Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement.

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined.Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis.Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis.Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis.Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

Iatrogenic pulmonary lesions.

Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes.

Impact of concomitant medications on obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A - randomized controlled trials (RCTs) with high statistical power; B - RCTs with lower power, non-randomized comparative studies and observational studies; C - retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as 'Z drugs' and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA-associated cardiovascular morbidity.

Usefulness of transcutaneous PCO2 to assess nocturnal hypoventilation in restrictive lung disorders.

BACKGROUND AND OBJECTIVE: Nocturnal hypoventilation is now an accepted indication for the initiation of non-invasive ventilation. Nocturnal hypoventilation may be an under diagnosed condition in chronic respiratory failure. The most appropriate strategy to identify sleep hypoventilation is not yet clearly defined. In clinical practice, it is indirectly assessed using nocturnal pulse oximetry (NPO) and morning arterial blood gases (mABG). Even though continuous transcutaneous carbon dioxide partial pressure (TcPCO2 ) monitoring is theoretically superior to NPO plus mABG, it is not routinely used. We aimed to prospectively compare NPO plus mABG with nocturnal TcPCO2 for the detection of alveolar hypoventilation in a cohort of patients with chronic restrictive respiratory dysfunction. METHODS: We assessed 80 recordings of mABG, nocturnal TcPCO2 and NPO in 72 consecutive patients with neuromuscular disease or thoracic cage disorders. Nocturnal hypoventilation was defined as a mean nightime TcPCO2 ≥50 mm Hg, and nocturnal hypoxaemia as ≥30% of the night with transcutaneous pulse oxygen saturation ≤90% and/or >5 consecutive minutes with transcutaneous pulse oxygen saturation ≤88%. RESULTS: Amongst the 80 recordings, 25 of 76 (32.9%) without nocturnal hypoxaemia and 16 of 59 (27.1%) without hypercapnia on mABG showed nocturnal hypoventilation on TcPCO2 . Amongst recordings showing both normal NPO and mABG, 16 of 52 (30.8%) had a mean TcPCO2 ≥50 mm Hg. Nocturnal hypoxaemia was associated with nocturnal hypoventilation in all recordings. However, 5 of 21 (23.8%) recordings that showed an absence of nocturnal hypoventilation at the chosen threshold showed hypercapnia on mABG. CONCLUSION: Morning arterial blood gases and NPO alone or in combination underestimate nocturnal hypoventilation in patients with chronic restrictive respiratory dysfunction of extrapulmonary origin.

Antifibrotic role of αB-crystallin inhibition in pleural and subpleural fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix accumulation. IPF typically starts in subpleural lung regions, and recent studies suggest that pleural mesothelial cells play a role in the onset of the disease. The transition of mesothelial cells into myofibroblasts (mesothelio-mesenchymal transition) is induced by the profibrotic cytokine, transforming growth factor (TGF)-ß1, and is thought to play a role in the development and progression of IPF. The Mothers Against Decapentaplegic homolog (Smad)-dependent pathway is the main TGF-ß1 pathway involved in fibrosis. αB-crystallin is constitutively expressed in the lungs, and is inducible by stress, acts as a chaperon, and is known to play a role in cell cytoskeleton architecture. We recently showed that the lack of αB-crystallin hampered TGF-ß1 signaling by favoring Smad4 monoubiquitination and nuclear export. We demonstrate here, for the first time, that αB-crystallin is strongly overexpressed in the pleura of fibrotic lungs from patients with IPF and in rodent models of pleural/subpleural fibrosis. αB-crystallin-deficient mice are protected from pleural/subpleural fibrosis induced by the transient adenoviral-mediated overexpression of TGF-ß1 or the intrapleural injection of bleomycin combined with carbon particles. We show that αB-crystallin inhibition hampers Smad4 nuclear localization in pleural mesothelial cells and the consequent characteristics of mesothelio-mesenchymal transition. αB-crystallin-deficient mesothelial cells fail to acquire the properties of myofibroblasts, thus limiting their migration in vivo and the progression of fibrosis in the lung parenchyma. In conclusion, our work demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF.

Haemoptysis in adults: a 5-year study using the French nationwide hospital administrative database.

Haemoptysis is a serious symptom with various aetiologies. Our aim was to define the aetiologies, outcomes and associations with lung cancer in the entire population of a high-income country.This retrospective multicentre study was based on the French nationwide hospital medical information database collected over 5 years (2008-2012). We analysed haemoptysis incidence, aetiologies, geographical and seasonal distribution and mortality. We studied recurrence, association with lung cancer and mortality in a 3-year follow-up analysis.Each year, ~15 000 adult patients (mean age 62 years, male/female ratio 2/1) were admitted for haemoptysis or had haemoptysis as a complication of their hospital stay, representing 0.2% of all hospitalised patients. Haemoptysis was cryptogenic in 50% of cases. The main aetiologies were respiratory infections (22%), lung cancer (17.4%), bronchiectasis (6.8%), pulmonary oedema (4.2%), anticoagulants (3.5%), tuberculosis (2.7%), pulmonary embolism (2.6%) and aspergillosis (1.1%). Among incident cases, the 3-year recurrence rate was 16.3%. Of the initial cryptogenic haemoptysis patients, 4% were diagnosed with lung cancer within 3 years. Mortality rates during the first stay and at 1 and 3 years were 9.2%, 21.6% and 27%, respectively.This is the first epidemiological study analysing haemoptysis and its outcomes in an entire population. Haemoptysis is a life-threatening symptom unveiling potentially life-threatening underlying conditions.

Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case.

BACKGROUND: BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man. CASE PRESENTATION: While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation. CONCLUSION: These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.

The small heat-shock protein αB-crystallin is essential for the nuclear localization of Smad4: impact on pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by the proliferation of myofibroblasts and the accumulation of extracellular matrix (ECM) in the lungs. TGF-ß1 is the major profibrotic cytokine involved in IPF and is responsible for myofibroblast proliferation and differentiation and ECM synthesis. αB-crystallin is constitutively expressed in the lungs and is inducible by stress, acts as a chaperone and is known to play a role in cell cytoskeleton architecture homeostasis. The role of αB-crystallin in fibrogenesis remains unknown. The principal signalling pathway involved in this process is the Smad-dependent pathway. We demonstrate here that αB-crystallin is strongly expressed in fibrotic lung tissue from IPF patients and in vivo rodent models of pulmonary fibrosis. We also show that αB-crystallin-deficient mice are protected from bleomycin-induced fibrosis. Similar protection from fibrosis was observed in αB-crystallin KO mice after transient adenoviral-mediated over-expression of IL-1ß or TGF-ß1. We show in vitro in primary epithelial cells and fibroblasts that αB-crystallin increases the nuclear localization of Smad4, thereby enhancing the TGF-ß1-Smad pathway and the consequent activation of TGF-ß1 downstream genes. αB-crystallin over-expression disrupts Smad4 mono-ubiquitination by interacting with its E3-ubiquitin ligase, TIF1γ, thus limiting its nuclear export. Conversely, in the absence of αB-crystallin, TIF1γ can freely interact with Smad4. Consequently, Smad4 mono-ubiquitination and nuclear export are favoured and thus TGF-ß1-Smad4 pro-fibrotic activity is inhibited. This study demonstrates that αB-crystallin may be a key target for the development of specific drugs in the treatment of IPF or other fibrotic diseases.

Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-ß1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT. In vitro, we have up- and down-modulated HSP27 expression in mesothelial and epithelial cell lines and studied the expression of different EMT markers induced by TGF-ß1. In vivo, we inhibited HSP27 with the antisense oligonucleotide OGX-427 (in phase II clinical trials as anticancer agent) in our rat subpleural/pulmonary fibrosis models. We demonstrate that HSP27 is strongly expressed during the fibrotic process in patients with IPF and in different in vivo models. We showed that HSP27 binds to and stabilizes Snail and consequently induces EMT. Conversely, HSP27 knockdown leads to Snail proteasomal degradation, thus inhibiting TGF-ß1-induced EMT. Inhibition of HSP27 with OGX-427 efficiently blocks EMT and fibrosis development. Controls in vivo were an empty adenovirus that did not induce fibrosis and a control antisense oligonucleotide. The present work opens the possibility of a new therapeutic use for HSP27 inhibitors against IPF, for which there is no conclusively effective treatment.

[Drug-induced interstitial lung diseases]. / Pneumopathies interstitielles iatrogéniques.

Drug-induced infiltrative lung disease may manifest as variable clinical radiological patterns, including subacute or chronic interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia, organising pneumonia, pulmonary edema, or sarcoidosis. A large amount of drugs have been incriminated, including those used in cardiovascular diseases (amiodarone, statins and angiotensin converting enzyme inhibitors), antibiotics (minocycline, nitrofurantoin), most of anticancer drugs (and especially chemotherapy and chest radiation), treatment of rheumatoid arthritis, as well as more recent drugs. A high index of suspicion is therefore required in any patient with infiltrative lung disease and the web-based tool www.pneumotox.com will help to list possible causative drugs. The following steps are necessary: history and timing of drug exposure, clinical and imaging pattern, exclusion of other causes of infiltrative lung disease, improvement following drug discontinuation. Rechallenge, dangerous, is not recommended.

Statins and the risk of interstitial lung disease: a cohort study.

BACKGROUND: Case reports have suggested that the use of statins may be associated with an increase in the risk of interstitial lung disease (ILD). METHODS: Within a large cohort of users of respiratory medications identified in the Quebec health administrative databases during 1990-2005, we carried out a nested case-control analysis of the relationship between statins and the risk of ILD as defined by specialist visits or hospitalisations. RESULTS: The cohort included over 1.4 million patients, of which 6665 possible or probable cases of ILD were identified during follow-up. These were compared with 26 660 controls matched for age, gender and calendar time. After adjustment for confounders and comorbid conditions, there was no association between current use of statins and risk of ILD (adjusted OR 0.99, 95% CI 0.91 to 1.08). The results were similar when any use of statins within the previous 1 or 2 years was considered or when the analysis was limited to more definite cases. CONCLUSIONS: This large cohort study did not find an association between statin use and the incidence of ILD.

Drug-Induced Interstitial Lung Diseases.

Drug-induced interstitial lung disease (DI-ILD) is an increasingly common cause of morbidity and mortality as the list of culprit drugs continues to grow. Unfortunately, DI-ILD is difficult to study, diagnose, prove, and manage. This article attempts to raise awareness of the challenges in DI-ILD and discusses the current clinical landscape.

The Spectrum of Airway Involvement in Inflammatory Bowel Disease.

Inflammatory bowel disease is associated with a wide spectrum of central, large, and small airway abnormalities, including bronchiectasis. The bronchiectasis associated with inflammatory bowel disease has a distinct phenotype, with marked inflammation and at times severe sterile bronchorrhea that can be responsive to inhaled corticosteroids.

Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma.

RATIONALE: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. OBJECTIVES: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. METHODS: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. MEASUREMENTS AND MAIN RESULTS: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). CONCLUSIONS: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).

[Drug-induced lung diseases]. / Pneumopathies médicamenteuses.

Drug-induced interstitial pneumonias are systematically considered in the differential diagnosis of the interstitial pneumonias. The presentation may be acute, sub-acute or chronic, with the same drug possibly leading to either acute or subacute/chronic interstitial lung disease (e.g. amiodarone). There is no definite diagnostic criterion, the final diagnosis relying on the clinical and imaging features, the chronology of pulmonary manifestations, and the prevalence of reported cases with the suspected drug.