Median DLCO Research Articles

Long-term consequences of the functional state of the respiratory system after SARS-CoV-2-associated lung damage

Aim. To study the dynamics of respiratory system function in patients without a history of bronchopulmonary pathology after SARS-CoV-2 infection with virus-associated lung damage.Materials and methods. A retrospective study was conducted on 29 patients (median age 46 [43-51] years) at two stages: visit 1 (1-4 months) and visit 2 (8-13 months) from the onset of COVID-19. Data from spirometry, bodyplethysmography, diffusion capacity test, impulse oscillometry (IOS), and chest computed tomography (CT) obtained during the acute phase of the disease (CTmax), as well as dyspnea assessed by the mMRC scale, were analyzed.Results. The median CTmax was 75%, and 66% of patients received treatment in the intensive care unit. At visit 1, dyspnea was of mild or moderate severity. Medians of vital capacity (VC), total lung capacity (TLC), residual volume (RV), and diffusion capacity of the lungs (DLco) were reduced (<80% predicted). The median forced expiratory volume in the first second (FEV1) and IOS parameters were within normal ranges. However, increased reactance area (AX) and absolute frequency dependence of resistance (R5–R20) were found in 59% and 24% of cases, respectively. At visit 2, mild dyspnea persisted. Lung volumes were within normal limits, with statistically significant differences between visits. The median DLco was reduced at visit 1 but increased to normal at visit 2, with statistically significant differences between visits. The median IOS parameters remained within normal limits, with no statistically significant differences between visits. However, in visit 1 increased AX and (R5–R20) were observed in 59% and 24%, in visit 2 – 45% and 17% of cases, respectively, with no statistically significant differences between visits.Conclusions. Among the long-term functional consequences of SARS-CoV-2 infection with virus-associated lung damage, decreased lung diffusion capacity (reduced DLco) and small airway dysfunction (increased AX and/or R5-R20) were noted in some patients. Impulse oscillometry should be included in the comprehensive functional assessment plan for patients after SARS-CoV-2 infection to diagnose small airway dysfunction.

“Bubbly lung”, a honeycombing variant with more favorable outcome

BackgroundAlthough radiologic honeycombing is generally associated with progressive fibrosis and a dismal prognosis, some patients display an unexpectedly indolent clinical course. We aimed to assess for variants of honeycombing associated with a more favorable prognosis. MethodsA computer-assisted search was conducted to identify patients encountered at Mayo Clinic from 1998 to 2022 who had undergone chest CT that manifested exuberant honeycombing. Medical records and chest imaging studies were reviewed to identify clinical, pulmonary function and radiologic features. ResultsAmong 136 patients with exuberant honeycombing, 23 patients were identified with CT features of what we termed “bubbly lung” characterized by extensive macrocystic fibrosis; 17 (74%) were female with a median age of 71 years (range, 32–88) at baseline. Underlying diagnoses were ANCA associated vasculitis (22%), overlap CTD (22%), rheumatoid arthritis (17%), IPF (17%), IPAF (9%), systemic sclerosis (4%), undifferentiated CTD (4%), and dermatomyositis (4%). Median FVC was 78% predicted (range 35–112), median DLco was 41% predicted (range 10–92), and median TLC was 73% predicted (range 57–116). Serial FVC measurements were available for 19 (83%) patients with a median interval of 4.7 years (range: 0.4–20); median FVC change per year was 23 ml (range −279 to +232) and median FVC % predicted change per year was 0.00% (range −3.20 to +6.79%). The median survival was 7.1 years, 5-year survival was 76% (95% CI: 58%–100%) and 10-year survival was 48%. Conclusions“Bubbly lung” is a variant of exuberant honeycombing that is associated with better-than-expected outcome and FVC decline per year.

Presenting clinical and imaging features of patients with clinically amyopathic interstitial lung disease associated with myositis-specific autoantibodies.

Lung involvement in the context of idiopathic inflammatory myopathies has significant impact on outcome; early and accurate diagnosis is important but can be difficult to achieve. In particular, patients without clinically evident muscle involvement pose a significant diagnostic challenge. A computer-assisted search was conducted to identify patients with amyopathic interstitial lung disease associated with the presence of myositis-specific autoantibodies. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features at presentation. Of the 35 patients with amyopathic interstitial lung disease associated with myositis-specific autoantibodies, the median age was 65 years (range 43-78) and 20 were women (57%). Of the patients, 34% had previously visited the rheumatology department. Presenting symptoms consisted of dyspnea (94%), cough (43%), and arthritis (23%). Raynaud phenomenon, "mechanic hands," Gottron papules, and inspiratory crackles were present in 23, 31, 9, and 74% of patients, respectively. After a detailed history, none of the patients reported muscle weakness, while four (11%) exhibited increased CK levels; of these four, two had a concomitant increase in aldolase levels. Median FVC was 79% predicted (range: 49-135) and median DLco was 50% predicted (range: 17-103). HRCT pattern was suggestive of an alternative to UIP pattern in 31/33 (94%) patients; the most common imaging patterns were NSIP (49%) and NSIP/OP (39%). In patients with NSIP and NSIP/OP pattern, the presence of amyopathic interstitial lung disease associated with myositis-specific autoantibodies should be considered even in the absence of clinical evident myositis.

Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

Bleomycin Affects Lung Function for at Least 5 Years after Treatment for Hodgkin Lymphoma - Data from the International, Randomised Phase 3 Rathl Trial

Introduction: Bleomycin has been an integral part of classical Hodgkin lymphoma (HL) treatment for decades but carries significant toxicity. In particular, acute bleomycin-related lung toxicity occurs in a minority of patients (pts) but has mortality rates as high as 25%. The long-term effects of bleomycin in HL and its impact on lung function are not well known and there is no established guidance for lung screening. The aim of this analysis was to evaluate the impact of bleomycin dose on lung function up to 5 years after treatment in pts recruited to the international, phase 3 RATHL trial. Methods: RATHL recruited pts with intermediate- or advanced-stage HL aged ≥18 years. Pts received 2 cycles of standard ABVD followed by PET assessment. Pts with complete metabolic response (CMR) received 4 further cycles of chemotherapy, with (ABVD arm; n=469) or without (AVD arm; n=464) bleomycin (12 or 4 doses bleomycin in total, respectively). PET-positive pts switched to BEACOPP-based treatment (total 8-10 doses bleomycin; n=172). Pulmonary function tests (PFTs) were performed at baseline, end of treatment (EOT) and annually for 5 years. Linear regression was used to assess changes in DLCO from baseline and Cox regression used to assess the time to return to within 10% of baseline values, censoring at relapse or death, in all pts, and those with a more than 10% reduction at EOT. Results: Median age was 33 years (range 18 - 79), 8.2% were aged &amp;gt;60 and 15.1% had a pre-existing respiratory disorder, including asthma in 8.4%. In pts with available data, 18.2% were smokers and 22.2% were ex-smokers with a median of 10 pack-years (IQR: 4 - 20). Baseline DLCO values were low (&amp;lt;75%) in 339 (29.8%) pts and were influenced by disease burden, with lower median DLCO in pts with mediastinal bulk (79%, IQR: 69.0 - 89.4) than in those without (83.1% (73- 94), p=0.006). Grade ≥3 respiratory adverse events occurred more frequently in the ABVD arm (17 events; 3.6%) than with AVD (7 events; 1.5%), p = 0.041. There was one respiratory death (pulmonary fibrosis) in the ABVD arm. PFT data were available for 779 pts at EOT, 386 pts at 2-year follow up and 196 pts at 5 years; uptake of repeat PFT was unaffected by treatment arm or presence of prior abnormal results. Changes in DLCO adjusted to baseline values for randomised patients are shown in the Figure. Pts randomised to AVD had a significantly smaller reduction in DLCO at EOT compared to those given ABVD or escalated to BEACOPP: +4.1% (95%CI: 1.8 to 6.5, p = 0.001 and +4.1 (0.1 to 8.0) p = 0.043). Other factors associated with a reduction in DLCO were age (-1.6% (-2.4 to -0.8) for a 10-year increase, p&amp;lt;0.001), female sex (-2.7% (-5.0 to -0.44), p=0.019) and baseline pulmonary disease (-4.9 (-8.4 to -1.4), p = 0.006). There was no evidence of an association with abnormal baseline DLCO values. DLCO had reduced to &amp;lt;90% of baseline values for 247 pts (59.8%) in the ABVD arm compared with 167 pts (40.6%; p&amp;lt;0.001) with AVD, and 63 (53.1%) with BEACOPP. At 2 years after EOT, DLCO had recovered to within 90% of baseline for 69.6% (95% CI: 64.9 - 74.1) of pts in the ABVD arm, 81.4% (77.4 - 85.2) with AVD and 68.5% (59.8 - 76.9) with BEACOPP. DLCO values remained &amp;lt;90% of baseline for 136 pts during follow-up with no reported recovery, with a median PFT follow-up of 18.3 months (IQR: 6.4 - 42.7) after registration. 58 pts had persistent reductions in DLCO at ≥2-year follow up (35 ABVD arm, 10 AVD; 13 BEACOPP arm). Factors associated with a slower recovery of DLCO on univariable analysis were treatment on the ABVD arm (HR 0.71, 95% CI: 0.57 - 0.90; p=0.004 compared with AVD), history of pulmonary disease (HR 0.66 (0.46 - 0.95; p=0.023) and female sex (HR 1.25, 1.01 - 1.54; p=0.041). DLCO values were consistently higher in the AVD arm than with ABVD throughout follow-up with a mean difference of 3.2% (95% CI: 0.3 to 6.1; p=0.029) at 2 years and 5.0% (1.20 to 8.8; p=0.010) at 5 years, after adjustment for baseline DLCO values (see Figure). Findings were consistent after excluding the minority of pts that received radiotherapy. Conclusions: Baseline RFTs are influenced by disease burden and do not predict subsequent bleomycin-related changes in lung function. Whilst individual grade ≥3 events were uncommon, there was a population-wide reduction in diffusion capacity that was only partially reversible at 5 years, findings that might have clinical consequences in later years for pts cured of HL. These data strongly support efforts to minimise bleomycin use in the treatment of HL.

Retrospective analysis of confirmed cases of pulmonary veno-occlusive disease: a single tertiary referral center study

Abstract Background Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary hypertension that primarily results in intimal fibrosis of the pulmonary venules and veins, the venous lesions are often associated with changes in interlobular septa, lung parenchyma, and pulmonary arterioles and arteries. Purpose We sought to study the clinical characteristics of patients with confirmed PVOD at a single large referral center. Methods We retrospectively reviewed data from a total of 675 patients with pulmonary hypertension (identified by ICD codes or search of text) from 2017 and 2022 from a database obtained from electronic medical records at our institution. Patients with group 2 pulmonary hypertension were excluded. Only 29 cases were confirmed by histology or genetic testing. Results Out of the 29 patients confirmed with PVOD, 28 (96.5%) had a characteristic histology (lung biopsy (55.1%), explanted lung for transplant (27.5%) and autopsy (13.7%)) and 1 (3.4%) had a positive genetic test for EIF2AK4 biallelic mutation. The age at diagnosis was 53±16 years, 14 (48.2%) were men, 2 (6.8%) had systemic scleroderma, 2 (6.8%) had psoriasis, 2 (6.8%) were exposed to cytotoxic agents, 16 (55.1%) were smokers and 2 (6.8%) had a family history of pulmonary hypertension. All patients had computed tomography of the chest but only 12 (41.3%) had all 3 typical features found in PVOD (ground glass opacities, interlobular septal thickening, and lymphadenopathy). The most common feature was interlobular septal thickening in 26 (89.6%), followed by ground glass opacities present in 25 (86.2%) and lymphadenopathy in 12 (41.3%) of the patients. At diagnosis, mean pulmonary artery pressure was 45±15 mmHg and pulmonary vascular resistance was 9±6 WU. The median DLCO was 41 (34-58) %. On echocardiogram, 14 (48.2%) had severely enlarged right ventricle (RV), RV function was ≥moderately reduced in 17 (58.6%), RV systolic pressure was 63±20 mmHg and 6 (20.6%) had pericardial effusion. Out of 21 (72.4%) patients who received pulmonary vasodilators, 4 (13.7%) received single agent. 10 (34.4%) received 2 agents, 6 (20.6%) 3 agents, and 1 (3.4%) received 4 agents. 35.7% of these treated patients reported an improvement or initial worsening of symptoms with subsequent improvement afterwards. 18 (62%) patients with PVOD died, 12 (41.3%) had a lung transplant and 6 (20.6%) were still alive without the transplant until the day data was collected. Mean duration from diagnosis to death and lung transplantation was 446 ± 405 days and 274±479 days respectively. Conclusion PVOD is a rare and lethal cause of pulmonary hypertension. When suspected, a trial of medical therapy should be initiated carefully. The evaluation for lung transplant should be considered early given its high mortality.

Assessment of Precision Irradiation in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease (ASPIRE-ILD): Primary Analysis of a Phase II Trial

The use of stereotactic ablative radiotherapy (SABR) in patients with fibrotic interstitial lung disease (ILD) has been associated with an increased risk of toxicity, but patients with ILD and lung cancer may have no other options for curative-intent treatment. The goal of the ASPIRE-ILD trial was to assess the benefits and toxicities of SABR in patients with fibrotic ILD. We enrolled patients with fibrotic ILD and a diagnosis of T1-2N0 NSCLC who were not candidates for surgery. All patients were centrally reviewed prior to enrollment to confirm the presence and subtype of ILD. After stratification by the ILD-GAP score (a measure of ILD severity and prognosis), patients were treated with SABR to a dose of 50 Gy in 5 fractions EOD (BED = 100 Gy10), with a built-in de-escalation protocol in case of unacceptable toxicity. The primary endpoint was overall survival (OS), powered to distinguish 1-year OS >70% vs. an unacceptable rate of ≤50%. Secondary endpoints included toxicity (CTC-AE version 4.0), progression-free survival (PFS), local control (LC), patient-reported outcomes (FACT-L quality of life and cough severity), and changes in pulmonary function tests (PFTs). The study pre-specified that SABR would be considered worthwhile if median OS was >1 year, with a grade 3-4 toxicity risk <35% and a grade 5 toxicity risk <15%. Target accrual was 39 treated patients. Thirty-nine patients were enrolled and treated with SABR between March 2019 and January 2022, all to a dose of 50 Gy in 5 fractions, at 5 institutions in Canada and 1 in Scotland. Median age was 78 years (interquartile range: 67-83), 59% were male, and 92% had a history of smoking (median 43 pack-years). At baseline, 70% reported dyspnea, median FEV1 was 80% predicted and median DLCO was 49% predicted. ILD-GAP scores were as follows: ≤2 (i.e., best ILD status): n = 14; 3-5: n = 23; ≥6 (i.e., worst ILD status): n = 2. Median follow-up was 19 months. OS at 1-year was 78.9% (p<0.001 by binomial test vs. the unacceptable rate). Median OS was 25 months, median PFS was 19 months, and 2-year LC was 92%. AE rates (possibly, probably or definitely related) were as follows (highest grade per patient): grade 1-2: n = 12 (31%); grade 3: n = 4 (10%); grade 4; n = 0; grade 5 n = 3 (7.7%, all due to respiratory deterioration). AE rates did not differ by ILD-GAP category or ILD subtype. FACT-L scores trended downward over time (p = 0.07), and cough severity scale scores worsened over time (p = 0.02). Comparing last-available PFTs with baseline, DLCO declined (median: -4%; p = 0.046), FVC trended downward (median: -2.5%; p = 0.11), and FEV1 remained stable (median change: 0%). The use of SABR in patients with ILD met the pre-specified acceptability thresholds for both toxicity and efficacy, supporting the use of SABR for curative-intent treatment after a careful discussion of risks and benefits. Further studies exploring pharmacologic options to reduce toxicity may be beneficial in this population. ().

Lung diffusion capacity correlates with pre-implant pulmonary hypertension and predicts outcome after LVAD implantation.

Diffusing capacity of the lung for carbon monoxide (DLCO ) reduction is common in heart failure (HF) and is associated with a worse prognosis. Correlations between DLCO and pulmonary hypertension (PH) are unclear, and published data are conflicting; it has been shown that DLCO impairment may persist or even worsen after normalization of pulmonary pressures following left ventricle assist device (LVAD) implantation, maybe reflecting persistent pulmonary damage. We aimed to investigate the impact of pre-implant DLCO and central haemodynamics on outcome in patients with advanced HF implanted with a LVAD. We retrospectively analysed pre-implant and post-implant data from 42 patients implanted with a LVAD at our institution. Out of 42 patients, 35 had post-capillary PH before implantation, including 17 with combined post- and pre-capillary PH (Cpc-PH). Median DLCO was 59% (IQR 47-68%), and it inversely correlated with pulmonary vascular resistance (PVR) (P 0.037) and diastolic pulmonary gradient (DPG) (P 0.042). Compared with baseline, LVAD resulted in improvement in LV diameter (LVDd, P<0.001), mitral regurgitation (P 0.022), and PH (mPAP 24 vs. 36mmHg, P<0.001; PAWP 12 vs. 23mmHg, P 0.001; pulmonary artery compliance, CPA 3.1 vs. 1.9mL/mmHg, P 0.021). Lower DLCO and Cpc-PH at baseline were associated with a better LV reverse remodelling post-implantation (P 0.027 for LVDd) but also with a smaller gain in CPA (P 0.049). Before LVAD implantation, DLCO impairment is associated with higher PVR and DPG, suggesting that it might be an expression of persistent pulmonary damage occurring in Cpc-PH. After LVAD implantation, both LV dimension and haemodynamics improve. Lower pre-implant DLCO is associated with better LV reverse remodelling.

Pulmonary Function Testing (PFT) after Photon and Proton Radiotherapy for Stage II-III Breast Cancer

<h3>Purpose/Objective(s)</h3> The Breast Cancer Lung Late Effects (BELLE) study prospectively enrolled patients with breast cancer who received adjuvant photon (XRT) or proton (PT) radiotherapy (RT) to evaluate potential early markers of induced lung injury, including pulmonary function tests (PFTs). <h3>Materials/Methods</h3> Patients ≥18 years with AJCC 8^th edition anatomic stage II-III or greater breast cancer were enrolled into the BELLE study between May 27, 2016 and May 26, 2020. All patients underwent clinical evaluation, computed tomography imaging, PFTs, and QoL questionnaires at baseline, 6 months, and 12 months relative to RT start. Fisher's exact tests and Kruskal-Wallis rank sum tests were used to compare the XRT and PT groups. <h3>Results</h3> A total of 37 patients were included in the final analysis (XRT, n=21; PT, n=16). Median age at diagnosis was 51 years (range, 31-76); 26 patients identified as white (70.3%), 8 as Black (21.6%), and 3 other (7.1%). Most patients did not have pre-existing respiratory disease (83.8%) or prior smoking history (62.2%), while 35.1% were former smokers and 1 was a current smoker (2.7%). The median BMI was 29.4 (range, 18.9-44.2). Most patients received chemotherapy (75.7%) and regional nodal irradiation (RNI; 78.4%). Median lung V20 was 25.3% (range, 5.6-39.7) and median lung V5 was 59.6% (range, 29.7-86.4). XRT patients had more pre-existing respiratory disease and were less likely to receive RNI (p=0.027 and p=0.006, respectively). There was no statistically significant difference between the XRT and PT cohorts for median lung V20 or V5. The median FEV1/FVC ratio at baseline, 6 months, and 12 months were not significantly different between the XRT and PT cohorts (80.2 % vs 81.5%, p=0.81; 79.3% vs 81.3%, p=0.95; and 80.6% vs 79.4% p>0.99, respectively). Similarly, the median FVC values at baseline, 6 months, and 12 months were not significantly different between the XRT and PT cohorts (3.4 L vs 3.1 L, p=0.76; 3.2 L vs 3.0 L, p=0.38; and 3.5 L vs 3.0 L, p=0.23, respectively). While the median DLCO at baseline was significantly worse for the PT cohort (91% vs 76%, p=0.005), there was no difference between cohorts at 6 and 12 months (79.0% vs 78.0%, p=0.38; 89.0% vs 84.0%, p=0.80, respectively). Four patients developed radiation pneumonitis (RP) within a year of RT including 3 with transient grade 1 (n=1 PT; n=2 XRT) and 1 with grade 3 (XRT). <h3>Conclusion</h3> Despite high variability among patients across all PFT parameters, the median FEV1/FVC ratio and FVC were stable over time and did not cross the threshold for concern of restrictive lung disease in either cohort. Although DLCO decreased at 6 months in the XRT cohort, both cohorts showed improvement at one year without diagnosis of restrictive lung disease. Utilizing PFTs as an early marker of RT-induced lung injury, neither patients treated with XRT nor PT exhibited sustained PFT abnormalities with 1 year of follow-up.

Α1-ANTITRYPSIN DEFICIENCY IN GREEKS: FOCUS ON RARE VARIANTS

TYPE: Abstract TOPIC: Genetic and Developmental Disorders PURPOSE: This study aimed to investigate genotype and phenotype characteristics of a Greek cohort of A1AT deficiency patients. METHODS: A1AT deficiency patients followed-up in Greece and analyzed in A1AT Laboratory, Universitätsklinikum Gießen und Marburg GmbH, Germany were enrolled in the study. Patients underwent A1AT measurement for early emphysema RESULTS: Included are 24 adults, 54.2% males, 28.6% never-smokers, diagnosed at a median age (IQR) of 49 (43.0-59.5) years with A1AT levels of 0.255 (0.185-0.380) g/L. Patients presented with a median (IQR) FEV1 (% predicted), FEV1/FVC% and DLCO (% predicted) of 40.9 (29.9, 59.8), 50.5 (39.3, 63.0) and 52.8 (35.8, 68.0) respectively. Ten patients (41.7%) presented PI*ZZ genotype, 4 patients (16.7%) PI*Q0Q0 genotypes and 3 patients (12.5%) PI*ZQ0 genotypes. Q0 alleles corresponded to PI*Q0-Bellingham (1/7pts), PI*Q0-Amersfoort (3/7 pts) and PI*Q0-Granitefalls 3/7pts), ultra-rare null variants. Four patients (16.7%) were carriers of at least one of the following rare variants MHeerlen, MProcida and MMalton. In 3 patients (12.5%) sequencing indicated other ultra-rare mutations. Null variants were significantly associated with lowest A1AT levels and lower FVC values, compared to other variants [p=0.023 and p=0.034 respectively]. A1AT protein levels significantly correlated to FEF25-75% (% predicted) [p=0.013, r=0.559] CONCLUSIONS: The present study provides new evidence about an increased incidence of rare and ultra-rare A1AT variants in Greece of clear pathogenic significance, confirming an established North to South European geographical trend in A1AT deficiency. CLINICAL IMPLICATIONS: The interpretation of novel SERPINA1 variants highlighted the importance of unravelling new mechanisms of A1AT deficiency pathophysiology in a personalized medicine era DISCLOSURE: Nothing to declare. KEYWORD: A1 ANTITRYPSIN DEFIECIENCY

3D-quantitated lung perfusion SPECT/CT: Impact on intended management compared to lung perfusion scan in marginal candidates for lung resection surgery

Abstract Objective Based on previous studies, single-photon emission computed tomography/computed tomography (SPECT/CT) has been proven to be more accurate and reproducible than planar lung perfusion scintigraphy. We conducted a study to evaluate the impact of 3D-quantitated lung perfusion SPECT/CT on intended management in candidates for lung resection surgery. Methods Retrospective study including candidates for lung resection surgery with lung perfusion imaging. Patients underwent preoperative evaluation according to ERS/ESTS algorithm. The lobar contribution to the total lung perfusion was estimated using planar antero-posterior, posterior oblique and three-dimensional anatomical SPECT/CT method (CT Pulmo 3D and xSPECT- Quant, Siemens). The difference in lobar perfusion with resulting changes in the extent of lung resection were analyzed to reveal possible changes in operability. Results 120 patients (46 females) with known lung cancer or pulmonary lesion considered for resection with available lung perfusion scintigraphy and SPECT/CT were enrolled. The mean age (±SD) of patients was 68 ±9 years, the target lesions were located in upper lobe in 57.7% and in lower lobe in 33.5%. The median [IQR] FEV1 was 70.5% [52–84] and median DLCO 56.6% [47.1–67.4]. The planar posterior oblique method, compared to 3D-quantitated SPECT/CT, underestimated the perfusion of upper lobes by a median difference of 5% (right [2–9; IQR]; left [2.5–8], p= &amp;lt; 0.0001), while it overestimated the both lower lobes (left by 4% [2–7]; right by 6% [2–9], p= &amp;lt; 0.0001). In contrast to the planar scintigraphy based evaluation, 4(3.3%) patients with upper lobe lesions were classified as inoperable when 3D-quantitated SPECT/CT was used for calculation of predicted postoperative lung function. Conclusion In selected patients with upper lobe lesions, 3D-quantitated SPECT/CT would have changed the treatment strategy from operable to inoperable. Importantly, post-operative mortality in this particular subgroup was disproportionally high. 3D-quantitated SPECT/CT shall be further evaluated as it might improve preoperative risk stratification in marginal lung resection candidates.

Efficacy and Safety of Rituximab in Autoimmune Disease-Associated Interstitial Lung Disease: A Prospective Cohort Study.

Objectives: To analyze the efficacy and safety of rituximab (RTX) in connective tissue disease associated with interstitial lung disease (CTD-ILD). Methods: We performed a multicenter, prospective, observational study of patients with CTD-ILD receiving rituximab between 2015 and 2020. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline, at 12 months, and at the end of follow-up. The main outcome measure at the end of follow-up was forced vital capacity (FVC) > 10% or diffusing capacity of the lungs for carbon monoxide (DLCO) > 15% and radiological progression or death. We recorded clinical characteristics, time to initiation of RTX, concomitant treatment, infections, and hospitalization. A Cox regression analysis was performed to identify factors associated with worsening ILD. Results: We included 37 patients with CTD-ILD treated with RTX for a median (IQR) of 38.2 (17.7–69.0) months. At the end of the follow-up, disease had improved or stabilized in 23 patients (62.1%) and worsened in seven (18.9%); seven patients (18.9%) died. No significant decline was observed in median FVC (72.2 vs. 70.8; p = 0.530) or DLCO (55.9 vs. 52.2; p = 0.100). The multivariate analysis showed the independent predictors for worsening of CTD-ILD to be baseline DLCO (OR (95% CI), 0.904 (0.8–0.9); p = 0.015), time to initiation of RTX (1.01 (1.001–1.02); p = 0.029), and mycophenolate (0.202 (0.04–0.8); p = 0.034). Only 28 of the 37 patients (75.6%) were still undergoing treatment with RTX: two patients (5.4%) stopped treatment due to adverse events and seven patients (18.9%) died owing to progression of ILD and superinfection. Conclusion: Lung function improved or stabilized in more than half of patients with CTD-ILD treated with RTX. Early treatment and combination with mycophenolate could reduce the risk of progression of ILD.

Spirometry for the diagnosis of airway obstruction in patients with risk factors for COPD: the GOLD and lower limit of normal criteria.

ABSTRACTObjective:The identification of persistent airway obstruction is key to making a diagnosis of COPD. The GOLD guidelines suggest a fixed criterion-a post-bronchodilator FEV1/FVC ratio < 70%-to define obstruction, although other guidelines suggest that a post-bronchodilator FEV1/FVC ratio < the lower limit of normal (LLN) is the most accurate criterion. Methods:This was an observational study of individuals ≥ 40 years of age with risk factors for COPD who were referred to our pulmonary function laboratory for spirometry. Respiratory symptoms were also recorded. We calculated the prevalence of airway obstruction and of no airway obstruction, according to the GOLD criterion (GOLD+ and GOLD−, respectively) and according to the LLN criterion (LLN+ and LLN−, respectively). We also evaluated the level of agreement between the two criteria. Results:A total of 241 individuals were included. Airway obstruction was identified according to the GOLD criterion in 42 individuals (17.4%) and according to the LLN criterion in 23 (9.5%). The overall level of agreement between the two criteria was good (k = 0.67; 95% CI: 0.52-0.81), although it was lower among the individuals ≥ 70 years of age (k = 0.42; 95% CI: 0.12-0.72). The proportion of obese individuals was lower in the GOLD+/LLN+ category than in the GOLD+/LLN− category (p = 0.03), as was the median DLCO (p = 0.04). Conclusions:The use of the GOLD criterion appears to be associated with a higher prevalence of COPD. The agreement between the GOLD and LLN criteria also appears to be good, albeit weaker in older individuals. The use of different criteria to define airway obstruction seems to identify individuals with different characteristics. It is essential to understand the clinical meaning of discordance between such criteria. Until more data are available, we recommend a holistic, individualized approach to, as well as close follow-up of, patients with discordant results for airway obstruction.

Prognostic Effect of Decline in Pulmonary Function Testing after Autologous Stem Cell Transplantation

BackgroundLarge retrospective analyses of patients (pts) undergoing allogeneic stem cell transplant have demonstrated association between decline in pulmonary function and increases in mortality. There is a paucity of similar evidence for pts undergoing autologous stem cell transplant (ASCT). We conducted a retrospective study of lymphoma pts undergoing ASCT to investigate association between early post-transplant decrease in pulmonary function tests (PFTs) and mortality. We hypothesized that decreases in pulmonary function in the early post-transplant period in ASCT pts would be associated with greater risk of overall and non-relapse mortality.Methods and PatientsWe identified 853 lymphoma pts age ≥18 years who underwent ASCT at Cleveland Clinic between 2000-2016 and had completed both pre- and post-ASCT PFTs. Two PFT values were assessed: percent predicted FEV1 and DLCO. Endpoints for the study included overall survival (OS) and non-relapse mortality (NRM). Decrease from pre- to post-ASCT for each was defined as ≤5%, 5.01-10%, or >10%. Variables associated with decrease in PFTs were identified with Cochran-Mantel-Haenszel trend tests. Risk factors were identified with Cox analysis (OS) or Fine and Gray regression (NRM); results are presented as hazard ratio (HR) and 95% confidence interval (CI).ResultsThe study cohort was predominantly male (63%) and Caucasian (92%) with a median age of 54 years (range 19-78). Primary diagnosis included Hodgkin lymphoma (19%) and non-Hodgkin lymphoma: B cell low-grade (16%) and high-grade (57%), and T cell (8%). The majority had advanced stage disease (79%), received <3 prior chemotherapy regimens (74%), no prior radiation (77%) and were never smokers (56%). Prior bleomycin (23%) and brentuximab (2%) exposure was low. Busulfan, etoposide and cyclophosphamide was the preparative regimen in 98% of pts. Median time to neutrophil and platelet engraftment were 10 and 15 days respectively. At a median follow up of 64 months (range 3-208) 62% of our cohort was alive and 43% had relapsed. Pre-ASCT PFTs were performed at a median of 51 days (range 9-205) prior to transplant. Median pre-transplant FEV1 and DLCO were 93% and 75% of predicted respectively when corrected for anemia. Post-transplant PFTs were obtained at a median 43 days post-transplant (25-92). Decreases in FEV1 of ≤5%, 5.01-10%, and >10% were observed in 71%, 15%, and 15% of pts, respectively. Corresponding decreases in DLCO were 70%, 11%, and 20%, respectively. Decrease in FEV1 was associated with male gender, intermediate risk disease, chemo-mobilization, and increased days of apheresis. Decreasing DLCO was associated with Caucasian ethnicity, and advanced stage. Pts with FEV1 decline were more likely to experience increased hospital stay and readmission within 100 days post ASCT. Prior bleomycin use did not impact PFTs or outcomes.For our cohort, 5- and 10-year NRM were 10% and 15% respectively; 5- and 10-year OS were 63% and 53% . In univariate analysis, pts with >10% FEV1 decrease had significantly worse NRM (HR 2.07, 95% CI 1.27-3.38, p=0.004) (Figure 1) and OS (HR: 1.42, 95% CI 1.07-1.89, p=0.016) (Figure 1a) than those with ≤5% decrease; pts with 5.01-10% FEV1 decrease had similar NRM (HR 1.58, 95% CI 0.92-2.72, p=0.10) and OS (HR 1.15, CI 0.85-1.57, p=0.37) to those with ≤5% decrease . Only minimal decreases in DLCO (0.01-5%) impacted NRM (HR: 0.23, CI = 0.06 - 0.95, p=0.042), while >5% decline had no significance on NRM or OS. In multivariable analysis, >10% FEV1 decrease retained significance for NRM (HR 1.96, 95% CI 1.20-3.20, p=0.008), with a trend towards poor OS (HR 1.33, CI 0.99-1.77, p=0.06) (Figure 2). Pts with 5.01-10% decrease had marginally higher risk of NRM (HR 1.55, 95% CI 0.90-2.66, p=0.11) but not OS (HR 1.14, 95% CI 0.83-1.55, p=0.42). Other prognostic factors for increased NRM included older age, chemo-mobilization, and more days of apheresis. These three were also prognostic for worse OS along with more prior chemotherapy and high-risk disease.ConclusionDecrements of FEV1 >10% in the early post-transplant period are associated with increased NRM and inferior OS in lymphoma pts undergoing ASCT. Greater decrease in DLCO was not associated with decreased OS or increased NRM. Further stratification and analysis of the population with large decreases in pulmonary function may help with development of screening and interventional strategies in high risk pts. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Majhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Surgical Morbidity and Lung Function Changes After Laser-Assisted Pulmonary Metastasectomy: A Prospective Bicentric Study.

Objective: The surgical resection of pulmonary metastases is associated with a survival benefit in selected patients. The use of laser devices for pulmonary metastasectomy (PM) is believed to facilitate the complete resection of metastases while preserving a maximum of healthy parenchyma. This is a prospective study to evaluate surgical outcome including the changes of lung function after laser–assisted surgery (LAS).Methods: A total of 77 operations in 61 patients in which PM was carried out in a curative intent were analyzed. A 1.320 nm diode-pumped Nd: YAG-Laser was used for resection of the metastases. Surgical and clinical data were collected using a standardized form and postoperative lung function changes 3 and 6 months after surgery were assessed using whole body plethysmography and diffusion capacity for carbon monoxide (DLCO). Size and distance of metastases to the pleural surface were measured radiologically.Results: A median of two metastases were resected per operation (range 1–13). The median duration of postoperative air leak was 1 day (range 0–11). LAS associated postoperative minor and major complications were observed in 4 (5%) cases and 1 (1%) case, respectively; there were no mortalities. The analysis of perioperative lung function showed that mean VC 3 months after surgery was reduced by 11 %, FEV1 by 11% and median DLCO by 11% (all p < 0.0001). There was almost no recovery of lung function between 3 and 6 months in the whole cohort. Patients with two or less metastases showed a recovery of lung function after 3 months regarding DLCO (p = 0.003). Decline of DLCO in the whole cohort correlated with the number of resected metastases at 3 months (r = 0.45, p = 0.006) and at 6 months (r = 0.42, p = 0.02) as well as depth of metastases in the parenchyma at 6 months (r = 0.48, p = 0.001).Conclusions: LAS is a safe and effective method for PM even for higher numbers of metastases, with short duration of postoperative air leak and little morbidity. Number and depth, but not size of metastases affect lung function changes after resection.

POS0700 TREATMENT OF INTERSTITIAL LUNG DISEASE IN PATIENTS WITH PRIMARY SJOGREN SYNDROME: A SINGLE-CENTER RETROSPECTIVE ANALYSIS

Background:Interstitial lung disease (ILD) is one of the main contributor to morbidity and mortality in patients with primary Sjogren syndrome (pSS), and whether immunosuppressive treatments are effective for pSS-ILD is uncertain. Cyclophosphamide (CYC) and rituximab (RTX) are effective in stabilizing pulmonary function in patients with ILD caused by systemic sclerosis, inflammatory myositis, and rheumatoid arthritis1,2. Reports regarding the treatment response for cyclophosphamide or rituximab in pSS-ILD patients are lacking.Objectives:To investigate whether add-on CYC or RTX in addition to steroid and oral DMARDs leads to greater improvement in pulmonary function test than conventional treatment in patients with pSS-ILD with impaired baseline pulmonary function.Methods:pSS-ILD patients with ILD confirmed by a chest computed tomography were screened. Those with imparied baseline pulmonary function test (FVC&lt;80% and DLCO&lt;80%) and available results of pulmonary function tests at 6th-18th month post-treatment were retrospectively enrolled. The patients were clustered into two groups: steroid and oral DMARDs alone (steroid/oDMARD group), and add-on CyC and/or RTX (Add-on CyC/RTX group).Results:This study enrolled 22 patients. The median age of these patients was 65. Among them, 68% were female and 18% were smokers. The median baseline FVC was 63.5% and the median DLCO was 54.4%. The predominant CT pattern was NSIP (54%), followed by UIP (22%), LIP (13.6%) and OP (9%) (table 1).Five patients received steroid and oral DMARDs alone (hydroxychloroquine +/- azathioprine), while 17 patients received add-on CYC and/or RTX (8 patients received CYC, 3 received RTX, and 6 received CYC and RTX). There was no significant difference in baseline characteristic between these two groups (table 1).With a median follow-up period of 9.8 months (interquartile range 7.6 - 13.4 months) after treatment, the FVC improved significantly from 61.3% to 65.5% (p=0.013) in CYC/RTX group, while the FVC improvement was not significant in steroid/oDMARD group (figure 1A). In CYC/RTX group, patients with non-UIP pattern (NSIP, LIP and OP) on chest CT had significant FVC improvement (p=0.021), contrasting to the patients with UIP pattern on chest CT (figure 1B).Conclusion:In pSS patients with ILD and impairment of pulmonary function at baseline (FVC&lt;80%, DLCO&lt;80%), FVC improved significantly in patients received add-on cyclophosphamide and/or rituximab therapy.

Increased monocyte count and red cell distribution width as prognostic biomarkers in patients with Idiopathic Pulmonary Fibrosis

BackgroundIdiopathic Pulmonary Fibrosis (IPF) represents a chronic lung disease with unpredictable course.MethodsWe aimed to investigate prognostic performance of complete blood count parameters in IPF. Treatment-naïve patients with IPF were retrospectively enrolled from two independent cohorts (derivation and validation) and split into subgroups (high and low) based on median baseline monocyte count and red cell distribution width (RDW).ResultsOverall, 489 patients (derivation cohort: 300, validation cohort: 189) were analyzed. In the derivation cohort, patients with monocyte count ≥ 0.60 K/μL had significantly lower median FVC%pred [75.0, (95% CI 71.3–76.7) vs. 80.9, (95% CI 77.5–83.1), (P = 0.01)] and DLCO%pred [47.5, (95% CI 44.3–52.3) vs. 53.0, (95% CI 48.0–56.7), (P = 0.02)] than patients with monocyte count < 0.60 K/μL. Patients with RDW ≥ 14.1% had significantly lower median FVC%pred [75.5, (95% CI 71.2–79.2) vs. 78.3, (95% CI 76.0–81.0), (P = 0.04)] and DLCO%pred [45.4, (95% CI 43.3–50.5) vs. 53.0, (95% CI 50.8–56.8), (P = 0.008)] than patients with RDW < 14.1%. Cut-off thresholds from the derivation cohort were applied to the validation cohort with similar discriminatory value, as indicated by significant differences in median DLCO%pred between patients with high vs. low monocyte count [37.8, (95% CI 35.5–41.1) vs. 45.5, (95% CI 41.9–49.4), (P < 0.001)] and RDW [37.9, (95% CI 33.4–40.7) vs. 44.4, (95% CI 41.5–48.9), (P < 0.001)]. Patients with high monocyte count and RDW of the validation cohort exhibited a trend towards lower median FVC%pred (P = 0.09) and significantly lower median FVC%pred (P = 0.001), respectively. Kaplan–Meier analysis in the derivation cohort demonstrated higher all-cause mortality in patients with high (≥ 0.60 K/μL) vs. low monocyte count (< 0.60 K/μL) [HR 2.05, (95% CI 1.19–3.53), (P = 0.01)].ConclusionsIncreased monocyte count and RDW may represent negative prognostic biomarkers in patients with IPF.

P157 Potential benefit of intravenous immunoglobulin in connective tissue disease associated interstitial lung diseases

Abstract Background/Aims Intravenous immunoglobulin (IVIg) confers significant benefit in range of connective tissue diseases (CTD) including inflammatory myopathy (IM) of which interstitial lung diseases (ILD) are a major complication. This study aimed to assess the efficacy of IVIg on pulmonary involvement in refractory active CTD including systemic sclerosis (SSc). Methods All patients with CTD-ILD confirmed on HRCT either with IM or SSc overlap myositis who did not achieve satisfactory clinical response to standard immunosuppressive agents and subsequently received regular IVIg infusions for IM were retrospectively identified. Serial lung function tests and immunosuppressive treatment regimen 9-12 months prior and 9-12 months after repeat courses of IVIg were recorded. Progressive ILD was considered when, despite immunosuppressive treatment, a relative FVC decline≥10% and/or relative DLco decline ≥15% were identified during the 9-12 months preceding IVIg treatment. The significance of median DLco and FVC percentage relative change to IVIg treatment was assessed by Wilcoxon signed-rank test. Results 22 patients (mean age 50.5±13.1 years old) with IM-ILD treated with IVIg were identified. ILD occurred in association with IM in 10 patients, overlap SSc myositis in another 11 patients, while one had mixed connective tissue disease with myositis. Lung function results were available for 19/22 (86%). Eight patients (42.1%) were found to have progressive ILD(four with IM and four with overlap SSc-myositis). The median change in FVC% predicted and DLco% predicted in the 9-12 months before and after IVIg treatment is presented in Table 1. There was a significant difference in the DLco% predicted rate of relative change before and after IVIg treatment (p = 0.035) for the overall cohort. However, no differences in lung function were observed in the rate of relative change between patients with IM and patients with SSc myositis overlap. Significant improvement in DLco% predicted values was identified in the subgroup analysis of patients with progressive ILD(p = 0.012). P157 Table 1:The median change in FVC and DLco% predicted values prior and after the IVIg treatmentPatients with myositis related ILD9-12 months before IVIg treatment (relative change)9-12 months after IVIg treatment (relative change)p-valueAll (n = 19)FVC % predicted-3.8 (-54.4 - 14.6)2.1 (-33 - 33.7)0.145DLco % predicted-9.2 (-60.7 - 9.2)-2.3 (-26 - 41.9)0.035PM/DM (n = 10)FVC % predicted-1.8 (-20.2 - 14.6)0.8 (-33 - 30.9)0.401DLco % predicted-9.6 (-60.7 - 9.2)-2.4 (-26 - 41.9)0.093SSc-PM/DM overlap (n = 11)FVC % predicted-6 (-54.4 - 10.6)3.4 (-19.9 - 33.7)0.139DLco % predicted-10.8 (-47.1 - 2.5)4.2 (-22.7 - 16.8)0.173Progressive ILD (n = 8)FVC % predicted-14.5 (-54.4 - 14.6)5.7 (-11.9 - 33.7)0.123DLco % predicted-25.3 (-60.6 - -14.1)12 (-2.3 - 41.9)0.012 Conclusion IVIg may be an effective rescue therapy in the prevention of further lung function decline in refractory myositis and SSc overlap in particular in subgroups with progressive ILD. Future studies to determine its role in CTD-ILD are warranted. Disclosure V. Kouranos: None. L.V. Host: None. C. Campochiaro: None. A. Wells: None. C.P. Denton: None. V.H. Ong: None. E. Renzoni: None.

Diffusion Lung Capacity (DLCO) Correlates with Pre-Implant Pulmonary Hypertension and Predicts Outcome in Patients with HF Implanted with a LVAD

Purpose DLCO reduction is commonly observed in HF and is associated with a worse outcome. Correlations between DLCO and PH are unclear and published data are conflicting; moreover, it has been shown that even after normalization of pulmonary pressures driven by the LVAD, a DLCO impairment may persist or worsen, maybe reflecting the persistence of pulmonary vascular remodeling. In this study we investigated correlations between pre-implant DLCO, hemodynamics and post-implant outcome in patients with advanced HF implanted with a LVAD. Methods We retrospectively analyzed pre-implant clinical data and post-implant outcome of 42 patients implanted with a LVAD at our institution in whom a DLCO measurement was performed before surgery. Results Out of 42 patients (71% males, mean age 53 y), 35 (83%) had post-capillary PH, including 17 (40%) with combined post and pre-capillary PH (CpcPH; defined in1). At baseline, median DLCO was 59% (range 21-100%) and it inversely correlated with PVR (p 0.037) and DPG (p 0.042).Early after surgery, more than mild right HF (RHF) occurred in 12 patients, 4 of which died; neither RHF severity nor intensive care unit length of stay were associated with DLCO. Compared to baseline, the LVAD resulted in a significant reduction in LV dimension (Dd 61 vs 69 mm, p Conclusion We showed a significant improvement in hemodynamics after LVAD implantation. Reduced DLCO is associated with CpcPH suggesting that impaired DLCO may be a marker of pulmonary vascular remodeling. 1Galie N et al Eur Heart J 2015; doi:10.1093/eurheartj/ehv317

Markers of inflammation and immune activation are associated with lung function in a multi-center cohort of persons with HIV.

Studies have shown that people with HIV (PWH) may be at increased risk for chronic lung diseases and lung function abnormalities, which may be associated with immune activation. We tested the association of a panel of 12 immune activation and inflammation biomarkers with spirometry and single-breath diffusing capacity for carbon monoxide (DLco). Cross-sectional, observational study. Participants were enrolled from the Inflammation, Aging, Microbes and Obstructive Lung Disease cohort of PWH at two US sites. Biomarkers were examined and standardized spirometry and DLco testing were performed. We tested associations between each biomarker and lung function, examined individually and in combination, using multi-variable linear and logistic regression. Among 199 participants, median forced expiratory volume in 1 s (FEV1) was normal (90% predicted) and median DLco was abnormal (69% predicted). The most common lung function abnormality (57%) was a normal FEV1 to forced vital capacity ratio with an abnormal DLco of 80% or less predicted (iso↓DLco). Two markers (IL-6, high-sensitivity C-reactive protein) were associated with FEV1% predicted, whereas eight markers (soluble CD14, soluble CD163, inducible protein-10, soluble CD27, IL-6, soluble tumor necrosis factor receptors 1 and 2, D-dimer) were associated with DLco% predicted. Compared with those participants with normal spirometry and DLco, five markers (soluble CD14, soluble CD163, interferon gamma inducible protein-10, soluble tumor necrosis factor receptors 1 and 2) were associated with iso↓DLco. Among PWH, different markers of immune activation and inflammation are associated with FEV1% predicted than with DLco% predicted and with an iso↓DLco, representing possible unique pathways of chronic lung disease. Identifying plausible drivers of these inflammatory pathways may clarify mechanisms underlying impaired lung function in HIV infection and may identify therapeutic avenues.