Interstitial lung disease research: annual report

Interstitial lung disease (ILD) consists of a heterogeneous group of diseases with varying amounts of interstitial inflammation and fibrosis. Survival in the most severe form of lung fibrosis, idiopathic pulmonary fibrosis or IPF, is particularly poor; however, there is heterogeneity in outcome. Some patients gradually deteriorate; some undergo stepwise progression, whilst others decline rapidly. Moreover, much of the prognostic data heralds from an era when the criteria for diagnosing IPF were less well and differently defined than at present. There is a definite need to find prognostic biomarkers to predict outcome in IPF patients.

Positron emission tomography (PET) offers the ability to non-invasively investigate cellular metabolism in vivo. PET studies in animals have yielded valuable insights into the biology of IPF and ILD and there is potentially encouraging evidence that PET may aid the development of therapeutic interventions to treat these debilitating conditions. It has been recently demonstrated that 18F-Fluorodeoxyglucose (18F-FDG) PET signal is consistently raised and can be objectively measured in patients with IPF. Moreover, these PET signals are shown to be stable and reproducible.

We have shown over several years and imaging hundreds of patients with ILD that the baseline measures of pulmonary 18F-FDG PET signal to predict survival in patients with IPF compared to other more established prognostic data. We have also shown that combing PET data with our clinical scoring system based on gender, age and physiology (GAP) data (“PET modified GAP score”) refined the ability to predict mortality. We took advantage of the COVID-19 pandemic to investigate our findings in patients with post-COVID ILD and made some interesting observations. The FDG-PET signal does reduce with time and most patients will get better. This was published in 2021.

Most excitingly, we now have data showing a correlation between histology on lung biopsy and the 18FDG-PET signal so that we can find out why these areas of the lung take up so much glucose and perhaps understand what this is telling us about the disease process and therefore how we can change it to be a healing, rather than a destructive, response.  We have shown that the PET signal appears to correlate with new blood vessel formation (neo-angiogenesis) in the damaged lung. We are investigating this further with Ga-68 PSMA, another marker of neo-angiogenesis, and have now shown that FDG-PET also predicts outcomes in systemic sclerosis-associated ILD. This strengthens the case for PET as a prognostic tool across a range of ILDs.

Future studies are to investigate the role of FDG-PET scanning in other ILDs, such as bronchiolitis obliterans (post lung transplant), rheumatoid arthritis-associated ILD and systemic sclerosis.

RA is a chronic debilitating disease estimated to afflict 13% of the world population. Around 10% of patients with RA will develop an ILD that is very similar to the lung fibrosis that we see with IPF. Dr Akif Khawaja was funded by Rosetrees and UCL to carry out a PhD into the aetiology of RA-ILD. His work proposed that RA is a disease that starts in the lung. That chronic lung damage caused by smoking, infection and other insults causes the immune response to recognise the lungs and joints as “foreign” and attack them causing chronic damage. His work implicated neutrophils in this process and, in particular, the p38 MAPkinase pathway. Dr Richard Beatson has taken this a step further to show that monocytes and macrophages in the lung are the first to sense lung damage and produce signals that recruit neutrophils. We are hoping to develop a new test using blood or sputum to detect early activation of inflammatory cells that may suggest that a patient is at risk of developing ILD. This same test may act as a biomarker for prognosis and to detect early response to novel therapies.

At present, we do not know the exact cause of idiopathic pulmonary fibrosis (IPF), although research has identified lots of processes that are likely to be involved. Currently, we believe that microscopic injury occurs in patients with IPF and then the body responds to repair this, but does so in a way that leads to more damage and scarring. One of the processes involved in repair pathway is coagulation, which minimises blood loss when tissues are damaged. Patients with IPF are at increased risk of blood clots and this can reduce their already low life expectancy. We also think that these blood clots drive the worsening of their lung disease. Researchers have shown that clotting is over-activated in the lungs of IPF patients and we want to investigate how reducing this might improve the disease. Based on work carried out at UCL, we believe that anticoagulation with heparin is safe and may even prevent disease progression in IPF.

We have completed our study in which patients took the oral anticoagulant, dabigatran, for 3 weeks to reduce clotting. We performed blood tests and FDG-PET scans before and after taking the drug to judge response. We have shown a difference in PET scans in those patients that took the dabigatran, but only if they had additional blood markers of active coagulation. We hope to have this work reported completely next year.

Assessing effectiveness of treatments for IPF is difficult as often they do not make patients feel better, despite decelerating disease. Currently, we are guided by regular breathing tests and special imaging of the lungs, which are insensitive to changes and may be unpleasant for patients. We need better tests like a simple blood test to predict the prognosis for individual patients, and their responses to treatment. Causes of IPF are unknown, but we have found that specific white blood cells, called neutrophils, are increased in the lungs of patients with IPF. We also found that the more neutrophils in the lungs, the faster the decline from IPF. This suggests that neutrophils are actively worsening IPF. We have also shown that a simple measurement from the blood, called the neutrophil:lymphocyte ratio is a power predictor of outcomes in IPF. We have not validated our initial findings in groups of IPF patients from around the country. Our paper was published in one of the prestigious – The Lancet eClinicalMedicine in 2023.

In 2025, we extended this work by characterising neutrophils in IPF in more detail. Our ERJ Open Research paper, “Neutrophils in idiopathic pulmonary fibrosis patients are phenotypically distinct to controls”, has shown that neutrophils in IPF are functionally and phenotypically different from those in healthy individuals, supporting the idea that they may be active drivers of fibrotic progression rather than innocent bystanders.

We are currently working with Vicore Pharma to assess the safety and efficacy of twice daily oral C21 in the treatment of IPF. Patients will be treated with active C21 for 9 months. C21 is an oral angiotensin II agonist. It has already been shown to be well tolerated and safe in the treatment of patients with COVID-19 pneumonitis and appears to help the lungs to repair. Initial findings are encouraging and a further study is planned.

It is unclear what causes IPF, but it is thought to be a response to damage to the lining of the airways (epithelium) following an unidentified injury. This results in the formation of excessive scar tissue which disrupts the delicate architecture of the lung and ultimately death follows from respiratory failure. We have shown from research previously sponsored by The Rosetrees Trust that a certain type of white blood cell which is specialised in fighting infections, called neutrophils, may play a role in PF. We have found that neutrophils are increased in the blood and lungs of patients with PF and the more neutrophils you have, the worse the individual’s outcome. In addition, it is recognised that you are more likely to develop IPF if you have a commonly occurring genetic mutation that causes increased mucus production by the lung epithelium, and in particular a protein called Mucin or MUC5B that gives sputum its stringy quality. We propose that the overproduction of MUC5B may stress the epithelium, making it more prone to damage and scarring. In addition, the increased MUC5B will attract and activate neutrophils from the blood and these white blood cells can cause further damage. We hope that, by identifying treatments that limit the

number of neutrophils moving into the lung, we can protect patients from developing PF or from PF progressing. We will use neutrophils and epithelial samples from patients and healthy volunteers to compare differences and see how the MUC5B affects neutrophil activation in the lung. Lastly, we plan to block neutrophil activation and recruitment with a specific treatment that is already being developed for other indications and has an excellent safety profile. If our results are encouraging, we can take this medication into an early clinical trial for patients with IPF.

We have also shown that we can detect very early changes in the CT scans of patients that make too much MUC5B and this might be a very early sign, even before the scan looks abnormal, that these patients are at risk of lung disease.

Malik Althobiani, a respiratory therapist, with Professor John Hurst and Professor Jo Porter, investigated the potential of remote monitoring of patients with lung diseases including IPF. Our research looked at whether remote monitoring of signs (such as heart rate and oxygen saturation) and symptoms (such as shortness of breath or reduced exercise tolerance) and lung function (such as walk tests and spirometry) using wearable sensors and questionnaires is feasible. Malik has defended his PhD at examination in 2024 and is now an Associate Professor back in Saudi Arabia.

In 2025, we saw two major advances in this area. First, our ERJ Open Research paper showed that the respiratory microbiome in patients with post-COVID residual lung abnormalities looks much more like that of healthy individuals and is quite distinct from the microbiome seen in IPF. This supports the idea that post-COVID changes represent a different biological process from pulmonary fibrosis, and this has been reassuring to many patients. Second, Dr Emma Denneny and Dr Sharenja Ratnakumar successfully completed and published their systematic review of lung function after pulmonary tuberculosis in The Lancet Global Health, highlighting the substantial long-term burden of post-infectious lung impairment worldwide.

We also remain part of a much larger national study to investigate the incidence of ILD after COVID-19 infections. Our work is aimed at understanding the mechanisms underlying the development of ILD in the hope of developing novel treatments. We have already published on the radiological changes in FDG-PET seen post-acute COVID-19, but now need to understand what happens with time in patients with these changes: will they get better completely, remain stable or worsen?

Dr Richard Beatson, an expert in glycobiology in cancer, was working with Dr Megha Sravani-Bondada to develop a biomarker in ILD that is based on mucins. The biology behind this is very complicated and challenging, but if successful, this high-risk project would be a game changer. We already have some exciting preliminary data generated by a Masters student, Osama Alsuhimi, who returned to us as a PhD student in 2023. Dr Beatson is now an honorary associate Professor at UCL, well done Richard. We also have two new PhD students, Abdullah Alharbi and Emily Self who are both working on aberrant glycosylation of the alveolar epithelium in PF and how this translates into epithelial-immune cell interactions.

We have been interested in NETs in ILD for many years. During the COVID-19 pandemic, it was also clear that NETs played a role in COVID-19 pneumonitis. We were funded by LifeArc to carry out a study of nebulised dornase alfa in patients with COVID-19 pneumonitis. This has been completed with very positive results and has now been published in eLife in 2024. In parallel, our 2025 ERJ Open Research paper showed that neutrophils in IPF are phenotypically distinct, further supporting the importance of neutrophil and NET biology in fibrotic lung disease.

We have become very interested in sarcopenia, or muscle wasting, in ILD and how this may impact on outcomes for patients with ILD. We are very excited to have recruited Osama Alsuhimi, a respiratory therapist, to complete a PhD in this area. Work is ongoing to characterise how body composition, muscle function, inflammation and physical activity interact in ILD and PF.

We have always had an interest in drug-induced ILD, by which we mean therapeutic drugs often given as part of cancer treatment, but even innocent antibiotics can cause drug-induced pneumonitis or ILD in some patients.

Therapy-Induced pneumonitis is a serious and potentially life-threatening condition estimated to impact 8% of cancer patients undergoing treatment. After immune checkpoint inhibitors, tyrosine kinase inhibitors, antibody-drug conjugates and M-TOR inhibitors are the most associated causative agents. The incidence is particularly pronounced in individuals with pre-existing ILD or previous respiratory issues, and paradoxically, its impact can be most severe in patients showing the most positive response to therapy.

It is anticipated that approximately 1 in 2000 individuals in the UK will experience this condition at some point, potentially limiting their chances of a complete cure from the original cancer, as it may necessitate discontinuation or modification of the drug. This concern becomes particularly significant when the cancer treatment is proving effective. Furthermore, therapy-induced pneumonitis has the potential to independently compromise both the quality and duration of an individual’s life.