Antisynthetase syndrome-related interstitial lung disease (ASyS-ILD): longitudinal imaging findings.

OBJECTIVES: Interstitial lung disease (ILD) impacts mortality in antisynthetase syndrome (ASyS). Computed tomographic (CT) patterns and evolution in ASyS ILD are not well described. We report longitudinal CT patterns in ASyS-ILD and their impact on survival. METHODS: This is a monocentric retrospective study of 47 patients with ASyS-ILD. Longitudinal CT patterns and fibrosis severity (severity of radiographic features indicating fibrosis) were analyzed by two radiologists in consensus. The association between imaging features and survival was examined using univariate Cox regression analysis. RESULTS: In total, 211 CT scans were analyzed with an average of 4 ± 2 CT scans/patient with a median follow-up of 79 months in 47 patients. Non-fibrotic patterns were present initially in 63.8% (n = 30) of patients, while fibrotic patterns occurred in 36.2% (n = 17). The initial non-fibrotic patterns/abnormalities resolved in 23.3% (n = 7), evolved in 6.7% (n = 2), persisted in 13.3% (n = 4), and progressed in 56.7% (n = 17), while initial fibrotic patterns persisted in 82.4% (n = 14) and progressed in 17.6% (n = 3). Radiographic progression of ILD (progression in CT pattern or increased fibrosis severity) occurred in 53.2% (n = 25) of patients. Advanced age and radiographic progression were associated with decreased survival (all p < 0.05). The presence of ground-glass opacities (GGO) and predominant lower lung distribution of abnormalities on initial CTs were associated with increased survival (all p < 0.05). CONCLUSION: Progression occurred in 56.7% of ASyS-ILD patients presenting with non-fibrotic patterns. Fibrotic patterns tended to persist. Age and radiographic progression were associated with reduced survival while the initial presence of GGO and predominant lower lobe distribution were associated with increased survival. KEY POINTS: • In ASyS-ILD, initial non-fibrotic patterns such as OP, cNSIP, or OP-cNSIP tended to progress to fNSIP. • Fibrotic patterns such as fNSIP or UIP in ASyS-ILD tended to persist without pattern changes. • GGO and lower lung predominance on initial CT were associated with better survival while advanced baseline age and radiographic ILD progression during follow-up were associated with decreased survival.

Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage.

Rett syndrome (RTT) is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in the gene Methyl-CpG-binding protein 2 (MECP2), which encodes the MeCP2 protein. RTT is a MECP2-related disorder, along with MECP2 duplication syndrome (MDS), caused by gain-of-function duplications of MECP2. Nearly two decades of research have advanced our knowledge of MeCP2 function in health and disease. The following review will discuss MeCP2 protein function and its dysregulation in the MECP2-related disorders RTT and MDS. This will include a discussion of the genetic underpinnings of these disorders, specifically how sporadic X-chromosome mutations arise and manifest in specific populations. We will then review current diagnostic guidelines and clinical manifestations of RTT and MDS. Next, we will delve into MeCP2 biology, describing the dual landscapes of methylated DNA and its reader MeCP2 across the neuronal genome as well as the function of MeCP2 as a transcriptional modulator. Following this, we will outline common MECP2 mutations and genotype-phenotype correlations in both diseases, with particular focus on mutations associated with relatively mild disease in RTT. We will also summarize decades of disease modeling and resulting molecular, synaptic, and behavioral phenotypes associated with RTT and MDS. Finally, we list several therapeutics in the development pipeline for RTT and MDS and available evidence of their safety and efficacy.

Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder caused predominantly by loss-of-function mutations in MECP2, encoding transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Although no disease-modifying therapies exist at this time, some proposed therapeutic strategies aim to supplement the mutant allele with a wild-type allele producing typical levels of functional MeCP2, such as gene therapy. Because MECP2 is a dosage-sensitive gene, with both loss and gain of function causing disease, these approaches must achieve a narrow therapeutic window to be both safe and effective. While MeCP2 supplementation rescues RTT-like phenotypes in mouse models, the tolerable threshold of MeCP2 is not clear, particularly for partial loss-of-function mutations. We assessed the safety of genetically supplementing full-length human MeCP2 in the context of the R294X allele, a common partial loss-of-function mutation retaining DNA-binding capacity. We assessed the potential for adverse effects from MeCP2 supplementation of a partial loss-of-function mutant and the potential for dominant negative interactions between mutant and full-length MeCP2. In male hemizygous R294X mice, MeCP2 supplementation rescued RTT-like behavioral phenotypes and did not elicit behavioral evidence of excess MeCP2. In female heterozygous R294X mice, RTT-specific phenotypes were similarly rescued. However, MeCP2 supplementation led to evidence of excess MeCP2 activity in a motor coordination assay, suggesting that the underlying motor circuitry is particularly sensitive to MeCP2 dosage in females. These results show that genetic supplementation of full-length MeCP2 is safe in males and largely so females. However, careful consideration of risk for adverse motor effects may be warranted for girls and women with RTT.

R-scale for pulmonary fibrosis: a simple, visual tool for the assessment of health-related quality of life.

RATIONALE: Patients with idiopathic pulmonary fibrosis (IPF) experience impaired health-related quality of life (HRQoL). Several tools have been developed to objectively assess HRQoL in this patient population, but none are in use in routine clinical practice. OBJECTIVES: To develop a rapid, specific tool that can be used for patients with IPF during routine clinic visits. METHODS: A novel and simple five-item numerical rating scale was developed and compared with two other previously validated tools. 100 consecutive patients with IPF managed at a centre for interstitial lung disease were recruited to complete the Raghu scale for pulmonary fibrosis (R-Scale-PF), King's Brief Interstitial Lung Disease questionnaire (K-BILD), and the EuroQol Five-Dimensional Five-Level questionnaire (EQ-5D-5L) in addition to pulmonary function and 6-min walk tests. MEASUREMENTS AND MAIN RESULTS: All 100 patients successfully completed the three HRQoL tools with 53 completing them again at follow-up visits. Internal consistency was high (Cronbach's α 0.825) with minimal floor/ceiling effect. Concurrent validity of the R-Scale-PF was moderate to high compared with the K-BILD (r=-0.713) and the EQ-5D-5L (r=-0.665). Concurrent validity was moderate with physiologic measures (forced vital capacity, r=-0.307, 6-min walking distance, r=-0.383). The R-Scale-PF demonstrated good known-groups validity when comparing scores across stages of disease severity. CONCLUSIONS: The R-Scale-PF correlates well with the K-BILD and EQ-5D-5L. It is hoped that this novel simple numerical rating scale tool, subject to validation in patients from other centres, will provide an opportunity to objectively measure HRQoL in routine clinical practice for patients with IPF.

Diagnosis and Management of Fibrotic Interstitial Lung Diseases.

Nonidiopathic pulmonary fibrosis (non-IPF) progressive fibrotic interstitial lung diseases (PF-ILDs) are a heterogeneous group of ILDs, often challenging to diagnose, although an accurate diagnosis has significant implications for both treatment and prognosis. A subgroup of these patients experiences progressive deterioration in lung function, physical performance, and quality of life after conventional therapy. Risk factors for ILD progression include older age, lower baseline pulmonary function, and a usual interstitial pneumonia pattern. Management of non-IPF P-ILD is both pharmacologic and nonpharmacologic. Antifibrotic drugs, originally approved for IPF, have been considered in patients with other fibrotic ILD subtypes, with favorable results in clinical trials.

Identification and Remediation of Environmental Exposures in Patients With Interstitial Lung Disease: Evidence Review and Practical Considerations.

A relationship between inhalational exposure to materials in the environment and development of interstitial lung disease (ILD) is long recognized. Hypersensitivity pneumonitis is an environmentally -induced diffuse parenchymal lung disease. In addition to hypersensitivity pneumonitis, domestic and occupational exposures have been shown to influence onset and progression of other ILDs, including idiopathic interstitial pneumonias such as idiopathic pulmonary fibrosis. A key component of the clinical evaluation of patients presenting with ILD includes elucidation of a complete exposure history, which may influence diagnostic classification of the ILD as well as its management. Currently, there is no standardized approach to environmental evaluation or remediation of potentially harmful exposures in home or workplace environments for patients with ILD. This review discusses evidence for environmental contributions to ILD pathogenesis and draws on asthma and occupational medicine literature to frame the potential utility of a professional evaluation for environmental factors contributing to the development and progression of ILD. Although several reports suggest benefits of environmental assessment for those with asthma or certain occupational exposures, lack of information about benefits in broader populations may limit application. Determining the feasibility, long-term outcomes, and cost-effectiveness of environmental evaluation and remediation in acute and chronic ILDs should be a focus of future research.

Survival predictors of interstitial lung disease in India: Follow-up of Interstitial Lung Disease India registry.

BACKGROUND: Predictors of survival for interstitial lung disease (ILD) in the Indian population have not been studied. The primary objective of the study was to assess the Modified-Gender Age and Physiology (M-GAP) score to predict survival in patients with ILD seen in clinical practice. We also analyzed the role of demographic and radiological characteristics in predicting the survival of patients with ILD. MATERIALS AND METHODS: In the ILD India registry, data were collected from 27 centers across 19 cities in India between March 2012 and June 2015. A single follow-up was conducted at 18 centers who agreed to participate in the follow-up in 2017. M-GAP score (range 0-5) was calculated with the following variables: age (≤60 years 0, 61-65 years 1, and >65 years 2), gender (female 0, male 1), and forced vital capacity% (>75% 0, 50%-75% 1, and >75% 2). A score of 0-3 and score of 4 and 5 were classified into Stage 1 and 2, respectively. Other predictors of survival, such as the history of tuberculosis, smoking, and the presence of honeycombing on computed tomography scan, were also evaluated. RESULTS: Nine hundred and seven patients were contacted in 2017. Among them, 309 patients were lost to follow-up; 399 were alive and 199 had died. M-GAP was significantly associated with survival. Similarly, other predictors of survival were ability to perform spirometry (hazard ratio [HR]: 0.49, 95% confidence interval [CI]: 0.34-0.72), past history of tuberculosis (HR: 1.57, 95% CI: 1.07-2.29), current or past history of smoking (HR: 1.51, 95% CI: 1.06-2.16), honeycombing (HR: 1.81, 95% CI: 1.29-2.55), a diagnosis of connective tissue disease -ILD (HR: 0.41, 95% CI: 0.22-0.76), and sarcoidosis (HR: 0.24, 95% CI: 0.08-0.77). CONCLUSION: In a subgroup of patients with newly diagnosed ILD enrolled in ILD India registry and who were available for follow-up, M-GAP score predicted survival. Honeycombing at the time of diagnosis, along with accurate history of smoking, and previous history of tuberculosis were useful indices for predicting survival.

Systemic sclerosis-associated interstitial lung disease.

PURPOSE OF REVIEW: In this review, the authors discuss systemic sclerosis-associated interstitial lung disease (SSc-ILD) with a focus on recent developments in diagnosis, surveillance, and management. RECENT FINDINGS: With advances in the management of SSc, the importance of ILD has been increasingly recognized and is the leading cause of mortality. Early detection is essential, and a combination of lung function testing and chest imaging are key tools in diagnosis and surveillance. The foundation of treatment is immunomodulation with recent studies identifying several potential new agents. The use of therapies targeting pro-fibrotic pathways have demonstrated significant effects on lung function decline and represent the latest advance in therapy for SSc-ILD. SUMMARY: Recent studies support the use of newer therapies in SSc-ILD including antifibrotic agents. The identification and management of comorbidities is important, and lung transplantation is a viable option for patients with advanced disease.

Diagnosis of Hypersensitivity Pneumonitis in Adults. An Official ATS/JRS/ALAT Clinical Practice Guideline.

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.

Detection of SARS-CoV-2 by bronchoscopy after negative nasopharyngeal testing: Stay vigilant for COVID-19.

PURPOSE: Real-time polymerase chain reaction (RT-PCR) detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is required for diagnosis of coronavirus disease 2019 (COVID-19). Sensitivity of RT-PCR nasopharyngeal (NP) testing is presumed to be high, but there is no gold standard against which this has been determined. The objective was to determine whether lower respiratory tract infection (LRTI), detected in bronchoalveolar lavage fluid (BALF), occurs in the absence of upper respiratory tract infection with clinical testing of both specimen types. METHODS: Between March 26, 2020 and April 17, 2020 at the University of Washington Medical Center all patients with BALF specimens clinically tested for SARS-CoV-2 were identified. We assessed the proportion of patients with positive RT-PCR for SARS-CoV-2 in BALF after negative NP testing. We describe 3 cases with positive testing in BALF. RESULTS: Among 16 patients with BALF samples, 3 cases (19%) had SARS-CoV-2 detected in BALF. In Case 1, negative NP testing occurred early in the infection and respiratory symptoms may have been missed due to neurologic injury. In Case 2, outpatient diagnosis was aspiration pneumonia, but clinical suspicion remained high for COVID-19 at hospitalization based on epidemiological and clinical features. All 3 cases involved older adults (age >65 years), one of whom was immunosuppressed in the setting of lung transplantation (Case 3). CONCLUSIONS: These data demonstrate that SARS-CoV-2 LRTI occurs in the presence of negative NP testing. NP testing may underestimate the prevalence of COVID-19 and has implications for spread of SARS-CoV2 in the community and healthcare setting.

Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). More than 35% of affected individuals have nonsense mutations in MECP2. For these individuals, nonsense suppression has been suggested as a possible therapeutic approach. To assess the viability of this strategy, we created and characterized a mouse model with the common p.R294X mutation introduced into the endogenous Mecp2 locus (Mecp2R294X). Mecp2R294X mice exhibit phenotypic abnormalities similar to those seen in complete null mouse models; however, these occur at a later time point consistent with the reduced phenotypic severity seen in affected individuals containing this specific mutation. The delayed onset of severe phenotypes is likely due to the presence of truncated MeCP2 in Mecp2R294X mice. Supplying the MECP2 transgene in Mecp2R294X mice rescued phenotypic abnormalities including early death and demonstrated that the presence of truncated MeCP2 in these mice does not interfere with wild-type MeCP2. In vitro treatment of a cell line derived from Mecp2R294X mice with the nonsense suppression agent G418 resulted in full-length MeCP2 protein production, demonstrating feasibility of this therapeutic approach. Intraperitoneal administration of G418 in Mecp2R294X mice was sufficient to elicit full-length MeCP2 protein expression in peripheral tissues. Finally, intracranial ventricular injection of G418 in Mecp2R294X mice induced expression of full-length MeCP2 protein in the mouse brain. These experiments demonstrate that translational read-through drugs are able to suppress the Mecp2 p.R294X mutation in vivo and provide a proof of concept for future preclinical studies of nonsense suppression agents in RTT.

Clinical manifestations and treatment of antisynthetase syndrome.

Antisynthetase syndrome (ASyS) is an autoimmune disease clinically manifested most often by interstitial lung disease, myositis, and arthritis. Raynaud's syndrome, fever, and rashes are also commonly seen. This syndrome is characterized by the highly specific presence of antibodies against various aminoacyl transfer RNA synthetases, including Jo-1 and others. In this chapter, we provide an overview of ASyS, including pathogenesis, common clinical manifestations, and treatment strategies. We discuss the spectrum of disease seen with specific antisynthetase antibodies and examine the differences in phenotype between patients with different antisynthetase antibodies. We outline common treatment strategies, which should generally target the most severe and life- or organ-threatening disease manifestations. Finally, we discuss short- and long-term prognosis in ASyS.

Hypersensitivity pneumonitis: Clinical manifestations - Prospective data from the interstitial lung disease-India registry.

CONTEXT: Multiple environmental factors are associated with development of hypersensitivity pneumonitis (HP), and diagnostic algorithms for the diagnosis of HP have been proposed in recent perspectives. AIMS: We analyzed the data of patients with HP from interstitial lung disease (ILD)-India registry. The analysis was performed to (1) find the prevalence of HP, (2) reclassify HP as per a recently proposed classification criterion to assess the level of diagnostic certainty, and (3) identify the causative agents for HP. SETTING AND DESIGNS: This was a prospective multicenter study of consecutive, consenting adult patients with new-onset ILD from 27 centers across India (March 2012-April 2015). MATERIALS AND METHODS: The diagnoses were based on prespecified working clinical criteria and multidisciplinary discussions. To assess strength of diagnosis based on available clinical information, patients with HP were subclassified into definite HP, HP with high level of confidence, and HP with low level of confidence using a recent classification scheme. RESULTS: Five hundred and thirteen of 1084 patients with new-onset ILD were clinically diagnosed with HP and subclassified as HP with high level of confidence (380, 74.1%), HP with low level of confidence (106, 20.7%), and definite HP (27, 5.3%). Exposures among patients with HP were birds (odds ratios [OR]: 3.52, P < 0.001), air-conditioners (OR: 2.23, P < 0.001), molds (OR: 1.79, P < 0.001), rural residence (OR: 1.64, P < 0.05), and air-coolers (OR: 1.45, P < 0.05). CONCLUSIONS: About 47.3% of patients with new-onset ILD in India were diagnosed with HP, the majority of whom were diagnosed as HP with a high level of confidence. The most common exposures were birds, cooling devices, and visible molds.