Cluster analysis based clinical profiling of Idiopathic Pulmonary Fibrosis patients according to comorbidities evident prior to diagnosis: a single-center observational study.

BACKGROUND: The characterization and clinical profiling of people affected by Idiopathic Pulmonary Fibrosis (IPF), based on clinical events occurring prior to the diagnosis of the fibrotic disease, may facilitate the understanding of events and comorbidities that occur before the diagnosis of IPF and aid in identifying patients at an earlier stage of the disease. METHODS: In this observational study, a cohort of 96 patients, obtained from a community-based pulmonary clinic, were studied retrospectively. These patients were diagnosed with IPF between January 2008 and November 2016, based on findings on lung biopsy and/or high-resolution CT. Using clinical data obtained within the five years before diagnosis and the two-step method of cluster analysis, patients were assigned to one of four groups. The distribution of clinical characteristics and comorbidities present prior to diagnosis was analyzed among the clusters. RESULTS: Cluster 1 is composed of male patients, smokers, with ischemic heart disease. Cluster 2 is composed of male patients, smokers with dyspnea at rest, dry cough and prevalent emphysema. Cluster 3 is composed of male patients without other significant comorbidities, half of whom had dyspnea at exertion. Cluster 4 includes female patients only, most of whom never-smokers and the largest portion of patients with hypothyroidism. The majority of patients had basal end-inspiratory crackles at time of diagnosis, equally distributed among clusters. CONCLUSION: Different clinical phenotypes of IPF emerge years before time of diagnosis and if confirmed in larger cohorts may help in forming diagnostic algorithms that would allow earlier diagnosis of IPF.

Ventilatory compensation during the incremental exercise test is inversely correlated with air trapping in COPD.

Background: Air trapping and gas exchange abnormalities are major causes of exercise limitation in chronic obstructive pulmonary disease (COPD). During incremental cardiopulmonary exercise testing, ventilatory equivalents for carbon dioxide (V E/VCO 2) and oxygen (V E/VO 2) may be difficult to identify in COPD patients because of limited ventilatory compensation capacity. Therefore, we aimed to detect a possible correlation between the magnitude of ventilation augmentation, as manifested by increments in ventilatory equivalents from nadir to peak effort values and air trapping, detected with static testing.    Methods: In this observational study, we studied data obtained previously from 20 COPD patients who, during routine follow-up, underwent a symptom-limited incremental exercise test and in whom a plethysmography was obtained concurrently. Air trapping at rest was assessed by measurement of the residual volume (RV) to total lung capacity (TLC) ratio (RV/TLC). Gas exchange data collected during the symptom-limited incremental cardiopulmonary exercise test allowed determination of the nadir and peak effort values of V E/VCO 2 and V E/VO 2, thus enabling calculation of the difference between peak effort value and nadir values of  V E/VCO 2 and V E/VO 2, designated ΔV E/VCO 2 and ΔV E/VO 2, respectively. Results: We found a statistically significant inverse correlation between both ΔV E/VCO 2 (r = -0. 5058, 95% CI -0.7750 to -0.08149, p = 0.0234) and ΔV E/VO 2 (r = -0.5588, 95% CI -0.8029 to -0.1545, p = 0.0104) and the degree of air trapping (RV/TLC). There was no correlation between                ΔV E/VCO 2 and peak oxygen consumption, forced expiratory volume in the first second, or body mass index.  Conclusions: The ventilatory equivalents increment to compensate for acidosis during incremental exercise testing was inversely correlated with air trapping (RV/TLC) and may be a candidate prognostic biomarker.

Increased energy expenditure during posture maintenance and exercise in early Parkinson disease.

BACKGROUND: Evidence for the effects of Parkinson disease on energy expenditure is incomplete and contradictory. A number of studies showed increased resting energy expenditure among patients with Parkinson disease whereas others did not. It was hypothesized that energy expenditure increases during exercise, based on findings in patients with a variable regime of anti-parkinsonian therapies and at different stages of the disease. However, energy expenditure during posture maintenance has been neglected. To better understand these issues, we studied energy expenditure in a homogenous population of Parkinson patients in an early stage of the disease and different states of activity. METHODS: Oxygen consumption was assessed in a group of 10 males with early Parkinson disease without dopaminergic treatment and controls matched for age and body composition. Oxygen consumption was measured at rest, during trunk unsupported sitting, and during exercise at different intensities (unloaded and loaded cycling). RESULTS: Resting energy expenditure was similar between groups. Higher energy consumption was observed during maintenance of trunk posture at rest and during light intensity aerobic exercise (P < .05 for all conditions). The increment in energy expenditure associated with increased physical demand tended to be steeper in Parkinson disease. CONCLUSION: Resting energy expenditure is normal in Parkinson disease. However, energy expenditure increases during physical activity and even during the maintenance of unsupported posture among patients with Parkinson disease.

Interpreting the Incremental Cardiopulmonary Exercise Test.

The incremental cardiopulmonary exercise test (CPET) is an increasingly used diagnostic method that serves to evaluate patients with chief complaint of dyspnea during exercise. Performing maximal symptom-limited CPET can show if the tested subject has a reduced exercise capacity and give clues to the mechanism of such exercise capacity reduction, cardiac, pulmonary, or pulmonary vascular source. In this review, it is suggested that the evaluation of the complex results of CPET should be performed by first determining if myocardial/circulatory insufficiency is present and second if there is gas exchange abnormality. By looking with scrutiny at the oxygen consumption (VO2) versus work rate plot, one can see if oxygen delivery is adequate or if it is hampered by abnormally reduced blood flow through skeletal muscle. Elevated ventilatory equivalent of carbon dioxide at the ventilatory threshold and or arterial oxygen desaturation during effort, strongly suggest gas exchange abnormalities. The absence of circulatory insufficiency and gas exchange abnormalities, almost always suggest normal response to effort or deconditioning whenever peak VO2 is below the maximal predicted value.

Natural history of five children with surfactant protein C mutations and interstitial lung disease.

Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7-38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families. Three of the patients, aged now 32, 29, and 37 years, feel well and have normal lung function, while two of the patients, both females, aged 28 and 37 years, conduct normal activities of daily living, have healthy children but have clinical, physiological and rentgenological evidence of restrictive lung disease. All five patients were found to have surfactant protein C gene (SFTPC) mutations, three of them with the most common mutation (p.I73T) and the other two with new mutations of surfactant protein C gene (p.I38F and p.V39L). We conclude that detection of surfactant protein mutations should be attempted in all children presenting with interstitial lung disease. Furthermore, treatment with hydroxychloroquine should be considered in children with SFTPC mutations. Prospective evaluation of hydroxychloroquine therapy in a greater number of patients is needed.

Failure of chimerism formation and tolerance induction from Fas ligand mutant bone marrow donors after nonmyeloablative conditioning.

Formation of donor-recipient mixed chimerism after nonmyeloablative conditioning allows co-existence of donor and recipient hematopoietic stem cells, with solid organ allograft tolerance and less likeliness of graft versus host development. Using a post-transplant bronchiolitis obliterans murine model, we aimed to test the hypothesis that allograft preservation after mixed chimerism formation is dependent on the presence of a functional Fas ligand (FasL) on donor hematopoietic cells. To form mixed chimerism, two aliquots of 30 × 10(6) whole bone marrow cells (BMC) from either wild-type C57BL/6 in one group, or transgenic gld mice with mutant FasL (d = 0 and 2+) in the other were used, with both groups receiving intravenous busulfan (10mg/kg) on d-1 and intraperitoneal cyclophosphamide (200mg/kg) on d+1. Tracheal allografts obtained from C57BL/6 mice were implanted into recipient BALB/c mice subcutaneously on d = 0. Tracheal allografts were harvested at d+28 post-transplant and were evaluated by histopathology. Mixed chimerism formation was detected in wild type C57BL/6 whole BMC recipients, which was accompanied by tracheal allograft acceptance with near normal structure at d+28 post implantation. However, in recipients of FasL mutant whole BMC, neither mixed chimerism formation nor tracheal allograft acceptance was obtained. We thus conclude that bone marrow cells lacking functional FasL molecules could not be engrafted in allogeneic recipients to form stable mixed chimerism after nonmyeloablative conditioning, thus not allowing tracheal allograft acceptance.

Hypothyroidism-induced myocardial damage and heart failure: an overlooked entity.

BACKGROUND: Hypothyroid state may induce cardiac muscle impairment such as diastolic dysfunction and abnormal relaxation time. Advanced heart failure in hypothyroid patients has been described only in severe symptomatic cases, mostly during myxedematous coma. METHODS AND RESULTS: We describe an unusual case of asymptomatic patient with hypothyroidism who presented with severely reduced cardiac function with elevated cardiac enzymes reflecting significant myocardial injury. Comprehensive evaluation for heart failure was suggestive only for long-standing untreated hypothyroidism. Endomyocadial biopsy demonstrated unique histological findings of mucopolysaccharide accumulation attributed to hypothyroid state. CONCLUSIONS: Asymptomatic hypothyroidism may cause severe reduction in cardiac function accompanied with elevated cardiac enzymes. To our knowledge, this is the first description of human myocardial biopsy revealing mucopolysaccharide accumulation attributed to hypothyroid state.

Positron emission tomography in interstitial lung disease.

BACKGROUND AND OBJECTIVES: A high rate of glycolysis may reflect the inflammatory activity of interstitial lung disease (ILD). This prospective study investigated whether PET can distinguish IPF, a primarily fibrotic process, from other entities of ILD that have a marked inflammatory component. METHODS: Twenty-one patients referred for surgical lung biopsy because of diffuse ILD underwent PET at the time of the lung biopsy. PET transmission scans were obtained after injecting (18)FDG intravenously. Regions of interest (ROI) were drawn on the lung images, and the standardized uptake value (SUV) was calculated for these ROI. RESULTS: Of the 21 patients studied, 14 had IPF, four had non-specific interstitial pneumonia, and the remaining three patients each had respiratory bronchiolitis-ILD, sarcoidosis and Langerhan's cell histiocytosis. There was no statistically significant difference in the SUV between IPF patients and non-IPF patients (P = 0.26), although patients with IPF tended to have higher SUV. Radiographic changes tended to be more prominent in the lung bases in patients with IPF compared with non-IPF patients; however, the median ratio of SUV measured in the upper fields to the whole lungs in IPF patients was not significantly different compared with the median ratio in non-IPF patients (P = 0.31). CONCLUSION: PET does not allow differentiation of IPF from a non-IPF diffuse interstitial pulmonary process.

Simultaneous donor marrow cell transplantation with reduced intensity conditioning prevents tracheal allograft obliteration in a bronchiolitis obliterans murine model.

STUDY OBJECTIVES: Prolonged survival of transplanted kidney or liver allografts has been associated with prolonged chimerism resulting from donor-origin leukocytes carried within the allograft parenchyma. The present study, performed in a murine model, examined whether simultaneous administration of donor bone marrow cells after reduced intensity conditioning allows acceptance of heterotopic tracheal allografts and prevents the formation of the airway fibroproliferative lesion, which mimics bronchiolitis obliterans (BO). METHODS: Allogeneic tracheal allografts from C57BL/6 mice were grafted subcutaneously into BALB/c mice (n = 6) [day 0]. Conditioning consisted of total lymphoid irradiation (200 cGy) at day - 1, donor marrow cells (3 x 10(7)) administered IV on day 0, intraperitoneal cyclophosphamide (200 mg/kg) on day 1 to eliminate alloreactive marrow cells, followed by a repeated dose of donor marrow cells on day 2. Control groups consisted of one group (n = 4) that underwent similar conditioning without donor marrow cells, and another group (n = 4) that received syngeneic BALB/c marrow cells. None of these groups were administered maintenance immunosuppression. Grafts were harvested and histopathology findings were evaluated semiquantitatively at day 28, day 55, and day 95. RESULTS: Tracheal allografts from donor marrow cell recipients still maintained a patent airway with intact airway epithelium at 95 days after transplant. However, grafts from control animals not receiving donor marrow cells or mice administered syngeneic marrow cells had lumen obliteration by 28 days after transplant. Chimerism in animals receiving allogeneic bone marrow was confirmed. Graft vs host disease did not develop in animals receiving allogeneic marrow cells. CONCLUSIONS: Further investigation may verify this approach to be applicable for the prevention of posttransplantation BO.

Resolving impaired response to exercise in hepatopulmonary syndrome after liver transplantation.

A series of graded cardiopulmonary exercise tests (CPET) in a patient with hepatopulmonary syndrome (HPS) who was evaluated before and after liver transplantation are described. HPS associated with marked dyspnea, results from abnormal intrapulmonary vascular dilatation with rapid transit of the blood in the pulmonary vascular bed, creating right-to-left shunt and hypoxemia. Decreased peak oxygen uptake, wasted ventilation and hypoxemia were corrected within 8 months after the transplant, thus making CPET a very useful tool for investigating and following these patients before and after transplant.

Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta- secreting tumor.

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

Disseminated Mycobacterium kansasii infection with pulmonary alveolar proteinosis in a patient with chronic myelogenous leukemia.

A 64-year-old woman with chronic myelogenous leukemia (CML) was admitted due to prolonged fever and lung infiltrates. An open lung biopsy was required to make the diagnosis of pulmonary alveolar proteinosis (PAP) and infection with Mycobacterium kansasii. She was treated successfully with combined antimycobacterial therapy for 14 months. However, the leukemia progressed and the patient developed recurrent bilateral lung infiltrates. Blood and bronchoalveolar fluid cultures yielded growth of Acinetobacter. She died shortly thereafter due to septic shock. The relationship between M. kansasii infection, PAP, and abnormal host defense in CML is discussed.

Pleural effusion with splenic rupture as manifestations of recurrence of sarcoidosis following prolonged remission.

A 55-year-old man presented with a 3-week history of dry cough and left pleuritic chest pain with a new exudative pleural effusion. Sixteen years earlier, he was diagnosed with sarcoidosis presenting with hilar lymphadenopathy, erythema nodosum, mildly disturbed liver function tests and noncaseating granulomata on liver biopsy, with no evidence of pulmonary parenchymal disease. He was treated with prednisone and in recent years maintained at a low daily dose, until it was eventually discontinued two years prior to his present illness. There was no evidence of infection or malignancy, and the fluid resolved following treatment with naproxen. Three weeks later the patient presented with sudden onset of dyspnea and left chest pain. After starting intravenous heparin for suspected pulmonary emboli, the patient developed hemodynamic instability which was accompanied by abdominal tenderness and decreasing hematocrit. Splenic rupture was diagnosed, and the patient underwent splenectomy. Pathology specimens revealed a hemorrhagic infarct with subcapsular hematoma, and numerous noncaseating granulomata within the splenic tissue. This patient had recurrent sarcoidosis with two rare manifestations of the disease, 2 years after withdrawing low dose prednisone, given for a prolonged time. The possibility of reemergence of the disease in organs other than the organs involved in the initial presentation should always be considered in sarcoidosis.