Joshua Sill

Cardiopulmonary exercise test interpretation using age-matched controls to evaluate exertional dyspnea.

BACKGROUND Cardiopulmonary exercise testing (CPET) is one method to diagnose unexplained dyspnea in young adults, yet few normal reference values exist in this population. This study evaluated interpretation of maximal CPET in a young adult cohort with known pulmonary disorders using published reference values compared to age-matched normal controls. METHODS A control population of 69 healthy military volunteers with normal chest radiographs, pulmonary function testing, and bronchoprovocation testing were compared to 105 patients with exertional dyspnea. Both groups underwent a standardized evaluation including CPET on a graded exercise treadmill to maximal exercise with expired gas analysis. RESULTS Measurements from CPET in the dyspnea group were interpreted using published reference values compared to control population results (mean +/- 1.65 x SD). Statistical comparison of predicted normals (reference vs. control) of maximal oxygen consumption (> 83% vs. 82%), ventilatory anaerobic threshold (> 40% vs. 53%), respiratory rate (< 60 vs. 56 breaths/min), tidal volume to inspiratory capacity (< 80% vs. 111%), ventilatory equivalent for carbon dioxide production (< 40 vs. 38), and maximal voluntary ventilation minus minute ventilation (> 11 vs. -1 L/min) was performed. The overall specificity for tidal volume to inspiratory capacity improved using age-matched controls but sensitivity was decreased. Other parameters were not significantly different. CONCLUSIONS The use of age-matched controls for CPET results in an increase in specificity and decrease in sensitivity for respiratory limitations to exercise, when compared to reference values. The study findings suggest that CPET may be insensitive in detecting mild disease in young healthy adults.

An Unusual Electrophoresis

A 41-year-old white male patient presented to the pulmonary clinic complaining of chronic exertional dyspnea. He had a 15-year history of smoking, but no prior diagnosis of lung disease. A comprehensive battery of laboratory tests was performed. Results for complete blood count, serum chemistry panel, hepatic function tests, and inflammatory markers were within reference intervals. …

Nodular granulomatous Pneumocystis jiroveci pneumonia consequent to delayed immune reconstitution inflammatory syndrome

Although Pneumocystis jiroveci pneumonia (PCP) is a frequent manifestation of acquired immune deficiency syndrome (AIDS), the granulomatous form is uncommon. Here, we present an unusual case of granulomatous PCP consequent to immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy. A 36-year-old woman with human immunodeficiency virus (HIV) presented with cough and dyspnea that were attributed to typical PCP associated with AIDS. She was successfully treated with antibiotic, steroid, and antiretroviral therapies. After six months, however, she presented with consolidating lung lesions caused by bronchial obstruction from PCP granulomatous disease. Although antibiotics were ineffective, the effectiveness of steroid therapy suggested a diagnosis of granulomatous IRIS caused by persistent PCP antigens. Physicians should strongly suspect PCP in HIV-positive patients with nodular lung lesions and must remain aware that these lesions, if immune in origin, might not respond to antimicrobial therapy.

Inhaled TRIM72 Protein Protects Ventilation Injury to the Lung through Injury-guided Cell Repair

&NA; Studies showed that TRIM72 is essential for repair of alveolar cell membrane disruptions, and exogenous recombinant human TRIM72 protein (rhT72) demonstrated tissue‐mending properties in animal models of tissue injury. Here we examine the mechanisms of rhT72‐mediated lung cell protection in vitro and test the efficacy of inhaled rhT72 in reducing tissue pathology in a mouse model of ventilator‐induced lung injury. In vitro lung cell injury was induced by glass beads and stretching. Ventilator‐induced lung injury was modeled by injurious ventilation at 30 ml/kg tidal volume. Affinity‐purified rhT72 or control proteins were added into culture medium or applied through nebulization. Cellular uptake and in vivo distribution of rhT72 were detected by imaging and immunostaining. Exogenous rhT72 maintains membrane integrity of alveolar epithelial cells subjected to glass bead injury in a dose‐dependent manner. Inhaled rhT72 decreases the number of fatally injured alveolar cells, and ameliorates tissue‐damaging indicators and cell injury markers after injurious ventilation. Using in vitro stretching assays, we reveal that rhT72 improves both cellular resilience to membrane wounding and membrane repair after injury. Image analysis detected rhT72 uptake by rat alveolar epithelial cells, which can be inhibited by a cholesterol‐disrupting agent. In addition, inhaled rhT72 distributes to the distal lungs, where it colocalizes with phosphatidylserine detection on nonpermeabilized lung slices to label wounded cells. In conclusion, our study showed that inhaled rhT72 accumulates in injured lungs and protects lung tissue from ventilator injury, the mechanisms of which include improving cell resilience to membrane wounding, localizing to injured membrane, and augmenting membrane repair.

Inhibition of Macrophage Complement Receptor CRIg by TRIM72 Polarizes Innate Immunity of the Lung

Abstract The complement system plays a critical role in immune responses against pathogens. However, its identity and regulation in the lung are not fully understood. This study aimed to explore the role of tripartite motif protein (TRIM) 72 in regulating complement receptor (CR) of the Ig superfamily (CRIg) in alveolar macrophage (AM) and innate immunity of the lung. Imaging, absorbance quantification, and flow cytometry were used to evaluate in vitro and in vivo AM phagocytosis with normal, or altered, TRIM72 expression. Pulldown, coimmunoprecipitation, and gradient binding assays were applied to examine TRIM72 and CRIg interaction. A pneumonia model was established by intratracheal injection of Pseudomonas aeruginosa. Mortality, lung bacterial burden, and cytokine levels in BAL fluid and lung tissues were examined. Our data show that TRIM72 inhibited CR‐mediated phagocytosis, and release of TRIM72 inhibition led to increased AM phagocytosis. Biochemical assays identified CRIg as a binding partner of TRIM72, and TRIM72 inhibited formation of the CRIg‐phagosome. Genetic ablation of TRIM72 led to improved pathogen clearance, reduced cytokine storm, and improved survival in murine models of severe pneumonia, specificity of which was confirmed by adoptive transfer of wild‐type or TRIM72KO AMs to AM‐depleted TRIM72KO mice. TRIM72 overexpression promoted bacteria‐induced NF‐&kgr;B activation in murine alveolar macrophage cells. Our data revealed a quiescent, noninflammatory bacterial clearance mechanism in the lung via AM CRIg, which is suppressed by TRIM72. In vivo data suggest that targeted suppression of TRIM72 in AM may be an effective measure to treat fatal pulmonary bacterial infections.

Diagnosis of α1-antitrypsin deficiency using capillary zone electrophoresis.

*Corresponding author: Carine Garcia Hejl, PERCY Military Medical Treatment Facility, Laboratory of Biochemistry, 101 Avenue Henri Barbusse, 92140 Clamart, France, E-mail: cgbiopercy@yahoo.fr Denis Chianea, Julie Plantamura and Philippe Vest: PERCY Military Medical Treatment Facility, Laboratory of Biochemistry, 101 Avenue Henri Barbusse, 92140 Clamart, France Frederic Riviere: PERCY Military Medical Treatment Facility Hospital, Pneumology Clinic, Clamart, France Joshua Sill: Eastern Virginia Medical School, Department of Internal Medicine, Pulmonary/Critical Care Division, Norfolk, VA, USA Isabelle Cuvelier: CERBA Laboratory, Cergy Pontoise, France Christophe Renard: Val de Grâce Military Medical Treatment Facility, Laboratory of Biology, Paris, France Letter to the Editor