Emerging therapies and respiratory infections: Focus on the impact of immunosuppressants and immunotherapies.

Host defences to infection are based upon an integrated system of physical and biochemical barriers, innate and adaptive immunity. Weakness in any of these defensive elements leads to increased susceptibility to specific pathogens. Understanding how medical therapies disrupt host defences is key to the successful prevention, diagnosis and management of respiratory infection in the immunocompromised host.

Investigating the role of platelets and platelet-derived transforming growth factor-ß in idiopathic pulmonary fibrosis.

Transforming growth factor-ß1 (TGFß1) is the key profibrotic cytokine in idiopathic pulmonary fibrosis (IPF), but the primary source of this cytokine in this disease is unknown. Platelets have abundant stores of TGFß1, although the role of these cells in IPF is ill-defined. In this study, we investigated whether platelets, and specifically platelet-derived TGFß1, mediate IPF disease progression. Patients with IPF and non-IPF patients were recruited to determine platelet reactivity, and separate cohorts of patients with IPF were followed for mortality. To study whether platelet-derived TGFß1 modulates pulmonary fibrosis (PF), mice with a targeted deletion of TGFß1 in megakaryocytes and platelets (TGFß1fl/fl.PF4-Cre) were used in the well-characterized bleomycin-induced pulmonary fibrosis (PF) animal model. In a discovery cohort, we found significantly higher mortality in patients with IPF who had elevated platelet counts within the normal range. However, our validation cohort did not confirm this observation, despite significantly increased platelets, neutrophils, active TGFß1, and CCL5, a chemokine produced by inflammatory cells, in the blood, lung, and bronchoalveolar lavage (BAL) of patients with IPF. In vivo, we showed that despite platelets being readily detected within the lungs of bleomycin-treated mice, neither the degree of pulmonary inflammation nor fibrosis was significantly different between TGFß1fl/fl.PF4-Cre and control mice. Our results demonstrate for the first time that platelet-derived TGFß1 does not significantly mediate inflammation or fibrosis in a PF animal model. Furthermore, our human studies revealed blood platelet counts do not consistently predict mortality in IPF but other platelet-derived mediators, such as C-C chemokine ligand 5 (CCL5), may promote neutrophil recruitment and human IPF.NEW & NOTEWORTHY Platelets are a rich source of profibrotic TGFß; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFß in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFß does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Insights into Personalised Medicine in Bronchiectasis.

Bronchiectasis is a heterogenous disease with multiple aetiologies resulting in inflammation and dilatation of the airways with associated mucus production and chronic respiratory infection. The condition is being recognised ever more frequently as the availability of computed tomography increases. It is associated with significant morbidity and healthcare-related costs. With new understanding of the disease process, varying endotypes, identification of underlying causes and treatable traits, the management of bronchiectasis can be increasingly personalised.

Airway disease in hematologic malignancies.

INTRODUCTION: Hematologic malignancies are cancers of the blood, bone marrow and lymph nodes and represent a heterogenous group of diseases that affect people of all ages. Treatment generally involves chemotherapeutic or targeted agents that aim to kill malignant cells. In some cases, hematopoietic stem cell transplantation (HCT) is required to replenish the killed blood and stem cells. Both disease and therapies are associated with pulmonary complications. As survivors live longer with the disease and are treated with novel agents that may result in secondary immunodeficiency, airway diseases and respiratory infections will increasingly be encountered. To prevent airways diseases from adding to the morbidity of survivors or leading to long-term mortality, improved understanding of the pathogenesis and treatment of viral bronchiolitis, BOS, and bronchiectasis is necessary. AREAS COVERED: This review focuses on viral bronchitis, BOS and bronchiectasis in people with hematological malignancy. Literature was reviewed from Pubmed for the areas covered. EXPERT OPINION: Airway disease impacts significantly on hematologic malignancies. Viral bronchiolitis, BOS and bronchiectasis are common respiratory manifestations in hematological malignancy. Strategies to identify patients early in their disease course may improve the efficacy of treatment and halt progression of lung function decline and improve quality of life.

Effects of Expression of Streptococcus pneumoniae PspC on the Ability of Streptococcus mitis to Evade Complement-Mediated Immunity.

Streptococcus pneumoniae and Streptococcus mitis are genetically closely related and both frequently colonise the naso-oropharynx, yet S. pneumoniae is a common cause of invasive infections whereas S. mitis is only weakly pathogenic. We hypothesise that sensitivity to innate immunity may underlie these differences in virulence phenotype. We compared the sensitivity of S. pneumoniae and S. mitis strains to complement-mediated immunity, demonstrating S. mitis strains were susceptible to complement-mediated opsonophagocytosis. S. pneumoniae resistance to complement is partially dependent on binding of the complement regulator Factor H by the surface protein PspC. However, S. mitis was unable to bind factor H. The S. pneumoniae TIGR4 strain pspC was expressed in the S. mitis SK142 strain to create a S. mitis pspC+ strain. Immunoblots demonstrated the S. mitis pspC+ strain expressed PspC, and flow cytometry confirmed this resulted in Factor H binding to S. mitis, reduced susceptibility to complement and improved survival in whole human blood compared to the wild-type S. mitis strain. However, in mouse models the S. mitis pspC+ strain remained unable to establish persistent infection. Unlike S. pneumoniae strains, culture in serum or blood did not support increased CFU of the S. mitis strains. These results suggest S. mitis is highly sensitive to opsonisation with complement partially due to an inability to bind Factor H, but even when complement sensitivity was reduced by expression of pspC, poor growth in physiological fluid limited the virulence of S. mitis in mice.

ICAM-1 and ICAM-2 Are Differentially Expressed and Up-Regulated on Inflamed Pulmonary Epithelium, but Neither ICAM-2 nor LFA-1: ICAM-1 Are Required for Neutrophil Migration Into the Airways In Vivo.

Neutrophil migration into the airways is an important process to fight infection and is mediated by cell adhesion molecules. The intercellular adhesion molecules, ICAM-1 (CD54) and ICAM-2 (CD102) are known ligands for the neutrophil integrins, lymphocyte function associated antigen (LFA)-1 (αLß2; CD11a/CD18), and macrophage-1 antigen (Mac-1;αMß2;CD11b/CD18) and are implicated in leukocyte migration into the lung. However, it is ill-defined how neutrophils exit the lung and the role for ICAMs in trans-epithelial migration (TEpM) across the bronchial or alveolar epithelium. We found that human and murine alveolar epithelium expressed ICAM-1, whilst the bronchial epithelium expressed ICAM-2, and both were up-regulated during inflammatory stimulation in vitro and in inflammatory lung diseases such as cystic fibrosis. Although ß2 integrins interacting with ICAM-1 and -2 mediated neutrophil migration across human bronchial epithelium in vitro, neither ICAM-2 nor LFA-1 binding of ICAM-1 mediated murine neutrophil migration into the lung or broncho-alveolar space during LPS-induced inflammation in vivo. Furthermore, TEpM of neutrophils themselves resulted in increased epithelial junctional permeability and reduced barrier function in vitro. This suggests that although ß2 integrins interacting with ICAMs may regulate low levels of neutrophil traffic in healthy lung or early in inflammation when the epithelial barrier is intact; these interactions may be redundant later in inflammation when epithelial junctions are disrupted and no longer limit TEpM.

A Closer Look at the Role of Anti-CCP Antibodies in the Pathogenesis of Rheumatoid Arthritis-Associated Interstitial Lung Disease and Bronchiectasis.

Rheumatoid arthritis (RA) is an articular disease with extra-articular manifestations. Pulmonary manifestations are not uncommon and can involve all compartments of the lungs with airway disease in the form of bronchiectasis or bronchiolitis, interstitial lung disease (ILD), pleural effusions and parenchymal lung nodules. The pulmonary features may present synchronously or after the articular disease, but, importantly, it may be the first presentation in 10% of patients in the absence of articular symptoms. Here we discuss the pathogenesis of RA lung involvement, particularly interstitial lung disease and bronchiectasis, focusing on the role anti-CCP antibodies (ACPAs). We highlight the complex interplay among genetic, environmental and immune factors. Furthermore, we explore the relationship of citrullination and smoking as well as the concept of interstitial pneumonia with autoimmune features (IPAF), where patients do not have evidence of another known cause of interstitial pneumonia and have incomplete features of connective tissue disease (CTD). We surmise that the frequency and titers of rheumatoid factor (RF) and ACPAs are increased in bronchiectasis and RA-bronchiectasis compared to RA patients without lung disease. ACPA is associated with more severe disease in both RA-ILD and RA-bronchiectasis even in the absence of articular symptoms. There is no clear prediction of development of articular RA with high ACPA levels in the context of positive ACPA and ILD; however, in RA-bronchiectasis, patients with positive antibodies can develop RA within a year after diagnosis of bronchiectasis. Though the primary focus of this narrative is to highlight the role of ACPA in pathogenesis and clinical practice, we also discuss the current treatment options and trials in RA-ILD and RA-bronchiectasis. Currently, there are no clear treatment guidelines. The treatments are now focusing on using a combination of immunosuppression and antifibrotic agents. Combination treatment targets both the fibrotic and inflammatory components of the disease process. Further studies are needed to identify the use of ACPA as a biomarker to tailor the treatment in RA-ILD and RA-bronchiectasis.

Clinical and Radiological Phenotypes and Endotypes.

Bronchiectasis is a heterogenous disease with multiple etiologies and associated comorbidities. As bronchiectasis is a complex disease, it is unsound to think of it as a single disease particularly when the differing etiologies are likely to be driving bronchiectasis through initial divergent molecular pathways, known as endotypes, that phenotypically present as the same disease due to protracted airway inflammation, but revealing potential differing underlying mechanisms that may have disparity of drug responses. Improved understanding of the cellular immune, inflammatory, and microbiological milieu associated with clinical and radiological features of bronchiectasis has resulted in the recognition of important endotypes and phenotypes that will allow for personalized treatments to improve quality of life and outcomes of patients with bronchiectasis. Here we discuss clinical and radiological phenotypes, as well as emerging molecular endotypes that are possible treatable traits in bronchiectasis.

Pneumococcal Vaccination in Immunocompromised Hosts: An Update.

Infections with the pathogen, Streptococcus pneumoniae, are a common cause of morbidity and mortality worldwide. It particularly affects those at the extremes of age and immunocompromised individuals. Preventing pneumococcal disease is paramount in at risk individuals, and pneumococcal vaccination should be offered. Here, we discuss the role of pneumococcal vaccination in specific groups of immunocompromised hosts.

Targeting coagulation activation in severe COVID-19 pneumonia: lessons from bacterial pneumonia and sepsis.

Novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has rapidly spread throughout the world, resulting in a pandemic with high mortality. There are no effective treatments for the management of severe COVID-19 and current therapeutic trials are focused on antiviral therapy and attenuation of hyper-inflammation with anti-cytokine therapy. Severe COVID-19 pneumonia shares some pathological similarities with severe bacterial pneumonia and sepsis. In particular, it disrupts the haemostatic balance, which results in a procoagulant state locally in the lungs and systemically. This culminates in the formation of microthrombi, disseminated intravascular coagulation and multi-organ failure. The deleterious effects of exaggerated inflammatory responses and activation of coagulation have been investigated in bacterial pneumonia and sepsis and there is recognition that although these pathways are important for the host immune response to pathogens, they can lead to bystander tissue injury and are negatively associated with survival. In the past two decades, evidence from preclinical studies has led to the emergence of potential anticoagulant therapeutic strategies for the treatment of patients with pneumonia, sepsis and acute respiratory distress syndrome, and some of these anticoagulant approaches have been trialled in humans. Here, we review the evidence from preclinical studies and clinical trials of anticoagulant treatment strategies in bacterial pneumonia and sepsis, and discuss the importance of these findings in the context of COVID-19.

COVID-19 follow-up planning: what will we be missing?

There is a real need for a discharge plan for COVID-19 survivors in the UK. Follow-up imaging could help assess the resolution of infection, exclude underlying malignancy and identify post-inflammatory fibrosis. https://bit.ly/2YJ8hyg.

Opportunistic bacterial, viral and fungal infections of the lung.

Opportunistic infections are a major cause of morbidity and mortality in severely immunocompromised patients, such as those given chemotherapy or biological therapies, and those with haematological malignancy, aplastic anaemia or HIV infection, or recipients of solid organ or stem cell transplants. The type and degree of immune defect dictates the profile of potential opportunistic pathogens; T-cell-mediated defects increase the risk of viral (cytomegalovirus, respiratory viruses) and Pneumocystis jirovecii infections, whereas neutrophil defects are associated with bacterial pneumonia and invasive aspergillosis. However, patients often have combinations of immune defects, and a wide range of other opportunistic infections can cause pneumonia. Importantly, conventional non-opportunistic pathogens are frequently encountered in immunocompromised hosts and should not be overlooked The radiological pattern of disease (best assessed by computed tomography) and speed of onset help identify the likely pathogen(s); this can then be supported by targeted investigation including early use of bronchoscopy in selected patients. Rapid and expert clinical assessment can identify the most likely pathogens, allowing timely appropriate therapy.

De novo bronchiectasis in haematological malignancies: patient characteristics, risk factors and survival.

Bronchiectasis occurs de novo in haematological malignancy and is associated with significant mortality and morbidity. Rituximab predisposes to IgG deficiency and survival time is significantly associated with age, FEV1 % and stem cell transplantation. http://bit.ly/2KZwCZt.

Review of the British Thoracic Society Winter Meeting 2016, 7-9 December, London, UK.

This article reviews the British Thoracic Society Winter Meeting 2016 and highlights the new developments in scientific and clinical research across the breadth of respiratory medicine.