ERS International Congress 2022: highlights from the Thoracic Surgery and Lung Transplantation Assembly

The positive downside of the COVID-19 pandemic on advances in thoracic surgery

René Petersen presented the important advances in thoracic surgery that occurred in 2022 despite the coronavirus disease 2019 (COVID-19) pandemic. The aims of his talk were the following: 1) to demonstrate the superiority of video-assisted thoracoscopic surgery (VATS) when performing lobectomy over the open approach, 2) to show the impact of implementing enhanced recovery after surgery (ERAS) strategies after performing VATS, 3) to demonstrate the evidence for superiority of segmentectomy over lobectomy in selected cases, and 4) to highlight the future potential of combining immunotherapy with salvage surgery.

R. Petersen began his presentation with a recent study on VATS versus open lobectomy for early-stage lung cancer by Lim et al. [1]. This was a multicentre superiority randomised controlled trial (RCT) that compared patients (1:1 VATS versus open lobectomy) in early-stage lung cancer (T1-T3, N0-N1) [1]. The primary endpoint was physical functioning at 5 weeks using the EORTC QLQ-C30 questionnaire. The patients treated with VATS had superior physical functioning at 5 weeks after the procedure when compared to open lobectomy, but this difference was not seen at 12 months. Other endpoints like pain, length of stay, number of lymph nodes, and R0 resection did not differ between groups. Although the number of severe adverse events was similar between groups there were significantly fewer adverse events in the VATS-treated group. Consequently, VATS was associated with an enhanced physical function at 5 weeks after the procedure, but overall outcomes needs further follow-up to be fully unveiled.

The next topic discussed was the impact of enhanced recovery on clinical outcomes following VATS surgery. According to a single-centre observational cohort study conducted by Huang et al. [2], age and low lung function were significant risk factors for an extended length of in-hospital stay. In addition, another study by the same team [3] highlighted the significant role of “days alive out of hospital” as a new metric of clinical outcomes following VATS in the context of an ERAS pathway. They also showed that air leaks, pneumonia, and recurrence represent the most common reasons for readmission and extended hospitalisation following VATS [3].

A novel concept was the comparison between segmentectomy and lobectomy for small-sized peripheral non-small cell lung cancer (NSCLC). In this context, R. Petersen presented the outcomes from the RCT JCOG0802, a multicentre, non-inferiority trial that incorporated patients from 70 Japanese institutions [4]. There was a median follow-up of 7.3 years, and segmentectomy was associated with a significantly higher median survival than lobectomy (94.3% versus 91.1%, respectively; p=0.0082). Although the recurrence-free survival was similar between the two groups, the JCOG0802 trial showed the incidence of local relapse to be significantly higher after segmentectomy (10.5%) than after lobectomy (5.4%) (p=0.0018).

Finally, R. Petersen presented data on the role of minimally invasive surgery following immuno-chemotherapy in 51 patients with initially unresectable stage III NSCLC [5]. Following immuno-chemotherapy, 31 patients (61%) were considered operable and all of them underwent VATS [5]. According to their findings, the addition of surgery after immuno-chemotherapy in initially unresectable cIIIB NSCLC is safe and is associated with significantly higher disease-free survival compared to those without (27.5 versus 16.7 months).

Thoracic surgery and the COVID-19 pandemic: an unexpected intimate relationship

In this session, experts debated the impact of COVID-19 on the field of thoracic surgery.

In the first part of her talk, Isabelle Opitz described the most common COVID-19-related complications that required surgical intervention, namely persistent pneumothorax, pneumatocele with persistent air leak, empyema, haemothorax and acute respiratory distress syndrome (ARDS) that required extracorporeal membrane oxygenation and in some cases progressing into lung fibrosis with the occasional use of lung transplantation.

A monocentre observational study from the USA showed that 13 (0.7%) out of 1954 patients admitted to hospital for COVID-19 (March–July 2020) required surgery, mostly due to pneumothorax and pneumatocele, with a survival rate of 77% [6].

Another retrospective multicentre study including 83 patients with similar surgical complications (March–May 2021) had an overall 72% survival, with the most common cause of death being ARDS. Going into detail, survival after surgical intervention for pneumothorax was reasonable (64%), surgical intervention of empyema had the best survival (76%), while haemothorax (46%) and haemoptysis (62%) had the worst prognosis. Multivariate analysis of morbidities related to postoperative complications showed an increased risk for older patients (HR 1.05, 95% CI 1.01–1.10, p=0.023) [7].

In the second part of her talk, I. Opitz described the relationship between COVID-19 and thoracic malignancies. Data from the University Hospital of Zurich between 2019 and 2020 showed that despite the ongoing pandemic prompt surgical treatment of patients with thoracic malignancies was guaranteed, without any increased incidence of advanced-stage thoracic malignancies. Moreover, among 50 patients hospitalised for thoracic surgery during the pandemic, only six experienced COVID-19 symptoms [8].

The TERAVOLT analysis, a multicentre (28 institutions from Europe, North America, South America and Asia) collaborative study on 346 patients with chest malignancies (86% NSCLC) and COVID-19 reported different results. In this cohort a delayed cancer treatment was found in 57% of patients. Furthermore, patients with NSCLC showed an increased risk of contracting COVID-19 infection, with a worse course of the disease. This could be explained by the wide range of centres from many countries with different exposure to the pandemic. COVID-19 vaccination showed a protective effect on hospitalisation and death (OR 0.30, 95% CI 0.15–0.57, p=0.0003) [9].

This was also seen in a nationwide analysis from Asia, where a considerable number of cancer patients experienced complications due to COVID-19 infection (HR 3.56, 95% CI 1.65–7.69) [10].

Exploring the possible transmission of COVID-19 to healthcare providers while performing minimally invasive surgery through the CO₂ or the plume created by electrocautery was not shown [11].

Marco Lucchi discussed tracheal complications related to COVID-19. He reported a cohort of 98 patients with COVID-19 who developed severe respiratory failure, and of whom 30 underwent prolonged invasive ventilation (≥14 days). Severe tracheal complications occurred in 47% of cases: full-thickness tracheal lesions (10/30, 33%) or tracheo-oesophageal fistulas (4/30, 13%), The clinical manifestations were subcutaneous emphysema (43%), pneumomediastinum (33%) and pneumothorax (20%) with a high mortality rate (27%). Factors that might be related to the incidence of tracheal complications are pronation manoeuvres (increasing the cuff pressure on the tracheal wall), high doses of systemic steroids, microvascular injury related to COVID-19 and high viral replication of the virus within the tracheal epithelium [12].

M. Lucchi further reported a single-centre experience from the University Hospital of Pisa, regarding tracheal laceration related to intubation or tracheotomy. Out of 10 tracheal lacerations, eight patients were treated conservatively, while two cases required surgical intervention, according to their previously reported technique [13]. Four cases with tracheo-oesophageal fistula were treated either conservatively or with the standard Grillo's technique, where the oesophageal wall is sutured directly and the sternocleidomastoid muscle interposed between the oesophagus and trachea, followed by tracheal resection and reconstruction. The two patients who were treated conservatively died while the two who underwent surgery were successfully discharged.

Lastly, one of the most important late complications of tracheotomy or prolonged intubation is tracheal stenosis [14]. M. Lucchi presented a case of laryngotracheal resection after post-tracheotomy stenosis in a patient with COVID-19, showing that both macroscopically and microscopically, the mucosa and tracheal tissues were characterised by inflammatory infiltrate and necrosis that may delay healing of the anastomosis [15].

Lung involvement in common variable immunodeficiency: from diagnosis to lung transplantation

Pere Soler discussed the pathogenesis and diagnosis of common variable immunodeficiency (CVID) in both paediatric and adult patients. CVID is characterised by genetic, immunological and clinical heterogeneity, which makes the process of reaching this diagnosis challenging. Currently over 40 genetic defects have been identified in patients with a CVID phenotype, which is not considered CVID. Excluding other primary antibody deficiencies or secondary causes of hypogammaglobulinaemia is important when establishing the CVID diagnosis [16–19]. The common immune defects in CVID patients are loss of B-cell function, a relative loss of T-cell function and defects in thymus maturation, monocyte/dendritic cell defects, and impaired innate immune responses including loss of natural killer cells [16–19]. For the diagnosis, it is important to use age-adapted reference values for immunoglobulins and T- and B-cell subsets, and also to perform a differential diagnosis of hypogammaglobulinaemia [20, 21]. CVID patients present with recurrent upper and lower respiratory tract infections, bronchiectasis, lung function decline, gastrointestinal infections, autoimmune enteropathy and lymphadenopathies, thus requiring a multidisciplinary approach. P. Soler emphasised the importance of genetics in CVID and recommended testing all patients, and especially those with early age onset of disease (younger than 5 years of age), those with infection-plus phenotype (presence of infection), and those with increased number of transitional B-cells.

David M. Lowe pointed out that the respiratory tract (both upper and lower) is abnormal in CVID patients. Sputum analysis of these patients showed an increase in pro-inflammatory cytokines like interleukin (IL)-1, IL-6, IL-8, tumour necrosis factor-α, IL-5 and IL-13, even in patients with radiologically normal airways, thus suggesting the presence of chronic inflammation. In contrast to normal, patients with CVID do not excrete IgA in their airways but do have increased IgG as a consequence of treatment with immunoglobulin replacement, which is considered standard. Nonetheless, this is insufficient to completely prevent pulmonary inflammation and infections [22]. Moreover, CVID patients have an altered microbiome. The more diverse the microbiome, the more inflammation and airway damage occurs [22]. Another problem with the recurrent usage of antibiotics for this group of patients, including macrolide prophylaxis, is the increased incidence of antimicrobial resistance.

Antibiotic use is frequent in this group: on average 0.36 courses of antibiotics per patient month [23]. Because viruses are especially dominant in acute respiratory infections, antibiotics are often not required, and should be selected for established bacterial infection, where treatment should be extended and be given for 2 weeks.

Antibiotic prophylaxis to prevent infections has been shown to delay the time to antibiotic usage and reduce hospitalisation, but had no effect on forced expiratory volume in 1 s [24]. Other measures to prevent infections, apart from intravenous immunoglobulin (IVIG) treatment and antibiotic prophylaxis, are advice on nutritional intake, occupation, travel, smoking, sputum clearance, physiotherapy and vaccines for patients and their household members.

Additional challenges that can be encountered in patients with CVID are colonisation with Haemophilus influenzae or Pseudomonas aeruginosa, chronic sinusitis, mycobacterial infections, and atypical extrapulmonary infections. Presentations may be atypical, and diagnosis and treatment are challenging.

Elisabetta Renzoni discussed the non-infectious lung involvement in CVID patients with a focus on CVID-associated interstitial lung disease (granulomatous–lymphocytic interstitial lung disease (GLILD)), which is a lung manifestation of systemic immune dysregulation. According to the British Lung Foundation (BLF)/United Kingdom Primary Immunodeficiency Network (UKPIN) consensus statement, GLILD is a distinct clinic-radiopathological interstitial lung disease (ILD) occurring in patients with CVID, associated with a lymphocytic infiltrate and/or granulomata in the lung, and in whom other conditions have been considered and excluded [25]. GLILD occurs in approximately 10–30% of CVID patients and consists of a multi-system immune dysregulation often associated with splenomegaly, adenopathy, autoimmune diseases and gastrointestinal/hepatic disease [26, 27]. GLILD can be misdiagnosed as sarcoidosis and patients should be tested for serum (pan) hypogammaglobulinaemia and lack of antibody production following immunisation (especially used in patients with sarcoidosis) [28]. Recurrent infections, autoimmune disease, splenomegaly, hepatomegaly and diffuse adenopathies are findings that are more common in GLILD [28]. There is a wide range of histopathological findings that often include a combination of granulomatous and lymphocytic infiltrates and a variety of patterns like follicular bronchiolitis, lymphocytic interstitial pneumonia, diffuse or nodular lymphoid hyperplasia together with areas of organising pneumonia [29]. Management of the disease according to the BLF/UKPIN consensus includes IVIG and GLILD-specific treatment in case of deteriorating lung function. This consists of corticosteroids as the first-line treatment and azathioprine, rituximab or mycophenolate as a second-line therapy [25]. The treatment should be individualised according to comorbidities and patient preferences. Management is highly complex due to limited experience and further studies are needed.

Lastly, Michael Perch pointed out that the primary goal of lung transplantation is to provide a survival benefit. The mean survival of lung transplant patients, even though it has improved over the years, is still on average 7 years [30]. According to the latest version of the consensus document for the selection of lung transplant candidates, patients are classified according to risk factors [31]. Candidates with conditions classified as absolute contraindications are at too high a risk for achieving a successful outcome post lung transplantation and should not undergo transplantation except in very exceptional circumstances [31]. Candidates who have risk factors with high or substantially increased risk should only be considered in centres with expertise for these specific conditions as these risk factors are associated with unfavourable short- and/or long-term outcomes. Some of these risk factors are high age and body mass index, heart or kidney disease, difficult to treat chronic infections etc. [31]. The presence of more than one risk factor is thought to be multiplicative in terms of increasing the risk of adverse outcomes post-transplant [31].

Lung transplantation should be considered for adults with chronic, end-stage lung disease who meet the following criteria: 1) high risk of death from lung disease within 2 years if transplantation is not performed; and 2) high likelihood of 5-year post-transplant survival from a general medical perspective provided that there is adequate graft function [31, 32]. Listing for transplantation should occur when life expectancy is greatly reduced but nonetheless greater than the expected waiting time. Modifiable conditions should be optimised if possible.

Regarding lung transplantation for end-stage lung disease in CVID there is a limited experience, mostly obtained from cases. In several cases it was found that patients can mount sufficient T-cell responses to cause acute cellular rejection and at the same time had signs of both infection and inflammation, resulting in early mortality and limited survival benefit [33].

Nathan et al. [34] reported a median survival of 4 years after lung transplantation for bronchiectasis related to immunodeficiency, despite receiving IVIG after transplantation. In this series, survival was similar to patients transplanted for other indications, but overall this survival was rather limited and not in line with current aims after transplantation.

Taking in consideration the present data, CVID is not simply the absence of IgG. Lung transplantation for CVID is highly complicated and needs a multidisciplinary approach in an experienced transplant centre. After transplantation, continuation of IVIG treatment and antimicrobial prophylaxis should be tailored carefully and further studies regarding complications and outcome are needed regarding this complex group of patients.

Interstitial lung diseases in connective tissue diseases: the patient's journey from diagnosis and new treatment strategies to transplantation

Antoine Froidure started the session on ILD in connective tissue diseases (CTD) and highlighted that genetic testing has changed the way we practise medicine in recent years. From a physician's perspective, it can help understand underlying disease mechanisms, refine diagnosis, identify patients at risk, genetic counselling and prevention, and may have therapeutic implications [35]. There are also advantages from a patient's perspective, such as the ability to understand their own disease and to know whether relatives are at risk. On the other hand, genetic testing can also negatively affect the patient with fear, stress, uncertainty and socio-economic consequences [35].

With regard to ILD, we know that the risk of CTD-ILD is higher in patients with systemic sclerosis and inflammatory myositis compared to rheumatoid arthritis (RA) and Sjögren syndrome [36]. It was recently detected that variants of the MUC5B promoter are not only related to idiopathic pulmonary fibrosis, but also make patients with RA more prone to develop lung fibrosis [37, 38]. Along with other risk factors such as male and age, the risk to develop subclinical RA-ILD can be as high as 94.5% [37, 38]. However, the presence of a MUC5B variant is not a predictor for disease progression [38].

Finally, A. Froidure emphasised the importance of telomere-related gene mutations, which are not only correlated with a risk of idiopathic pulmonary fibrosis, but also lung fibrosis in CTD [39].

Secondly, Bruno Crestani focused on the diagnosis of CTD-ILD and new treatment strategies. CTD-ILD accounts for an important part of ILD and multidisciplinary discussion is essential because of heterogeneity of phenotypes [40]. High-resolution computed tomography remains the gold standard for diagnosis and is also the best screening tool, although other tools such as lung ultrasound, electronic stethoscope, exhaled air, blood biomarkers and risk scores are being investigated [41].

Treatment of CTD-ILD is evolving rapidly and ranges from corticosteroids and immunomodulators (e.g. rituximab [42, 43], cyclophosphamide, mycophenolate mofetil, tocilizumab [44, 45]) to antifibrotic agents (nintedanib [46–48], pirfenidone [49, 50]) based on the degree of inflammation and fibrosis. Interestingly, methotrexate may delay the onset of ILD in patients with RA [51], while withdrawal can accelerate disease progression [52]. As such, methotrexate might become the treatment of choice in RA-ILD and should not be discontinued upon ILD detection unless there is clear suspicion of methotrexate-associated ILD, although rare [53]. To determine the best therapeutic strategies, disease-specific algorithms should be pursued and an ERS/European Alliance of Associations for Rheumatology (EULAR) clinical practice guideline for CTD-ILD screening, diagnosis and treatment is underway.

Lung transplantation is a reasonable treatment option for carefully selected end-stage CTD-ILD patients and José Cifrián addressed the main challenges if a CTD-ILD patient is referred for lung transplantation. An updated consensus document on the selection of lung transplant candidates from the International Society for Heart and Lung Transplantation has recently become available [31], as is a consensus document on the evaluation of CTD candidates [54]. The latter aims to standardise the evaluation, listing and post-transplant management of CTD candidates to allow for risk stratification, as these patients often have specific risk factors that may increase the risk of unfavourable short- and long-term post-transplant outcomes [54]. On the other hand, outcomes comparable to patients with other types of ILD were observed in well-selected patients with systemic sclerosis and RA, and outcomes for systemic lupus erythematosus and polymyositis and dermatomyositis were comparable to idiopathic pulmonary fibrosis [54].

When considering a CTD-ILD patient for lung transplantation, thorough evaluation of extrapulmonary manifestations of CTD is critical. Involvement of a multidisciplinary team in pre-transplant evaluation and selection and post-transplant care is essential to optimise outcomes [55]. Detailed organ-specific evaluation recommendations can be found in the consensus document and the ones highlighted by J. Cifrián are summarised in table 1 [54]. Absolute contraindications for lung transplantation are mainly related to persistent, active extrapulmonary manifestations despite maximal therapy [54].

Because of the medical complexity of CTD patients, early referral (“the sooner the better”) to a lung transplant centre is recommended, also to identify modifiable risk factors that could improve the candidacy for lung transplantation or survival [54].

Lastly, Ingrid Lundberg concluded the session by discussing new trends in the treatment of myositis associated ILD. An increasing number of autoantibodies specific for myositis have been detected that are not found in other auto-immune diseases [56]. These 16 myositis-specific antibodies are associated with specific clinical phenotypes [56], some of which have a strong association with lung disease (i.e. anti-melanoma differentiation-associated protein 5 (MDA5) [57] and anti-synthetase antibodies [58]). Detection of antibodies can guide the diagnosis as patients may present with symptoms varying from myositis, ILD, concomitant myositis and ILD to polyarthritis without ILD or myositis [59]. Patients with anti-MDA5 antibodies are especially at risk for rapidly progressive ILD [57].

Currently, no RCTs regarding optimal treatment are available. Expert recommendations divide treatment of myositis-associated ILD into two groups based on disease severity (mild-moderate and severe) and treatment options are relatively similar to those for other CTD-ILD, including corticosteroids, cyclophosphamide, rituximab, mycophenolate mofetil, calcineurin inhibitors but also Janus kinase inhibitors. For progressive disease, abatacept is being tested in clinical trials [60].

Finally, as mentioned in all CTD-ILD presentations, I. Lundberg ended by emphasising the importance of multidisciplinary management because of the complexity of cases.