Hypersensitivity Pneumonitis: Updates in Evaluation, Management, and Ongoing Dilemmas.

Hypersensitivity pneumonitis (HP) is a heterogenous disease entity characterized by an aberrant immune response to inhalational antigens. Disease modification hinges on early antigen remediation with a goal to attenuate immune dysregulation. Disease severity and progression are mediated by an interface between degree, type and chronicity of exposure, genetic predisposition, and biochemical properties of the inducing agent. Guidelines have provided a standardized approach; however, decision-making remains with many clinical dilemmas. The delineation of fibrotic and nonfibrotic HP is crucial to identify the differences in clinical trajectories, and further clinical trials are needed to understand optimal therapeutic strategies.

Treatment Outcomes for Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Real-World, Multisite Study of the Impact of Immunosuppression on Pulmonary Function Trajectory.

BACKGROUND: Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice. RESEARCH QUESTION: How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD? STUDY DESIGN AND METHODS: Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia [UIP] vs non-UIP) on treatment trajectory. RESULTS: Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression. INTERPRETATION: Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings.

A Phase IIb Randomized Clinical Study of an Anti-αvß6 Monoclonal Antibody in Idiopathic Pulmonary Fibrosis.

Rationale: Treatment options for idiopathic pulmonary fibrosis (IPF) are limited. Objectives: To evaluate the efficacy and safety of BG00011, an anti-αvß6 IgG1 monoclonal antibody, in the treatment of patients with IPF. Methods: In a phase IIb randomized, double-blind, placebo-controlled trial, patients with IPF (FVC ⩾50% predicted, on or off background therapy) were randomized 1:1 to once-weekly subcutaneous BG00011 56 mg or placebo. The primary endpoint was FVC change from baseline at Week 52. Because of early trial termination (imbalance in adverse events and lack of clinical benefit), endpoints were evaluated at Week 26 as an exploratory analysis. Measurements and Main Results: One hundred six patients were randomized and received at least one dose of BG00011 (n = 54) or placebo (n = 52). At Week 26, there was no significant difference in FVC change from baseline between patients who received BG00011 (n = 20) or placebo (n = 23), least squares mean (SE) -0.097 L (0.0600) versus -0.056 L (0.0593), respectively (P = 0.268). However, after Week 26, patients in the BG00011 group showed a worsening trend. Eight (44.4%) of 18 who received BG00011 and 4 (18.2%) of 22 who received placebo showed worsening of fibrosis on high-resolution computed tomography at the end of treatment. IPF exacerbation/or progression was reported in 13 patients (all in the BG00011 group). Serious adverse events occurred more frequently in BG00011 patients, including four deaths. Conclusions: The results do not support the continued clinical development of BG00011. Further research is warranted to identify new treatment strategies that modify inflammatory and fibrotic pathways in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT03573505).

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study.

BACKGROUND: Recombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151-202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks. METHODS: Patients who completed the randomized PRM-151-202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis). RESULTS: All 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, - 6.2% (- 7.7; - 4.6) and - 5.7% (- 8.0; - 3.3) for percent predicted FVC and - 36.3 m (- 65.8; - 6.9) and - 28.9 m (- 54.3; - 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128. CONCLUSIONS: Long-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect. Trial registration NCT02550873; EudraCT 2014-004782-24.

Diagnosis, course and management of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a complex and heterogeneous interstitial lung disease (ILD) that occurs when susceptible individuals develop an exaggerated immune response to an inhaled antigen. In this review, we discuss the latest guidelines for the diagnostic evaluation of patients with suspected HP, the importance of identifying patients with fibrotic and progressive disease, and the evidence supporting the drugs commonly used in the treatment of HP. Differential diagnosis of HP can be challenging and requires a thorough exposure history, multidisciplinary discussion of clinical and radiologic data, and, in some cases, assessment of bronchoalveolar lavage lymphocytosis and histopathologic findings. Patients with HP may be categorised as having non-fibrotic or fibrotic HP. The presence of fibrosis is associated with worse outcomes. A proportion of patients with fibrotic HP develop a progressive phenotype, characterised by worsening fibrosis, decline in lung function and early mortality. There are no established guidelines for the treatment of HP. Antigen avoidance should be implemented wherever possible. Immunosuppressants are commonly used in patients with HP but have not been shown to slow the worsening of fibrotic disease. Nintedanib, a tyrosine kinase inhibitor, has been approved by the US Food and Drug Administration for slowing the progression of chronic fibrosing ILDs with a progressive phenotype, including progressive fibrotic HP. Non-pharmacological interventions, such as oxygen therapy, pulmonary rehabilitation and supportive care, may be important components of the overall care of patients with progressive HP.

The spectrum of progressive fibrosis interstitial lung disease: clinical and managed care considerations.

Progressive fibrosing interstitial lung diseases (ILDs) encompass a wide range of diseases, including hypersensitivity pneumonitis, occupational diseases, granulomatous diseases, drug-induced diseases, and idiopathic pneumonitis. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, understanding their clinical and economic impact presents significant challenges. Historically, treatment options for progressive fibrosing ILDs include anti-inflammatory drugs and immunosuppressive. The lack of effective options and guideline recommendations, however, has rendered treatment difficult. In March 2020, nintedanib was approved by the FDA for the treatment of patients with chronic fibrosing ILDs with a progressive phenotype, becoming the first therapeutic agent to receive an indication for this set of diseases. The approval was based on data from the phase 3 randomized, double-blind, placebo-controlled, parallel-group INBUILD trial. Questions regarding the cost of medications, their effects on disease and comorbidities, patient selection, and combination strategies remain to be answered.

Assessment of Optimal Screening Tests for the Detection of an Inflammatory Myositis-associated Interstitial Lung Disease.

Background Interstitial lung disease (ILD) is a common pathologic consequence of the idiopathic inflammatory myopathies, and it may be the initial presentation of autoimmune disease in many cases. There are no well-established guidelines to direct the evaluation of this disease in these cases. This study looked at the utility of four common serologic tests to screen for a myositis-associated ILD. Methods This is a single institution retrospective analysis of four common serologic tests (antinuclear antibody [ANA], creatine kinase [CK], aldolase, and anti-Sjögren's syndrome A [anti-SSA]) to detect a positive antibody on an extended myositis antibody panel. Results The serum aldolase was the most sensitive test to detect the presence of a positive antibody on an extended myositis antibody panel with a sensitivity of 54.5%. The anti-SSA was the least sensitive at 21.4%. A positive result for anti-SSA antibodies was associated with a 100% positive predictive value when all other screening tests (ANA, aldolase, and CK) were also positive.  Conclusion No single screening test was sufficient for the evaluation of a myositis-associated ILD. A positive serum aldolase had higher sensitivity, and a positive SSA had a high positive predictive value when other screening markers were also elevated, but clinicians still need to maintain a high index of suspicion for myositis-associated ILD.

Myocarditis Causing Premature Ventricular Contractions: Insights From the MAVERIC Registry.

BACKGROUND: Premature ventricular contractions are a common clinical presentation that drives further diagnostic workup. We hypothesize the presence of underlying inflammation is often unrecognized in these patients with a potential for continued disease progression if not diagnosed and treated early in the disease course. METHODS: This is a single-center, prospective study including 107 patients with frequent symptomatic premature ventricular contractions (>5000/24 h) and no known ischemic heart disease. Patients underwent a combination of laboratory testing, 18F-fluorodeoxyglucose positron emission tomography scan, cardiac magnetic resonance imaging, and biopsy. Patients were diagnosed with myocarditis based on a multidisciplinary approach and treated with immunosuppressive therapy. RESULTS: The mean age of the cohort was 57±15 years, 41% were males, and left ventricular ejection fraction was 47±11.8%. Positive positron emission tomography scan was seen in 51% (55/107), of which 51% (28/55) had preserved left ventricle function. Based on clinical profile, 18F-fluorodeoxyglucose-positron emission tomography imaging, cardiac magnetic resonance, and histological data 58% patients (32/55) received immunosuppressive therapy alone and 25.4% (14/55) received immunosuppressive therapy and catheter ablation. Optimal response was seen in 67% (31/46) over a mean follow-up of 6±3 months. In patients with left ventricle systolic dysfunction, 37% (10/27) showed an improvement in mean left ventricular ejection fraction of 13±6%. CONCLUSIONS: Approximately 51% of patients presenting with frequent premature ventricular contractions have underlying myocardial inflammation in this cohort. 18F-fluorodeoxyglucose-positron emission tomography scan can be a useful modality for early diagnosis and treatment with immunosuppressive therapy in selected patients can improve clinical outcomes.

Long-term treatment with recombinant human pentraxin 2 protein in patients with idiopathic pulmonary fibrosis: an open-label extension study.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. METHODS: Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. FINDINGS: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224). INTERPRETATION: Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF. FUNDING: Promedior.

Effect of Recombinant Human Pentraxin 2 vs Placebo on Change in Forced Vital Capacity in Patients With Idiopathic Pulmonary Fibrosis: A Randomized Clinical Trial.

Importance: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. Approved therapies do not halt disease progression. Objective: To determine the effect of recombinant human pentraxin 2 vs placebo on change from baseline to week 28 in mean forced vital capacity (FVC) percentage of predicted value. Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 7 countries of eligible patients with IPF (N = 117; aged 40-80 years; FVC ≥50% and ≤90% predicted; ratio of forced expiratory volume in the first second/FVC >0.70; diffusing capacity for carbon monoxide [Dlco] ≥25% and ≤90% predicted; and distance of ≥150 m on the 6-minute walk test). Study period was August 2015-May 2017. Interventions: Patients were randomized to receive either recombinant human pentraxin 2 (10 mg/kg intravenous every 4 weeks, n = 77) or placebo (n = 39) for 24 weeks, and stratified by concurrent IPF treatment status. Main Outcomes and Measures: The primary end point was the least-squares mean change in FVC percentage of predicted value from baseline to week 28 (minimal clinically important difference, decline of 2%-6%). Secondary end points included mean change in lung volumes (total, normal, and interstitial lung abnormalities) on high-resolution computed tomography (HRCT) and 6-minute walk distance (minimal clinically important difference, 24-45 m). Results: Of 117 randomized patients, 116 received at least 1 dose of study drug (mean age, 68.6 years; 81.0% men; mean time since IPF diagnosis, 3.8 years), and 111 (95.7%) completed the study. The least-squares mean change in FVC percentage of predicted value from baseline to week 28 in patients treated with recombinant human pentraxin 2 was -2.5 vs -4.8 for those in the placebo group (difference, +2.3 [90% CI, 1.1 to 3.5]; P = .001). No significant treatment differences were observed in total lung volume (difference, 93.5 mL [90% CI, -27.7 to 214.7]), quantitative parenchymal features on HRCT (normal lung volume difference, -1.2% [90% CI, -4.4 to 1.9]; interstitial lung abnormalities difference, 1.1% [90% CI, -2.2 to 4.3]), or measurement of Dlco (difference, -0.4 [90% CI, -2.6 to 1.7]). The change in 6-minute walk distance was -0.5 m for patients treated with recombinant human pentraxin 2 vs -31.8 m for those in the placebo group (difference, +31.3 m [90% CI, 17.4 to 45.1]; P < .001). The most common adverse events in the recombinant human pentraxin 2 vs placebo group were cough (18% vs 5%), fatigue (17% vs 10%), and nasopharyngitis (16% vs 23%). Conclusions and Relevance: In this preliminary study, recombinant human pentraxin 2 vs placebo resulted in a slower decline in lung function over 28 weeks for patients with idiopathic pulmonary fibrosis. Further research should more fully assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT02550873.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series.

OBJECTIVE: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-α. METHODS: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. RESULTS: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. CONCLUSIONS: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis.

In chronic hypersensitivity pneumonitis (CHP), lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs) and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA), 93 (71%) received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC) and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04) and 66% less frequent with mycophenolate mofetil (p=0.002). FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

Lovastatin Inhibits Low Molecular Weight Hyaluronan Induced Chemokine Expression via LFA-1 and Decreases Bleomycin-Induced Pulmonary Fibrosis.

BACKGROUND: Lovastatin has a unique ability to bind Leukocyte Function Antigen-1 (LFA-1), an integrin necessary for the full expression of inflammatory cytokines induced by the low molecular weight form of the extracellular matrix glycosaminoglycan hyaluronan (LMW HA). We hypothesized that lovastatin could inhibit LMW HA inflammatory signals via interaction with LFA-1, and attenuate bleomycin induced pulmonary fibrosis. METHODS: We evaluated the effects of lovastatin, pravastatin, LFA-1 blocking antibodies, and a novel LFA-1 inhibitor LFA 878 on LMW HA induced cytokine production in alveolar macrophages. We evaluated the effect of lovastatin in a bleomycin model of lung injury. RESULTS: Lovastatin immediately inhibited the LMW HA induced cytokine MIP 1-α (p=0.001) independent of HMG CoA reductase. Pravastatin showed no inhibitory profile when administered simultaneously with LMW HA. LFA-1 blocking antibodies and the small molecule statin derivative LFA 878 showed an inhibitory profile similar to lovastatin. Lovastatin showed decreased fibrosis on histopathology and improved survival at day 14, with a decrease in fibrocytes noted at day 8. CONCLUSION: Lovastatin and LFA 878 inhibit LMW HA inflammatory signaling independent of HMG-CoA decreasing the chemotactic cytokine MIP 1-α. Lovastatin treatment improves survival in bleomycin lung injury with decreased fibrocytes and fibrosis.

Hyaluronan fragments induce IFNß via a novel TLR4-TRIF-TBK1-IRF3-dependent pathway.

BACKGROUND: The extracellular matrix plays a critical role in insuring tissue integrity and water homeostasis. However, breakdown products of the extracellular matrix have emerged as endogenous danger signals, designed to rapidly activate the immune system against a potential pathogen breach. Type I interferons play a critical role in the immune response against viral infections. In the lungs, hylauronan (HA) exists as a high molecular weight, biologically inert extracellular matrix component that is critical for maintaining lung function. When lung tissue is injured, HA is broken down into lower molecular weight fragments that alert the immune system to the breach in tissue integrity by activating innate immune responses. HA fragments are known to induce inflammatory gene expression via TLR-MyD88-dependent pathways. METHODS: Primary peritoneal macrophages from C57BL/6 wild type, TLR4 null, TLR3 null, MyD88 null, and TRIF null mice as well as alveolar and peritoneal macrophage cell lines were stimulated with HA fragments and cytokine production was assessed by rt-PCR and ELISA. Western blot analysis for IRF3 was preformed on cell lysates from macrophages stimulate with HA fragments RESULTS: We demonstrate for the first time that IFNß is induced in murine macrophages by HA fragments. We also show that HA fragments induce IFNß using a novel pathway independent of MyD88 but dependent on TLR4 via TRIF and IRF-3. CONCLUSIONS: Overall our findings reveal a novel signaling pathway by which hyaluronan can modulate inflammation and demonstrate the ability of hyaluronan fragments to induce the expression of type I interferons in response to tissue injury even in the absence of viral infection. This is independent of the pathway of the TLR2-MyD88 used by these matrix fragments to induce inflammatory chemokines. Thus, LMW HA may be modifying the inflammatory milieu simultaneously via several pathways.

Surfactant addition and alternating current electrophoretic oscillation during size fractionation of nanoparticles in channels with two or three different height segments.

An array of parallel planar nanochannels containing two or three segments with varying inner heights was fabricated and used for size fractionation of inorganic and biological nanoparticles. A liquid suspension of the particles was simply drawn through the nanochannels via capillary action. Using fluorescently labeled 30 nm polyacrylonitrile beads, different trapping behaviors were compared using nanochannels with 200-45 nm and 208-54-30 nm height segments. Addition of sodium dodecyl sulfate (SDS) surfactant to the liquid suspension and application of an AC electric field were shown to aid in the prevention of channel clogging. After initial particle trapping at the segment interfaces, significant particle redistribution occurred when applying a sinusoidal 8V peak-to-peak oscillating voltage with a frequency of 150 Hz and DC offset of 4V. Using the 208-54-30 nm channels, 30 nm hepatitis B virus (HBV) capsids were divided into three fractions. When the AC electric field was applied to this trapped sample, all of the virus particles passed through the interfaces and accumulated at the channel ends.

Capillary flow in sacrificially etched nanochannels.

Planar nanochannels are fabricated using sacrificial etching technology with sacrificial cores consisting of aluminum, chromium, and germanium, with heights ranging from 18 to 98 nm. Transient filling via capillary action is compared against the Washburn equation [E. W. Washburn, Phys. Rev. 17, 273 (1921)], showing experimental filling speeds significantly lower than classical continuum theory predicts. Departure from theory is expressed in terms of a varying dynamic contact angle, reaching values as high as 83° in channels with heights of 18 nm. The dynamic contact angle varies significantly from the macroscopic contact angle and increases with decreasing channel dimensions.

Rheumatoid arthritis-associated interstitial lung disease: diagnostic dilemma.

Interstitial lung disease (ILD) is an increasingly recognized complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Diagnosis can be challenging since patients are unlikely to report dyspnea due to an overall decrease in physical activity with advanced arthritic symptoms. Additionally, infections, drug toxicity, and environmental toxins can mimic ILD, creating significant diagnostic dilemmas for the clinician. In this paper we will explore an effective clinical algorithm for the diagnosis of RA-ILD. We will also discuss features of drug-related toxicities, infections, and environmental toxins that comprise the main entities in the differential diagnosis of RA-ILD. Finally, we will explore the known and experimental treatment options that may have some benefit in the treatment of RA-ILD.

Selective trapping and concentration of nanoparticles and viruses in dual-height nanofluidic channels.

Nanofluidic systems offer advantages for chemical analysis, including small sample volumes, size-selective particle trapping, sample concentration and the ability to separate and detect single molecules. Such systems can be fabricated using planar nanochannels, which rely on standard photolithographic techniques. Nanochannel fluid flow can be driven by capillary action, which benefits from simple injection and reasonably high flow rates. We demonstrate an analysis chip fabricated with planar nanochannels that consist of two adjoining segments of different heights. When nano-analytes elute through the channel, they become physically trapped when the channel dimensions shrink below the size of the particles. We demonstrate the capability of these devices to trap and concentrate by using the following: 120-nm polymer beads, 30-nm polymer beads, Herpes simplex virus 1 capsids, and hepatitis B virus capsids. Each species was fluorescently labeled and its resulting fluorescent signal was detected using a cooled CCD camera. We show how the signal-to-noise ratio of trapped analyte intensity varies linearly with analyte concentration. The goal of this work is to eventually perform size-based fractionation of a variety of nanoparticles, including biomolecules such as proteins.

Thin film electro-osmotic pumps for biomicrofluidic applications.

Electro-osmotic flow (EOF) pumps are attractive for fluid manipulation in microfluidic channels. Open channel EOF pumps can produce high pressures and flow rates, and are relatively easy to fabricate on-chip or integrate with other microfluidic or electrical components. An EOF pump design that is conducive to on-chip fabrication consists of multiple small channel arms feeding into a larger flow channel. We have fabricated this type of pump design using a thin film deposition process that avoids wafer bonding. We have evaluated pumps fabricated on both silicon and glass substrates. Consistent flow rate versus electric field were obtained. For the range of 40-400 V, flow rates of 0.19-2.30 muLmin were measured. Theoretical calculations of pump efficiency were made, as well as calculations of the mechanical power generated by various pump shapes, to investigate design parameters that should improve future pumps.