Current Respiratory Medicine Reviews

ISSN: 1573-398X

Current Respiratory Medicine Reviews
Volume 2, Number 4, November 2006

Contents


Editorial Pp. 355-356

Infrequent Infections in COPD Pp. 357-371
Christian Domingo, Mª José Masdeu and Miguel Gallego
[Abstract]


cGMP-Dependent Protein Kinase in Regulation of the Pulmonary Circulation Pp. 373-381
Yuansheng Gao and J. Usha Raj
[Abstract]


Uncovering CNS Pathways Involved in State Dependent Control of Lower Airway Function Pp. 383-391
Musa A. Haxhiu, Kannan V. Balan, Sandra S. Acquah and Prabha Kc
[Abstract]


Possible Purinergic Mechanisms of Carotid Chemoreceptors Transmission at High Altitude Pp. 393-396
Sukhamay Lahiri, Santhosh M. Baby and Arijit Roy
[Abstract]


Physiological Insights Derived from Mathematical Models of Respiration Pp. 397-403
Guy Longobardo
[Abstract]


Disorders of Respiration and Sleep-Disordered Breathing in Patients with Chronic Renal Failure Pp. 405-417
Nikolaos K. Markou, Maria Athanasiou, Despina Hroni and Pavlos M. Myrianthefs
[Abstract]


Airway Inflammation and Airflow Limitation in COPD Pp. 419-426
Diahn-Warng Perng, Kang-Cheng Su and Lung-Yu Liu
[Abstract]


Oxygen Sensing in Health and Disease Pp. 427-429
Nanduri R. Prabhakar and Ganesh K. Kumar
[Abstract]


Chronic Thromboembolic Pulmonary Hypertension–Therapeutic Options Pp. 431-438
Hans-Jürgen Seyfarth, Stefan Hammerschmidt, Christian Gessner, Michael Halank and Hubert Wirtz
[Abstract]


Nitrofurantoin Pulmonary Toxicity: A Brief Review Pp. 439-442
Bobbak Vahid and Bernadette M.M. Wildemore
[Abstract]


Pulmonary Hamartoma: Curative Laser Resection Pp. 443
Salim Surani, Shezana Merchant and Joseph Varon



Bronchoscopic Appearance of Tracheal Adenoid Cystic Carcinoma Pp. 445
Salim Surani, Maqsood Ahmed, James Mullin and Joseph Varon





Abstracts

[Back to top]
Editorial

Chronic Thromboembolic Pulmonary Hypertension-Therapeutic Options

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].

Experience over the past two decades has demonstrated that CTEPH represents a potentially treatable form of pulmonary hypertension, and that PTE is capable of restoring severely compromised patients to a normal hemodynamic and symptomatic status. In my opinion, PTE still remains the first line therapy for the patients with CTEPH. Every attempt should be made to get the patients to the centers with experience in PTE. In patients who are not candidate for surgery, the role of medical therapy either single, or in combination, and also role of the balloon angioplasty need to be further studied with large multi-center trials. Till this time these therapies have a role in an experimental basis, and wide spread use cannot be recommended.

REFERENCES

[1] Fedullo PF, Auger WR, Kerr KM, et al. Chronic thromboembolic pulmonary hypertension. N Engl J Med 2001; 345: 1465-72.

[2] Gillum RF. Pulmonary embolism and thrombophlebitis in the United States 1970-1985. Am Heart J 1987; 114: 1262-64.

[3] Lilienfield DE, Chan E, Ehland J, et al. Mortality from pulmonary embolism in the United States: 1962-1984. Chest 1990; 98: 1067-72.

[4] Olman MA, Marsh JJ, Lang IM, et al. Endogenous fibrinolytic system in chronic large vessel thromboembolic pulmonary hypertension. Circulation 1992; 86: 1241-48.

[5] Lang IM, Marsh JJ, Olman MA et al. Parallel analysis of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in plasma and endothelial cells derived from patients with chronic pulmonary thromboemboli. Circulation 1994; 90: 706-12.

[6] Lang IM, Marsh JJ, Olman MA et al. Expression of type I plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994; 89: 2715-21.

[7] Moser KM, Auger WR, Fedullo PF. Chronic major vessel thrmboembolic pulmonary hypertension. Circulation 1990; 81: 1735-43.

[8] Long IM, Klepetho W, Pabinger I. No increased prevalence of factor V Leiden mutation in chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Thromb Hemost 1996; 76: 476-7.

[9] Benotti JR, Ockene S, Alpert JS, Dalen JE. The clinical profile of unresolved pulmonary embolism. Chest 1983; 84: 669-78.

[10] Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107: I22.

[11] Ribeiro A, Lindmarker P, Johnson H et al. Pulmonary embolism: one year follow-up with echocardiography Doppler and five-year survival analysis. Circulation 1999; 99: 1325-30.

[12] Pengo V, Lensing W, Prins M, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257-64.

[13] Bonderman D, Turecek PL, Jakowitsch J, et al. High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension. Thromb haemost 2003; 90: 372-376.

[14] Auger WR, Permpikul P, Moser KM. Lupus anticoagulant, heparin use and thrombocytopenia in patients with chronic thromboembolic pulmonary hypertension: A preliminary report. Am J Med 1995; 99: 392-96.

[15] Riedel M, Stanek V, Widimsky J, Prerovsky I. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982; 81: 151-8.

[16] Dartevelle P, Fadel E, Mussot S, et al. Chronic thromboembolic pulmonary hypertension. Eur respire J 2004; 23: 637-48.

[17] Snyder WA, Kent DC, Baisch BF. Successful endarterectomy of chronically occluded pulmonary artery. Clinical report and physiologic studies. J Thorac Cardiovasc surg 1963; 45: 482-9.

[18] Moser KM, Houk VN, Jones RC, et al. Chronic, massive thrombotic obstruction of the pulmonary arteries. Analysis of four operated cases. Circulation 1965; 32: 377-85.

[19] Archibald CJ, Auger WR, Fedullo PF, et al. Long-term outcome after pulmonary thrombendarterectomy. Am J Respir Crit Care Med 1999; 160: 523-28.

[20] Kramm T, Mayer E, Dahm, et al. Long-term results after thrombendarterectomy for chronic pulmonary embolism. Eur J Cardiothorac Surg 1999; 15: 579-84.

[21] Hagl C, Khaladji N, Peters T, et al. Technical advances of pulmonary thrombendarterectomy for chronic thromboembolic pulmonary hypertension. Eur J Cardiothorac Surg 2003; 23: 776-81.

[22] Jamieson SW, Kapelanski DP, Sakakibara N, et al. Pulmonary endarterectomy: experience and lessons learned in 1500 cases. Ann Thorac Surg 2003; 76: 1457-64.

[23] Moser KM, Daily Po, Peterson K, et al. Thrombendarterectomy for chronic major vessel thromboembolic pulmonary hypertension. Immediate and long-term results in 42 patients. Ann Intern Med 1987; 107: 560-65.

[24] Moser KM, Spragg RG, Utley J, Daily PO. Chronic thrombotic obstruction of major pulmonary arteries. Results of thrombendarterectomy in 15 patients. Ann Intern Med 1983; 99: 299-305.

[25] Seyfarth HJ, Hammerschmidt S, Gessner C, et al. Chronic thromboembolic pulmonary hypertension- therapeutic options. Curr Respir Med Rev 2006; 2: 431-38.

[26] Nagaya N, Shimizu Y, Satoh T, et al. Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension. Heart 2002; 87: 340-5.

[27] Ono F, Nagaya N, Okumura H, et al. Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest 2003; 123: 1583-88.

[28] Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-9.

[29] Kramm T, Eberle B, Krummennauer F, Guth S, Oelert H, Mayer E. Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thrombendarterectomy. Ann Thorac Surg 2003; 76: 711-18.

[30] Bresser P, Fedullo PF, Auger WR, et al. Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur Respir J 2004; 23: 595-600.

[31] Scelsi L, Ghio S, Campana C, et al. Epoprostenol in chronic thromboembolic pulmonary hypertension with distal lesions. Ital Heart J 2004; 5(8): 618-23.

[32] Feinstein JA, Goldhaber SZ, Lock JE, et al. Balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension. Circulation 2001; 103: 10-13.


Salim Surani
Texas A&M University
Corpus Christi Texas
613 Elizabeth Street
Suite 813
Corpus Christi
Texas 78404
USA
E-mail: srsurani@hotmail.com


[Back to top]
Infrequent Infections in COPD
Christian Domingo, Mª José Masdeu and Miguel Gallego

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.


[Back to top]
cGMP-Dependent Protein Kinase in Regulation of the Pulmonary Circulation
Yuansheng Gao and J. Usha Raj

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.


[Back to top]
Uncovering CNS Pathways Involved in State Dependent Control of Lower Airway Function
Musa A. Haxhiu, Kannan V. Balan, Sandra S. Acquah and Prabha Kc

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.


[Back to top]
Possible Purinergic Mechanisms of Carotid Chemoreceptors Transmission at High Altitude
Sukhamay Lahiri, Santhosh M. Baby and Arijit Roy

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.


[Back to top]
Physiological Insights Derived from Mathematical Models of Respiration
Guy Longobardo

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.


[Back to top]
Disorders of Respiration and Sleep-Disordered Breathing in Patients with Chronic Renal Failure
Nikolaos K. Markou, Maria Athanasiou, Despina Hroni and Pavlos M. Myrianthefs

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.


[Back to top]
Airway Inflammation and Airflow Limitation in COPD
Diahn-Warng Perng, Kang-Cheng Su and Lung-Yu Liu

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 air-flow limitation is not as clear as that in asthma. Understanding the characters of inflammation and the pathogenesis of air-flow limitation may help to provide optimal treatment for patients with COPD.


[Back to top]
Oxygen Sensing in Health and Disease
Nanduri R. Prabhakar and Ganesh K. Kumar

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.


[Back to top]
Chronic Thromboembolic Pulmonary Hypertension–Therapeutic Options
Hans-Jürgen Seyfarth, Stefan Hammerschmidt, Christian Gessner, Michael Halank and Hubert Wirtz

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, throm-bendarterectomy 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.


[Back to top]
Nitrofurantoin Pulmonary Toxicity: A Brief Review
Bobbak Vahid and Bernadette M.M. Wildemore

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.