Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease.

RATIONALE: Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. OBJECTIVES: Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. METHODS: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. MEASUREMENTS AND MAIN RESULTS: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. CONCLUSIONS: Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

CT virtual endoscopy in the evaluation of large airway disease: review.

OBJECTIVE: The purpose of this article is to illustrate the usefulness and limitations of CT virtual endoscopy in the evaluation of large airway disease. CONCLUSION: CT virtual endoscopy is a postprocessing tool that is easy to perform and that can aid in depicting disorders of the large airways without additional radiation or cost other than added time in postprocessing. The benefits of this technique include noninvasive diagnostic surveillance and preoperative planning.

Computed tomography and the idiopathic form of proliferative fibrosing mediastinitis.

Fibrosing mediastinitis is characterized by abnormal proliferation of acellular collagen and fibrous tissue in the mediastinum. Although most cases in the United States are attributed to Histoplasma capsulatum, there is a different and important idiopathic subset, with potentially different treatment and prognosis implications. We reviewed 12 such cases encountered from 1995 to 2004. Computed tomography showed that the masses were large, averaging 5 x 9 cm, with none showing significant calcification. Five had extension into the neck, and all had some vascular or airway involvement. Mimics may include the precalcific form of postinflammatory mediastinal fibrosis, mediastinal granuloma, malignancy (esp. lymphoma), sarcoidosis, and Castleman disease.

Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy.

RATIONALE: Neuroendocrine cell hyperplasia of infancy (NEHI) is a diffuse lung disease that presents in infancy and improves during childhood. Long-term outcomes have not previously been described. In one familial cohort, we have reported that NEHI is associated with a heterozygous variant of NKX2.1/TTF1. OBJECTIVES: Our objective was to determine whether pulmonary abnormalities persist in adults with NEHI, to aid in elucidating the natural history of this disease. METHODS: Four adult relatives with heterozygous NKX2.1 mutation and with clinical histories compatible with NEHI enrolled in a prospective study that included questionnaires, pulmonary function tests, and chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS: Mild radiologic abnormalities including mosaicism were seen in all four cases. Three individuals had obstruction on pulmonary function tests, two had marked air trapping, and three had symptomatic impairments with exercise intolerance. CONCLUSIONS: Although clinical improvement occurs over time, NEHI may result in lifelong pulmonary abnormalities in some cases. Further studies are required to better describe the natural history of this disease and would be facilitated by additional delineation of genetic mechanisms to enable improved case identification.

Revised curriculum on cardiothoracic radiology for diagnostic radiology residency with goals and objectives related to general competencies.

This document is a revision of a previously published cardiothoracic curriculum for diagnostic radiology residency, and reflects interval changes in the clinical practice of cardiothoracic radiology and changes in the Accreditation Council for Graduate Medical Education (ACGME) requirements for diagnostic radiology training programs. The revised ACGME Program Requirements for Residency Education in Diagnostic Radiology went into effect December 2003.

Histoplasmomas of uncommon size.

Histoplasma capsulatum infection demonstrates a broad spectrum of acute and chronic clinical manifestations. Unlike the acute reaction to proliferating organisms, the chronic complications are often the result of excessive or prolonged host response with a paucity of organisms. Lung nodules (histoplasmomas) may be noted decades after initial infection and present a challenging clinical problem, as they can be difficult to distinguish from malignancy or tuberculomas. Typically, histoplasmomas are small (<1 cm), asymptomatic, and may be stable in size or slowly enlarge over time. Here we report three patients with unusually large, or giant, histoplasmomas (>3 cm) and describe their extreme phenotype. Importantly, two of the patients presented with subacute symptomatic disease, a presentation that is very atypical for histoplasmoma. The term "buckshot" calcification has been used to describe dozens of small (2-4 mm) calcified nodules, so it may be appropriate to label masses that exceed 3 cm as "cannonball" histoplasmoma.

Added value of a serum proteomic signature in the diagnostic evaluation of lung nodules.

BACKGROUND: Current management of lung nodules is complicated by nontherapeutic resections and missed chances for cure. We hypothesized that a serum proteomic signature may add diagnostic information beyond that provided by combined clinical and radiographic data. METHODS: Cohort A included 265 and cohort B 114 patients. Using multivariable logistic regression analysis we calculated the area under the receiver operating characteristic curve (AUC) and quantified the added value of a previously described serum proteomic signature beyond clinical and radiographic risk factors for predicting lung cancer using the integration discrimination improvement (IDI) index. RESULTS: The average computed tomography (CT) measured nodule size in cohorts A and B was 37.83 versus 23.15 mm among patients with lung cancer and 15.82 versus 17.18 mm among those without, respectively. In cohort A, the AUC increased from 0.68 to 0.86 after adding chest CT imaging variables to the clinical results, but the proteomic signature did not provide meaningful added value. In contrast, in cohort B, the AUC improved from 0.46 with clinical data alone to 0.61 when combined with chest CT imaging data and to 0.69 after adding the proteomic signature (IDI of 20% P = 0.0003). In addition, in a subgroup of 100 nodules between 5 and 20 mm in diameter, the proteomic signature added value with an IDI of 15% (P ≤ 0.0001). CONCLUSIONS: The results show that this serum proteomic biomarker signature may add value to the clinical and chest CT evaluation of indeterminate lung nodules. IMPACT: This study suggests a possible role of a blood biomarker in the evaluation of indeterminate lung nodules.

Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC.

A man with usual interstitial pneumonia (age of onset 58 years) was previously found to have an Ile73Thr (I73T) surfactant protein C (SFTPC) mutation. Genomic DNA from the individual and two daughters (aged 39 and 43 years) was sequenced for the I73T mutation and variations in ATP-binding cassette A3 (ABCA3). All three had the I73T SFTPC mutation. The father and one daughter (aged 39 years) also had a transversion encoding an Asp123Asn (D123N) substitution in ABCA3. The daughters were evaluated by pulmonary function testing and high-resolution CT (HRCT). Neither daughter had evidence of disease, except for focal subpleural septal thickening on HRCT scan in one daughter (aged 39 years). This daughter underwent bronchoscopy with transbronchial biopsies revealing interstitial fibrotic remodeling. These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.