Pulmonary Hypertension in Patients with Idiopathic Pulmonary Fibrosis – The Predictive Value of Exercise Capacity and Gas Exchange Efficiency

Exercise capacity and survival of patients with IPF is potentially impaired by pulmonary hypertension. This study aims to investigate diagnostic and prognostic properties of gas exchange during exercise and lung function in IPF patients with or without pulmonary hypertension.In a multicentre setting, patients with IPF underwent right heart catheterization, cardiopulmonary exercise and lung function testing during their initial evaluation. Mortality follow up was evaluated.Seventy-three of 135 patients [82 males; median age of 64 (56; 72 years)] with IPF had pulmonary hypertension as assessed by right heart catheterization [median mean pulmonary arterial pressure 34 (27; 43) mmHg]. The presence of pulmonary hypertension was best predicted by gas exchange efficiency for carbon dioxide (cut off ≥152% predicted; area under the curve 0.94) and peak oxygen uptake (≤56% predicted; 0.83), followed by diffusing capacity. Resting lung volumes did not predict pulmonary hypertension. Survival was best predicted by the presence of pulmonary hypertension, followed by peak oxygen uptake [HR 0.96 (0.93; 0.98)].Pulmonary hypertension in IPF patients is best predicted by gas exchange efficiency during exercise and peak oxygen uptake. In addition to invasively measured pulmonary arterial pressure, oxygen uptake at peak exercise predicts survival in this patient population.     

Chronic Obstructive Pulmonary Emphysema—Is Exercise Beneficial?

Following a six-week program of training in a series of exercises, a significant number of patients with chronic obstructive pulmonary emphysema showed decided improvement in functional activity. Subjective improvement also was noted and kept the patient motivation high.Preliminary observations indicated that the improvement could be maintained long after the end of the training period.     

CIGARETTE SMOKE—Its Effect on Pulmonary Function Measurements

Inhaling cigarette smoke with each breath, with the subject at rest, by use of a smoking device that brought more smoke into the lungs than would be the case in ordinary smoking, produced consistent significant decreases in arterial blood oxygen saturation and in arterial pO₂ in most subjects who had severe or very severe pulmonary emphysema. In normal subjects and in those with a moderate degree of emphysema no significant changes in blood gas exchange resulted.No consistent significant changes in blood gas exchange were noted after the smoking of two cigarettes, either with the subject at rest or after a one-minute step-up exercise.A decrease in oxygen uptake occurred when treadmill exercise was done after smoking two cigarettes, and the ventilation volume was also decreased, probably accounting for part of the oxygen decrease.Pulmonary compliance measurements after smoking one cigarette were consistently and significantly decreased in most subjects—normal as well as those with pulmonary emphysema. The elastic work of breathing was increased in the majority of cases.In two cases in which studies were done after the subjects stopped smoking, one for three months and one for two years, significant reductions in residual air were noted.The results indicated that persons with severe or very severe emphysema would be better off to stop smoking.     

The PPARβ/δAgonist GW0742 Relaxes Pulmonary Vessels and Limits Right Heart Hypertrophy in Rats with Hypoxia-Induced Pulmonary Hypertension

Background

Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension.

Methodology/Principal Findings

Here we show that the PPARβ/δ agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARβ/δ or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model.

Conclusions/Significance

These observations are the first to show a therapeutic benefit of ‘PPARβ/δ’ agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.     

Immunomodulation with Recombinant Interferon-γ1b in Pulmonary Tuberculosis

Background

Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-γ1b (rIFN-γb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance.

Methodology/Principal Findings

We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-γ1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1β, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-γ1b group from baseline to week 16. Both rIFN-γ1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-γ1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-γ1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-γ1b versus DOTS alone.

Conclusion

Recombinant interferon-γ1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00201123","term_id":"NCT00201123"}}NCT00201123     

CRITERIA FOR MITRAL VALVOTOMY—Roentgen Evidence in Pulmonary Hypertension

Although catheterization is the most accurate and sometimes the only adequate method of measuring pulmonary hypertension as an indication for mitral valvotomy in rheumatic heart disease, it is so costly and complex that simpler methods are desirable. Clinical evidence of pulmonary hypertension is least accurate; electrocardiography is confirmatory in half of all cases. Roentgenologic findings are more helpful; moderate or severe enlargement in the pulmonary arteries has been associated in 92 per cent of cases with resting systolic pressure of 50 to 90 mm. of mercury in the pulmonary artery. In cases in which there is little or no enlargement, hypertension may still be present and demonstrable only by catheterization. Other roentgen signs noted as helpful are abrupt narrowing of the large branches of the pulmonary artery in the middle and lower lobes, and the septal lines of Kerley.     

IFN-γ Mediated Signaling Improves Fungal Clearance in Experimental Pulmonary Mucormycosis

Mycopathologia - We established three immunocompetent murine models of pulmonary mucormycosis to determine the involvement of the adaptive immune response in host resistance in pulmonary...     

Pulmonary and renal pressure-flow relationships: what should be taught?

This article is from a symposium presented at the annual meeting of the Human Anatomy and Physiology Society (HAPS) on June 11, 2000. The presentation was funded under the auspices of a National Science Foundation Course, Curriculum, and Laboratory Improvement Program entitled "Development of Active Learning Materials for Physiology and Functional Anatomy: A Cooperative HAPS-APS Initiative." This symposium was part of the first module to be developed on "gradients and conductances: what flows where and why?" This presentation was designed to model the usefulness of the general model of gradients and conductances in the physiology and pathophysiology of the respiratory and renal systems. Thirteen different examples of pressure-flow-resistance and concentration-flux relationships are introduced; several ideas for active-learning activities and simple figures appropriate for undergraduate physiology classes are included. The symposium assumes that undergraduate students have already learned about diffusion, osmosis, and the basic principles of cardiovascular physiology. The presentation was designed to follow a symposium entitled: "Cardiovascular pressure-flow relationships: what should be taught?"     

“I Can't Find Anything Wrong: It Must Be a Pulmonary Embolism”: Diagnosing Suspected Pulmonary Embolism in Primary Care,a Qualitative Study

Background

Before using any prediction rule oriented towards pulmonary embolism (PE), family physicians (FPs) should have some suspicion of this diagnosis. The diagnostic reasoning process leading to the suspicion of PE is not well described in primary care.

Objective

to explore the diagnostic reasoning of FPs when pulmonary embolism is suspected.

Method

Semi-structured qualitative interviews with 28 FPs. The regional hospital supplied data of all their cases of pulmonary embolism from June to November 2011. The patient''s FP was identified where he/she had been the physician who had sent the patient to the emergency unit. The first consecutive 14 FPs who agreed to participate made up the first group. A second group was chosen using a purposeful sampling method. The topic guide focused on the circumstances leading to the suspicion of PE. A thematic analysis was performed, by three researchers, using a grounded theory coding paradigm.

Results

In the FPs'' experience, the suspicion of pulmonary embolism arose out of four considerations: the absence of indicative clinical signs for diagnoses other than PE, a sudden change in the condition of the patient, a gut feeling that something was seriously wrong and an earlier failure to diagnose PE. The FPs interviewed did not use rules in their diagnostic process.

Conclusion

This study illustrated the diagnostic role of gut feelings in the specific context of suspected pulmonary embolism in primary care. The FPs used the sense of alarm as a tool to prevent the diagnostic error of missing a PE. The diagnostic accuracy of gut feelings has yet to be evaluated.     

Pulmonary vein isolation: do all roads lead to Rome?

Pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF) appears to be here to stay. In just a few years since the landmark publications by Haissaguerre and Pappone, countless variations on the theme of ostial or antral PVI, with or without additional lines or point lesions, have been published. The procedure has found its way into daily practice and international guidelines, and is currently the most performed ablation in the Netherlands.     

Pulmonary intravascular macrophages and lung health: what are we missing?

Pulmonary intravascular macrophages (PIMs) are constitutively found in species such as cattle, horse, pig, sheep, goat, cats, and whales and can be induced in species such as rats, which normally lack them. It is believed that human lung lacks PIMs, but there are previous suggestions of their induction in patients suffering from liver dysfunction. Recent data show induction of PIMs in bile-duct ligated rats and humans suffering from hepato-pulmonary syndrome. Because constitutive and induced PIMs are pro-inflammatory in response to endotoxins and bacteria, there is a need to study their biology in inflammatory lung diseases such as sepsis, asthma, chronic obstructive pulmonary diseases, or hepato-pulmonary syndrome. We provide a review of PIM biology to make an argument for increased emphasis and better focus on the study of human PIMs to better understand their potential role in the pathophysiology and mechanisms of pulmonary diseases.