Interstitial Lung Disease

Case presentation: This case report describes a 27-year-old Pakistani, Asian man, a medical student, with no previous comorbidities or significant family history who presented with a 3 months ’ history of low grade fever and lower respiratory tract infections, associated with exertional dyspnea, arthralgias, and gradual weight loss. During these 3 months, he had received multiple orally administered antibiotics for suspected community-acquired pneumonia. When he presented to us, he was pale and febrile. A chest examination was significant for bi-basal end-inspiratory crackles. Preliminary investigations revealed raised erythrocyte sedimentation rate. High resolution computed tomography of his chest showed fine ground-glass attenuation in posterior basal segments of both lower lobes suggestive of interstitial lung disease. He was started on dexamethasone, to which he responded and showed improvement. However, during the course of events, he developed progressive proximal muscle weakness. Further investigations revealed raised creatinine phosphokinase and lactate dehydrogenase. A thorough autoimmune profile was carried out which showed positive anti-Jo-1 antibodies in high titers. A muscle biopsy was consistent with inflammatory myopathy. Clinical, radiological, serological, and histopathological markers aided in making the definitive diagnosis of antisynthetase syndrome. Antisynthetase syndrome is a variant of polymyositis but with visceral involvement, that is, interstitial lung disease and positive anti-Jo-1 antibodies. Our patient responded very well to glucocorticoids and azathioprine. Conclusion: Antisynthetase syndrome is a rare clinical entity which apart from clinical presentation requires specific serological investigations for diagnosis. Concomitant association of interstitial lung disease gives it a guarded prognosis.

SP-C mutations were found to be associated with ILD in neonates and children with sporadic or autosomal-domi- nant inheritance. The majority of these mutations were missenses or deletions leading to skipping of exon 4 or substitution of highly conserved amino acids in the region of the proSP-C molecule. In vitro studies support the hypothesis that the identified SP-C mutations were caus- ally related to the associated lung disease. The phenotype covers a wide range of clinical features and age of onset. Reported symptoms include respiratory distress with dys- pnoea, tachypnea, cyanosis, asthmatic bronchitis and fail- ure to thrive. The histological diagnosis was mostly NSIP, in some cases combined with PAP. Adults with SP-C mutations showed UIP or DIP while other subjects remained asymptomatic. The phenotype of lung disease associated with SP-C mutations may represent pleiotropic manifestations of the same underlying pathogenesis. Affected individuals may carry a genetic risk for interstitial lung disease, which becomes apparent in dependence of the genetic background, i.e. modifier genes and environ- mental influences. These findings have essential implica- tionsfor the diagnosis of ILD in children as genetic diagnoses can be made and underlying etiologies of famil- iar cases of ILD may be identified. In children with ILD, where no underlying cause can be found, the patient's DNA, BAL and lung tissue and the parents' DNA should be conserved for genetical, biochemical and histological analysis. Since the incidence and prevalence of ILD asso- ciated with SP-C gene mutations are unknown it is neces- sary to analyse larger subsets of clinically well defined patient cohorts.

MDD combines the ability of radiology to evaluate the entire lung, the capacity of pathology for investigating features at the cellular level, and the myriad of clinical clues from the interaction of pulmonologist and patient. This combination of data has emerged as a powerful tool in diagnosing interstitial lung disease [51, 52]. The use of the term unclassifiable interstitial lung disease has led to some concern that patients with poorly evaluated disease will be placed into this category without proper due diligence resulting in a group of patients with extraordinary heterogeneity [10]. To address this concern, among others, a working group was assembled to help create a framework or diagnostic ontology for terminology, classification and approach to patients with pulmonary interstitial fibrotic disease [53]. In the proposed schema, patients are divided into four tiers following MDD: those with confident diagnosis (meets current guideline criteria or has >90% certainty), provisional diagnosis with high confidence (70 – 90% certainty) or low confidence (50 – 70% certainty), and unclassifiable interstitial lung disease (<50% certainty). The goal of this framework is to help standardise the terminology of fibrotic lung disease. One of the likely consequences of this approach will be a decrease in patients categorised as having unclassifiable interstitial lung disease.

Systemic sclerosis–associated interstitial lung disease (SSc-ILD) is common, is associated with a poor progno- sis, and is the leading cause of death in people with SSc [1]. The pathogenesis of SSc-ILD involves a complex interplay of vascular injury, inflammation, and fibrosis (reviewed in [2–6]). The most common pathological finding in lung biopsies of patients with SSc-ILD (ap- proximately 78 % patients) is nonspecific interstitial pneumonia [7]. Usual interstitial pneumonia, the patho- logical finding in idiopathic pulmonary fibrosis (IPF), as well as other patterns are present in approximately 10– 15 % of patients with SSc-ILD [7]. However, open lung bi- opsy is usually not performed for SSc-ILD, and high- resolution computed tomography (HRCT) has become the gold standard for diagnosis and classification of ILD [8, 9]. In addition to diagnosis of ILD, moderate to severe fibrosis or total lung involvement (TLI) by SSc-ILD visualized on the baseline HRCT scan is an independent predictor of re- sponse to cyclophosphamide (CYC) therapy [10], poor sur- vival [11], and future decline in percentage of predicted forced vital capacity (FVC% predicted) [12].

Interstitial lung disease (ILD) is a major pulmonary manifestation of connective tissue disease (CTD), leading to significant morbidity and mortality. Chest high-resolution computed tomography (HRCT) is presently considered the diagnostic gold standard for pulmonary fibrosis diagnosis and quantification in the clinical arena. However, not negligible doses of ionizing radiation limit the use of HRCT, especially for serial follow-up in younger female patients. In the past decade, lung ultrasound (LUS) has been proposed to assess ILD by detecting and quantifying sonographic B-lines. Previous studies demonstrate that B-lines have a good diagnostic accuracy, especially high sensitivity, and correlate well with HRCT findings, suggesting LUS as a novel, non-invasive, and non-ionizing imaging method to be used in patients with CTD-ILD. Although preliminary data are promising, challenges and controversies still remain. For example, the mechanisms of B-line generation are not fully understood; the diagnostic accuracy and performance characteristics of LUS partially depend on the scanning scheme and scoring system used; and up-to-date B-lines cannot discriminate the early cellular inflammation from the chronic fibrotic phase in CTD-ILD. Therefore it is important for clinicians to understand the strengths and limitations of LUS in CTD-ILD patients, to maximize its value.

Purpose: Some patients with interstitial lung disease (ILD) related to connective tissue disease (CTD) have a delayed diagnosis of the underlying CTD when the ILD is categorized as idiopathic. In this study, we evaluated the frequency of myosi- tis autoantibodies in patients diagnosed with idiopathic ILD and investigated the clinical significance stemming from the presence of the antibodies. Materials and Methods: A total 32 patients diagnosed with idiopathic ILD were enrolled in this study. We analyzed a panel of 11 myositis autoantibody specificities in the patients using a line blot immunoassay. Then, we divided them into myositis autoantibody- positive and -negative groups and compared the clinical features and laboratory data between the two groups. Results: Of the 32 idiopathic ILD patients, 12 patients had myositis autoantibodies encompassing 9 specificities, except for anti-Mi-2 and anti- PM-Scl 100 (12/32, 38%). Anti-synthetase autoantibodies including Jo-1, EJ, OJ, PL-7, and PL-12 were present in 7 patients (7/32, 22%). The group with myositis autoantibodies presented more frequently with the symptom of mechanic’s hand and showed abnormal pulmonary function test results with low forced vital capaci- ty, diffusing capacity for carbon monoxide, total lung capacity, and high lactate de- hydrogenase values in blood when compared with the group without myositis anti- bodies. Conclusion: We strongly suggest that patients undergo an evaluation of myositis autoantibodies, if they are diagnosed with idiopathic ILD in the presence of clinical characteristics including mechanic’s hand, arthralgia, and autoantibodies which are insufficient to make a diagnosis of a specific CTD category.

Any of the anatomic compartments of the lung – airways (bronchiectasis, bronchiolitis), vasculature (pulmonary hyper- tension, vasculitis), pleura (pleuritis, effusions) or parenchyma (rheumatoid nodules, interstitial lung disease [ILD]) (Table 1) can be primarily or directly affected by RA. Patients are also at risk for secondary pulmonary complications, with drug toxicities during treatment and opportunistic infections from immunosuppressive therapy being the major concerns. 19

Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting 0.5–1% of the worldwide population. Interstitial lung disease (ILD) is the most common respiratory manifestation of RA. It significantly affects the prognosis and limited treatment options for RA. With the current state of evidence, most treatments of RA are associated with a risk of onset or exacerbation of ILD, but with very different prevalence. However, methotrexate is associated with a risk of hypersensitivity pneumonitis, its link with a chronic ILD are unlikely. Cyclosporine appears effective and tolerated in ILD associated to other connective tissue diseases. Regarding biologic agents, rituximab remains relatively the best tolerated drug. Moreover, it is difficult to differentiate drug-induced toxicity from ILD related to rheumatoid arthritis or infections. In practice, the occurrence of ILD in RA requires an etiologic screening and pulmonary function tests. The decision to start cDMARDs or a biologic agent in patients at risk for ILD should be based only on its potential for improvement, especially in the absence of an alternative drug, with close monitoring and an extensive explanation to the patient.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. The main characteristic is a persistent synovitis of joints, often symmetrical in distribution, resulting in pain, stiffness, and loss of function. RA has a wide clinical spectrum varying from mild joint symptoms to severe inflammation and damage to joints. In addition, being a systemic rather than a localized disease, a wide variety of extra-articular features like rheumatoid nodules, vasculitis, lymphadenopathy, serositis, and amyloidosis may develop. Our study focuses on one such extra articular manifestation namely interstitial lung disease (ILD).

connective tissue disease was 9.7%, and that of interstitial lung disease due to rheumatoid arthritis was 7.2%, while the percentages in other countries were 15% [12] and 7% [8] respectively. The rates in China are lower than other countries, which might be related to the patients’ characteristics, the diagnostic method of rheumatism, and the doctors’ under- standing of rheumatism, as we collected the data in departments of respiration medicine instead of rheumatic depart- ments. The initial symptom of most connective tissue disease is pulmonary fibrosis, and then other symptoms will show up gradually, so the patients with connective tissue disease will be first treated in department of respiration medicine, which calls the doctor’s atten- tion. To avoid erroneous diagnosis, im- munological tests should be regular pro- cedure for the patients in the respiration department, and chest X-ray and pulmo- nary function testing should be regular tests for patients in the Rheumatology Department, while chest CT scans, bron- choalveolar lavage and biopsies should be done when necessary. The propor- tion of ILD caused by inhalation of dust has decreased in China, which shows that the sense of occupational health protection is increasing in China. The proportion of EEA and sarcoidosis were high in other studies in China and other countries, however, the proportions of these two diseases were relatively low in our study, which may indicate their low incidence rates in Tianjin.

Presentation of Case: We report two patients with interstitial lung disease (ILD), severe persistent bronchospasm not responding to conventional therapy, and raised chromogranin-A (Cg-A) levels. A neuroendocrine tumour (NET) was suspected and both were given a therapeutic trial of octreotide. This led not only to a dramatic clinical improvement but also to the normalization of Cg- A levels. Cg-A levels were elevated in 6 additional patients with interstitial involvement but without bronchospasm. The raised Cg-A levels in these 8 patients and the response to octreotide in two

Abstract: We herein describe the case of a 67-year-old woman with advanced lung adenocarcinoma who developed interstitial lung disease (ILD) with alveolar hemorrhage induced by pembrolizumab. She received four courses of pembrolizumab therapy and achieved a partial response. She had no respiratory symptoms; however, chest radiography and computed tomography (CT) revealed ground-glass opacities (GGOs) and crazy-paving pattern. Based on findings of bloody bronchoalveolar lavage fluid and transbronchial lung biopsy samples, pembrolizumab-induced ILD with alveolar hemorrhage was diagnosed. Corticosteroid therapy rapidly improved alveolar hemorrhage and regressed GGOs on CT scan. This is the first report on ILD with alveolar hemorrhage induced by pembrolizumab.

Childhood interstitial lung disease (chILD) represents a highly heterogeneous group of rare disorders associated with substantial morbidity and mortality. Although our understanding of chILD remains limited, important advances have recently been made, the most important being probably the appreciation that disorders that present in early life are distinct from those occurring in older children and adults, albeit with some overlap. chILD manifests with diffuse pulmonary infiltrates and nonspecific respiratory signs and symptoms, making exclusion of common conditions presenting in a similar fashion an essential preliminary step. Subsequently, a systematic approach to diagnosis includes a careful history and physical examination, computed tomography of the chest, and some or all of bronchoscopy with bronchoalveolar lavage, genetic testing, and if diagnostic uncertainty persists, lung biopsy. This review focuses on chILD presenting in infants younger than 2 years of age and discusses recent advances in the classification, diagnostic approach, and management of chILD in this age range. We describe novel genetic entities, along with initiatives that aim at collecting clinical data and biologic samples from carefully characterized patients in a prospective and standardized fashion. Early referral to expert centers and timely diagnosis may have important implications for patient management and prognosis, but effective therapies are often lacking. Following massive efforts, international collaborations among the key stakeholders are finally starting to be in place. These have allowed the setting up and conducting of the first randomized controlled trial of therapeutic interventions in patients with chILD.

The inter-rater/test–retest reliability and construct validity of a palliative care needs assessment tool in interstitial lung disease (NAT:PD-ILD) were tested using NAT:PD- ILD-guided video-recorded consultations, and NAT:PD-ILD-guided consultations, and patient and carer-report outcomes (St George’s Respiratory Questionnaire (SGRQ)- ILD, Carer Strain Index (CSI)/Carer Support Needs Assessment Tool (CSNAT)). 11/16 items reached at least fair inter-rater agreement; 5 items reached at least moderate test– retest agreement. 4/6 patient constructs demonstrated agreement with SGRQ-I scores (Kendall’s tau-b, 0.24–20.36; P<0.05). 4/7 carer constructs agreed with the CSI/CSNAT items (kappa, 0.23–20.53). The NAT:PD-ILD is reliable and valid. Clinical effectiveness and implementation are to be evaluated.

Vasculitis has historically been associated with ANCA- positivitiy and rarely with interstitial lung disease and pancytopenia. There have been selective case reports documenting pancytopenia with vasculitis, interstitial lung disease with vasculitis and ANCA-negativity with vasculitis. Despite extensive research, we were unable to find a single case report of a patient presenting with ANCA-negativity, interstitial lung disease and pancytopenia. This patient had a negative double- stranded DNA (ds-DNA) and presented with pancytopenia which is an unusual presentation. The chief reason for admission of the patient discussed above was respiratory failure. Lung involvement is a common presenting finding of vasculitis. It can initially manifest like idiopathic pulmonary fibrosis and precede the full-blown clinical manifestations and diagnosis of MPA by years [4, 5, 6]. Historically, the incidence of fibrosis in MPA has been insignificant. A study published in Arthritis and Rheumatism in 1999 reported the incidence of lung findings in MPA as 24%, the most common being alveolarhemorrhage (11.8%), pneumonitis (10.6%) and pleuritis (5.9%) [7]. The majority of these patients have a predominant myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA) positive pattern [7]. However, more recently, there have been an increasing number of studies recognizing pulmonary fibrosis in vasculitis. In 2016, a German study that followed the clinical course of small-vessel vasculitis found that in a series of 144 patients with MPA, 12% presented with fibrosing interstitial lung disease, which subsequently developed in 15% over the long term follow-up [8]. Fibrosing ILD was associated with a poor prognosis in this study. Interestingly, fibrosing ILD is more commonly associated with MPO-ANCA than with other subtypes [9, 10]. This is in contrast to our patient who, being ANCA-negative, presented with ILD.

The decision for a lung transplant requires the knowledge of the severity of interstitial lung disease (ILD). A manual scoring sheet was developed for discriminating ILD cases from non-ILD cases based on eleven indicators selected by the radiologist. The manual scoring sheet requires the radiologists to score the severity of general ILD from visual inspection on the changes of lung tissue using the high resolution computed tomography images. This paper investigates the use of logistic regression in developing a scoring index,    x , to investigate the presence of ILD. The result shows that the scoring index,    x , is robust and has discriminatory potentials. The threshold (c, d) having values (0.7, 0.24) allowed correct classifications of 80% of ILD cases and 61% of non-ILD cases in a total sample of 134 cases. This study suggests that    x may be used as a simple and practical scoring index in initial investigations for ILD detection.

Interstitial lung disease is a rare disorder that has various etiologies and clinical presentations. Some interstitial lung diseases are more common in infancy period, which is not similar to interstitial lung disease in childhood or adult. Every infant presenting with early respiratory distress/failure or chronic respiratory symptoms without reasonable cause together with diffuse pulmonary infiltration should be sought out for interstitial lung diseases after excluding other common conditions of diffuse lung disease. This review focuses on interstitial lung disease in infant or in first year of life in the scope of classification system, systematic approach, investigations, clinical presentations, imaging findings, pathological findings, managements and prognosis. Early recognition of clinical and characteristic of imaging findings of ILD in infants can lead to prompt diagnosis and proper management.

The MEDLINE (PubMed), Embase (Ovid), and Web of Science databases were searched on July 05, 2016 to identify all potentially relevant studies since January 1949. ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) were also searched for clinical trial registrations. Additionally, the reference lists of all studies identified via the electronic searches and adhering to the inclusion criteria were manually curated for further potentially eligible studies. The search strategy, designed in consultation with a professional librarian, consisted of three main search terms: 1) systemic sclerosis; 2) interstitial lung disease; and 3) pulmonary function test. The detailed search strategy for the MEDLINE database is available in the supplementary material (e-Appendix 1).

ABSTRACT Children’s interstitial lung diseases (chILD) are increasingly recognised and contain many lung developmental and genetic disorders not yet identified in adult pneumology. Worldwide, several registers have been established. The Australasian Registry Network for Orphan Lung Disease (ARNOLD) has identified problems in estimating rare disease prevalence; focusing on chILD in immunocompetent patients, a period prevalence of 1.5 cases per million children and a mortality rate of 7% were determined. The chILD-EU register highlighted the workload to be covered per patient included and provided protocols for diagnosis and initial treatment, similar to the United States chILD network. Whereas case reports may be useful for young physicians to practise writing articles, cohorts of patients can catapult progress, as demonstrated by recent studies on persistent tachypnoea of infancy, hypersensitivity pneumonitis in children and interstitial lung disease related to interferonopathies from mutations in transmembrane protein 173. Translational research has linked heterozygous mutations in the ABCA3 transporter to an increased risk of interstitial lung diseases, not only in neonates, but also in older children and adults. For surfactant dysfunction disorders in infancy and early childhood, lung transplantation was reported to be as successful as in adult patients. Mutual potentiation of paediatric and adult pneumologists is mandatory in this rapidly extending field for successful future development.

Ab: Antibody; ANA: Anti-nuclear antibodies; Anti-ARS Ab: Anti-aminoacyl transfer RNA synthetase antibody; Anti-MDA5 Ab: Anti-melanoma differentiation-associated protein 5 antibody; Anti-SS-A Ab: Anti-Sjögren ’ s syndrome A antibody; Anti-TIF1- γ Ab: Anti-transcriptional intermediary factor 1- γ antibody; CADM: Clinically amyopathic dermatomyositis; CAM: Cancer- associated myositis; CK: Creatine kinase; CMV: Cytomegalovirus; CT: Computed tomography; DM: Dermatomyositis; HRCT: High-resolution computed tomography; IIM: Idiopathic inflammatory myopathies; ILD: Interstitial lung disease; IVCY: Intravenous cyclophosphamide; IVIg: Intravenous immunoglobulin; Jo-1: anti-histidyl-tRNA synthetase; mPSL: Intravenous methyl-prednisolone; MSA: Myositis-specific autoantibodies; OR: Odds ratio; PaCO 2 : arterial partial pressure of carbon dioxide; PM: Polymyositis;