Lung and airway disorders in immunoglobulin G4- related disease

gG4-related disease (IgG4-RD) is an immune-mediated condition, characterized by the formation of fibroinflammatory tumefactive lesions that can cause progressive tissue damage and subsequent organ failure. Although initially described as a disease of unknown etiology confined to the pancreas, IgG4-RD has been realized over time as an important entity that has underlies numerous pathologic conditions such as autoimmune pancreatitis, Riedel thyroiditis, Mikulicz syndrome, inflammatory pseudotumors and many others. IgG4-RD can affect almost any organ. However, the most commonly affected are the pancreas, hepatobiliary system, exocrine glands (salivary, lacri mal), retroperitoneum, kidneys and intrathoracic structures. Within the thorax, involvement of the lung parenchyma, airways, mediastinum, and pleura have been reported. The pulmonary involvement, therefore, is very diverse and can present as pulmonary nodule(s) or mass(es), alveolar or interstitial infiltrates, airflow obstruction, lymphadenopathy, mediastinal fibrosis, and pleural thickening and/or effusion. It is therefore important to recognize the diverse manifestations of this condition, as it can involve multiple organs and have various forms of expression within the same organ. As a consequence, IgG4-RD has presented a fascinating diagnostic challenge for many different specialties. In this review, we focus on the diagnosis and management of the intrathoracic involvement in this multisystem disease

Advances in the management of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease and usually results in progressive respiratory insufficiency and death. Steady progress has been made in understanding the pathogenesis of IPF and multiple clinical trials are ongoing, but effective therapy remains elusive

Spectrum of Disorders Associated with Elevated Serum IgG4 Levels Encountered in Clinical Practice

IgG4-related disease (IgG4-RD) is a recently described systemic fibroinflammatory disease associated with elevated circulating levels of IgG4 and manifests a wide spectrum of clinical presentations. Although serum IgG4 level has been described to be the most sensitive and specific laboratory test for the diagnosis of IgG4-RD, it is recognized that an elevated serum IgG4 level can be encountered in other diseases. In this study, we sought to identify the frequency of IgG4-RD and other disease associations in patients with elevated serum IgG4 levels seen in clinical practice. Among 3,300 patients who underwent IgG subclass testing over a 2-year period from January 2009 to December 2010, 158 (4.8%) had an elevated serum IgG4 level (>140 mg/dL). IgG4 subclass testing was performed for evaluation of suspected IgG4-RD or immunodeficiency. Twenty-nine patients (18.4%) had definite or possible IgG4-RD. Among those patients without IgG4-RD, a broad spectrum of biliary tract, pancreatic, liver, and lung diseases, as well as systemic vasculitis, was diagnosed. We conclude that patients with elevated serum IgG4 levels encountered in clinical practice manifest a wide array of disorders, and only a small minority of them has IgG4-RD

Increased IgG4-Positive Plasma Cells in Granulomatosis with Polyangiitis: A Diagnostic Pitfall of IgG4-Related Disease

Granulomatosis with polyangiitis (Wegener's) (GPA) may mimic IgG4-related disease (IgG4-RD) on histologic examination of some biopsies, especially those from head and neck sites. IgG4 immunostain is often performed in this context for differential diagnosis with IgG4-RD. However, the prevalence of IgG4+ cells in GPA has not been explored. We examined the IgG4+ cells in 26 cases confirmed as GPA by a thorough clinical and pathologic assessment. Twenty-six biopsies consisted of 14 sinonasal/oral cavity/nasopharynx, 7 orbit/periorbital, 3 lung/pleura, 1 iliac fossa/kidney, and 1 dura specimens. Eight of 26 (31%) biopsies revealed increased IgG4+ cells (>30/HPF and >40% in IgG4+/IgG+ ratio). The IgG4+ cells and IgG4+/IgG+ ratio ranged 37–137/hpf and 44–83%, respectively. Eight biopsies with increased IgG4+ cells were from sinonasal (n = 4) or orbital/periorbital (n = 4) sites. In conclusion, increased IgG4+ cells are not uncommonly seen in sinonasal or orbital/periorbital biopsies of GPA, which could pose as a diagnostic pitfall

Diagnosis of interstitial lung diseases: from Averill A. Liebow to artificial intelligence

Histopathologic criteria of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) were defined over the years and endorsed by leading organizations decades after Dr. Averill A. Liebow first coined the term UIP in the 1960s as a distinct pathologic pattern of fibrotic interstitial lung disease. Novel technology and recent research on interstitial lung diseases with genetic component shed light on molecular pathogenesis of UIP/IPF. Two antifibrotic agents introduced in the mid-2010s opened a new era of therapeutic approaches to UIP/IPF, albeit contentious issues regarding their efficacy, side effects, and costs. Recently, the concept of progressive pulmonary fibrosis was introduced to acknowledge additional types of progressive fibrosing interstitial lung diseases with the clinical and pathologic phenotypes comparable to those of UIP/IPF. Likewise, some authors have proposed a paradigm shift by considering UIP as a stand-alone diagnostic entity to encompass other fibrosing interstitial lung diseases that manifest a relentless progression as in IPF. These trends signal a pendulum moving toward the tendency of lumping diagnoses, which poses a risk of obscuring potentially important information crucial to both clinical and research purposes. Recent advances in whole slide imaging for digital pathology and artificial intelligence technology could offer an unprecedented opportunity to enhance histopathologic evaluation of interstitial lung diseases. However, current clinical practice trends of moving away from surgical lung biopsies in interstitial lung disease patients may become a limiting factor in this endeavor as it would be difficult to build a large histopathologic database with correlative clinical data required for artificial intelligence models

Saddle pulmonary embolism diagnosed by CT angiography: Frequency, clinical features and outcome

SummaryObjectiveTo assess the frequency, clinical presentation and outcome associated with saddle pulmonary embolism (PE) diagnosed by computed tomographic angiography (CTA).PatientsRetrospective review of 546 consecutive patients diagnosed to have acute PE by CTA from 1 September 2002 to 31 December 2003.ResultsFourteen of 546 patients (2.6%) had saddle PE; 10 were men (71%). None of these patients had pre-existing cardiopulmonary disease. Most common presenting symptoms included dyspnea (72%) and syncope (43%). Hypotension was documented in 2 patients (14%). The most common risk factor for PE was obesity (64%). CTA revealed saddle PE and additional filling defects in the main pulmonary arteries in all patients. Echocardiography was performed within 48h of the PE diagnosis in 10 patients and revealed right ventricular dysfunction in 8 (80%). All patients were initially managed in the hospital, median length of stay of 4 days (range, 1–45 days). Standard anticoagulant therapy with heparin and warfarin was administered to all patients. Five patients (36%) received additional therapy; thrombolytic therapy was administered to 1 patient (7%) and 4 patients (29%) received an inferior vena cava filter. None of the patients died during their hospitalization. Four patients (29%) died following their hospitalization after intervals of 1, 5, 6, and 12 months, respectively. Causes of death were known in 3 patients, all of whom died from progressive malignancy.ConclusionSaddle PE in patients without pre-existing cardiopulmonary disease is associated with a relatively low in-hospital mortality rate and may not necessitate aggressive medical management

Histopathologic Overlap between Fibrosing Mediastinitis and IgG4-Related Disease

Fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases). We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted

Iron deposition and increased alveolar septal capillary density in nonfibrotic lung tissue are associated with pulmonary hypertension in idiopathic pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Early diagnosis of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) has potential prognostic and therapeutic implications but can be difficult due to the lack of specific clinical manifestations or accurate non-invasive tests. Histopathologic parameters correlating with PH in IPF are also not known. Remodeling of postcapillary pulmonary vessels has been reported in the nonfibrotic areas of explanted lungs from IPF patients. We hypothesized that iron deposition and increased alveolar capillaries, the findings often seen in postcapillary PH, might predict the presence of clinical PH, independent of the severity of fibrosis or ventilatory dysfunction in IPF patients. To test this hypothesis, we examined the association between these histologic parameters and the degree of PH, with consideration of the severity of disease in IPF.</p> <p>Methods</p> <p>Iron deposition and alveolar septal capillary density (ASCD) were evaluated on histologic sections with hematoxylin-eosin, iron, elastin and CD34 stainings. Percentage of predicted forced vital capacity (FVC%) was used for grading pulmonary function status. Fibrosis score assessed on high resolution computed tomography (HRCT) was used for evaluating overall degree of fibrosis in whole lungs. Right ventricular systolic pressure (RVSP) by transthoracic echocardiography was used for the estimation of PH. Univariate and multivariate regression analyses were performed.</p> <p>Results</p> <p>A cohort of 154 patients was studied who had the clinicopathological diagnosis of IPF with surgical lung biopsies or explants during the period of 1997 to 2006 at Mayo Clinic Rochester. In univariate analysis, RVSP in our IPF cases was associated with both iron deposition and ASCD (p < 0.001). In multivariate analysis with FVC% and HRCT fibrosis score included, iron deposition (p = 0.02), but not ASCD (p = 0.076), maintained statistically significant association with RVSP. FVC% was associated with RVSP on univariate analysis but not on multivariate analysis, while fibrosis score lacked any association with RVSP by either univariate or multivariate analyses.</p> <p>Conclusions</p> <p>Iron deposition and ASCD in non fibrotic lung tissue showed an association with RVSP, suggesting that these features are possible morphologic predictors of PH in IPF.</p

Thermo-mechanical reliability of 3-D ICs containing through silicon vias

In 3-D interconnect structures, process-induced thermal stresses around through-silicon-vias (TSVs) raise serious reliability issues such as Si cracking and performance degradation of devices. In this study, the thermo-mechanical reliability of 3-D interconnect was investigated using finite element analysis (FEA) combined with analytical methods. FEA simulation demonstrated that the thermal stresses in silicon decrease as a function of distance from an isolated TSV and increase with the TSV diameter. Additional simulation suggested that hybrid TSV structures can significantly reduce the thermal stresses. An analytical stress solution was introduced to deduce the stress distribution around an isolated TSV, which was further developed to deduce the stress interaction in TSV arrays based on linear superposition of the analytical solution. We calculated the crack driving force in TSV lines under a thermal load. The effects of TSV diameter, pitch size, and the line configuration on crack driving force were investigated