Current Respiratory Medicine Reviews - Volume 2, Issue 4, 2006

The pulmonary circulation is normally a low-pressure, low resistance circuit due to its large cross-sectional area and high capacitance. Pulmonary hypertension is defined as a mean pulmonary arterial pressure >25 mm Hg at rest or 30 mm Hg at exercise at catheterization. Chronic thromboembolic pulmonary disease is a cause of pulmonary hypertension [1-9]. The condition is defined by absence of thrombus resolution after one or more episodes of acute pulmonary event that causes sustained obstruction of the pulmonary arteries and subsequent pulmonary hypertension. The extent of vascular obstruction is the major determinant of chronic thromboembolic pulmonary hypertension (CTEPH). Although exact incidence of CTEPH is not known with certainty, it is generally estimated to affect no more than 0.5% of embolic survivors [10-11]. However, it is felt that this condition is under diagnosed, and one well-executed prospective longitudinal study found the incidence to be 3.8% after two years of acute pulmonary embolism [12]. Preliminary reports suggested that an underlying hypercoagulable state may be responsible for the development of CTEPH [13, 14]. Once pulmonary hypertension develops, the prognosis is poor, and this prognosis worsens in the absence of intracardiac shunt. In fact, once mean pulmonary artery pressure in patients with chronic thromboembolic disease exceed 50 mm hg, the 5 year mortality approaches 90% [15]. In view of the severity of disease, and poor prognosis the therapy is urgently needed. CTEPH can be effectively treated by pulmonary thrombendarterectomy (PTE) [16-21]. At The University of California-San Diego Medical Center, the perioperative mortality rate in the 1181 patients who underwent PTE through 1999 was 8.6% overall. Survival has continued to improve over time, with a mortality of 15.8 percent before 1990, 7.2 percent between 1990 and 1999, and 4.4 percent between 1998 and 2002 [22]. Among the survivors of PTE, they observed immediate dramatic improvement in pulmonary artery pressure from 46 mm Hg preoperative to 28 mm Hg post operative, and pulmonary vascular resistance decreasing from 901 (dynes x sec x cm-5) to 261 (dynes x sec x cm-5) [23,24]. In this issue of Current Respiratory Medicine Reviews, Hans-Jurgen Seyfarth and coworkers [25], review in detail the different therapies in patients with CTEPH. Hans-Jurgen Seyfarth and colleagues raised important questions regarding the role of alternate therapies (mainly medical therapies) for the patients who are deemed not to be candidate for PTE. These authors present an excellent review regarding current medical therapies for patients with CTEPH. There are several small studies reviewed in the article by Hans-Jurgen Seyfarth [25]. The role of Beraprost in patients with CTEPH, for example, was marginal though minimal survival benefit was seen. However, some of these studies have very few patients and response was not as adequate [26, 27]. Studies on inhaled Iloprost for patient with CTEPH who cannot go for PTE has been described, moreover a role for bridging therapy has been considered prior to PTE [28]. In a study by Kramm and coworkers [29], preoperative use of inhaled Iloprost significantly increased cardiac index, and reduced mean pulmonary artery pressure and pulmonary vascular resistance, which in turn could reduce the risk of pulmonary reperfusion injury following PTE. The continuous intravenous epoprostenol for CTEPH has also been studied, which has shown to have promising result both as perioperative bridging as well as for distal lesions. There are few studies, as mentioned in article by Hans-Jurgen Seyfarth et al. regarding the role of phosphodiesterase 5-inhibitors and endothelin receptor antagonists, as well as combination therapy with inhaled Iloprost and sildenafil, and another study with addition of bosentan in patients who are being treated with Iloprost [30, 31]. These studies once again had very small number of patients. In addition to medical therapy, balloon angioplasties (BAP) have been used in the treatment for CTEPH. 18 patients evaluated for BAP for CTEPH underwent intervention. Distally surgically inaccessible disease was present in 16 patients; 9 were deemed “nonsurgical” on additional referral to other national centers for PTE. Proximal disease with severe concomitant medical illness was present in 2 patients; the proximal disease with morbid obesity in one and a combination of severe coronary artery disease and chronic obstructive pulmonary disease in other. 16 of 18 patients remained alive at an average of 34.2 months after initial catheterization. Average NYHA class improved from 3.3 preoperatively to 1.8 post-operatives, and 6 minute walking capacity increased from 209 yards preoperatively to 497 yards post-operative [32].........

Due to their long survival and high cumulative corticosteroid dose, COPD patients become susceptible to unusual microorganisms that commonly affect immunosuppressed patients. Among them, fungi such as Aspergillus and Pneumocystis jiroveci and a bacterium Nocardia, a slow growing Gram-positive and acid-fast staining filamentous branching rod, have been reported in the last decade. Aspergillus can affect immunocompromised patients in different ways: by colonizing a cavity (aspergilloma), by local chronic invasion of lung parenchyma (chronic necrotizing aspergillosis or semi-invasive aspergillosis) or through a devastating vascular dissemination disease (invasive pulmonary aspergillosis). Nocardia is a pathogen that tends to act opportunistically, although it has also been reported in immunocompetent patients. It causes chronic lung infection, although systemic nocardiosis with or without central nervous system involvement is quite often found. Before the AIDS epidemic, Pneumocystis jiroveci (formerly known as Pneumocystis carinii f.sp. hominis) was known to affect malnourished patients. Recently it has been found colonizing chronic respiratory patients with conditions such as COPD or cystic fibrosis,but its role in the pathogenesis or evolution of COPD deterioration is unknown. The clinical presentation, diagnosis and therapeutic approach of each type of infection is discussed herein.

Cyclic GMP-dependent protein kinase (PKG) plays a central role in the responses of the pulmonary vasculature to nitric oxide, nitrovasodilators, and natriuretic peptides. In mammalian cells, PKG is present in two forms, PKG I and PKG II, and the type I isoform is the primary enzyme involved in cGMP-dependent regulation of cardiovascular function. PKG can mediate vasodilation by lowering cytosolic Ca2+ levels by stimulating calcium-activated potassium channels and by phosphorylating inositol 1,4,5-triphosphate receptor associated PKG I substrate (IRAG). PKG can also cause vasodilation by reducing the Ca2+ sensitivity of myofilments by directly stimulating myosin light chain phosphatases (MLCP) and by interfering with the inhibition of MLCP exerted by Rho kinase. Recent studies show that PKG activity is regulated by oxygen and may be an important mechanism involved in postnatal adaptation of the pulmonary circulation. In chronically hypoxic lungs, PKG-dependent activation of calcium-dependent potassium channels may be impaired and thus contribute to an abnormally high vasomotor tone. A decrease in PKG activity may also contribute to the tolerance that the pulmonary vasculature develops to nitric oxide after prolonged therapy with nitric oxide inhalation for persistent pulmonary hypertension of the newborn (PPHN). Thus, the PKG appears to have multiple roles in the pulmonary circulation that can be affected by pathological conditions. With an increasing understanding of the mechanisms of PKG actions, the development of more selective tools to target the PKG pathway may lead to potential therapy for pulmonary vascular disease.

Our understanding of mechanisms involved in worsening of airway function during sleep is incomplete. Therefore, this work is aimed to link central neuronal structures alternating wakefulness and sleep with the neuronal network regulating the activity of airway-related vagal preganglionic neurons (AVPNs). Based on knowledge derived from previous studies, we build a dynamic model in which AVPNs transmit excitatory signals to the intrinsic tracheo-bronchial ganglia controlling airway and lung effector cells. The model indicates that cholinergic outflow to the airways depends on the inhibitory inflow from the monoaminergic and GABAergic cell groups to AVPNs. Inhibitory neurons projecting to the AVPNs are connected to the hypothalamic sleep-promoting region. When activated, this cell group, using GABA and/or galanin as mediators, downregulate activity of inhibitory neurons that project to AVPNs. In airway disorders, diminished inhibitory transmission contributes to impaired withdrawal of cholinergic outflow and long lasting bronchoconstriction. Therefore, changes that occur during sleep result in a shift from inhibitory to excitatory transmission to the AVPNs, leading to increased cholinergic outflow to the airways. This framework can be safely used in explaining sleep-related worsening of bronchial asthma, and might, hopefully, contribute to the further development of research in this field.

In the last three decades studies of respiration have embarked on a new phase eliciting exciting new areas of investigation. At this juncture we are happy to contribute a brief article honoring NS Cherniack. During this transition period, features like oxygen sensing in the carotid body in the context of whole body has emerged. ATP has been proposed as a key mediator of peripheral chemosensory transduction at sea level. What role it can play at altitude acclimatization has not been discussed before. This brief review article raises some of the question looking for answers.

The structure of several respiratory models are reviewed and the physiological foundations of salient features are explained. The models reviewed include an early model of Cheyne-Stokes breathing, the gas stores of the body following alterations in ventilation, sleep apnea considered as instability in the respiratory control system, a neurochemical model describing effects of neural drives on breathing in respiratory control of awake people, and inclusion in the neurochemical control system a respiratory pattern generator, as a potential source of apneas. Finally, current work is described to quantify obstructive apneas, and their interdependence with central apneas and the respiratory control system.

Chronic renal failure may be associated with a wide spectrum of respiratory disorders, varying from relatively minor derangements in pulmonary function testing, to frank pulmonary edema. Although complications like uremic lung are becoming increasingly rare in these patients with timely initiation of dialysis, dialysis itself can also exert a transient deleterious influence on gas exchange. Moreover, patients with chronic renal failure often exhibit disorders of the chemical control of breathing that probably contribute to sleep-disordered breathing. Sleep -disordered breathing is a common problem in patients with chronic renal failure, with a reported prevalence possibly exceeding 70% for end-stage renal disease. Sleep disorders, have a serious impact in the quality of life in chronic renal failure, and are probably associated with increased morbidity and mortality. The role of polysomnography and of active intervention in sleep disorders in these patients needs to be further elucidated.

The Global Initiative for Chronic Obstructive Lung Disease guidelines stated that COPD is a disease of airflow limitation that is associated with abnormal inflammatory response. Targeting inflammation and improving airflow is a central goal to treat this disease. Corticosteroids are currently the most popular anti-inflammatory agents for obstructive airway disease. Several long-acting bronchodilators are available to improve airflow. Suppression of inflammation in the asthmatic airway is associated with an increase of expiratory flow. In COPD, the relation between inflammation and airflow limitation is not as clear as that in asthma. Understanding the characters of inflammation and the pathogenesis of airflow limitation may help to provide optimal treatment for patients with COPD.

Carotid bodies are the sensory organs for detecting systemic hypoxia and the ensuing reflexes prevent the development of tissue/cellular hypoxia. Reflexes arising from carotid body play important roles in pathophysiology involving chronic hypoxia. The purpose of this article is to: a) present a brief overview of the current concepts of O2 sensing by the carotid body, and b) how chronic intermittent hypoxia (CIH) such as that seen in recurrent apneas affects the carotid body function and its consequences on physiological systems. Hypoxic sensing in the carotid body requires an initial transduction step involving O2 sensor(s) and transmitter(s) for subsequent activation of the afferent nerve ending. The proposed O2 sensors in the carotidbody include heme containing enzymes and O2 sensitive K+ channels. It has been proposed that transduction process involves interactions between heme-containing proteins and O2-sensitive K+ channel proteins functioning as a “chemosome”. Hypoxia releases both excitatory and inhibitory transmitters from the carotid body. Excitatory transmitters contribute to afferent nerve activation by hypoxia, whereas inhibitory transmitters prevent over excitation. Thus, excitatory and inhibitory transmitters act in concert like a “push-pull” mechanism. CIH augments the hypoxic sensory response of the carotid body and induces a novel form of plasticity manifested as sensory long-term facilitation. Available evidence indicates that increased generation of reactive oxygen species (ROS) mediate CIH-induced functional form alteration in the carotid body. It has been proposed that CIH-induced functional alterations in the carotid body contribute to cardio-respiratory morbidities associated with CIH caused by recurrent apneas.

Approximately 4% of all individuals that develop pulmonary embolism will go on to have chronic thromboembolic pulmonary hypertension (CTEPH). Patients with severe CTEPH will eventually be evaluated for thrombendarterectomy, the only curative treatment for this disease. However, only a subgroup of these patients is eligible for this invasive procedure. In addition, a number of patients will not benefit tremendously from thrombendarterectomy. Finally, thrombendarterectomy may not be possible for functional reasons. In these situations medical treatment, i.e. diuretics, oxygen and anticoagulation remains and is recommended. However, no proven specific e.g. vasodilating medical treatment has been demonstrated in CTEPH. Patients with CTEPH exhibit the same symptoms and a comparable prognosis compared with pulmonary arterial hypertension (PAH) patients. Although the occlusion of pulmonary vessels in CTEPH is caused by repetitive embolism histological similarities to PAH were observed in the pulmonary vascular bed, possibly a reaction to the developing high vascular pressure. Considering these similarities it would certainly make sense to study medical PAH treatment in patients with CTEPH. A few smaller studies exist, which do suggest beneficial effects of endothelin receptor antagonists, prostanoids and phosphodiesterase-5 antagonists in CTEPH. The evidence for the various forms of treatment of for CTEPH will be reviewed.

Nitrofurantoin is an antimicrobial agent that is commonly used for the treatment of recurrent urinary tract infection. Nitrofurantoin pulmonary toxicity can present as acute, subacute, or chronic respiratory disease. Common manifestations are dry cough, chest pain, dyspnea, and hypoxemia. Skin rash, arthralgia, and abnormal transaminases are occasionally present. Chest imaging shows patchy infiltrates and fibrosis. Treatment includes discontinuing the medication. Although the role of corticosteroids has not been well described, patients with respiratory symptoms or hypoxemia may benefit from a trial of corticosteroid therapy.

Pulmonary hamartoma usually presents as a single lesion in the periphery of the lung. It occurs in 0.3% of general population, with a higher frequency in male gender and in the sixth decade of life. Endobronchial hamartomas are unusual. This image corresponds to a 81 year-old man with history of coronary artery disease, hypertension, and rheumatoid arthritis who was admitted to the hospital with chest pain and shortness of breath. Cardiac catheterization revealed multi-vessel disease. He underwent coronary artery bypass therapy (CABG). Post CABG, his clinical course was complicated by right upper lobe and left lower lobe atelectasis. Bedside bronchoscopy revealed a right upper lobe entrance mucus plug and a left lower bronchus endobronchial lesion (Fig. 1, Panel A). Biopsy of the lesion was consistent with an endobronchial hamartoma. The patient underwent complete resection of endobronchial hamartoma using argon laser (Fig. 1, Panel B), with significant clinical improvement.

Primary tracheal malignancies are very infrequent, and data relating to them is limited. We recently encountered an 82 yearold woman with a history of aortic stenosis, hypertension, and hypothyroidism, that presented to the clinic with cough and shortness of breath of six month duration. A computed tomography (CT) scan of the chest revealed tracheal thickening with nonspecific nodularity. The patient underwent fiberoptic bronchoscopy that revealed a tracheal mass with significant airway narrowing (Fig. 1). Biopsy of the tracheal mass revealed a tumor composed of small-to-medium size nests that contained lumen -forming eosinophil cells centrally, and smaller basaloid cells peripherally (Fig. 2). The cystic spaces within the basaloid cells made the diagnosis of adenoid cystic carcinoma. There was no evidence of tumor spread on positron emission tomography (PET) scan. Because of the extent of the lesion and in view of her pre-existing conditions, the patient elected non-operative treatment. Adenoid cystic carcinomas in the trachea are rare, but represent around 40% of all tracheal tumors.