Reduced Diffusion Capacity Research Articles

SARS-CoV-2 infection induces hyaluronan production in vitro and hyaluronan levels in COVID-19 patients relate to morbidity and long-term lung impairment: a prospective cohort study.

We previously demonstrated that the lungs of deceased COVID-19 patients were filled with a clear hydrogel consisting of hyaluronan (HA). In this translational study, we investigated the role of HA at all stages of COVID-19 disease to map the consequences of elevated HA on morbidity and identify the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced HA production. A reduced alveolar surface area was observed in the lungs of deceased COVID-19 patients compared to healthy controls, as visualized by a 3D rendering of lung morphology using light-sheet fluorescence microscopy. We confirmed the presence of HA in lung biopsies and found large quantities of proinflammatory fragmented HA. The association of systemic HA in blood plasma and disease severity was assessed in patients with mild (WHO Clinical Progression Scale, WHO-CPS, 1-5) and severe COVID-19 (WHO-CPS, 6-9) during the acute and convalescent phases and related to lung function. We found that systemic levels of HA were high during acute COVID-19 disease, remained elevated during convalescence, and were associated with a reduced diffusion capacity. In vitro 3D-lung models, differentiated from primary human bronchial epithelial cells, were used to study the effects of SARS-CoV-2 infection on HA metabolism, and transcriptomic analyses revealed a dysregulation of HA synthases and hyaluronidases, both contributing to increased HA in apical secretions. Furthermore, corticosteroid treatment reduced the inflammation and downregulated HA synthases. Our findings demonstrate that HA plays a role in COVID-19 morbidity and that sustained elevated HA concentrations may contribute to long-term respiratory impairment.IMPORTANCEThis study provides insights into the role of hyaluronan (HA) in the severity and long-term impact of COVID-19 on lung function. Through extensive morphological examination of lung tissues and a multicenter study, we identified that HA levels are significantly elevated in COVID-19 patients, correlating with a reduced lung diffusion capacity during convalescence. Using a 3D-lung model, we further uncovered how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 infection causes a dysregulated HA metabolism, leading to increased HA production. Our findings provide valuable insights into the pathogenesis of SARS-CoV-2 and suggest that targeting HA metabolism could offer new therapeutic avenues for managing COVID-19, particularly to prevent long-term lung impairment. Additionally, HA holds potential as a biomarker for predicting disease severity, which could guide personalized treatment strategies.

Maximal respiratory pressure after COVID-19 compared with reference material in healthy adults: A prospective cohort study (The SECURe study).

After COVID-19 long term respiratory symptoms and reduced lung function including maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) have been reported. However, no studies have looked at MIP and MEP in all disease groups and the reference materials collection methods differ substantially. We aimed to determine MIP and MEP in individuals after COVID-19 infection with different disease severity using reference material of healthy control group obtained using the same standardized method. Patients with COVID-19 were included March 2020-March 2021 at Rigshospitalet, Denmark. MIP and MEP were measured using microRPM. Predicted MIP and MEP were calculated using reference material obtained from 298 healthy adults aged 18-97 years using the same method. In SECURe, 145 participants were measured median 5 months after COVID-19 diagnosis and of these 16% had reduced MIP and/or MEP. There was reduced spirometry and total lung capacity, but not reduced diffusion capacity in those with abnormal MIP and/or MEP compared with normal MIP and MEP. Of those with reduced MIP and/or MEP at 5 months, 80% still had reduced MIP and/or MEP at 12 months follow-up. In conclusion, few have reduced MIP and/or MEP 5 months after COVID-19 and little improvement was seen over time.

Pulmonary function trajectories in COVID-19 survivors with and without pre-existing respiratory disease

A significant proportion of COVID-19 survivors still experience a reduced diffusion capacity three and twelve months after discharge. We aimed to compare pulmonary function trajectories between hospitalized COVID-19 patients with pre-existing respiratory disease (PRD) and patients without pre-existing respiratory disease (Non-PRD) at three and twelve months after hospital discharge. This single-centre retrospective cohort study included COVID-19 patients admitted to the VieCuri Medical Centre (Venlo, the Netherlands) between February and December 2020 that were invited to the outpatient clinic at three and twelve months after discharge. During this visit, pulmonary function tests were performed and impairments were based on lower limit of normal. Data of 239 patients were analysed (65% male, 66 ± 10 years, and 26% with a history of respiratory disease). Three months after discharge, 49% and 64% of the Non-PRD patients (n = 177) and PRD patients (n = 62) had a low diffusion capacity, respectively. This improved over time in Non-PRD patients (p = 0.003), but not in PRD patients (p = 0.250). A low diffusion capacity was still observed in 34% and 57% of the Non-PRD and PRD group, respectively, twelve months after discharge. Pulmonary function impairments, mainly a reduced diffusion capacity, are observed among hospitalized COVID-19 patients with PRD and Non-PRD, at three and twelve months follow-up. Although diffusion capacity impairments restore over time in Non-PRD patients, poor recovery was observed among PRD patients.

Complete blood count, coagulation biomarkers, and lung function 6 months after critical COVID-19.

Understanding the recovery of post-COVID-19 organ dysfunction is essential. We evaluated coagulation 6 months post-COVID-19, examining its recovery and association with lung function. Patients treated for COVID-19 at intensive care units between 3/2020 and 1/2021 were analyzed for complete blood count (CBC) and coagulation biomarkers (prothrombin time activity (%) (PT%), activated partial thromboplastin time (APTT), fibrinogen, coagulation factor VIII (FVIII), antithrombin (AT), and D-dimer) during the 6 months post-hospitalization. Results were compared with acute phase values and correlated with pulmonary function tests (PFT), including forced vital capacity (FVC) and hemoglobin-corrected diffusing capacity percentage of predicted (DLCOc%), recorded 6 months post-hospitalization. We examined the association between coagulation biomarkers and DLCOc% using linear regression with age, sex, and invasive mechanical ventilation (IMV) duration, and FVIII (correlated with DLCOc%) as covariates. Most CBCs and coagulation biomarkers had median values within the normal range. However, only 21% (15/70) of patients achieved full normalization of all biomarkers. Compared to acute COVID-19, hemoglobin, PT%, and AT increased, while leukocytes, fibrinogen, FVIII, and D-dimer decreased. Despite decreased levels, FVIII remained elevated in 46% (31/68), leukocytes in 26% (18/70), and D-dimer in 27% (18/67) at 6 months. A weak negative correlation (r = -0.37, p = .036) was found between DLCOc% and FVIII. Multivariable analysis revealed a weak, independent association between DLCOc% and FVIII. Excluding patients with anticoagulation therapy, FVIII no longer correlated with DLCOc%, while AT showed a moderate correlation with DLCOc%. Only a few patients had normal CBC and coagulation biomarker values 6 months after critical COVID-19. A weak negative correlation between DLCOc% and FVIII suggests that deranged coagulation activity may be associated with reduced diffusing capacity.

Post-COVID-19 respiratory sequelae two years after hospitalization: an ambidirectional study

COVID-19 lung sequelae can impact the course of patient lives. We investigated the evolution of pulmonary abnormalities in post-COVID-19 patients 18-24 months after hospital discharge. A cohort of COVID-19 patients admitted to the Hospital das Clínicas da Faculdade de Medicina da USP in São Paulo, Brazil, between March and August of 2020, were followed-up 6-12 months after hospital discharge. A subset of patients with pulmonary involvement and chest computed tomography (CT) scans were eligible to participate in this second follow-up (18-24 months). Data was analyzed in an ambidirectional manner, including retrospective data from the hospitalization, and from the first follow-up (6-12 months after discharge), and compared with the prospective data collected in this new follow-up. From 348 patients eligible, 237 (68%) participated in this follow-up. Among participants, 139 (58%) patients presented ground-glass opacities and reticulations, and 80 (33%) presented fibrotic-like lesions (traction bronchiectasis and architectural distortion). Five (2%) patients improved compared to the 6-12-month assessment, but 20 (25%) of 80 presented worsening of lung abnormalities. For those with relevant assessments on both occasions, comparing the CT findings between this follow-up with the previous assessment, there was an increase in patients with architectural distortion (43 [21%] of 204 vs 57 [28%] of 204, p=0.0093), as well as in traction bronchiectasis (55 [27%] of 204 vs 69 [34%] of 204, p=0.0043). Patients presented a persistent functional impairment with demonstrated restrictive pattern in both follow-ups (87 [42%] of 207 vs 91 [44%] of 207, p=0.76), as well as for the reduced diffusion capacity (88 [42%] of 208 vs 87 [42%] of 208, p=1.0). Length of hospitalization (OR 1.04 [1.01-1.07], p=0.0040), invasive mechanical ventilation (OR 3.11 [1.3-7.5] p=0.011), patient's age (OR 1.03 [1.01-1.06] p=0.0074 were consistent predictors for development of fibrotic-like lung lesions in post-COVID-19 patients. Post-COVID-19 lung sequelae can persist and progress after hospital discharge, suggesting airways involvement and formation of new fibrotic-like lesions, mainly in patients who were in intensive care unit (ICU). São Paulo Research Foundation (22/01769-5) and Instituto Todos pela Saúde (C1721).

Long-term radiological and pulmonary function abnormalities at 3 years after COVID-19 hospitalisation: a longitudinal cohort study.

This study aimed to evaluate the longitudinal progression of residual lung abnormalities (ground-glass opacities, reticulation and fibrotic-like changes) and pulmonary function at 3 years following coronavirus disease 2019 (COVID-19). This prospective, longitudinal cohort study enrolled COVID-19 survivors who exhibited residual lung abnormalities upon discharge from two hospitals. Follow-up assessments were conducted at 6 months, 12 months, 2 years and 3 years post-discharge, and included pulmonary function tests, 6-min walk distance (6MWD), chest computed tomography (CT) scans and symptom questionnaires. Non-COVID-19 controls were retrospectively recruited for comparative analysis. 728 COVID-19 survivors and 792 controls were included. From 6 months to 3 years, there was a gradual improvement in reduced diffusing capacity of the lung for carbon monoxide (D LCO <80% predicted: 49% versus 38%; p=0.001), 6MWD (496 versus 510 m; p=0.002) and residual lung abnormalities (46% versus 36%; p<0.001), regardless of disease severity. Patients with residual lung abnormalities at 3 years more commonly had respiratory symptoms (32% versus 16%; p<0.001), lower 6MWD (494 versus 510 m; p=0.003) and abnormal D LCO (57% versus 27%; p<0.001) compared with those with complete resolution. Compared with controls, the proportions of D LCO impairment (38% versus 17%; p<0.001) and respiratory symptoms (23% versus 2.2%; p<0.001) were significantly higher in the matched COVID-19 survivors at the 3-year follow-up. Most patients exhibited improvement in radiological abnormalities and pulmonary function over time following COVID-19. However, more than a third continued to have persistent lung abnormalities at the 3-year mark, which were associated with respiratory symptoms and reduced diffusion capacity.

Persistence of Diffusion Capacity Impairment and Its Relationship with Dyspnea 12 Months after Hospitalization for COVID-19.

Background: Dyspnea is a common persistent symptom after acute coronavirus disease 2019 illness (COVID-19). One potential explanation for post-COVID-19 dyspnea is a reduction in diffusion capacity. This longitudinal study investigated diffusion capacity and its relationship with dyspnea on exertion in individuals previously hospitalized with COVID-19. Methods: Eligible participants had been hospitalized for the treatment of acute COVID-19 and were assessed at 6 weeks, 6 months, and 12 months after discharge. Pulmonary function testing, diffusion capacity of carbon monoxide (DLCO), blood gas analysis and the level of dyspnea (Borg scale; before and after a 6 min walk test [6 MWT]) were performed. Participants were divided into subgroups based on the presence or absence of dyspnea during the 6 MWT at 12 months after hospitalization. Results: Seventy-two participants (twenty-two female, mean age 59.8 ± 13.5 years) were included. At 12 months after discharge, 41/72 participants (57%) had DLCO below the lower limit of normal and 56/72 (78%) had DLCO < 80% of the predicted value. Individuals with exertional dyspnea had significantly lower DLCO than those without exertional dyspnea (p = 0.001). In participants with DLCO data being available at three timepoints over 12 months (baseline, 6 months, and 12 months) after discharge (n = 25), DLCO improved between 6 weeks and 6 months after hospital discharge, but not thereafter (p = 0.017). Conclusions: About 2/3 of the post-COVID individuals in this study had impaired diffusion capacity at 12 months after hospital discharge. There was an association between persisting dyspnea on exertion and significantly reduced DLCO. Impaired diffusion capacity improved over the first 6 months after hospitalization but not thereafter.

COVID-19 after 2 Years from Hospital Discharge: A Pulmonary Function and Chest Computed Tomography Follow-Up Study

Introduction: Serial follow-up with pulmonary function testing (PFT) and chest computed tomography (CT) after severe COVID-19 are recommended. As a result, many longitudinal studies have been published on COVID-19 of different grade of severity up to 1-year follow-up. Therefore, we aimed at a long-term observational study throughout 2 years after severe COVID-19. Methods: Severe COVID-19 patients were consecutively recruited after hospital discharge between March and June 2020 and prospectively followed up for 24 months, with mMRC dyspnea scale and PFT at 6, 12, and 24 months. Chest CT was performed when clinically indicated. Results: One hundred one patients enrolled completed the observational study. At 24 months, those with reduced total lung capacity (TLC) were 16%, associated with fibrotic ground glass opacity (GGO) and mMRC score >1, respectively, in 75% and 69% of them. At 24 months, those with a reduced diffusing capacity of the lung for CO were 41%, associated with fibrotic GGO and mMRC score >1, respectively, in 53% and 22% of them. Conclusion: Two years after hospitalization for severe COVID-19, a non-negligible number of patients still suffer from “long COVID” due to respiratory damage.

Two-year diffusion capacity trajectory in COVID-19 pneumonia survivors.

Reduced diffusion capacity (DLCO) after COVID 19 pneumonia was reported in hospitalised patients after discharge. Here, we studied the restoration of DLCO over a 24months period in COVID-19 pneumonia survivors (n = 317), who were categorised into "moderate" cases (no oxygen supply; no need for hospitalisation), "severe" cases (respiratory frequency > 30/min and/or peripheral oxygen SpO2 < 93%), and "critical" cases (respiratory failure and admission into the intensive care unit). COVID-19 pneumonia survivors with a decreased DLCO (<80%) at 3months (n = 133) were invited for 6- and 24-months follow-up. At 3months, impairment of DLCO was more severe in critical case (p < .01). Over time, the subgroups showed a similar level of improvement; and, there was no difference in recovery over time between the subgroups. At 24months, the DLCO did not differ between the subgroups, with a mean DLCO of 73% for all patients. At 24months, 65% of patients still had a DLCO < 80%, and in 40% of patients DLCO was <70% of predicted. Regardless the initial disease severity, all COVID-19 survivors showed improvement in DLCO during follow-up; however, DLCO had not normalised in the majority of patients with a DLCO <80% 3months after hospital discharge.

Correlation between chest computed tomography findings and pulmonary function test results in the post-recovery phase of COVID-19.

The radiological and functional lung sequelae in COVID-19 survivors remain unclear. We compared the chest computed tomography findings of COVID-19 patients with normal and abnormal pulmonary function test results in the post-recovery phase. The data of consecutive patients who underwent pulmonary function tests and chest computed tomography within 14 days after recovery from COVID-19 at two medical centers between May and October 2020 were collected retrospectively. Two thoracic radiologists who were blinded to the clinical information and pulmonary function test results classified the patients according to the computed tomography features, evidence of fibrotic-like changes, and semi-quantitative quantification of the extent of pulmonary abnormalities. The clinical characteristics and computed tomography findings of patients with normal pulmonary function test results were compared with those of patients with abnormal results. A total of 101 COVID-19 survivors, comprising 48 ambulatory and 53 hospitalized patients, were included at a median of 95 days from initial symptom onset. Computed tomography revealed fibrotic-like changes in 10.9% of patients. A reduction in the diffusion capacity of carbon monoxide was the most common lung function abnormality (19.8%). Abnormal diffusion capacity of carbon monoxide was associated with the presence and extension of lung opacities on chest computed tomography scans and fibrotic pulmonary abnormalities. The sensitivity, specificity, and accuracy of reduced diffusion capacity of carbon monoxide for detecting fibrotic-like pulmonary changes on chest computed tomography scans were 72.7%, 87.8%, and 86.1%, respectively. Our study suggests that the presence of an abnormal diffusion capacity of carbon monoxide in the post-recovery phase of COVID-19 is associated with a greater risk of long-term parenchymal lung disease, as evidenced by the presence of fibrotic-like changes on chest computed tomography scans, such as traction bronchiectasis and architectural distortion.

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.

Relationship between exercise capacity and fatigue, dyspnea, and lung function in non-hospitalized patients with long COVID.

Long COVID is a global health problem that impairs patients' functional status. More than 200 reported symptoms have been identified where fatigue, dyspnea, and exercise impairment are most common. This study aimed to describe exercise capacity, fatigue, dyspnea, and lung function in previously non-hospitalized patients with long COVID, and examine the relationship between exercise capacity and fatigue, dyspnea, and lung function. Sixty-five patients, 54 women (83%), mean age of 39 standard deviation (12) years, were included and completed spirometry, cardiopulmonary exercise test, stair climbing test (SCT), 30 second sit-to-stand test (30STST), and questionnaires regarding fatigue and dyspnea. Fatigue was reported by 95% of the participants, whereas 65% reported severe fatigue, and 66% reported dyspnea. Mean exercise capacity measured with peak oxygen uptake (V̇O2peak % pred.) was ≥85% in 65% of the participants. Mean forced expiratory volume in 1 s. and forced vital capacity were 96.6 (10.7)% and 100.8 (10.9)%, respectively, while reduced diffusion capacity for carbon monoxide (DLCO ) was found in eight participants (13%). Reduced V̇O2peak kg-1 and increased time on SCT were significantly associated with increased dyspnea and reduced DLCO but not with fatigue, while 30STST was associated with increased fatigue and dyspnea in previously non-hospitalized patients with long COVID.

Circulating calprotectin levels four months after severe and non-severe COVID-19

BackgroundCalprotectin is an inflammatory marker mainly released by activated neutrophils that is increased in acute severe COVID-19. After initial recovery, some patients have persistent respiratory impairment with reduced diffusion capacity of the lungs for carbon monoxide (DLCO) months after infection. Underlying causes of this persistent impairment are unclear. We aimed to investigate the correlation between circulating calprotectin, persistent lung functional impairment and intensive care unit (ICU) stay after COVID-19 in two university hospital centres in Switzerland.MethodsCalprotectin levels were measured in serum from 124 patients (50% male) from the Bern cohort (post-ICU and non-ICU patients) and 68 (76% male) from the Lausanne cohort (only post-ICU patients) four months after COVID-19. Calprotectin was correlated with clinical parameters. Multivariate linear regression (MLR) was performed to evaluate the independent association of calprotectin in different models.ResultsOverall, we found that post-ICU patients, compared to non-ICU, were significantly older (age 59.4 ± 13.6 (Bern), 60.5 ± 12.0 (Lausanne) vs. 48.8 ± 13.4 years) and more obese (BMI 28.6 ± 4.5 and 29.1 ± 5.3 vs. 25.2 ± 6.0 kg/m2, respectively). 48% of patients from Lausanne and 44% of the post-ICU Bern cohort had arterial hypertension as a pre-existing comorbidity vs. only 10% in non-ICU patients. Four months after COVID-19 infection, DLCO was lower in post-ICU patients (75.96 ± 19.05% predicted Bern, 71.11 ± 18.50% Lausanne) compared to non-ICU (97.79 ± 21.70% predicted, p < 0.01). The post-ICU cohort in Lausanne had similar calprotectin levels when compared to the cohort in Bern (Bern 2.74 ± 1.15 µg/ml, Lausanne 2.49 ± 1.13 µg/ml vs. non-ICU 1.86 ± 1.02 µg/ml; p-value < 0.01). Calprotectin correlated negatively with DLCO (r= -0.290, p < 0.001) and the forced vital capacity (FVC) (r= -0.311, p < 0.001).ConclusionsSerum calprotectin is elevated in post-ICU patients in two independent cohorts and higher compared to non-ICU patients four months after COVID-19. In addition, there is a negative correlation between calprotectin levels and DLCO or FVC. The relationship between inflammation and lung functional impairment needs further investigations.Trial registrationNCT04581135.

Combined Pulmonary Fibrosis and Emphysema: Comparative Evidence on a Complex Condition

Combined pulmonary fibrosis and emphysema (CPFE) is a clinical syndrome characterized by upper lobe emphysema and lower lobe fibrosis manifested by exercise hypoxemia, normal lung volumes, and severe reduction of diffusion capacity of carbon monoxide. It has varying prevalence worldwide with a male predominance, and with smoking history of more than 40 pack-years being a common risk factor. The unique imaging features of CPFE emphasize its distinct entity, aiding in the timely detection of pulmonary hypertension and lung cancer, both of which are common complications. High-resolution computed tomography (HRCT) is an important diagnostic and prognostic tool, while lung cancer is an independent factor that alters the prognosis in CPFE patients. Treatment options for CPFE are limited, but smoking cessation, usual treatments of pulmonary fibrosis and emphysema, and avoidance of environmental exposures are encouraged.

Impact of admission viral load on respiratory outcomes in hospitalized SARS-CoV-2 infected patients with cancer and without cancer: A 2-, 4- and 6-months follow-up prospective study

BackgroundThis prospective follow-up study aimed to determine the temporal changes in respiratory outcomes over 6 months period in patients with and without cancer hospitalized for severe COVID-19 and to determine the associated risk factors based on admission viral load. MethodsAll adult patients hospitalized with a confirmed diagnosis of severe SARS-CoV-2 infection were investigated using rRT-PCR on nasopharyngeal swab specimens. Patients were divided into three arbitrary groups according to their cycle threshold (CT) values obtained at admission as high (CT<25.0), medium (CT between 25.0 and 30.0), and low (CT>30.0) viral load. Patients had pulmonary function tests, chest high-resolution computed tomography (HRCT), and a 6-minute walking time distance measured at each follow-up visit. ResultsThis follow-up study had a total of 112 participants, of which 75 were cancer-free and 37 had active cancer. Overall, 29.5% had a low viral load, compared to 48.2% who had a high viral load, and 22.3% had a medium viral load. For patients who did not have cancer, the mean age was 57.3 (SD 15.4) and for those who had cancer, it was 62.3 (SD 18.4). Most patients had overall better temporal changes in pulmonary function and tolerance, as well as exercise capacity, even though severe and chronic respiratory abnormalities persisted in a fraction of the patients. In patients without cancer who had a high viral load, we have seen a substantial reduction in diffusion capacity of the lungs for carbon monoxide (DLCO) predicted value with a median of 65 (IQR 63–70) while in patients with cancer, it was 60 (IQR 56–67) at 2 months. At 4 and 6 months, the predicted DLCO values for patients without cancer were 65 (IQR 61–70), whereas the predicted DLCO values for patients with active cancer were 62 (IQR 60–67) and 67 (59−73). Importantly, radiological abnormalities persisted in 22 (29%) non-cancer patients and 16 (43%) cancer patients. Multivariate regression analysis showed an increased odds ratio of impaired HRCT associated with a high viral load of 3.04 (95% CI:1.68–6.14; p < 0.001) for patients without cancer and 5.07 (95% CI: 4.04–10.8; p < 0.0001) for patients with cancer. The CT pneumonia score at hospitalization was 2.25 (95% CI:1.76–3.08; p = 0.041) and 2.85 (95% CI:1.89–5.14; p = 0.031) for non-cancer and cancer patients respectively. ConclusionsThe evidence of persistent pulmonary abnormalities and radiographic changes was found in both patient groups who had high viral load at hospital admission and suggesting that SARS-CoV-2 viral load might serve as a useful indicator to predict the development of respiratory complications in patients with COVID-19.

Short Telomere Syndrome presenting with pulmonary fibrosis, liver cirrhosis and hepatopulmonary syndrome: a case report

BackgroundIdiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.Case presentationWe describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10th percentile for the patient’s age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18 months after the initial diagnosis was made.ConclusionsShort Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.

Cigarette Smoking, and Blood Monocyte Count Correlate with Chronic Lung Injuries and Mortality.

Cigarette smoking (CS)-related monocytosis contributes to the development of chronic lung injuries via complex mechanisms. We aim to determine correlations between measures of CS and monocytes, their capacities to predict chronic lung diseases, and their associations with mortality. A single-center retrospective study of patients undergoing surgical resection for suspected lung nodules/masses was performed. CS was quantified as cigarettes smoked per day (CPD), duration of smoking, composite pack years (CPY), current smoking status, and smoking cessation years. A multivariate logistic regression analysis was performed. Of 382 eligible patients, 88% were ever smokers. In this group, 45% were current smokers with mean CPD of 27.2±40.0. CPY and duration of smoking showed positive linear correlations with percentage monocyte count. Physiologically, CPY was associated with progressive obstruction, hyperinflation, and reduced diffusion capacity (DLCO). Across the quartiles of smoking, there was an accumulation of radiologic and histologic abnormalities. Anthracosis and emphysema were associated with CPD, while lung cancer, respiratory bronchiolitis (RB), emphysema, and honeycombing were statistically related to duration of smoking. Analysis using consecutive CPY showed associations with lung cancer (≥10 and <30), fibrosis (≥20 and <40), RB (≥50), anthracosis and emphysema (≥10 and onwards). Percentage monocytes correlated with organizing pneumonia (OP), fibrosis, and emphysema. The greater CPY increased mortality across the groups. Significant predictors of mortality included percentage monocyte, anemia, GERD, and reduced DLCO. Indices of CS and greater monocyte numbers were associated with endpoints of chronic lung disease suggesting a participation in pathogenesis. Application of these easily available metrics may support a chronology of CS-induced chronic lung injuries. While a relative lesser amount of smoking can be associated with lung cancer and fibrosis, greater CPY increases the risk for emphysema. Monocytosis predicted lung fibrosis and mortality. Duration of smoking may serve as a better marker of monocytosis and associated chronic lung diseases.

Pulmonary function three to five months after hospital discharge for COVID-19: a single centre cohort study

Some COVID-19 survivors suffer from persistent pulmonary function impairment, but the extent and associated factors are unclear. This study aimed to characterize pulmonary function impairment three to five months after hospital discharge and the association with disease severity. Survivors of COVID-19 after hospitalization to the VieCuri Medical Centre between February and December 2020 were invited for follow-up, three to five months after discharge. Dynamic and static lung volumes, respiratory muscle strength and diffusion capacity were measured. The cohort comprised 257 patients after a moderate (n = 33), severe (n = 151) or critical (n = 73) COVID-19 infection with a median follow-up of 112 days (interquartile range 96–134 days). The main sequelae included reduced diffusion capacity (36%) and reduced maximal expiratory pressure (24%). Critically ill patients were more likely to have reduced diffusion capacity than moderate (OR 8.00, 95% CI 2.46–26.01) and severe cases (OR 3.74, 95% CI 1.88–7.44) and lower forced vital capacity (OR 3.29, 95% CI 1.20–9.06) compared to severe cases. Many COVID-19 survivors, especially after a critical disease course, showed pulmonary function sequelae, mainly DLCO impairments, three to five months after discharge. Monitoring is needed to investigate the persistence of these symptoms and the longer-term implications of the COVID-19 burden.

Prevalence of reduced lung diffusing capacity and CT scan findings in smokers without airflow limitation: a population-based study

BackgroundPopulation distribution of reduced diffusing capacity of the lungs for carbon monoxide (DLCO) in smokers and main consequences are not properly recognised. The objectives of this study were to describe...

Long-term respiratory outcomes after COVID-19: a Brazilian cohort study.

To investigate the prevalence and risk factors for persistent symptoms up to 12 months after hospital discharge in COVID-19 survivors. This prospective cohort study included patients with COVID-19 discharged from a university hospital in Brazil. Follow-up was performed 2, 6, and 12 months after discharge. Lung function tests and chest computed tomography (CT) were performed 2 months after discharge and were repeated if abnormal. The primary outcomes were the symptoms present, work status, and limitations in daily activities. Eighty-eight patients were included. Dyspnea (54.5%), fatigue (50.0%), myalgia, and muscle weakness (46.6%) were the most common symptoms, which decreased over time. Anxiety was frequent (46.6%) and remained unchanged. One year after discharge, 43.2% of the patients reported limitations in daily activities, and 17.6% had not returned to work. Corticosteroid use was significantly associated with dyspnea and limitations in daily activities. Females had an increased risk of fatigue at the 12-month assessment, with marginal significance after multivariable adjustment. Young age and bronchial wall thickening on admission CT were also risk factors for dyspnea at follow-up. The most common lung function abnormalities were reduced diffusion capacity and small airway disease, which partially improved over time. One year after hospital discharge, more than one-third of patients still had persistent COVID-19-related symptoms, remarkable dyspnea, fatigue, and limitations in daily activities, regardless of acute disease severity. Age, female sex, corticosteroid use during hospitalization, and bronchial thickening on admission CT were associated with an increased risk of sequelae.