Proteome and Dihydrorhodamine Profiling of Bronchoalveolar Lavage in Patients with Chronic Pulmonary Aspergillosis.

Neutrophil and (alveolar) macrophage immunity is considered crucial for eliminating Aspergillus fumigatus. Data derived from bronchoalveloar lavage (BAL) characterizing the human immuno-pulmonary response to Aspergillus fumigatus are non-existent. To obtain a comprehensive picture of the immune pathways involved in chronic pulmonary aspergillosis (CPA), we performed proteome analysis on AL of 9 CPA patients and 17 patients with interstitial lung disease (ILD). The dihydrorhodamine (DHR) test was also performed on BAL and blood neutrophils from CPA patients and compared to blood neutrophils from healthy controls (HCs). BAL from CPA patients primarily contained neutrophils, while ILD BAL was also characterized by a large fraction of lymphocytes; these differences likely reflecting the different immunological etiologies underlying the two disorders. BAL and blood neutrophils from CPA patients displayed the same oxidative burst capacity as HC blood neutrophils. Hence, immune evasion by Aspergillus involves other mechanisms than impaired neutrophil oxidative burst capacity per se. CPA BAL was enriched by proteins associated with innate immunity, as well as, more specifically, with neutrophil degranulation, Toll-like receptor 4 signaling, and neutrophil-mediated iron chelation. Our data provide the first comprehensive target organ-derived immune data on the human pulmonary immune response to Aspergillus fumigatus.

Identification and management of interstitial lung abnormalities.

Interstitial lung abnormalities (ILA) are incidentally observed specific CT findings in patients without clinical suspicion of interstitial lung disease (ILD). ILA with basal and peripheral predominance and features suggestive of fibrosis in more than 5% of any part of the lung should be referred for pulmonologist review. The strategy for monitoring as described in this review is based on clinical and radiological risk factors. ILA are associated with risk of progression to ILD and increased mortality. Early identification and assessment of risk factors for progression are essential to improve outcome.

Aspergillus-specific IgG antibodies for diagnosing chronic pulmonary aspergillosis compared to the reference standard.

OBJECTIVES: To evaluate the performance of Aspergillus-specific IgG antibodies for diagnosing chronic pulmonary aspergillosis (CPA) by using a cohort of patients with histologically proven CPA as a reference standard. METHODS: We collected Aspergillus-specific IgG antibody titres from patients with histologically proven CPA in collaboration with CPAnet study sites in Denmark, Germany, Belgium, India, Moldova, and Pakistan (N = 47). Additionally, sera from diseased and healthy controls were prospectively collected at the Medical Clinic of the Research Center, Borstel, Germany (n = 303). Aspergillus-specific IgG antibody titres were measured by the ImmunoCAP® assay (Phadia 100, Thermo Fisher Scientific, Uppsala, Sweden). An Aspergillus-specific IgG antibody titre ≥50 mgA/L was considered positive. RESULTS: Using patients with histologically proven CPA as the reference standard, the ImmunoCAP® Aspergillus-specific IgG antibody test had a sensitivity and specificity of 85.1% (95% CI: 71.7-93.8%) and 83.6% (95% CI: 78.0-88.3%), respectively. Patients with histologically proven CPA had significantly higher Aspergillus-specific IgG antibody titre with a median of 83.45 mgA/L (interquartile range 38.9-115.5) than all other cohorts (p < 0.001). False-positive test results occurred in one-third of 79 healthy controls. DISCUSSION: Our study results confirm a high sensitivity of the Aspergillus-specific IgG antibody test for the diagnosis of CPA when using patients with histologically proven CPA as a reference standard. However, positive test results should always match radiological findings as false-positive test results limit the interpretation of the test.

Acute exacerbation of fibrotic interstitial lung diseases.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and other fibrotic interstitial lung diseases (AE-ILD) is defined by significant acute respiratory worsening and new widespread alveolar damage. This review summarises the current knowledge of diagnosis and treatment of these events. The diagnosis of AE-IPF and AE-ILD is based on typical HRCT findings of new and bilateral ground glass opacification and/or consolidation, and exclusion of fluid overload or cardiac failure. Treatment relies, despite low quality of evidence, on glucocorticoid in addition to supportive and palliative treatment. Despite treatment, the prognosis is poor, with a median survival of 2-4 months.

Comorbidity and mortality in systemic sclerosis and matched controls: Impact of interstitial lung disease. A population based cohort study based on health registry data.

OBJECTIVE: This population-based, matched cohort study evaluates the impact of comorbidities on mortality among systemic sclerosis (SSc) patients with and without interstitial lung disease (ILD). METHOD: Patients with a first-time SSc diagnosis between 2002 and 2015 were identified in the Danish National Patient Registry, separated into two cohorts - with ILD (SSc-ILD) and without ILD (non-ILD SSc), and matched 1:4 with controls from the general population on age, sex, residency and marital status. Comorbidity and mortality data were obtained from national registries. The Deyo-Charlson comorbidity score (DCcs) was used for assessment of the burden of comorbidities. RESULTS: 1732 patients with SSc and 6919 controls were included; 258 (14.9%) patients had SSc-ILD. The hazard ratio (HR) for death was 2.8 (95% CI 2.4-3.3) in SSc, and especially increased in SSc-ILD (HR 4.2 (95% CI 3.2-5.4)), males (HR 3.1 95% CI 2.4-4.1) and younger adults (aged 18-40 (HR 6.9, 95% CI 3.4-14.2) and 41-50 (HR 7.7, 95% CI 3.8-15.6)). In non-ILD SSc, mortality increased with increasing DCcs. Cancer was the most frequent cause of death in SSc (24.9% of deaths) and in controls (33.5%), in SSc followed by musculoskeletal and connective tissue diseases (22.7%); the cause of only 0.8% of deaths among controls. CONCLUSION: The high prevalence of comorbidities in SSc had extensive impact on mortality. Mortality was increased in males, in young adults and in SSc-ILD, underlining the excess mortality associated with ILD. These findings emphasise the importance of timely diagnosis and optimal management of organ involvement and comorbidities in SSc.

Diabetic retinopathy is a predictor of chronic respiratory failure: A nationwide register-based cohort study.

Purpose: Diabetic retinopathy (DR) is a hypoxic retinal disease, but so far, the association with systemic hypoxia is poorly understood. Hence, the aim of this study was to evaluate cross-sectional and longitudinal associations between DR and chronic respiratory failure (CRF) in a national cohort. Design: Cross-sectional and 5-year longitudinal register-based cohort study. Methods: Between 2013 and 2018, we included patients with diabetes from the Danish Registry of Diabetic Retinopathy, who were each age and sex matched with five controls without diabetes. At index date, the prevalence of CRF was compared between cases and controls, and the longitudinal relationship between DR and CRF was assessed in a five-year follow-up. Results: At baseline, we identified 1,980 and 9,990 patients with CRF among 205,970 cases and 1,003,170 controls. The prevalence of CRF was higher among cases than controls (OR 1.75, 95% CI 1.65-1.86), but no difference between cases with and without DR was found.During follow-up, we identified 1,726 and 5,177 events of CRF among cases and controls, respectively. The incidence of CRF was higher among both cases with and without DR compared to controls (DR level 0: HR 1.24, 95% CI 1.16-1.33, DR level 1-4: HR 1.86, 95% CI 1.63-2.12), and higher among cases with DR compared to cases without DR (HR 1.54, 95% CI 1.38-1.72). Conclusion: In this study based on nationwide data, we found an increased risk of present and incident CRF in patients with diabetes with or without DR, and we identified DR as a predictor of future CRF.

The multidisciplinary approach to eosinophilia.

Eosinophilic granulocytes are normally present in low numbers in the bloodstream. Patients with an increased number of eosinophilic granulocytes in the differential count (eosinophilia) are common and can pose a clinical challenge because conditions with eosinophilia occur in all medical specialties. The diagnostic approach must be guided by a thorough medical history, supported by specific tests to guide individualized treatment. Neoplastic (primary) eosinophilia is identified by one of several unique acquired genetic causes. In contrast, reactive (secondary) eosinophilia is associated with a cytokine stimulus in a specific disease, while idiopathic eosinophilia is a diagnosis by exclusion. Rational treatment is disease-directed in secondary cases and has paved the way for targeted treatment against the driver in primary eosinophilia, whereas idiopathic cases are treated as needed by principles in eosinophilia originating from clonal drivers. The vast majority of patients are diagnosed with secondary eosinophilia and are managed by the relevant specialty-e.g., rheumatology, allergy, dermatology, gastroenterology, pulmonary medicine, hematology, or infectious disease. The overlap in symptoms and the risk of irreversible organ involvement in eosinophilia, irrespective of the cause, warrants that patients without a diagnostic clarification or who do not respond to adequate treatment should be referred to a multidisciplinary function anchored in a hematology department for evaluation. This review presents the pathophysiology, manifestations, differential diagnosis, diagnostic workup, and management of (adult) patients with eosinophilia. The purpose is to place eosinophilia in a clinical context, and therefore justify and inspire the establishment of a multidisciplinary team of experts from diagnostic and clinical specialties at the regional level to support the second opinion. The target patient population requires highly specialized laboratory analysis and therapy and occasionally has severe eosinophil-induced organ dysfunction. An added value of a centralized, clinical function is to serve as a platform for education and research to further improve the management of patients with eosinophilia. Primary and idiopathic eosinophilia are key topics in the review, which also address current research and discusses outstanding issues in the field.

Diagnostic testing for interstitial lung disease in common variable immunodeficiency: a systematic review.

Introduction: Common variable immunodeficiency related interstitial lung disease (CVID-ILD, also referred to as GLILD) is generally considered a manifestation of systemic immune dysregulation occurring in up to 20% of people with CVID. There is a lack of evidence-based guidelines for the diagnosis and management of CVID-ILD. Aim: To systematically review use of diagnostic tests for assessing patients with CVID for possible ILD, and to evaluate their utility and risks. Methods: EMBASE, MEDLINE, PubMed and Cochrane databases were searched. Papers reporting information on the diagnosis of ILD in patients with CVID were included. Results: 58 studies were included. Radiology was the investigation modality most commonly used. HRCT was the most reported test, as abnormal radiology often first raised suspicion of CVID-ILD. Lung biopsy was used in 42 (72%) of studies, and surgical lung biopsy had more conclusive results compared to trans-bronchial biopsy (TBB). Analysis of broncho-alveolar lavage was reported in 24 (41%) studies, primarily to exclude infection. Pulmonary function tests, most commonly gas transfer, were widely used. However, results varied from normal to severely impaired, typically with a restrictive pattern and reduced gas transfer. Conclusion: Consensus diagnostic criteria are urgently required to support accurate assessment and monitoring in CVID-ILD. ESID and the ERS e-GLILDnet CRC have initiated a diagnostic and management guideline through international collaboration. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022276337.

Thoracic Ultrasound in Lung Transplantation-Insights in the Field.

The use of thoracic ultrasound (TUS) is a novel and dynamic diagnostic and monitoring modality that has shown remarkable advances within the last decade, with several published papers investigating its role within the field of lung transplantation. The aim of this current opinion review is to review the existing literature on the role of TUS in all stages of LTx, from in-donor lung evaluation to graft assessment on ex vivo lung perfusion and in the short- and long-term follow-up after LTx.

Humoral immune response following a third SARS-CoV-2 mRNA vaccine dose in solid organ transplant recipients compared with matched controls.

Background: Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated. Method: This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups. Results: Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80). Conclusion: A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups.

Using thoracic ultrasound to detect interstitial lung disease in patients with rheumatoid arthritis: a protocol for the diagnostic test accuracy AURORA study.

INTRODUCTION: Pulmonary diseases are significant contributors to morbidity and mortality in patients with rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) may be prevalent in up to 30% and clinically evident in 10% of patients with RA. Feasible methods to detect concomitant ILD in RA are warranted. Our objective is to determine the diagnostic accuracy of thoracic ultrasound (TUS) for ILD in patients with RA with respiratory symptoms, by using chest high-resolution CT (HRCT) as the reference standard. Further, we aim to evaluate the diagnostic accuracy for the promising blood biomarkers surfactant protein-D and microfibrillar-associated protein 4 in the detection of ILD in this group of patients. METHODS AND ANALYSIS: By use of a standardised 14 zone protocol patients suspected of having RA-ILD will undergo TUS as index test performed by a junior resident in rheumatology (BKS), who is certified by the European Respiratory Society in performing TUS assessments. Participants form a consecutive series of up to 80 individuals in total. The anonymised TUS images will be stored and scored by the junior resident as well as two senior rheumatologists, who have received training in TUS, and a TUS-experienced pulmonologist. HRCT will be used as the gold standard for ILD diagnosis (reference standard). The two basic measures for quantifying the diagnostic test accuracy of the TUS test are the sensitivity and specificity in comparison to the HRCT. ETHICS AND DISSEMINATION: Data will be collected and stored in the Research Electronic Data Capture database. The study is approved by the Committees on Health Research Ethics and the Danish Data Protection Agency. The project is registered at clinicaltrials.gov (NCT05396469, pre-results) and data will be published in peer-reviewed journals.

Oxygen therapy and interstitial lung disease.

Oxygen is a standard treatment for patients with chronic lung diseases and hypoxemia. The two main groups of lung diseases leading to oxygen treatment is chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Several guidelines for home oxygen therapy for patients with ILD is, however, based on older observation and extrapolations from studies on COPD. This review focuses on the different oxygen treatment modalities for patients with ILD focusing on present evidence and upcoming trials that might change the oxygen therapy approach for patients with ILD.

[Pulmonary manifestations in rheumatoid arthritis].

Rheumatoid arthritis (RA) affects more than 30,000 Danes. In this review, we discuss RA in connection with chronic obstructive pulmonary disease (COPD), bronchiectasis and interstitial lung disease (ILD) which are among the most common lung manifestations and are associated with increased mortality. Early suspicion based upon respiratory symptoms should prompt imaging and pulmonary function test. Smoking cessation, vaccination, and rehabilitation are important. COPD and bronchiectasis are treated according to guidelines. Multidisciplinary collaboration in RA-ILD is important and treatment decisions are based on clinical experience and imaging suggesting an inflammatory or fibrotic phenotype.

Trends and predictors of specialist assessments in oral corticosteroid treated asthma among young adults.

Background: Repeated oral corticosteroid use indicates uncontrolled disease among asthma patients, and referral for asthma specialist assessment is recommended. We aimed to describe trends and predictors associated with specialist contacts among young adults with asthma and repeated oral corticosteroid use. Methods: Individuals aged 18-45 years with two or more dispensed asthma medication prescriptions and two dispended oral corticosteroid prescriptions (including short-term and long-term treatments) within 12 months during 1999-2018 were identified by use of Danish healthcare registers. The frequency of specialist contacts within 1 year of follow-up was assessed among individuals without previous specialist contacts within 5 years of inclusion. Factors associated with specialist contact were identified using logistic regression models. Furthermore, oral corticosteroid prescriber sources were assessed. Results: For the 11 223 individuals included, 2444 (22%) had previous specialist-contact care within 5 years prior of inclusion, and additionally 926 (8.3%) within 1 year of follow-up. Among those without previous specialist contacts (n=8779), the frequency of incident specialist contacts within 1 year of follow-up increased from 6.3% in 1999 to 18% in 2017. Factors associated with incident specialist contacts included dispensing ≥12 short-acting ß-agonist canisters and previous asthma-related emergency department visits and hospitalisations. The majority of oral corticosteroid prescriptions at baseline (71%) were prescribed by general practitioners, although with decreasing proportions from 1999 to 2018. Conclusions: The majority (70%) of young adults with asthma and repeated oral corticosteroid use do not seem to receive specialist assessment in Denmark. This highlights a potential room for improvement in the patient referral pathway for at-risk asthma patients.

Determinants of Antibody Response to a Third SARS-CoV-2 mRNA Vaccine Dose in Solid Organ Transplant Recipients: Results from the Prospective Cohort Study COVAC-Tx.

BACKGROUND: We studied factors related to humoral response in solid organ transplant (SOT) recipients following a three-dose regimen of an mRNA-based SARS-CoV-2 vaccine. METHOD: This was a prospective study of SOT recipients who received a third homologous dose of the BNT162b2 (Pfizer-BioNTech) vaccine. The anti-spike S1 IgG response was measured using the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) with a cut-off of 7.1 BAU/mL. Multiple logistic regression was used to determine the factors associated with humoral response. RESULTS: In total, 395 SOT recipients were included. Anti-spike IgG was detected in 195/395 (49.4%) patients after the second dose and 261/335 (77.9%) patients after the third dose. The overall mean increase in antibody concentration after the third dose was 831.0 BAU/mL (95% confidence interval (CI) 687.4-974.5) and 159 (47.5%) participants had at least a 10-fold increase in antibody concentration after the third dose. The increase in antibody concentration was significantly higher among patients with detectable antibodies after the second dose than those without. Cumulative time from transplantation and liver recipients was positively associated with an antibody response, whereas older age, administration of prednisolone, and proliferation inhibitors were associated with diminished antibody response. CONCLUSION: Although the third dose of the BNT162b2 vaccine improved humoral responses among SOT non-responders following the second dose, the overall response remained low, and 22.1% did not develop any response. Patients at risk of a diminished vaccine response require repeated booster doses and alternative treatment approaches.

Prevalence of Chronic Pulmonary Aspergillosis in Patients Suspected of Chest Malignancy.

Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening fungal lung infection, and recent research suggests CPA to be more common than previously considered. Although CPA mimics other lung diseases including pulmonary cancer, awareness of this disease entity is still sparse. This study aimed to investigate the prevalence of CPA in a population of patients under suspicion of having lung cancer. We conducted a retrospective cohort study of 1200 patients and manually collected individual health record data from previous cancer examinations, with retrospective CPA status assessment using international criteria. Among 992 included patients, 16 (1.6%) fulfilled diagnostic criteria for CPA retrospectively, of whom 15 were undiscovered at initial lung cancer examination. The prevalence of CPA in this study population was 50 times higher than the reported prevalence of the overall European population. Our findings indicate that CPA is often missed in patients suspected of malignancy in the chest. Therefore, CPA should be kept in mind as a significant differential diagnosis.

Cavitating pulmonary lung lesions with more than one microbiological aetiology.

Non-tuberculous mycobacteria (NTM) are one of the predominant microbes observed in immunocompromised patients with structural lung disease. Especially in immunocompromised patients, the treating physician needs to be aware of concurrent lung infections with opportunistic pathogens. In this case report we present a man in his 60s with severe chronic obstructive pulmonary disease (COPD) and bullous emphysema, who was diagnosed with Mycobacterium europaeum but with persistent clinical deterioration despite relevant treatment for NTM. A subsequent bronchoalveolar lavage (BAL) revealed elevated Aspergillus galactomannan antigen which, when seen in relation to imaging-findings of cavitating opacities with aggravating surrounding consolidation, raised suspicion of concurrent subacute invasive aspergillosis. Antifungal treatment was initiated but due to intolerable side effects was discontinued after only a few weeks. This case highlights the importance of concurrent testing for pulmonary aspergillosis in NTM patients and vice versa before treatment initiation and if the disease and symptoms are progressing despite relevant treatment.

A retrospective cohort study of patients with eosinophilia referred to a tertiary centre.

INTRODUCTION: Patients with eosinophilia (an increased number of eosinophilic granulocytes > 0.5 × 108/l in the blood) are encountered in all medical specialties and frequently need thorough workup to identify the eliciting causes and decide whether treatment is indicated. In Denmark, highly specialised centres for eosinophilic diseases or conditions have been established to provide a foundation for the management of complicated cases. Here, we present experiences from such a multidisciplinary centre. METHODS: This was a retrospective study of all patients seen in our tertiary centre for eosinophilia in the 2016-2019 period. RESULTS: Referrals mainly derived from specialised secondary care and to a lesser degree from primary care physicians. Patients were either asymptomatic or exhibited symptoms from up to three organ systems and presented a median eosinophil count of 1.7 × 108/l. Up to eight new clonality analyses or imaging studies per patient were performed after referral. One of these, T-cell receptor analysis, was performed frequently but provided limited information, whereas, e.g., flow cytometry proved more clinically applicable owing to its broader diagnostic range. In total, 51 patients were evaluated and classified as secondary (59%), myeloid neoplasm with PDGFRA rearrangement (2%), idiopathic hypereosinophilic syndrome (31%) and idiopathic hypereosinophilia (8%). CONCLUSION: The value of a multidisciplinary and versatile approach in a highly specialised centre has a positive impact on diagnostic processes as well as on the evaluation of treatment need. FUNDING: none. TRIAL REGISTRATION: not relevant.