Background
Approximately one‐third of individuals with interstitial lung disease (ILD) have associated connective tissue disease (CTD). The connective tissue disorders most commonly associated with ...ILD include scleroderma/systemic sclerosis (SSc), rheumatoid arthritis, polymyositis/dermatomyositis, and Sjögren's syndrome. Although many people with CTD‐ILD do not develop progressive lung disease, a significant proportion do progress, leading to reduced physical function, decreased quality of life, and death. ILD is now the major cause of death amongst individuals with systemic sclerosis.
Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in autoimmune and inflammatory illnesses. However this comes with potential toxicities, including nausea, haemorrhagic cystitis, bladder cancer, bone marrow suppression, increased risk of opportunistic infections, and haematological and solid organ malignancies.
Decision‐making in the treatment of individuals with CTD‐ILD is difficult; the clinician needs to identify those who will develop progressive disease, and to weigh up the balance between a high level of need for therapy in a severely unwell patient population against the potential for adverse effects from highly toxic therapy, for which only relatively limited data on efficacy can be found. Similarly, it is not clear whether histological subtype, disease duration, or disease extent can be used to predict treatment responsiveness.
Objectives
To assess the efficacy and adverse effects of cyclophosphamide in the treatment of individuals with CTD‐ILD.
Search methods
We performed searches on CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to May 2017. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles.
Selection criteria
We included randomised controlled parallel‐group trials that compared cyclophosphamide in any form, used individually or concomitantly with other immunomodulating therapies, versus non‐cyclophosphamide‐containing therapies for at least six months, with follow‐up of at least 12 months from the start of treatment.
Data collection and analysis
We imported studies identified by the search into a reference manager database. We retrieved the full‐text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were change in lung function (change in forced vital capacity (FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted), adverse events, and health‐related quality of life measures. Secondary outcomes included all‐cause mortality, dyspnoea, cough, and functional exercise testing. When appropriate, we performed meta‐analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and created 'Summary of findings' tables.
Main results
We included in the analysis four trials with 495 participants (most with systemic sclerosis). We formed two separate comparisons: cyclophosphamide versus placebo (two trials, 195 participants) and cyclophosphamide versus mycophenolate (two trials, 300 participants). We found evidence to be of low quality, as dropout rates were high in the intervention groups, and as we noted a wide confidence interval around the effect with small differences, which affected the precision of results.
The data demonstrates significant improvement in lung function with cyclophosphamide compared with placebo (post‐treatment FVC % mean difference (MD) 2.83, 95% confidence interval (CI) 0.80 to 4.87; P = 0.006) but no significant difference in post‐treatment DLCO (% MD ‐1.68, 95% CI ‐4.37 to 1.02; P = 0.22; two trials, 182 participants).
Risk of adverse effects was increased in the cyclophosphamide treatment groups compared with the placebo groups, in particular, haematuria, leukopenia, and nausea, leading to a higher rate of withdrawal from cyclophosphamide treatment. The data demonstrates statistically significant improvement in one‐measure of quality of life in one trial favouring cyclophosphamide over placebo and clinically and statistically significant improvement in breathlessness in one trial favouring cyclophosphamide compared with placebo, with no significant impact on mortality.
Trialists reported no significant impact on lung function when cyclophosphamide was used compared with mycophenolate at 12 months (FVC % MD ‐0.82, 95% CI ‐3.95 to 2.31; P = 0.61; two trials, 149 participants; DLCO % MD ‐1.41, 95% CI ‐10.40 to 7.58; P = 0.76; two trials, 149 participants).
Risk of side effects was increased with cyclophosphamide versus mycophenolate, in particular, leukopenia and thrombocytopenia.
The data demonstrates no significant impact on health‐related quality of life, all‐cause mortality, dyspnoea, or cough severity in the cyclophosphamide group compared with the mycophenolate group. No trials reported outcomes associated with functional exercise tests.
We performed subgroup analysis to determine whether severity of lung function, connective tissue disease diagnosis, or radiological pattern had any impact on outcomes. One trial reported that cyclophosphamide protected against decreased FVC in individuals with worse fibrosis scores, and also showed that cyclophosphamide may be more effective in those with worse lung function. No association could be made between connective tissue disease diagnosis and outcomes.
Authors' conclusions
This review, which is based on studies of varying methodological quality, demonstrates that overall, in this population, small benefit may be derived from the use of cyclophosphamide in terms of mean difference in % FVC when compared with placebo, but not of the difference in % DLCO, or when compared with mycophenolate. Modest clinical improvement in dyspnoea may be noted with the use of cyclophosphamide. Clinical practice guidelines should advise clinicians to consider individual patient characteristics and to expect only modest benefit at best in preserving FVC. Clinicians should carefully monitor for adverse effects during treatment and in the years thereafter.
Further studies are required to examine the use of cyclophosphamide; they should be adequately powered to compare outcomes within different subgroups, specifically, stratified for extent of pulmonary infiltrates on high‐resolution computed tomography (HRCT) and skin involvement in SSc. Studies on other forms of connective tissue disease are needed. Researchers may consider comparing cyclophosphamide (a potent immunosuppressant) versus antifibrotic agents, or comparing both versus placebo, in particular, for those with evidence of rapidly progressive fibrotic disease, who may benefit the most.
Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in ...antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4
cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2
γC
mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity.
The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza ...virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus-specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza-specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and poor prognosis. In IPF, aberrant extracellular matrix production by activated, hyperproliferative ...fibroblasts drives disease progression but the exact mechanisms by which this occurs remains undefined. The transcription factor nuclear factor kappa-B (NF-ĸB) has been suggested as a potential therapeutic target in IPF and therefore the aim of this study was to investigate the efficacy of ACT001, an NF-ĸB inhibitor, on primary fibroblasts derived from patients with and without IPF. Primary lung fibroblasts derived from eight patients with IPF and eight age-matched non-diseased controls (NDC) were treated with 0–10 µM ACT001 and the effects on fibroblast activity (viability and proliferation, fibroblast-to-myofibroblast transition, fibronectin expression), interleukin (IL)-6 and IL-8 cytokine release were quantified. ACT001 inhibited fibroblast activity in a concentration-dependent manner in both groups of fibroblasts. ACT001 inhibited IL-6 but not IL-8 production in unstimulated fibroblasts. ACT001 is a water-soluble compound with a stable half-life in plasma, thus making it an attractive candidate for further investigation as a therapeutic in IPF. This study adds to the growing body of literature that demonstrates anti-fibrotic activity of NF-ĸB inhibition in the context of IPF.
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•Idiopathic pulmonary fibrosis is a fatal disease without known causal mechanism.•Pharmacological modulation of fibroblasts is a key therapeutic strategy in fibrosis.•Activated fibroblasts drive exaggerated scar tissue formation in lung fibrosis.•Novel drug ACT001 inhibits primary lung fibroblast activity in-vitro.
In an era of increasing ex vivo lung perfusion (EVLP) use, it remains important to describe what outcomes can be achieved without EVLP, by taking an aggressive approach to donor use to maximize lung ...transplantation.
Data for all lung transplant donor referrals to the Alfred Hospital in Melbourne, Australia were collected for 2012 to 2013. Donor variables were analyzed and calculated into a previously validated lung donor score. Lung transplant recipient outcome data included the following: primary graft dysfunction; duration of mechanical ventilation; need for cardiopulmonary bypass extracorporeal membrane oxygenation; intensive care and hospital length of stay; 30-day, 1-year, and 3- to 4-year survival rates; rates of acute rejection and chronic lung allograft dysfunction; and peak and 12-month lung function (forced expiratory volume in 1 second).
Of the 318 lung donor offers, 129 resulted in successful lung transplantation, with an overall donor use rate of 41%. There was no correlation between donor score and any of the recipient outcomes, and excellent short-term and longer-term survival was achieved.
Future studies examining lung transplantation outcomes with EVLP must consider the excellent results that can be achieved by using marginal lungs and conventional donor management. It is important to consider that adopting a strategy of perioperative lung donor evaluation and intervention allows use of what are considered marginal lungs to achieve promising results.
This review aims to establish the impact of oxygen therapy on dyspnoea, health-related quality of life (HRQoL), exercise capacity and mortality in interstitial lung disease (ILD).We included studies ...that compared oxygen therapy to no oxygen therapy in adults with ILD. No limitations were placed on study design or intervention type. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. The primary outcome was dyspnoea.Eight studies evaluated the acute effects of oxygen (n=1509). There was no effect of oxygen therapy on modified Borg dyspnoea score at end exercise (mean difference (MD) -0.06 units, 95% CI -0.24-0.13; two studies, n=27). However, effects on exercise outcomes consistently favoured oxygen therapy. One study showed reduction in dyspnoea at rest with oxygen in patients who were acutely unwell (MD visual analogue scale 30 mm
48 mm, p<0.05; n=10). Four studies of long-term oxygen therapy (n=2670) had high risk of bias and no inferences could be drawn.This systematic review showed no effects of oxygen therapy on dyspnoea during exercise in ILD, although exercise capacity was increased. Future trials should evaluate whether acute improvements in exercise capacity with oxygen can be translated into improved physical activity and HRQoL.
Tissue-resident memory T (Trm) cells are described as having a “sensing and alarming” function, meaning they can rapidly release cytokines in response to local cognate antigen recognition, which in ...turn, draws circulating immune cells into the tissue. Here, we show noncognate, bystander activation can also trigger the sensing and alarming function of pulmonary CD8+ Trm cells. Virus-specific CD8+ Trm cells lodged in the lung parenchyma, but not memory CD8+ T cells located in the vasculature, rapidly synthesize interferon γ (IFN-γ) following the inhalation of heat-killed bacteria or bacterial products, a process driven by interleukin-12 (IL-12)/IL-18 exposure. We show that a respiratory bacterial infection leads to bystander activation of lung Trm cells that boosts neutrophil recruitment into the airways and attenuates the severity of bacterial pneumonia. These data reveal that lung Trm cells have innate-like properties, enabling amplification of inflammation and participation in noncognate responses to bacterial infections.
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•Lung Trm cells undergo bystander activation following exposure to bacterial products•IL-12/IL-18 exposure triggers bystander activation of lung Trm cells•Bystander-activated lung Trm cells enhance neutrophil recruitment into the airways
Ge et al. show that lung tissue-resident memory T (Trm) cells undergo bystander activation in response to bacterial products. This boosts neutrophil recruitment into the airways and attenuates the severity of bacterial pneumonia. Lung Trm cells have innate-like properties, amplifying inflammation and participating in noncognate memory T cell responses to bacterial infections.
Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized ...diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.
To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαβ repertoires and promiscuous αβ-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαβ diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.
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•Analyses of SARS-CoV-2-specific CD8+ T cells ex vivo using peptide-HLA tetramers•Tetramer-specific CD8+ T cells in unexposed individuals display a naive phenotype•B7/N105+CD8+ T cells are seen in high numbers during COVID-19 and persist long term•High naive frequency and TCR plasticity underpin dominant B7/N105+CD8+ T cells
Examining unmanipulated SARS-CoV-2-specific T cells is important for understanding primary and recall responses during COVID-19. Nguyen et al. analyze ex vivo CD8+ T cells specific for SARS-CoV-2 epitopes and find that immunodominant B7/N105-specific CD8+ T cells are present at high frequencies in blood samples from unexposed, acute COVID-19, and convalescence individuals, which is underpinned by diverse TCR repertoires.
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