Use of FeNO to predict anti-IL-5 and IL-5R biologics efficacy in a real-world cohort of adults with severe eosinophilic asthma.

INTRODUCTION: Severe eosinophilic asthma (SEA) is associated with multiple exacerbations. Fractional exhaled nitric oxide (FeNO), a biomarker of airway T2 inflammation, is known to be correlated with the risk of exacerbations. While the use of FeNO is well established to predict the therapeutic response to dupilumab (anti-IL-4/IL-13), it remains uncertain for biologics targeting the IL-5 pathway. METHODS: We conducted an observational, retrospective, monocentric analysis of adults with SEA who started mepolizumab (anti-IL-5) or benralizumab (anti-IL-5R) between January 1, 2016 and December 31, 2020. RESULTS: Data were collected for 109 patients. All participants reported uncontrolled asthma with a median of 3 annual exacerbations and a median Asthma Control Test score of 12. They all had an initial blood eosinophilia >300/mm3, with a median at 610/mm3 (IQR 420-856). Patients with a baseline FeNO ≥50 ppb reported more exacerbations in the previous year than those with a FeNO <50 ppb (p = 0.02). After initiation of treatment, change in FeNO was not associated with therapeutic response. However, decrease in the annual number of exacerbations was significantly greater in patients with a baseline FeNO ≥50 ppb than in those with a baseline FeNO <50 ppb (-3.3 ± 2.7 vs -0.9 ± 2.4, respectively; p = 0.01). There was no association between baseline FeNO values and subsequent lung function, asthma control or reduction of oral corticosteroids use. CONCLUSION: In this real-world cohort, adults with SEA who had a baseline FeNO ≥50 ppb experienced a greater decrease in exacerbations after 12 months of anti-IL-5 or IL-5R biologics than those with a FeNO <50 ppb.

Total unilateral pulmonary collapse secondary to allergic bronchopulmonary aspergillosis: a case series of an unusual cause of complete atelectasis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a bronchopulmonary disease caused by a complex hypersensitivity to Aspergillus and is usually associated with underlying respiratory diseases such as asthma or cystic fibrosis. Mucus plugging can lead to segmental or lobar atelectasis, but complete lung atelectasis has been exceptionally reported in the literature, making it difficult to diagnose. The diagnosis of ABPA may however be suggested in patients without known predisposing respiratory disorder, even in the absence of other relevant radiographic findings. CASE PRESENTATION: We report five cases of total unilateral lung collapse secondary to ABPA in 70-81-year-old women. Two of them had a past history of ABPA, while total unilateral lung collapse was the first sign of the disease in the other three patients, contributing to the initial misdiagnosis. Flexible bronchoscopy was initially performed to remove mucus plugs from the obstructed airways but was inefficient in four cases. Corticosteroid and/or antifungal treatment was needed. CONCLUSION: ABPA can cause total unilateral lung collapse even in patients without known underlying chronic respiratory disease, making the diagnosis difficult. Flexible bronchoscopy should be considered when lung collapse is associated with respiratory distress but corticosteroids are the mainstay treatment for ABPA.

[Transbronchial lung cryobiopsy in interstitial lung diseases]. / Les cryobiopsies pulmonaires transbronchiques dans les pneumopathies infiltrantes diffuses.

In some cases of interstitial lung disease (ILD), clinical and biological findings associated with CT scan pattern during multidisciplinary discussion (MDD) fail to yield a confident diagnosis. In these cases, histology may be necessary. Transbronchial lung cryobiopsy (TBLC) is a bronchoscopic procedure that has been developed in recent years and currently contributes to diagnostic work-up in patients with ILD. TBLC provides tissue samples for histological analysis with an acceptable risk of complications, consisting mainly in pneumothorax or bleeding. In addition to higher diagnostic yield than conventional forceps biopsies, the procedure shows a better safety profile than surgical biopsies. The indication to perform TBLC is decided during a 1st MDD and during a 2nd MDD, results can provide a diagnostic yield approximating 80%. TBLC appears to be an attractive, minimally invasive technique to be proposed as a first-line procedure in selected patients in experienced centers, while surgical lung biopsy may be considered as a second-line solution.

[Immune-related pneumonitis: A differential diagnosis of SARS-CoV-2 pneumonia]. / Pneumopathie immuno-induite : un diagnostic différentiel de la pneumopathie à SARS-CoV-2.

INTRODUCTION: Immune checkpoint inhibitors have revolutionized the management of many cancers and achieved efficacy and durable response for some patients, including those with advanced cancers. However, immunotherapy is associated with side effects caused by the infiltration of immune cells into normal tissues, which can lead to disproportionate dysimmune reactions. While mostly of moderate intensity, these side effects can affect any organ, including the lung, the site of occasionally life-threatening interstitial lung disease. Their presentation can be similar to that of infectious pneumonia (COVID-19). OBSERVATIONS: We report the cases of 3 patients who presented between March and May 2020 with severe pulmonary toxicities secondary to immunotherapy, which led to with an initial hypothesis of SARS-CoV-2 pneumonia. After extensive investigations, the diagnosis of pulmonary toxicity to immunotherapy was given, and the clinical and radiological course following the initiation of corticosteroid therapy was favorable. CONCLUSION: Pulmonary toxicity secondary to immunotherapy remains a rare but potentially life-threatening side effect. The diagnostic approach requires the elimination of several differential diagnoses (infectious process, tumor progression, other etiologies of interstitial lung disease). This adverse event is reversible and evolution after initiation of corticosteroid therapy is usually favorable.

[Accidental silver nitrate inhalation]. / Inhalation accidentelle de nitrate d'argent.

INTRODUCTION: Silver nitrate pencil is often used to treat local granuloma caused by tracheotomy and tracheostomy cannula orifice. CASE REPORT: We report the case of a 69-year-old patient who accidentally inhaled silver nitrate lead from the tip of a pencil during treatment of local granuloma. Inhalation of this product, which is known to cause burns and a risk of perforation of the mucous membranes, could suggest locoregional complications. Clinical monitoring and radiological and endoscopic examinations were carried out. Antibiotics and corticosteroids were administered because of inflammatory lesions. After 6 months, the patient had recovered with restitutio ad integrum of anatomical structures. CONCLUSION: Silver nitrate pencil should be used with caution. Given the high risk of perforation, painstaking and repeated monitoring are necessary in case of accidental inhalation. Bronchial endoscopy is of central importance as a means of localizing the foreign substance, following which bronchial cleaning is performed, using physiological serum. Corticosteroid appears to be effective to limit the risk of inflammatory bronchial stenosis.

[Central control malfunction in Wolfram syndrome: Report of one case of difficult weaning]. / Dysfonction de la commande centrale dans le syndrome de Wolfram : à propos d'un cas de sevrage ventilatoire difficile.

INTRODUCTION: Wolfram syndrome is a rare autosomal recessive genetic disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A neurodegenerative syndrome is usually associated, including cerebellar ataxia. A few cases of central apnea have been reported in the literature. Here, we report a case of Wolfram syndrome with respiratory symptoms that led to the discovery of central apneas as well as complicated and delayed weaning in an intensive care unit (ICU). OBSERVATION: The patient is a 39-year-old woman diagnosed with Wolfram syndrome who was admitted to an ICU for septic shock. She experienced difficult weaning before central apneas were observed while spontaneous ventilation was being attempted. After two extubation failures, cerebral MRI was performed and revealed parenchymatous atrophy of the posterior brain fossa involving the cerebral trunk, cerebellar peduncles, as well as both cerebellum hemispheres and the cerebellar vermis. Even after the patient was tracheotomized, central apneas persisted when the patient breathed spontaneously with her tracheotomy, necessitating nocturnal ventilation. CONCLUSION: While central apneas Wolfram syndrome remain rare, they should be systematically investigated due to their association with severe morbimortality.

[Pneumo-Quest: A standardised self-questionnaire to be completed at home before a first appointment at a respiratory clinic]. / Pneumo-Quest, auto-questionnaire standardisé à compléter au domicile avant une première consultation en pneumologie : étude de validation.

The Pneumo-Quest self-questionnaire was developed to standardize the practice of recollection when welcoming a new patient. It consists of 82 main questions and 34 subsidiary questions to be completed at home by the patients before their first visit to a pulmonologist. This evaluation was carried out on the basis of 137 returned questionnaires. The feasibility (main criterion) was good with 93±5% of the questions answered and an average completion time of 15.1±9.8minutes (mean±SD). The reliability of the responses (secondary criterion) was good with the agreement between the patient's response and the doctor's opinion being excellent or good for the majority of medical histories and treatments, as evidenced by the high values of the kappa coefficient (>0.90; <0.90; <0.75). Patient and physician perception of the questionnaire was good with 99% and 90% positive ratings, respectively. The use of the questionnaire was unhelpful in the course of the consultation in only 2% of cases. Doctors found the tool useful for obtaining a comprehensive history in 87% of cases and patients declared that it helped them "forgot nothing" in 93% of the cases. The questionnaire helped the doctor to identify the patient's problems rapidly in 71% of cases and saved time in 64%. These positive results encourage a wide dissemination of the questionnaire (www.pneumo-quest.com).

[Guide for follow-up of patients with SARS-CoV-2 pneumonia. Management proposals developed by the French-language Respiratory Medicine Society. Version of 10 May 2020]. / Guide pour le suivi respiratoire des patients ayant présenté une pneumonie à SARS-CoV-2. Propositions de prise en charge élaborées par la Société de pneumologie de langue française. Version du 10 mai 2020.

The French-language Respiratory Medicine Society (SPLF) proposes a guide for the follow-up of patients who have presented with SARS-CoV-2 pneumonia. The proposals are based on known data from previous epidemics, on acute lesions observed in SARS-CoV-2 patients and on expert opinion. This guide proposes a follow-up based on three categories of patients: (1) patients managed outside hospital for possible or proven SARS-CoV-2 infection, referred by their physician for persistent dyspnoea; (2) patients hospitalized for SARS-CoV-2 pneumonia in a medical unit; (3) patients hospitalized for SARS-CoV-2 pneumonia in an intensive care unit. The subsequent follow-up will have to be adapted to the initial assessment. This guide emphasises the possibility of others causes of dyspnoea (cardiac, thromboembolic, hyperventilation syndrome…). These proposals may evolve over time as more knowledge becomes available.

Relaxation of tracheal smooth muscle is impaired in innate airway hyperresponsiveness.

The current study was designed to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F-344 rat strain is associated with impaired spontaneous relaxation of airway smooth muscle. Strips of the posterior portion of the trachea from 10 adult Fisher and 10 adult Lewis rats were electrically stimulated at pH 7.4, 2.5 mM Ca(2+)concentration, at 37 degrees C. Both isotonic and isometric relaxations of tracheal smooth muscle (TSM) were investigated. Half time for isotonic relaxation at preload was markedly prolonged in Fisher rats (8.33+/-3.21 s) compared with Lewis rats (3.53+/-0.54 s; p<0.001). Maximum lengthening velocity at preload and peak rate of isometric tension decline were significantly decreased in Fisher rats compared with Lewis rats. The ratio of shortening velocity to lengthening velocity at preload, as well as the ratio of the isometric peak rates of tension development to tension decline were higher in Fisher rat TSM than in Lewis rat TSM. These differences were associated with a six-fold higher expression of myosin light chain kinase in Fisher rats than in Lewis rats. In Fisher rats, these results suggest that innate airway hyperresponsiveness is associated with both a reduced level and a slower rate of TSM spontaneous relaxation, promoting maintenance of airway constriction.

Clinical characteristics and prognostic factors of pulmonary MALT lymphoma.

Mucosa-associated lymphoid tissue-derived (MALT) lymphoma, a low grade B-cell extranodal lymphoma, is the most frequent subset of primary pulmonary lymphoma. Our objective was to evaluate the initial extent of disease and to analyse the characteristics and long-term outcome of these patients. All chest and pathological departments of teaching hospitals in Paris were contacted in order to identify patients with a histological diagnosis of primary pulmonary lymphoma of the MALT subtype. 63 cases were identified. The median age was 60 yrs. 36% of cases had no symptoms at diagnosis. 46% of patients had at least one extrapulmonary location of lymphoma. The estimated 5- and 10-yr overall survival rates were 90% and 72%, respectively. Only two of the nine observed deaths were related to lymphoma. Age and performance status were the only two adverse prognostic factors for survival. Extrapulmonary location of lymphoma was not a prognostic factor for overall survival or for progression-free survival. Treatment with cyclophosphamide or anthracycline was associated with shorter progression-free survival, when compared with chlorambucil. The survival data confirm the indolent nature of pulmonary MALT lymphoma. Better progression-free survival was observed with chlorambucil when compared with cyclophosphamide or anthracycline.

[Update in severe asthma physiopathology and treatments]. / Actualités physiopathologiques et thérapeutiques dans l'asthme sévère.

Asthma is an inflammatory airway disease which presentation is highly heterogeneous. Last two decades provided new clinical and basic data concerning asthma physiopathology that make global understanding much complex. Phenotypes based on clinical settings and paraclinical investigations from large cohorts confirm old paradigm (eosinophilic vs. non-eosinophilic asthma) but also introduce new concepts (obesity-related asthma, late onset asthma, etc.). Conversely, improvement of big data analytics allows to initiate new cohorts aiming at better understanding the pathophysiology underlying those phenotypes and unraveling new ones. However, clinical and therapeutic impacts of those big data need to be further detailed. In parallel, biotherapies and innovative techniques as bronchial thermoplasty become available for severe asthmatic patients who did not respond to specific treatment in the past. Development of a personalized medicine in severe asthma becomes an important challenge for tomorrow. This review will focus on new pathophysiological concepts arisen from large cohorts and new therapeutic strategies available and in progress for severe asthma.

[Relationships between COPD and nontuberculous mycobacteria pulmonary infections]. / Relations entre la BPCO et les infections à mycobactéries non tuberculeuses.

Nontuberculous mycobacteria (NTM) pulmonary infections are increasingly frequent in pneumological practice. The diagnosis is based on an association of clinical, microbiological and radiological criteria. Some risk factors for NTM disease have been described, including chronic respiratory diseases, but without specific focus on chronic obstructive pulmonary disease (COPD). COPD patients have more risk to be infected by NTM than patients with the main other chronic respiratory diseases (except cystic fibrosis) (odds ratio [OR] at 15.7 in a case-control study). This NTM pulmonary infection is associated with a greater decline in forced expiratory volume in one second (FEV1) and an increased exacerbation rate. Inhaled corticosteroids (ICS) increase the risk of COPD patients developing an NTM infection (OR at 16.9), especially if ICS are still used at the time of diagnosis. Chronic macrolide treatment could possibly select resistant NTM strains and so could make the treatment clearly more difficult as macrolides are the cornerstone NTM treatment. NTM infections in patients with COPD are probably underestimated and should be kept in mind, particularly when patients have frequent exacerbations and display accelerated respiratory function decline, before implementing ICS or macrolides.

[Pneumocystis pneumonia in HIV-negative adults]. / La pneumocystose chez le patient adulte non infecté par le VIH.

In HIV-negative adults, Pneumocystis jirovecii pneumonia can be observed when immunodeficiency is present, especially in case of drug-induced immune suppression (steroids, chemotherapy, transplantation). Clinical, radiological, and biological presentations are different in HIV-positive and HIV-negative individuals with different immunodeficiency profiles. In HIV-negative patients, dyspnea occurs more quickly (median duration of 5 days to get a diagnosis), diagnosis is more difficult because of less Pneumocystis in bronchoalveolar lavage, and mortality is higher than in HIV-positive individuals. Lung CT-scan typically shows diffuse ground glass opacities, but peri-bronchovascular condensations or ground glass opacities clearly limited by interlobular septa can also be observed. Lymphopenia is common but CD4+ T-cells count is rarely performed. HIV-negative patients with Pneumocystis pneumonia are co-infected with bacteria, viruses or fungi in about 30% cases. Bronchoalveolar lavage is often more neutrophilic than in HIV-positive individuals. PCR and ß-D-glucan have good sensitivity but poor specificity to diagnose Pneumocystis pneumonia. Trimethoprim-sulfamethoxazole remains the first choice of treatment. Duration is 14 days in HIV-negative patients whereas it is typically of 21 days in HIV-positive individuals. Adjunctive corticosteroids are of beneficial effect in HIV-positive adult patients with substantial hypoxaemia but are not recommended in HIV-negative patients, as they could be deleterious in some individuals.

[Tuberculosis in 2015: From diagnosis to the detection of multiresistant cases]. / La tuberculose en 2015 : du diagnostic à la détection des formes résistantes.

Incidence of pulmonary tuberculosis, a contagious infectious disease, decreases in France with 4934 reported cases in 2013. Tuberculosis remains a global health problem as smear is positive in only 50% cases and culture methods require time. In such a context, genotypic diagnostic tools such as Xpert® MTB/RIF gained interest. This rapid and simple-to-use nucleic acid amplification test allows a diagnosis in two hours and prevents further invasive investigations in pulmonary and mediastinal tuberculosis. Because of its low sensitivity, it cannot be used in pleural fluid. Indirect immunologic tests are of no use to diagnose active tuberculosis disease. Another current area of interest is the emergence of resistant tuberculosis. In France, approximately 100 cases of multidrug resistant tuberculosis and a few extensively drug resistant tuberculosis have been reported in 2014. Even though these forms of tuberculosis are imported, it is crucial to identify hazardous situations and to optimize care of these patients. Xpert® MTB/RIF is again of marked interest here as it detects rifampin resistance with a 95% sensitivity and a 98% specificity. Interpretation of genotypic tests such as Genotype® MTBDR or Xpert® MTB/RIF depends on known detected mutations, although they do not always have a clinical or phenotypic expression. In multidrug resistant tuberculosis, the new drug bedaquiline obtained approval for temporarily use in combination with other molecules when there is no other treatment option. Results of bedaquiline are encouraging but adverse events like QT prolongation or the development of new specific drug resistance should convince clinicians to use it with caution.

[Gastro-esophageal reflux and chronic respiratory diseases]. / Reflux gastro-œsophagien et pathologies respiratoires chroniques.

Gastroesophageal reflux disease (GERD) frequently occurs in association with chronic respiratory diseases although the casual link is not always clear. Several pathophysiological and experimental factors are considered to support a role for GERD in respiratory disease. Conversely, respiratory diseases and bronchodilator treatment can themselves exacerbate GERD. When cough or severe asthma is being investigated, GERD does not need to be systematically looked for and a therapeutic test with proton pump inhibitors is not always recommended. pH impedance monitoring is now the reference diagnostic tool to detect non acid reflux, a form of reflux for which proton pump inhibitor treatment is ineffective. Recent data have shown a potential role of GERD in idiopathic pulmonary fibrosis and bronchiolitis obliterans following lung transplantation, leading to discussions about the place of surgery in this context. However, studies using pH impedance monitoring are still needed to better understand and manage the association between GERD and chronic respiratory diseases.

Myosin cross bridges in skeletal muscles: "rower" molecular motors.

Different classes of molecular motors, "rowers" and "porters," have been proposed to describe the chemomechanical transduction of energy. Rowers work in large assemblies and spend a large percentage of time detached from their lattice substrate. Porters behave in the opposite way. We calculated the number of myosin II cross bridges (CB) and the probabilities of attached and detached states in a minimal four-state model in slow (soleus) and fast (diaphragm) mouse skeletal muscles. In both muscles, we found that the probability of CB being detached was approximately 98% and the number of working CB was higher than 10(9)/mm(2). We concluded that muscular myosin II motors were classified in the category of rowers. Moreover, attachment time was higher than time stroke and time for ADP release. The duration of the transition from detached to attached states represented the rate-limiting step of the overall attached time. Thus diaphragm and soleus myosins belong to subtype 1 rowers.

Impaired load dependence of diaphragm relaxation during congestive heart failure in the rabbit.

The load dependence (LD) of relaxation was studied in the diaphragm of rabbits with congestive heart failure (CHF). CHF (n = 15) was induced by combined chronic volume and pressure overload. Aortic insufficiency was induced by forcing a catheter through the aortic sigmoid valves, followed 3 wk later by abdominal aortic stenosis. Six weeks after the first intervention, animals developed CHF. Sham-operated animals served as controls (C; n = 12). Diaphragm mechanics were studied in vitro on isolated strips, at 22 degrees C, in isotonic and isometric loading conditions. Contractility was lower in the CHF group, as reflected by lower total tension: 1.11 +/- 0.10 in CHF vs. 2.38 +/- 0.15 N/cm(2) in C in twitch (P < 0.001) and 2.46 +/- 0.22 in CHF vs. 4.90 +/- 0.25 N. cm(-2) in C in tetanus (P < 0.001). The index LD was used to quantify the load dependence of relaxation: LD is <1 in load-dependent muscles and tends toward 1 in load-independent muscles. LD was significantly higher in CHF than in C rabbits, in both twitch (0.99 +/- 0.01 vs. 0.75 +/- 0.03; P < 0. 001) and tetanus (0.95 +/- 0.02 vs. 0.84 +/- 0.02; P < 0.001). In the CHF rabbits' diaphragm, the fall in total tension was linearly related to the fall in load dependence of relaxation. The decrease in load dependence of relaxation in CHF animals suggests sarcoplasmic reticulum abnormalities. Impairment of the sarcoplasmic reticulum may also partly account for the decrease in contractile performance of diaphragm in CHF animals.