Post-COVID-19 condition: systemic inflammation and low functional exercise capacity.

Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported. Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment. Results: SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1ß serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.

Clinical, tomographic and functional comparison of sporadic and tuberous sclerosis complex-associated forms of lymphangioleiomyomatosis: a retrospective cohort study.

Background: Lymphangioleiomyomatosis (LAM) is a rare disease that can occur sporadically (S-LAM) or associated with the tuberous sclerosis complex (TSC-LAM). The natural history of LAM is not completely understood, including whether there is a difference between the clinical courses of the two forms. This study aimed to compare the clinical, functional and tomographic features between S-LAM and TSC-LAM, and evaluate the annual rates of change in lung function. Methods: This retrospective cohort study included patients with LAM followed up between 1994 and 2019. Clinical, functional and imaging variables were evaluated, and the lung cysts were automatically quantified. Quality of life and predictors of lung function impairment were accessed, and the annual rate of lung function decline was compared between S-LAM and TSC-LAM. Results: Of the 107 patients included, 77 had S-LAM and 30 had TSC-LAM. Although patients with TSC-LAM had a higher prevalence of renal angiomyolipomas and neurological and dermatological manifestations, pulmonary function tests were similar. Patients with S-LAM had a greater rate of forced expiratory volume in 1 s decline and a higher extent of cysts. Pneumothorax, desaturation in the 6-minute walking test and a higher extent of lung cysts were predictors of functional impairment. A greater impact on vitality and emotional health was observed in the TSC-LAM. Conclusion: Greater functional decline and a higher cystic extension were found in patients with S-LAM. Our study provides a broad clinical, functional and tomographic characterisation of patients with LAM, adding valuable information to the existing evidence to better understand the two forms of the disease.

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases.

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Small airways morphological alterations associated with functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare neoplastic and cystic pulmonary disease characterized by abnormal proliferation of the so-called LAM cells. Despite the functional obstructive pattern observed in most patients, few studies investigated the morphological changes in the small airways, most of them in patients with severe and advanced LAM undergoing lung transplantation. Understanding the morphological changes in the airways that may occur early in the disease can help us understand the pathophysiology of disease progression and understand the rationale for possible therapeutic approaches, such as the use of bronchodilators. Our study aimed to characterize the morphological alterations of the small airways in patients with LAM with different severities compared to controls, and their association with variables at the pulmonary function test and with LAM Histological Score (LHS). METHODS: Thirty-nine women with LAM who had undergone open lung biopsy or lung transplantation, and nine controls were evaluated. The histological severity of the disease was assessed as LHS, based on the percentage of tissue involvement by cysts and infiltration by LAM cells. The following morphometric parameters were obtained: airway thickness, airway closure index, collagen and airway smooth muscle content, airway epithelial TGF-ß expression, and infiltration of LAM cells and inflammatory cells within the small airway walls. RESULTS: The age of patients with LAM was 39 ± 8 years, with FEV1 and DLCO of 62 ± 30% predicted and 62 ± 32% predicted, respectively. Patients with LAM had increased small airway closure index, collagen and smooth muscle content, and epithelial TGF-beta expression compared with controls. Patients with LAM with the more severe LHS and with greater functional severity (FEV1 ≤ 30%) presented higher thicknesses of the airways. Bronchiolar inflammation was mild; infiltration of the small airway walls by LAM cells was rare. LHS was associated with an obstructive pattern, air trapping, and reduced DLCO, whereas small airway wall thickness was associated with FEV1, FVC, and collagen content. CONCLUSION: LAM is associated with small airway remodelling and partial airway closure, with structural alterations observed at different airway compartments. Functional impairment in LAM is associated with airway remodelling and, most importantly, with histological severity (LHS).

Organizing pneumonia and COVID-19.

Organizing pneumonia (OP) is an interstitial lung disease, and can be cryptogenic, if no cause is identified, or secondary to several conditions. COVID-19-induced persistent inflammation can be associated with interstitial lung disease. We present a review of literature of OP and COVID-19-induced OP with an illustrative case. A 38-year-old man was admitted with COVID-19 that required mechanical ventilation for 56 days. Initial chest computed tomography (CT) revealed diffuse bilateral ground-glass opacities in the lungs with consolidation areas involving 75 % of the parenchyma. After weaning from MV, the patient still required oxygen supplementation. A new chest CT scan also showed extensive diffuse areas of consolidation and ground-glass opacity. OP was hypothesized and 40 mg/day prednisone initiated and continued for six months with resolution of lung functional and image abnormalities. Organizing pneumonia should be included in the differential diagnosis of COVID-19 patients with respiratory symptoms after partial pulmonary recovery.

Tomographic pleuropulmonary manifestations in rheumatoid arthritis: a pictorial essay.

Rheumatoid arthritis (RA) is an autoimmune inflammatory and heterogeneous disease that affects several systems, especially the joints. Among the extra-articular manifestations of RA, pleuropulmonary involvement occurs frequently, with different presentations, potentially in all anatomic thoracic compartments, and may determine high morbidity and mortality. The most common pleuropulmonary manifestations in patients with RA include interstitial lung disease (ILD), pleural disease, pulmonary arterial hypertension, rheumatoid lung nodules, airway disease (bronchiectasis and bronchiolitis), and lymphadenopathy. Pulmonary hypertension and ILD are the manifestations with the greatest negative impact in prognosis. HRCT of the chest is essential in the evaluation of patients with RA with respiratory symptoms, especially those with higher risk factors for ILD, such as male gender, smoking, older age, high levels of rheumatoid factor, or positive anti-cyclic citrullinated peptide antibody results. Additionally, other etiologies that may determine tomographic pleuropulmonary manifestations in patients with RA are infections, neoplasms, and drug-induced lung disease. In these scenarios, clinical presentation is heterogeneous, varying from being asymptomatic to having progressive respiratory failure. Knowledge on the potential etiologies causing tomographic pleuropulmonary manifestations in patients with RA coupled with proper clinical reasoning is crucial to diagnose and treat these patients.

Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study.

BACKGROUND: Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. METHODS: A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. RESULTS: In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). CONCLUSION: ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.

Tomographic pleuropulmonary manifestations in rheumatoid arthritis: a pictorial essay / Manifestações pleuropulmonares tomográficas na artrite reumatoide: ensaio pictórico

ABSTRACT Rheumatoid arthritis (RA) is an autoimmune inflammatory and heterogeneous disease that affects several systems, especially the joints. Among the extra-articular manifestations of RA, pleuropulmonary involvement occurs frequently, with different presentations, potentially in all anatomic thoracic compartments, and may determine high morbidity and mortality. The most common pleuropulmonary manifestations in patients with RA include interstitial lung disease (ILD), pleural disease, pulmonary arterial hypertension, rheumatoid lung nodules, airway disease (bronchiectasis and bronchiolitis), and lymphadenopathy. Pulmonary hypertension and ILD are the manifestations with the greatest negative impact in prognosis. HRCT of the chest is essential in the evaluation of patients with RA with respiratory symptoms, especially those with higher risk factors for ILD, such as male gender, smoking, older age, high levels of rheumatoid factor, or positive anti-cyclic citrullinated peptide antibody results. Additionally, other etiologies that may determine tomographic pleuropulmonary manifestations in patients with RA are infections, neoplasms, and drug-induced lung disease. In these scenarios, clinical presentation is heterogeneous, varying from being asymptomatic to having progressive respiratory failure. Knowledge on the potential etiologies causing tomographic pleuropulmonary manifestations in patients with RA coupled with proper clinical reasoning is crucial to diagnose and treat these patients.

RESUMO A artrite reumatoide (AR) é uma doença inflamatória autoimune e heterogênea que afeta vários sistemas, principalmente as articulações. Dentre as manifestações extra-articulares da AR, o acometimento pleuropulmonar ocorre com frequência, com diferentes apresentações, potencialmente em todos os compartimentos anatômicos do tórax e pode determinar alta morbidade e mortalidade. As manifestações pleuropulmonares mais comuns em pacientes com AR incluem doença pulmonar intersticial (DPI), doença pleural, hipertensão arterial pulmonar, nódulos pulmonares reumatoides, doença das vias aéreas (bronquiectasia e bronquiolite) e linfadenopatia. A hipertensão pulmonar e a DPI são as manifestações com maior impacto negativo no prognóstico. A TCAR de tórax é essencial na avaliação de pacientes com AR sintomáticos respiratórios, principalmente aqueles com fatores de risco maiores para DPI, como sexo masculino, tabagismo, idade mais avançada, níveis elevados de fator reumatoide ou anticorpos antipeptídeos citrulinados cíclicos positivos. Além disso, outras etiologias que podem determinar manifestações pleuropulmonares tomográficas em pacientes com AR são infecções, neoplasias e doença pulmonar induzida por drogas. Nesses cenários, a apresentação clínica é heterogênea, variando de ausência de sintomas a insuficiência respiratória progressiva. O conhecimento das possíveis etiologias causadoras de manifestações pleuropulmonares tomográficas em pacientes com AR, aliado a um raciocínio clínico adequado, é fundamental para o diagnóstico e tratamento desses pacientes.