Background: Immune checkpoint blockade (ICB) has presented a breakthrough in the treatment of malignant tumors and increased the overall survival of patients with various tumor entities. ICB may also cause immune-related adverse events, such as pneumonitis or interstitial lung disease. The lung clearance index (LCI) is a multiple-breath washout technique offering information on lung pathology in addition to conventional spirometry. It measures the degree of pulmonary ventilation inhomogeneity and allows early detection of pulmonary damage, especially that to peripheral airways. Methods: This cross-sectional study compared the lung function of patients with melanoma or metastatic cutaneous squamous cell carcinoma who received programmed cell death 1 (PD-1) and cytotoxic T-Lymphocyte-associated Protein 4 (CTLA-4) antibodies, alone or in combination, to age- and sex-matched controls. Lung function was assessed using spirometry, according to American Thoracic Society and European Respiratory Society standards, the LCI, and a diffusion capacity of carbon monoxide (DLCO) measurement. Results: Sixty-one screened patients and thirty-eight screened controls led to nineteen successfully included pairs. The LCI in the ICB-treated patients was 8.41 ± 1.15 (mean ± SD), which was 0.32 higher compared to 8.07 ± 1.17 in the control group, but the difference was not significant (p = 0.452). The patients receiving their ICB therapy for under five months showed a significantly lower LCI (7.98 ± 0.77) compared to the ICB patients undergoing therapy for over five months (9.63 ± 1.22) at the point of testing (p = 0.014). Spirometric analysis revealed that the forced expiratory volume between 25 and 75% of the forced vital capacity (FEF25-75%) in the ICB-treated patients was significantly reduced (p = 0.047) compared to the control group. DLCO (%predicted and adjusted for hemoglobin) was 94.4 ± 19.7 in the ICB patients and 93.4 ± 21.7 in the control group (p = 0.734). Conclusions: The patients undergoing ICB therapy showed slightly impaired lung function compared to the controls. Longer periods of ICB treatment led to deterioration of the LCI, which may be a sign of a subclinical inflammatory process. The LCI is feasible and may be easily integrated into the clinical daily routine and could contribute to early detection of pulmonary (auto-)inflammation.

OBJECTIVE: Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) for lung cancer, however, the optimal practice for diagnosis, management, and follow-up for RP remains unclear. We thus sought to establish expert consensus recommendations through a Delphi Consensus study.
METHODS: In Round 1, open questions were distributed to 31 expert clinicians treating thoracic malignancies. In Round 2, participants rated agreement/disagreement with statements derived from Round 1 answers using a 5-point Likert scale. Consensus was defined as ≥ 75 % agreement. Statements that did not achieve consensus were modified and re-tested in Round 3.
RESULTS: Response rate was 74 % in Round 1 (n = 23/31; 17 oncologists, 6 pulmonologists); 82 % in Round 2 (n = 19/23; 15 oncologists, 4 pulmonologists); and 100 % in Round 3 (n = 19/19). Thirty-nine of 65 Round 2 statements achieved consensus; a further 10 of 26 statements achieved consensus in Round 3. In Round 2, there was agreement that risk stratification/mitigation includes patient factors; optimal treatment planning; the basis for diagnosis of RP; and that oncologists and pulmonologists should be involved in treatment. For uncomplicated radiation pneumonitis, an equivalent to 60 mg oral prednisone per day, with consideration of gastroprotection, is a typical initial regimen. However, in this study, no consensus was achieved for dosing recommendation. Initial steroid dose should be administered for a duration of 2 weeks, followed by a gradual, weekly taper (equivalent to 10 mg prednisone decrease per week). For severe pneumonitis, IV methylprednisolone is recommended for 3 days prior to initiating oral corticosteroids. Final consensus statements included that the treatment of RP should be multidisciplinary, the uncertainty of whether pneumonitis is drug versus radiation-induced, and the importance risk stratification, especially in the scenario of interstitial lung disease.
CONCLUSIONS: This Delphi study achieved consensus recommendations and provides practical guidance on diagnosis and management of RP.

UNASSIGNED: Immune checkpoint inhibitors (ICIs) have shown high efficacy in lung cancer. Adding ICIs to chemoradiation might increase the treatment efficacy, while the application of ICIs or chemoradiation alone can induce treatment-related pneumonitis, so whether combination therapy would increase the risk of pneumonitis needs careful evaluation. This study aimed to retrospectively analyze the incidence of pneumonitis in patients who underwent chemoradiation combined with ICIs compared with chemoradiation alone and explore the risk factors of pneumonitis in combination therapy.
UNASSIGNED: This was a retrospective cohort study. Patients who received conventional thoracic radiation with a minimum total dose of 50 Gy for lung cancer between January 2020 and December 2021 at West China Hospital were retrospectively reviewed and followed up for at least 6 months after radiation. Patients were divided into two groups according to whether chemoradiation was administered with or without ICIs. Pneumonitis was evaluated by chest computed tomography (CT) at least every 2 months in outpatient department. The clinical characteristics, including sex, age, smoking history, pathological diagnosis, baseline pulmonary disease [including chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD)], treatment strategy, location of primary tumor and radiological dosimetric parameters were recorded. Chi-squared tests or Fisher\'s exact tests were performed to analyze the difference between the combination group and control group for categorical variables and Mann-Whitney U test for continuous variables. Univariate and multivariate analyses were performed by logistic regression.
UNASSIGNED: A total of 152 patients who received chemoradiation were enrolled. The median age was 59 years. A total of 115 (75.7%) patients were non-small cell lung cancer (NSCLC), 22 (14.5%) were small cell lung cancer (SCLC), and 15 (9.9%) were other pathological types. Among them, 58 received chemoradiation combined with ICIs and 94 received chemoradiation alone. The rate of grade ≥2 pneumonitis was significantly higher in the combination therapy group (39.7% vs. 22.3%, P=0.028) and was associated with the use of ICIs [odds ratio (OR): 2.641, 95% confidence interval (CI): 1.244-5.608, P=0.011] and percent volume of the lung receiving ≥30 Gy (V30) (OR: 1.728, 95% CI: 1.214-2.460, P=0.002). The history of chronic lung disease was the independent risk factor (OR: 6.359, 95% CI: 1.953-20.705, P=0.002) of grade ≥3 pneumonitis. In the combination group, univariate and multivariate analyses revealed that V5, V20, V30, and mean lung dose (MLD) were not associated with pneumonitis, whereas the history of chronic lung disease was an independent risk factor of grade ≥3 pneumonitis (OR: 8.351, 95% CI: 1.469-47.484, P=0.017).
UNASSIGNED: The incidence of pneumonitis of ICIs combined with chemoradiation was higher than chemoradiation alone, but manageable. The combination therapy should be applied with caution especially in patients with history of chronic lung disease.

OBJECTIVE: This study aimed to predict the probability of grade ≥2 pneumonitis or dyspnea within 12 months of receiving conventionally fractionated or mildly hypofractionated proton beam therapy for locally advanced lung cancer using machine learning.
METHODS: Demographic and treatment characteristics were analyzed for 965 consecutive patients treated for lung cancer with conventionally fractionated or mildly hypofractionated (2.2-3 Gy/fraction) proton beam therapy across 12 institutions. Three machine learning models (gradient boosting, additive tree, and logistic regression with lasso regularization) were implemented to predict Common Terminology Criteria for Adverse Events version 4 grade ≥2 pulmonary toxicities using double 10-fold cross-validation for parameter hyper-tuning without leak of information. Balanced accuracy and area under the curve were calculated, and 95% confidence intervals were obtained using bootstrap sampling.
RESULTS: The median age of the patients was 70 years (range, 20-97), and they had predominantly stage IIIA or IIIB disease. They received a median dose of 60 Gy in 2 Gy/fraction, and 46.4% received concurrent chemotherapy. In total, 250 (25.9%) had grade ≥2 pulmonary toxicity. The probability of pulmonary toxicity was 0.08 for patients treated with pencil beam scanning and 0.34 for those treated with other techniques (P = 8.97e-13). Use of abdominal compression and breath hold were highly significant predictors of less toxicity (P = 2.88e-08). Higher total radiation delivered dose (P = .0182) and higher average dose to the ipsilateral lung (P = .0035) increased the likelihood of pulmonary toxicities. The gradient boosting model performed the best of the models tested, and when demographic and dosimetric features were combined, the area under the curve and balanced accuracy were 0.75 ± 0.02 and 0.67 ± 0.02, respectively. After analyzing performance versus the number of data points used for training, we observed that accuracy was limited by the number of observations.
CONCLUSIONS: In the largest analysis of prospectively enrolled patients with lung cancer assessing pulmonary toxicities from proton therapy to date, advanced machine learning methods revealed that pencil beam scanning, abdominal compression, and lower normal lung doses can lead to significantly lower probability of developing grade ≥2 pneumonitis or dyspnea.

UNASSIGNED: Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and potential risk factors in this population.
UNASSIGNED: We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis.
UNASSIGNED: The median follow-up was 10.2 months (range: 1.9-53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5-6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021).
UNASSIGNED: Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.

Background: The optimal approach for adult patients hospitalized with severe and critical coronavirus disease 2019 (COVID-19), non-responsive to antiviral and immunomodulatory drugs, is not well established. Our aim was to evaluate feasibility and safety of extracorporeal photopheresis (ECP) in this setting. Methods: A prospective, single-center investigational study was performed between 2021 and 2022 at a tertiary referral center for COVID-19. Patients diagnosed with COVID-19 were screened, and cases with severe or critical disease fulfilling pre-defined clinical and biochemical criteria of non-response for >5 days, despite remdesivir, dexamethasone and immunomodulation (tocilizumab, baricitinib, ruxolitinib), were consecutively enrolled. After patient inclusion, two ECP sessions on two consecutive days per week for 2 weeks were applied. Patients were followed-up per protocol from study inclusion, and clinical, virological and radiological outcomes were assessed at the end of treatment (EOT) +28 days. Results: A total of seven patients were enrolled. At inclusion, four out of seven (57.1%) were admitted to the ICU, all patients had ongoing cytokine storm. Additionally, 3/7 (42.9%) had radiological progression on chest CT. At EOT+28 days, 2/7 (28.6%) patients died due to non-ECP-related causes. Among the survivors, no additional requirement for intensive care unit admission or radiological progression was observed, and invasive mechanical ventilation could be weaned off in 1/5 (20.0%). All patients achieved whole-blood SARS-CoV-2 RNAemia clearance, while 3/7 (42.9%) no longer showed detectable respiratory SARS-CoV-2 RNA. According to immune biomarker profiling, ECP mainly facilitated a decrease in plasma IL-6 and IL-17A levels, as well as the physiological regeneration of peripheral blood immunocyte subpopulations, notably CD8+/CD45RO+ memory T-cells. No safety signals were identified. Conclusions: ECP appears to be a safe and feasible option for adults hospitalized with severe or critical COVID-19 who do not respond to pharmacological interventions. Further trial data are warranted to assess its optimal use. Trial registration: ClinicalTrials.gov NCT05882331 (retrospectively registered).

Continuous positive airway pressure (CPAP) has been increasingly deployed to manage patients with COVID-19 and acute respiratory failure, often for protracted periods. However, concerns about protracted CPAP have been raised. This study aimed to examine the use of CPAP for patients with COVID-19 and the outcomes after protracted use.
This was a national cohort study of all adults admitted to Scottish critical care units with COVID-19 from March 1, 2020 to December 25, 2021 who received CPAP. Protracted CPAP was defined as ≥ 5 continuous days of CPAP. Outcomes included CPAP failure rate (institution of invasive mechanical ventilation [IMV] or death), mortality, and outcomes after institution of IMV. Multivariable logistic regression was performed to assess the impact of protracted CPAP on mortality after IMV.
A total of 1961 patients with COVID-19 received CPAP for COVID-19 pneumonitis, with 733 patients (37.4%) receiving protracted CPAP. CPAP failure occurred in 891 (45.4%): 544 patients (27.7%) received IMV and 347 patients (17.7%) died in critical care without IMV. Hospital mortality rate was 41.3% for the population. For patients who subsequently commenced IMV, hospital mortality was 58.7% for the standard duration CPAP group and 73.9% for the protracted duration CPAP group (P=0.003); however, there was no statistical difference in hospital mortality after adjustment for confounders (odds ratio 1.4, 95% confidence interval 0.84-2.33, P=0.195).
Protracted CPAP was used frequently for managing patients with COVID-19. Whilst it was not associated with worse outcomes for those patients who subsequently required IMV, this might be due to residual confounding and differences in processes of care.

UNASSIGNED: Lung cancer patients undergoing treatment with immune checkpoint inhibitors (ICIs) are at risk of developing immune-related (ir-)pneumonitis. Since lung cancer patients have competing reasons for respiratory symptoms, this poses a diagnostic challenge. This study aimed to explore diagnosis and management of ir-pneumonitis in this patient group.
UNASSIGNED: Suspected ir-pneumonitis was frequent in this group of patients. The cohort was characterized by high heterogeneity and lack of unequivocal diagnostic conclusions. Treatment of ir-pneumonitis was longer than recommended and involvement of pulmonologist was very infrequent. The result of this study reflects the difficulties in a daily clinical setting to diagnose and manage patients with lung cancer presenting with pulmonary symptoms.
UNASSIGNED: Suspected ir-pneumonitis was frequent in this group of patients. The cohort was characterized by high heterogeneity and lack of unequivocal diagnostic conclusions. Treatment of ir-pneumonitis was longer than recommended and involvement of pulmonologist was very infrequent. The result of this study reflects the difficulties in a daily clinical setting to diagnose and manage patients with lung cancer presenting with pulmonary symptoms.

Radiotherapy of lung cancer may cause pneumonitis that generally occurs weeks or months following therapy and can be missed. This prospective trial aimed to pave the way for a mobile application (app) allowing early diagnosis of pneumonitis. The primary goal was the identification of the optimal cut-off of a score to detect pneumonitis of grade ≥2 after radiotherapy for lung cancer. Based on the severity of symptoms (cough, dyspnea, fever), scoring points were 0−9. Receiver operating characteristic (ROC)-curves were used to describe the sensitivity and specificity. The area under the ROC-curve (AUC) was calculated to judge the accuracy of the score, Youden-index was employed to define the optimal cut-off. Until trial termination, 57 of 98 patients were included. Eight of 42 patients evaluable for the primary endpoint (presence or absence of radiation pneumonitis) experienced pneumonitis. AUC was 0.987 (0.961−1.000). The highest sensitivity was achieved with 0−4 points (100%), followed by 5 points (87.5%), highest specificity with 5−6 points (100%). The highest Youden-index was found for 5 points (87.5%). The rate of patient satisfaction with the symptom-based scoring system was 93.5%. A cut-off of 5 points was identified as optimal to differentiate between pneumonitis and no pneumonitis. Moreover, pneumonitis was significantly associated with an increase of ≥3 points from baseline (p < 0.0001). The scoring system provided excellent accuracy and high patient satisfaction. Important foundations for the development of a mobile application were laid.

Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis.
We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge.
In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1-21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months - not reached).
Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.