Interstitial lung disease was suspected, but biopsy revealed pulmonary lymphangitis carcinomatosa.

Introduction: Pulmonary lymphangitis carcinomatosa is a rare and severe manifestation of metastatic disease that causes pulmonary symptoms and radiologic patterns similar to interstitial lung diseases. Case presentation: We report a case of a 78-year-old woman who presented to our department with insidiously developed symptoms of fatigue, dry cough, and severe dyspnea for 3 months. Chest radiography showed bilateral interstitial changes. On suspicion of interstitial lung disease, bronchoscopy and transbronchial cryobiopsy were carried out. Surprisingly, histopathological investigation revealed pulmonary lymphangitis carcinomatosa originating from primary breast adenocarcinoma. Conclusion: To achieve an accurate diagnosis and prevent delay of initiation of proper treatment a thorough diagnostic approach is necessary. In case of doubt, biopsy should be performed to secure clarification. In this case report we discuss the diagnostic value of transbroncial cryobiopsy for this purpose.

A new definition and treatment options of allergic alveolitis.

In this review, we discuss a new definition and treatment options of allergic alveolitis (AA). AA is an immune-mediated interstitial lung disease triggered by inhaled antigens, it is defined as non-fibrotic (inflammatory) and/or fibrotic, and diagnosis relies on a multidisciplinary approach using clinical, radiological and sometimes histological assessments. Treatment involves early antigen elimination and may include corticosteroids or other immunosuppressants. Prognosis varies from reversible inflammation to irreversible fibrosis. Early detection is crucial for better outcomes.

Transbronchial Lung Cryobiopsy for Diagnosing Interstitial Lung Diseases and Peripheral Pulmonary Lesions - A Stepwise Approach.

Transbronchial lung cryobiopsy (TBLC) is an invasive procedure increasingly implemented during the last decade as an alternative to video-assisted thoracic surgery lung biopsy (SLB) for diagnosing interstitial lung diseases (ILDs). The indication for TBLC has primarily been to sub-classify a specific ILD subtype when this cannot be achieved on the basis of a preceding multidisciplinary team discussion. Although SLB is considered the gold standard for establishing a histological diagnosis, TBLC has been gradually suggested as the first-choice histological diagnostic modality in patients with unclassified ILDs due to a comparable diagnostic yield with SLB, but superior to SLB in terms of complications, including mortality. During recent years, radial endobronchial ultrasound (R-EBUS) and electromagnetic navigation bronchoscopy (ENB)-guided TBLC for peripheral pulmonary lesions have also been described as safe procedures, which may improve the diagnostic yield compared to forceps biopsies. Still, the diagnostic properties of TBLC rely on the quality of the procedure's performance. This article aims to describe the stepwise approach to conducting TBLC with a flexible bronchoscope for the different indications mentioned, which might be helpful for novice bronchoscopists performing TBLC.

Association between Parenchymal B-Cell Follicles and CT-Proven Enlarged Mediastinal Lymph Nodes in Patients with Pulmonary Fibrosis.

BACKGROUND: Mediastinal lymph node enlargement (MLNE) is a finding described in a subset of patients with idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases (ILDs) and is associated with accelerated disease progression and increased mortality. The cause of MLNE is still not known. Our hypothesis is that there is an association between MLNE and B-cell follicles in lung tissue, another aspect detectable in the lung tissue of patients with IPF and other ILDs. OBJECTIVES: The aim of this study was to assess if there is an association between MLNE and B-cell follicles in lung tissue in patients with IPF and other ILDs. METHOD: Patients having transbronchial cryobiopsies performed as part of an investigation for ILD were included in this prospective observational study. MLNE (smallest diameter ≥10 mm) were assessed in station 7, 4R, and 4L on high-resolution computed tomography scans. B-cell follicles were assessed on haematoxylin-eosin-stained specimens. Lung function, 6-minute walk test, acute exacerbation, and mortality were registered after 2 years. In addition, we investigated if the finding of B-cell follicles was consistent in patients who underwent both surgical lung biopsies (SLBs) and cryobiopsies. RESULTS: In total, 93 patients were included for analysis (46% diagnosed with IPF, 54% diagnosed with other ILDs). MLNE was found in 26 (60%) of the IPF patients and in 23 (46%) of the non-IPF patients (p = 0.164). Diffusing capacity for carbon monoxide was significantly lower (p = 0.03) in patients with MLNE compared to patients without MLNE. B-cell follicles were found in 11 (26%) of the IPF patients and in 22 (44%) of the non-IPF patients (p = 0.064). Germinal centres were not seen in any of the patients. There was no association between MLNE and B-cell follicles (p = 0.057). No significant difference in change of pulmonary function test was seen at 2-year follow-up when comparing the patients with and without MLNE or B-cell follicles. In 13 patients, both SLBs and cryobiopsies were performed. The presence of B-cell follicles was not consistent when comparing the two different methods. CONCLUSION: MLNE is evident in a substantial part of patients with ILD and is associated with lower DLCO at inclusion. We could not demonstrate an association between histological B-cell follicles in biopsies and MLNE. A possible explanation for this is that the cryobiopsies might not have captured the changes we sought.

Current best clinical practices for monitoring of interstitial lung disease.

INTRODUCTION: Interstitial lung diseases (ILDs) are a heterogeneous group of inflammatory and/or fibrotic conditions with variable outcome and often a dismal prognosis. Since many ILDs are progressive in nature, monitoring of signs and symptoms of progression is essential to inform treatment decisions and patient counseling. Monitoring of ILDs is a multimodality process and includes all aspects of the disease, e.g. measurement of pulmonary function and exercise capacity, symptom registration and quality of life (QoL), imaging, comorbidities and/or involvement of other organs to assess disease activity, symptom burden, treatment effects, adverse events, the need for supportive and palliative care, and lung transplantation. AREAS COVERED: For this narrative review, we searched the PUBMED database to identify articles relevant for monitoring ILDs, including pulmonary function tests, exercise capacity, imaging, telemedicine, symptoms, and QoL. EXPERT OPINION: Due to the high heterogeneity of the ILDs and their disease course, an individualized multimodality approach must be applied. Future strategies include use of telemedicine for home monitoring of lung function and symptoms, use of artificial intelligence to support automatized guidance of patients, computerized evaluation of ILD changes on imaging, and new imaging tools with less radiation dosage.

Comorbidities in unclassifiable interstitial lung disease.

BACKGROUND: Comorbidities are common in interstitial lung diseases (ILD) and have an important association with survival, but the frequency and prognostic impact of comorbidities in unclassifiable interstitial lung disease (uILD) remains elusive. We aimed to describe the prevalence of comorbidities and assess the impact on survival in patients with uILD. Furthermore, we aimed to identify and characterize potential phenotypes based on clusters of comorbidities and examine their association with disease progression and survival. METHODS: Incident patients diagnosed with uILD were identified at two ILD referral centers in Denmark and Germany from 2003 to 2018. The diagnosis uILD was based on multidisciplinary team meetings. Clinical characteristics and comorbidities were extracted from ILD registries and patient case files. Survival analyses were performed using Cox regression analyses, disease progression was analyzed by linear mixed effects models, and clusters of comorbidities were analyzed using self-organizing maps. RESULTS: A total of 249 patients with uILD were identified. The cohort was dominated by males (60%), former (49%) or current (15%) smokers, median age was 70 years, mean FVC was 75.9% predicted, and mean DLCO was 49.9% predicted. One-year survival was 89% and three-year survival was 73%. Eighty-five percent of the patients had ≥ 1 comorbidities, 33% had ≥ 3 comorbidities and 9% had ≥ 5 comorbidities. The only comorbidity associated with excess mortality was dyslipidemia. No association between survival and number of comorbidities or the Charlson comorbidity index was observed. Three clusters with different comorbidities profiles and clinical characteristics were identified. A significant annual decline in FVC and DLCO % predicted was observed in cluster 1 and 2, but not in cluster 3. No difference in mortality was observed between the clusters. CONCLUSIONS: The comorbidity burden in uILD is lower than reported in other types of ILD and the impact of comorbidities on mortality needs further clarification. Three clusters with distinct comorbidity profiles were identified and could represent specific phenotypes. No difference in mortality was observed between clusters, but slower disease progression was observed in cluster 3. Better understanding of disease behavior and mortality will require further studies of subgroups of uILD with longer observation time.

[Antifibrotic therapy in other fibrotic interstitial lung diseases than idiopathic pulmonary fibrosis].

Numerous studies have shown that perioperative heparin bridging in patients treated with a vitamin K antagonist leads to an increased incidence of bleeding and so far, there is no evidence that it leads to a significant reduction in postoperative thromboembolism as summarised in this review. Prophylactic dosage of heparin is recommended after major surgery. Heparin bridging is not relevant in patients receiving a direct oral anticoagulant due to the rapid onset and offset of action of DOACs.

PD-L1 Expression in Patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common and severe form within the group of idiopathic interstitial pneumonias. It is characterized by repetitive alveolar injury in genetically susceptible individuals and abnormal wound healing, leading to dysregulated bronchiolar proliferation and excessive deposition of extracellular matrix, causing complete architectural distortion and fibrosis. Epithelial-to-mesenchymal transition is considered an important pathogenic event, a phenomenon also observed in various malignant neoplasms, in which tumor cells express programmed death-ligand one (PD-L1). The aim of this study was to assess the presence of PD-L1 in patients with IPF and other interstitial lung diseases (ILDs). METHOD: Patients with a clinically and radiologically suspected idiopathic interstitial pneumonia or other ILDs undergoing transbronchial cryobiopsy to confirm the diagnosis at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, were included in this prospective observational study. Cellular membrane PD-L1 expression in epithelial cells was determined using the DAKO PD-L1 IHC 22C3 PharmDx Kit. RESULTS: Membrane-bound PD-L1 (mPD-L1) was found in twelve (28%) of the forty-three patients with IPF and in five (9%) of the fifty-five patients with other ILDs (p = 0.015). When adjusting for age, gender and smoking status, the odds ratio of having IPF when expressing mPD-L1 in alveolar and/or bronchiolar epithelial cells was 4.3 (CI: 1.3-14.3). CONCLUSION: Expression of mPD-L1 in epithelial cells in the lung parenchymal zones was detected in a consistent subgroup of patients with IPF compared to other interstitial pneumonias. Larger studies are needed to explore the role of mPD-L1 in patients with IPF.

Pulmonary Alveolar Microlithiasis - A Review.

Pulmonary Alveolar Microlithiasis (PAM) is a rare genetic disorder causing widespread deposition of calcium-phosphate crystals in the alveolar space. A hallmark of the disease is the discrepancy between perceived symptoms upon diagnosis compared with the extensive, sandstorm-like appearance of the microliths on chest X-ray or HRCT. Caused by a defective sodium-dependent phosphate transport protein due to loss-of-function variants of the SLC34A2 gene, PAM is an autosomal recessive transmitted disorder, and as such has a high correlation to consanguinity. The most common variants of the SLC34A2 gene are single nucleotide biallelic changes, but larger deletions are described. Initial suspicion of PAM on radiological examination should be followed by genetic testing to verify the diagnosis and identify the disease-causing variant. When not available, the diagnosis can be made by means of invasive techniques, such as transbronchial forceps or cryobiopsy, or a surgical lung biopsy. In families with a history of PAM, genetic counseling should be offered, as well as preimplantation/prenatal testing if necessary. As of writing this review, no definitive treatment exists, and PAM may in some cases progress to severe pulmonary disease with respiratory failure and potential death. Patients with PAM should be offered preventative and symptomatic treatments such as vaccinations and oxygen therapy when needed. In some cases, lung transplantation may be required.

Integration of cryobiopsies for interstitial lung disease diagnosis is a valid and safe diagnostic strategy-experiences based on 250 biopsy procedures.

BACKGROUND: Transbronchial cryobiopsies has become increasingly used in the diagnostic workup in patients suspected of having interstitial lung disease. The procedure is associated with less complications, morbidity and mortality compared to surgical lung biopsies although with a diagnostic yield that is not as high, but close to that of surgical lung biopsies. The aim of the present study was to describe the complications and diagnostic yield and their prognostic factors. METHODS: All patients undergoing transbronchial cryobiopsies at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, were included in this prospective observational cohort study. RESULTS: A total of 250 patients were included [61% male, mean age 66 years (range, 22-81 years)]. Pneumothorax was detected in 70 (28%) of the patients, moderate hemorrhage in 53 (21%) and severe hemorrhage in 2 (1%) of the patients. Hemorrhage was associated with central biopsies, but not with anticoagulant therapy. None of the complications were related to lung function, exercise capacity, biopsy or probe size. Only one patient experienced an acute exacerbation. Three-month mortality was 0.4% (1 patient), caused by cancer and unrelated to the procedure. Cryobiopsies contributed to the final diagnosis in 72% of the patients and after multidisciplinary team discussion, a consensus diagnosis was obtained in 82% of the patients. The gender, the total sum of biopsy sizes, number of biopsies and presence of more than 50% alveolar tissue in biopsies increased the diagnostic yield. CONCLUSIONS: Our study confirms that using cryobiopsies in the diagnostic setup for interstitial lung diseases is safe with a limited risk of acute exacerbations and mortality. Cryobiopsies contribute to the diagnosis in the majority of patients.

Palliation of chronic breathlessness with morphine in patients with fibrotic interstitial lung disease - a randomised placebo-controlled trial.

BACKGROUND: Patients suffering from fibrotic interstitial lung diseases (fILD) have a poor prognosis and a high symptom burden. Palliative treatment includes relief of symptoms such as breathlessness. There is no evidence-based treatment for chronic breathlessness but opioids are often used despite concerns due to the hypothetical risk of respiratory depression. This study investigated the effect of oral morphine drops in patients with fILD on chronic breathlessness and safety. METHODS: In a double-blinded placebo-controlled study, 36 patients with fILD were randomised to either four daily doses of 5 mg of oral morphine drops or placebo for 1 week. Endpoints and safety parameters were obtained at baseline, at follow-up after 1 h and 1 week. RESULTS: The primary endpoint, the visual analogue score (VAS) of dyspnea was reduced by 1.1 ± 0.33 cm in the morphine group at follow-up compared to baseline (P < 0.01), whereas the reduction was 0.35 ± 0.47 cm in the placebo group. However, the difference between the two groups was not statistically significant (p = 0.2). Oral morphine drops did not affect respiratory frequency, pulse rate, blood pressure, peripheral saturation or the 6-min walk test. More patients treated with morphine reported constipation, nausea and confusion. CONCLUSION: Oral administration of morphine drops, 20 mg a day, in patients with fILD did not significantly reduce dyspnea VAS score during 1 week compared to placebo. Oral morphine did not induce respiratory depression, but was related to an increased risk of constipation, nausea and confusion. TRIAL REGISTRATION: The trial is registered in clinicaltrials.gov (Identifier: NCT02622022 ). Registered 4 December 2015.

Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians.

Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Other respiratory complications, such as chronic obstructive pulmonary disease and bronchiectasis, are frequent in RA. Infections and drug toxicity are important differential diagnoses and should be considered in the diagnostic work-up of patients with RA presenting with respiratory symptoms. This review provides an overview of the epidemiology and pathogenesis of RA-ILD, the radiological and histopathological characteristics of the disease as well as the current and future treatment options. Currently, there is no available evidence-based therapy for RA-ILD, and immunosuppressants are the mainstay of therapy. Ongoing studies are exploring the role of antifibrotic therapy in patients with progressive fibrotic ILD, which may lead to a new treatment approach for subgroups of patients with RA-ILD.

An HIV + patient with visceral enlarged lymph nodes.

An HIV positive patient with enlarged visceral lymph nodes was diagnosed to be affected by visceral leishmaniasis. Transesophageal endoscopic ultrasound with fine needle aspiration, a diagnostic approach used when mediastinal or intra-abdominal lymphadenopathy is evident, was the first diagnostic test.

Cryobiopsies are diagnostic in Pleuroparenchymal and Airway-centered Fibroelastosis.

BACKGROUND: Idiopathic pulmonary fibroelastosis (iPPFE) is a rare lung lesion characterized by pleural and subpleural parenchymal thickening due to accumulation of fibroelastotic tissue. Only recently, a few cases with a peribronchiolar distribution of fibroelastotic tissue have been reported. These lesions are more prominent in the upper lobes. Even though high resolution computed tomography (HRCT) scan features are considered characteristic, a histological confirmation is suggested, mainly when the clinical setting is not clearly defined. However, due to non-negligible complications, a surgical lung biopsy is not often recommended. The prognosis is usually poor and currently, the only effective treatment is lung transplantation. METHOD: Patients with a multidisciplinary diagnosis of iPPFE or airway-centered fibroelastosis (airway-centered FE), with histological confirmation by transbronchial cryobiopsy, were identified from an ongoing interstitial lung disease registry. Data on patient demographics, HRCT patterns, size and number of biopsies, histology patterns and complications were registered. RESULTS: Seven patients were diagnosed with iPPFE and one patient was diagnosed with airway-centered FE. Pneumothorax was documented in three cases, but none of them required a chest tube. No other complications during or after the procedure were observed. CONCLUSION: This study suggests that using cryobiopsies in the diagnostics of PPFE and airway-centered FE is safe and effective.

[Idiopathic pulmonary fibrosis is an overlooked disease].

Idiopathic pulmonary fibrosis is a chronic, progressive and fatal disease which primarily occurs in male patients over 60 years with a smoking history. Cryobiopsy is a new promising method for obtaining lung tissue for histologic analysis with fewer complications than surgical lung biopsy. Cryobiopsy allows more patients to be diagnosed. Antifibrotic treatment has shown to decrease progression and prolong survival time in both early and later stages of the disease. Early diagnosis and treatment are therefore of great importance to prevent disease progression and reduce mortality.

Hypersensitivity pneumonitis among wind musicians - an overlooked disease?

Hypersensitivity pneumonitis (HP) is a complex pulmonary disorder mediated by the immune system and caused by various inhaled antigens against which the subject has previously been sensitized. In about 50% of the cases, the antigen is not identified. Identification and removal of the eliciting antigen is important for the prognosis. We report two cases of HP caused by molds and atypical mycobacteria isolated from wind instruments. We present the first case of HP caused by bassoon playing and another case of HP caused by molds in a trombone. HP caused by fungi and bacteria in wind instruments may be much more common than previously thought. HP caused by fungi and bacteria in wind instruments is probably underdiagnosed; this calls for more clinical attention when HP is suspected.