Understanding the telehealth experience of care by people with ILD during the COVID-19 pandemic: what have we learnt?

INTRODUCTION: The COVID-19 pandemic resulted in a rapid transformation of health services. This study aimed to understand the experiences of healthcare by people with interstitial lung disease (ILD), to inform future service delivery. METHODS: Four specialist clinics in tertiary centres in Australia (Victoria:2 sites; New South Wales: 1 site; Western Australia: 1 site) recruited patients with ILD during an 8-week period from March 2021. Participants completed a COVID-specific questionnaire focused on health-related experiences during 2020. RESULTS: Ninety nine (65% of 153) participants completed the questionnaire. 47% had idiopathic pulmonary fibrosis or connective tissue disease-associated ILD, 62% were female and the average age was 66 years. Whilst 56% rated their overall health in 2020 as the same as months prior, 38% indicated a worsening in health attributed to reduced physical activity and fear of contracting the virus. Access to healthcare professionals was 'good' in 61%, and 'fair-to-poor' for 37% due to missed respiratory assessments, with telehealth (mainly telephone) being perceived as less effective. 89% had contact with respiratory physicians, 68% with general practitioners, predominantly via telephone, with few video consultations. High satisfaction with care was reported by 78%, with lower satisfaction attributed to delays in assessments, disruption to usual services such as pulmonary rehabilitation, and dissatisfaction with telehealth. CONCLUSION: People with ILD were generally satisfied with their care during 2020, however reduced access to healthcare professionals was challenging for those experiencing a deterioration in health. Telehealth was largely well received but did not always meet the needs of people with ILD particularly when unwell.

Coagulation factor-XII induces interleukin-6 by primary lung fibroblasts: a role in idiopathic pulmonary fibrosis?

The mechanisms driving idiopathic pulmonary fibrosis (IPF) remain undefined, however it is postulated that coagulation imbalances may play a role. The impact of blood-derived clotting factors, including factor XII (FXII) has not been investigated in the context of IPF. Plasma levels of FXII were measured by ELISA in patients with IPF and in age-matched healthy donors. Expression of FXII in human lung tissue was quantified using multiplex immunohistochemistry and Western blotting. Mechanistic investigation of FXII activity was assessed in vitro on primary lung fibroblasts using qPCR and specific receptor/FXII inhibition. The functional outcome of FXII on fibroblast migration was examined by high-content image analysis. Compared with 35 healthy donors, plasma levels of FXII were not higher in patients with IPF (n = 27, P > 0.05). Tissue FXII was elevated in IPF (n = 11) and increased numbers of FXII+ cells were found in IPF (n = 8) lung tissue compared with nondiseased controls (n = 6, P < 0.0001). Activated FXII induced IL6 mRNA and IL-6 protein in fibroblasts that was blocked by anti-FXII antibody, CSL312. FXII induced IL-6 production via PAR-1 and NF-κB. FXII induced migration of fibroblasts in a concentration-dependent manner. FXII is normally confined to the circulation but it leaks from damaged vessels into the lung interstitium in IPF where it 1) induces IL-6 production and 2) enhances migration of resident fibroblasts, critical events that drive chronic inflammation and therefore, contribute to fibrotic disease progression. Targeting FXII-induced fibroblastic processes in IPF may ameliorate pulmonary fibrosis.

Inhibition of NF-κB by ACT001 reduces fibroblast activity in idiopathic pulmonary fibrosis.

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.

CXCR4+ cells are increased in lung tissue of patients with idiopathic pulmonary fibrosis.

BACKGROUND: CXCR4, a transmembrane-receptor located on epithelial cells that is activated by CXCL12, may have a role in IPF via migration of CXCR4+ fibrocytes to the lung. However, its expression has not been fully characterised in idiopathic pulmonary fibrosis (IPF) or other fibrotic interstitial lung diseases (ILDs). CXCL12 is constitutively expressed in the bone marrow, and levels of CXCR4 regulate control of this signalling pathway. The aim of this study was to profile the expression of CXCR4 in lung tissue and peripheral circulation of patients with IPF and other fibrotic ILDs. METHODS: Expression of CXCR4 on peripheral blood mononuclear cells (PBMCs) was examined by flow cytometry in 20 patients with IPF and 10 age-matched non-disease control (NDC) donors. Levels of CXCL12 in human plasma were measured by ELISA. Expression of CXCR4, CXCL12, CD45, and e-cadherin was assessed in IPF (n = 10), other fibrotic ILD (n = 8) and NDC (n = 10) lung tissue by multiplex immunohistochemistry (OPAL) and slides were scanned using a Vectra 3 scanner. Cells were quantified with computer automated histological analysis software (HALO). RESULTS: In blood, the number of CXCR4+ cells was lower but the level of CXCL12 was higher in patients with IPF compared to NDC donors. Elevated CXCR4 expression was detected in lung tissue from patients with IPF and other fibrotic ILDs compared to NDC. There were higher levels of CXCR4+/e-cadherin+/CXCL12+ (epithelial) cells in IPF lung tissue compared to NDC, but there was no difference in the numbers of CXCR4+/CD45+/CXCL12+ (myeloid) cells between the two groups. CONCLUSIONS: This report demonstrates that CXCR4 is overexpressed not only in IPF but also in other ILDs and expression is particularly prominent within both honeycomb cysts and distal airway epithelium. This observation supports the hypothesis that CXCR4 may drive tissue fibrosis through binding its specific ligand CXCL12. Although CXCR4 expressing cells could be either of epithelial or myeloid origin it appears that the former is more prominent in IPF lung tissue. Further characterization of the cells of the honeycomb cyst may lead to a better understanding of the fibrogenic processes in IPF and other end-stage fibrotic ILDs.

Clinical impact of the interstitial lung disease multidisciplinary service.

BACKGROUND AND OBJECTIVE: Multidisciplinary discussions (MDDs) have been shown to improve diagnostic accuracy in interstitial lung disease (ILD) diagnosis. However, their clinical impact on patient care has never been clearly demonstrated. We describe the effect that an ILD multidisciplinary service has upon the diagnosis and management of patients with suspected ILD. METHODS: Patients at two specialized centres with suspected ILD underwent ILD multidisciplinary team review (ILD-MDT) (standard ILD clinic visit and diagnostic review at ILD-MDD). We compared changes in ILD diagnosis and management at referral to those following the ILD-MDT. RESULTS: Ninety patients, 60% males (54/90), aged 67.3 years (SD = 11.4) were reviewed for suspected ILD. Overall, the ILD-MDT resulted in a change in specific ILD diagnosis in 48/90 (53%) patients. Of the 27 patients referred with a diagnosis of idiopathic pulmonary fibrosis (IPF), the diagnosis was changed at MDD in 10 patients. In contrast, seven patients had their diagnosis changed to IPF. There was also a significant reduction in 'unclassifiable' diseases and disease behaviour classifications provided additional information beyond ILD diagnosis. CONCLUSION: Dedicated tertiary ILD-MDT service has an important clinical impact on the care of the ILD patient, with frequent changes in ILD diagnosis and subsequent management. Further research to investigate long-term clinical outcomes of ILD-MDT is required.

Ara h 2 peptides containing dominant CD4+ T-cell epitopes: candidates for a peanut allergy therapeutic.

BACKGROUND: Peanut allergy is a life-threatening condition; there is currently no cure. Although whole allergen extracts are used for specific immunotherapy for many allergies, they can cause severe reactions, and even fatalities, in peanut allergy. OBJECTIVE: This study aimed to identify short, T-cell epitope-based peptides that target allergen-specific CD4(+) T cells but do not bind IgE as candidates for safe peanut-specific immunotherapy. METHODS: Multiple CD4(+) T-cell lines specific for the major peanut allergen Ara h 2 were generated from PBMCs of 16 HLA-diverse subjects with peanut allergy by using 5,6-carboxyfluorescein diacetate succinimidylester-based methodology. Proliferation and ELISPOT assays were used to identify dominant epitopes recognized by T-cell lines and to confirm recognition by peripheral blood T cells of epitope-based peptides modified for therapeutic production. HLA restriction of core epitope recognition was investigated by using anti-HLA blocking antibodies and HLA genotyping. Serum-IgE peptide-binding was assessed by dot-blot. RESULTS: Five dominant CD4(+) T-cell epitopes were identified in Ara h 2. In combination, these were presented by HLA-DR, HLA-DP, and HLA-DQ molecules and recognized by T cells from all 16 subjects. Three short peptide variants containing these T-cell epitopes were designed with cysteine-to-serine substitutions to facilitate stability and therapeutic production. Variant peptides showed HLA-binding degeneracy, did not bind peanut-specific serum IgE, and could directly target T(H)2-type T cells in peripheral blood of subjects with allergy. CONCLUSION: Short CD4(+) T-cell epitope-based Ara h 2 peptides were identified as novel candidates for a T-cell-targeted peanut-specific immunotherapy for an HLA-diverse population.