDs (CTDs-ILDs) (16%), idiopathic pulmonary fibrosis (IPF) (11.6%), and occupational ILDs (5.0%), which corresponded to a crude prevalence of 30.2/105 for sarcoidosis, 12.1/105 for CTDs-ILDs and 8.2/105 for IPF. The prevalence of fibrotic idiopathic interstitial pneumonias, merging IPF, nonspecific interstitial pneumonia and cases registered with code J84.1 was 16.34/105 An adjusted multinomial model demonstrated an increased risk of sarcoidosis in North Africans and Afro-Caribbeans and of CTDs-ILDs in Afro-Caribbeans, compared to that in Europeans.This study, with a comprehensive recruitment and stringent diagnostic criteria, emphasises the importance of secondary ILDs, particularly CTDs-ILDs and the relatively low prevalence of IPF, and confirms that sarcoidosis is a rare disease in France.

A clinical in-hospital prognostic score for acute exacerbations of COPD.

BACKGROUND: The use of a severity score to help orientation decisions could improve the efficiency of care for acute exacerbations of COPD (AECOPD). We previously developed a score ('2008 score', based on age, dyspnea grade at steady state and number of clinical signs of severity) predicting in-hospital mortality in patients with AECOPD visiting emergency departments (EDs). External validity of this score remained to be assessed. OBJECTIVES: To test the predictive properties of the '2008 score' in a population of patients hospitalized in medical respiratory wards for AECOPD, and determine whether a new score specifically derived from this population would differ from the previous score in terms of components or predictive performance. METHODS: Data from a cohort study in 1824 patients hospitalized in a medical ward for an AECOPD were analyzed. Patients were categorized using the 2008 score and its predictive characteristics for in-hospital mortality rates were assessed. A new score was developed using multivariate logistic regression modeling in a randomly selected derivation population sample followed by testing in the remaining population (validation sample). Robustness of results was assessed by case-by-case validation. RESULTS: The 2008 score was characterized by a c-statistic at 0.77, a sensitivity of 69% and a specificity of 76% for prediction of in-hospital mortality. The new score comprised the same variables plus major cardiac comorbidities and was characterized by a c-statistic of 0.78, a sensitivity of 77% and specificity of 66%. CONCLUSIONS: A score using simple clinical variables has robust properties for predicting the risk of in-hospital death in patients hospitalized for AECOPD. Adding cardiac comorbidities to the original score increased its sensitivity while decreasing its specificity.

High-risk patients following hospitalisation for an acute exacerbation of COPD.

The aim of this study was to assess long-term mortality and predictive factors of death after hospital admission for acute exacerbation of chronic obstructive pulmonary disease (COPD). 1824 patients (23.2% female; mean age 70.3±11.3 years) consecutively admitted for acute exacerbation of COPD in the respiratory medicine departments of 68 general hospitals between October 2006 and June 2007 were prospectively enrolled in a follow-up cohort. Their vital status was documented between October 2010 and April 2011. Vital status was available for 1750 patients (95.9%), among whom 787 (45%) died during follow-up. Multivariate analysis found that age (60-80 years and ≥80 years versus <60 years, relative risk 2.99, 95% CI 2.31-3.89), lower body mass index (25-30 kg·m(-2) versus ≤20 kg·m(-2), relative risk 0.80, 95% CI 0.66-0.97), lung cancer (relative risk 2.08, 95% CI 1.43-3.01), cardiovascular comorbidity (relative risk 1.35, 95% CI 1.16-1.58), previous hospital admissions for acute exacerbation of COPD (four or more versus none, relative risk 1.91, 95% CI 1.44-2.53), use of accessory respiratory muscles (relative risk 1.19, 95% CI 1.01-1.40) or lower-limb oedema (relative risk 1.74, 95% CI (1.44-2.12)) at admission and treatment by long-term oxygen therapy at discharge (relative risk 2.09, 95% CI 1.79-2.45) were independent risk factors of death. Mortality rate during the 4 years following hospital admission for acute exacerbation of COPD was high (45%). Simple clinical information relating to respiratory and general status can help in identifying high-risk patients and targeting more intensive follow-up and care. Interestingly, cardiovascular comorbidities and past hospitalisations for acute exacerbation of COPD, but not forced expiratory volume in 1 s, independently predicted the risk of death.

4-year mortality in patients with non-small-cell lung cancer: development and validation of a prognostic index.

BACKGROUND: Lung cancer is the commonest cause of death due to cancer in the world. Non-small-cell lung carcinoma (NSCLC) represents about 80% of overall lung cancer cases worldwide. An accurate predictive model of mortality in patients with NSCLC could be useful to clinicians, policy makers, and researchers involved in risk stratification. The objective of this study was to develop and validate a simple prognostic index for 4-year mortality in patients with NSCLC by use of information obtained at the time of lung cancer diagnosis. METHODS: In 2000, 4669 patients with histologically or cytologically proven NSCLC were enrolled prospectively from 137 pneumology departments in French general hospitals. Patients not lost to follow-up (n=4479) were randomly assigned to the development cohort (n=2979) or the validation cohort (n=1500). Every patient's physician completed a standard and anonymous questionnaire. We used a Cox model to identify variables independently associated with mortality and weighted the variables to create a prognostic index. FINDINGS: Median follow-up for survivors was 49 months (IQR 46-51). There were 2585 deaths (87%) in the development cohort and 1310 deaths (87%) in the validation cohort. Five independent predictors of mortality were identified: age (>70 years, 1 point); sex (male, 1 point); performance status at diagnosis (reduced activity, 3 points; active >50%, 5 points; inactive >50%, 8 points; and total incapacity, 10 points); histological type (large-cell carcinoma, 2 points); and tumour-node-metastasis (TNM) staging system (IIA or IIB, 3 points; IIIA or IIIB, 6 points; and IV, 8 points). The minimum and maximum possible point scores were 0 and 22, respectively. Scores of the prognostic index were strongly associated with 4-year mortality in the development cohort: 0-1 points predicted a 35% (95% CI 28-43) risk, 2-4 points a 59% (52-66) risk, 5-7 points a 77% (72-81) risk, 8-10 points an 88% (85-90) risk, 11-14 points a 97% (96-98) risk, and 15-22 points a 99% (97-100) risk. The corresponding percentages in the validation cohort were 36% (24-47), 60% (50-70), 77% (71-83), 89% (86-93), 96% (95-98), and 99% (98-100), respectively. The prognostic index showed good discrimination, with mean bootstrap c statistics of 0.85 (95% CI 0.84-0.86) in the development cohort and 0.86 (95% CI 0.85-0.87) in the validation cohort. INTERPRETATION: This prognostic index, incorporating personal, tumour, and functional information would be helpful in guiding patient management, resource use, and the design of clinical trials.

[Frequency and type of adverse drug reactions in two Seine-Saint-Denis departments of pneumology]. / Estimation de l'incidence des événements iatrogènes médicamenteux dans les services de pneumologie de deux hôpitaux de Seine-Saint-Denis.

The aim of this study was to explore the frequency and type of adverse drug reactions between January and June 2001 in hospitalised patients. A prospective study was conducted in two pneumology departments of public hospitals in the Seine-Saint-Denis area. Adverse drug reactions were collected by hospital pharmacists after spontaneous notification by nurses and physicians, except for deliberate drug overdose. The drugs implicated, causality and the severity of each adverse drug reaction were analysed. The mean age of patients was 69 +/- 15 years (63% male and 37% female). The total sample comprised 1598 patients. During the period of the study, 190 patients experienced at least one adverse drug reaction. This amounts to a prevalence of 12% (95% confidence interval [95% CI: 7.4-16.6%). The percentage of severe adverse effects was 28.4% (95% CI: 25.1-31.6%) and adverse reactions were rated avoidable in 35.8% of cases (95% CI: 32.3-39.3%). Antibiotics (23%), corticosteroids (15%), analgesics (13%) and anticoagulants (9%) were the drugs most frequently implicated in adverse effects. Preventable adverse drug events were more serious than non-preventable adverse events (p = 0.001). With regard to the level of severity, antibiotics, corticosteroids and bronchodilators were associated with a low severity level, whereas anticoagulants and antineoplastics were associated with a high severity level.