Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis.

INTRODUCTION: Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis. METHODS: Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression. RESULTS: Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (-0.036; 95% CI -0.068 to -0.004; p=0.029), associations with fibrotic sequelae did not reach significance (-0.021; 95% CI -0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864). DISCUSSION: Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity. PROSPERO REGISTRATION NUMBER: CRD42020183139.

Growing small solid nodules in lung cancer screening: safety and efficacy of a 200 mm3 minimum size threshold for multidisciplinary team referral.

The optimal management of small but growing nodules remains unclear. The SUMMIT study nodule management algorithm uses a specific threshold volume of 200 mm3 before referral of growing solid nodules to the multidisciplinary team for further investigation is advised, with growing nodules below this threshold kept under observation within the screening programme. Malignancy risk of growing solid nodules of size >200 mm3 at initial 3-month interval scan was 58.3% at a per-nodule level, compared with 13.3% in growing nodules of size ≤200 mm3 (relative risk 4.4, 95% CI 2.17 to 8.83). The positive predictive value of a combination of nodule growth (defined as percentage volume change of ≥25%), and size >200 mm3 was 65.9% (29/44) at a cancer-per-nodule basis, or 60.5% (23/38) on a cancer-per-participant basis. False negative rate of the protocol was 1.9% (95% CI 0.33% to 9.94%). These findings support the use of a 200 mm3 minimum volume threshold for referral as effective at reducing unnecessary multidisciplinary team referrals for small growing nodules, while maintaining early-stage lung cancer diagnosis.

Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities.

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=-0.7; 95%CI=-0.2 to -1.2, p=0.019), St George's Respiratory Questionnaire-score (SGRQ Δ=-6; 95% CI=-1 to -11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

Respiratory function and CT abnormalities among survivors of COVID-19 pneumonia: a nationwide follow-up study.

INTRODUCTION: Considering the pulmonary burden caused by acute COVID-19, questions remain of respiratory consequences after recovery. The aim of the study was to describe respiratory function of COVID-19 pneumonia survivors at mid-term follow-up (median 68 days) and assess whether impairments were predicted by acute illness severity or residual CT abnormalities. METHODS: Residents of Iceland that had COVID-19 and oxygen saturation ≤94% from 28 February 2020 to 30 April 2021 were offered a clinical follow-up visit with an interview, a 6 min walk test (6MWT), spirometry with gas exchange measurement and chest CT. The results of these examinations were described, grouped by the level of care during acute illness. The associations of disease severity and CT abnormalities at follow-up with subjective dyspnoea, 6MWT results and lung function test results were estimated with regression analyses. RESULTS: Of 190 eligible patients, 164 (86%) participated in the study. Of those, 32 had never been admitted to hospital, 103 were admitted to hospital without intensive care and 29 had required intensive care. At a follow-up, need for intensive care during acute illness was associated with shorter walking distance on 6MWT, lower oxygen saturation and lower DLCO. Imaging abnormalities at follow-up were observed for most participants (74%) and the magnitude of these changes was associated with decrements in 6MWT distance, oxygen saturation, forced vital capacity and DLCO. CONCLUSIONS: The findings show that impaired exercise capacity and lung physiology at follow-up were primarily observed for patients with COVID-19 pneumonia that required intensive care treatment and/or had persistent imaging abnormalities.

129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised people with post-acute COVID-19 syndrome.

BACKGROUND: Patients often report persistent symptoms beyond the acute infectious phase of COVID-19. Hyperpolarised 129Xe MRI provides a way to directly measure airway functional abnormalities; the clinical relevance of 129Xe MRI ventilation defects in ever-hospitalised and never-hospitalised patients who had COVID-19 has not been ascertained. It remains unclear if persistent symptoms beyond the infectious phase are related to small airways disease and ventilation heterogeneity. Hence, we measured 129Xe MRI ventilation defects, pulmonary function and symptoms in ever-hospitalised and never-hospitalised patients who had COVID-19 with persistent symptoms consistent with post-acute COVID-19 syndrome (PACS). METHODS: Consenting participants with a confirmed diagnosis of PACS completed 129Xe MRI, CT, spirometry, multi-breath inert-gas washout, 6-minute walk test, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnoea scale, modified Borg scale and International Physical Activity Questionnaire. Consenting ever-COVID volunteers completed 129Xe MRI and pulmonary function tests only. RESULTS: Seventy-six post-COVID and nine never-COVID participants were evaluated. Ventilation defect per cent (VDP) was abnormal and significantly greater in ever-COVID as compared with never-COVID participants (p<0.001) and significantly greater in ever-hospitalised compared with never-hospitalised participants who had COVID-19 (p=0.048), in whom diffusing capacity of the lung for carbon-monoxide (p=0.009) and 6-minute walk distance (6MWD) (p=0.005) were also significantly different. 129Xe MRI VDP was also related to the 6MWD (p=0.02) and post-exertional SpO2 (p=0.002). Participants with abnormal VDP (≥4.3%) had significantly worse 6MWD (p=0.003) and post-exertional SpO2 (p=0.03). CONCLUSION: 129Xe MRI VDP was significantly worse in ever-hospitalised as compared with never-hospitalised participants and was related to 6MWD and exertional SpO2 but not SGRQ or mMRC scores. TRIAL REGISTRATION NUMBER: NCT05014516.

COVID-19 associated phrenic nerve mononeuritis: a case series.

This study characterised the hemidiaphragm elevation on 3-month interval chest X-rays (CXRs) of patients post COVID-19 pneumonia. 467 CXRs were screened; 19 (4.1%) had an elevated hemidiaphragm. There were 15 (3.2%) patients of interest with new hemidiaphragm elevation, persisting on average 7 months post COVID-19 diagnosis. Symptomatic patients underwent diaphragm ultrasound (n=12), pulmonary function test (n=10), muscle function test (n=6) and neurophysiology (n=5), investigating phrenic nerve function. Ultrasound demonstrated reduced/paradoxical diaphragmatic movements in eight; four of eight had reduced thickening fraction. Neurophysiology peripheral limb studies did not support the differential diagnoses of critical illness neuropathy/myopathy. We propose that, in selected patients, COVID-19 may cause phrenic nerve mononeuritis.

Immediate smoking cessation support versus usual care in smokers attending a targeted lung health check: the QuLIT trial.

OBJECTIVES: Lung cancer screening programmes offer an opportunity to address tobacco dependence in current smokers. The effectiveness of different approaches to smoking cessation in this context has not yet been established. We investigated if immediate smoking cessation support, including pharmacotherapy, offered as part of a lung cancer screening programme, increases quit rates compared to usual care (Very Brief Advice to quit and signposting to smoking cessation services). MATERIALS AND METHODS: We conducted a single-blind randomised controlled trial of current smokers aged 55-75 years attending a Targeted Lung Health Check. On randomly allocated days smokers received either (1) immediate support from a trained smoking cessation counsellor with appropriate pharmacotherapy or (2) usual care. The primary outcome was self-reported quit rate at 3 months. We performed thematic analysis of participant interview responses. RESULTS: Of 412 people attending between January and March 2020, 115 (27.9%) were current smokers; 46% female, mean (SD) 62.4 (5.3) years. Follow-up data were available for 84 smokers. At 3 months, quit rates in the intervention group were higher 14/48 (29.2%) vs 4/36 (11%) (χ2 3.98, p=0.04). Participant interviews revealed four smoking-cessation related themes: (1) stress and anxiety, (2) impact of the COVID-19 pandemic, (3) CT scans influencing desire to quit and (4) individual beliefs about stopping smoking. CONCLUSION: The provision of immediate smoking cessation support is associated with a substantial increase in quit rates at 3 months. Further research is needed to investigate longer-term outcomes and to refine future service delivery. TRIAL REGISTRATION NUMBER: ISRCTN12455871.

Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.

The risk factors for development of fibrotic-like radiographic abnormalities after severe COVID-19 are incompletely described and the extent to which CT findings correlate with symptoms and physical function after hospitalisation remains unclear. At 4 months after hospitalisation, fibrotic-like patterns were more common in those who underwent mechanical ventilation (72%) than in those who did not (20%). We demonstrate that severity of initial illness, duration of mechanical ventilation, lactate dehydrogenase on admission and leucocyte telomere length are independent risk factors for fibrotic-like radiographic abnormalities. These fibrotic-like changes correlate with lung function, cough and measures of frailty, but not with dyspnoea.

Prevalence and significance of pulmonary disease on lung ultrasonography in outpatients with SARS-CoV-2 infection.

BACKGROUND: The majority of patients with SARS-CoV-2 infection are diagnosed and managed as outpatients; however, little is known about the burden of pulmonary disease in this setting. Lung ultrasound (LUS) is a convenient tool for detection of COVID-19 pneumonia. Identifying SARS-CoV-2 infected outpatients with pulmonary disease may be important for early risk stratification. OBJECTIVES: To investigate the prevalence, natural history and clinical significance of pulmonary disease in outpatients with SARS-CoV-2. METHODS: SARS-CoV-2 PCR positive outpatients (CV(+)) were assessed with LUS to identify the presence of interstitial pneumonia. Studies were considered positive based on the presence of B-lines, pleural irregularity and consolidations. A subset of patients underwent longitudinal examinations. Correlations between LUS findings and patient symptoms, demographics, comorbidities and clinical outcomes over 8 weeks were evaluated. RESULTS: 102 CV(+) patients underwent LUS with 42 (41%) demonstrating pulmonary involvement. Baseline LUS severity scores correlated with shortness of breath on multivariate analysis. Of the CV(+) patients followed longitudinally, a majority showed improvement or resolution in LUS findings after 1-2 weeks. Only one patient in the CV(+) cohort was briefly hospitalised, and no patient died or required mechanical ventilation. CONCLUSION: We found a high prevalence of LUS findings in outpatients with SARS-CoV-2 infection. Given the pervasiveness of pulmonary disease across a broad spectrum of LUS severity scores and lack of adverse outcomes, our findings suggest that LUS may not be a useful as a risk stratification tool in SARS-CoV-2 in the general outpatient population.

Chest radiograph-based artificial intelligence predictive model for mortality in community-acquired pneumonia.

BACKGROUND: Chest radiograph (CXR) is a basic diagnostic test in community-acquired pneumonia (CAP) with prognostic value. We developed a CXR-based artificial intelligence (AI) model (CAP AI predictive Engine: CAPE) and prospectively evaluated its discrimination for 30-day mortality. METHODS: Deep-learning model using convolutional neural network (CNN) was trained with a retrospective cohort of 2235 CXRs from 1966 unique adult patients admitted for CAP from 1 January 2019 to 31 December 2019. A single-centre prospective cohort between 11 May 2020 and 15 June 2020 was analysed for model performance. CAPE mortality risk score based on CNN analysis of the first CXR performed for CAP was used to determine the area under the receiver operating characteristic curve (AUC) for 30-day mortality. RESULTS: 315 inpatient episodes for CAP occurred, with 30-day mortality of 19.4% (n=61/315). Non-survivors were older than survivors (mean (SD)age, 80.4 (10.3) vs 69.2 (18.7)); more likely to have dementia (n=27/61 vs n=58/254) and malignancies (n=16/61 vs n=18/254); demonstrate higher serum C reactive protein (mean (SD), 109 mg/L (98.6) vs 59.3 mg/L (69.7)) and serum procalcitonin (mean (SD), 11.3 (27.8) µg/L vs 1.4 (5.9) µg/L). The AUC for CAPE mortality risk score for 30-day mortality was 0.79 (95% CI 0.73 to 0.85, p<0.001); Pneumonia Severity Index (PSI) 0.80 (95% CI 0.74 to 0.86, p<0.001); Confusion of new onset, blood Urea nitrogen, Respiratory rate, Blood pressure, 65 (CURB-65) score 0.76 (95% CI 0.70 to 0.81, p<0.001), respectively. CAPE combined with CURB-65 model has an AUC of 0.83 (95% CI 0.77 to 0.88, p<0.001). The best performing model was CAPE incorporated with PSI, with an AUC of 0.84 (95% CI 0.79 to 0.89, p<0.001). CONCLUSION: CXR-based CAPE mortality risk score was comparable to traditional pneumonia severity scores and improved its discrimination when combined.

Clinical characteristics and outcomes of adult patients admitted with COVID-19 in East London: a retrospective cohort analysis.

BACKGROUND: Descriptions of clinical characteristics of patients hospitalised withCOVID-19, their clinical course and short-term inpatient and outpatient outcomes in deprived urban populations in the UK are still relatively sparse. We describe the epidemiology, clinical course, experience of non-invasive ventilation and intensive care, mortality and short-term sequelae of patients admitted to two large District General Hospitals across a large East London National Health Service Trust during the first wave of the pandemic. METHODS: A retrospective analysis was carried out on a cohort of 1946 patients with a clinical or laboratory diagnosis of COVID-19, including descriptive statistics and survival analysis. A more detailed analysis was undertaken of a subset of patients admitted across three respiratory units in the trust. RESULTS: Increasing age, male sex and Asian ethnicity were associated with worse outcomes. Increasing severity of chest X-ray abnormalities trended with mortality. Radiological changes persisted in over 50% of cases at early follow-up (6 weeks). Ongoing symptoms including hair loss, memory impairment, breathlessness, cough and fatigue were reported in 70% of survivors, with 39% of patients unable to return to work due to ongoing symptoms. CONCLUSIONS: Understanding the acute clinical features, course of illness and outcomes of COVID-19 will be crucial in understanding the effect of differences in risk, as well as the effectiveness of new interventions and vaccination between the successive waves of the pandemic.

SARS-CoV-2 organising pneumonia: 'Has there been a widespread failure to identify and treat this prevalent condition in COVID-19?'

Reviews of COVID-19 CT imaging along with postmortem lung biopsies and autopsies indicate that the majority of patients with COVID-19 pulmonary involvement have secondary organising pneumonia (OP) or its histological variant, acute fibrinous and organising pneumonia, both well-known complications of viral infections. Further, many publications on COVID-19 have debated the puzzling clinical characteristics of 'silent hypoxemia', 'happy hypoxemics' and 'atypical ARDS', all features consistent with OP. The recent announcement that RECOVERY, a randomised controlled trial comparing dexamethasone to placebo in COVID-19, was terminated early due to excess deaths in the control group further suggests patients present with OP given that corticosteroid therapy is the first-line treatment. Although RECOVERY along with other cohort studies report positive effects with corticosteroids on morbidity and mortality of COVID-19, treatment approaches could be made more effective given that secondary OP often requires prolonged duration and/or careful and monitored tapering of corticosteroid dose, with 'pulse' doses needed for the well-described fulminant subtype. Increasing recognition of this diagnosis will thus lead to more appropriate and effective treatment strategies in COVID-19, which may lead to a further reduction of need for ventilatory support and improved survival.

Histopathological findings in fatal COVID-19 severe acute respiratory syndrome: preliminary experience from a series of 10 Spanish patients.

In December 2019, an outbreak of severe acute respiratory syndrome associated to SARS-CoV2 was reported in Wuhan, China. To date, little is known on histopathological findings in patients infected with the new SARS-CoV2. Lung histopathology shows features of acute and organising diffuse alveolar damage. Subtle cellular inflammatory infiltrate has been found in line with the cytokine storm theory. Medium-size vessel thrombi were frequent, but capillary thrombi were not present. Despite the elevation of biochemical markers of cardiac injury, little histopathological damage could be confirmed. Viral RNA from paraffin sections was detected at least in one organ in 90% patients.