Current Respiratory Medicine Reviews - Volume 4, Issue 3, 2008

Congenital diaphragmatic hernia (CDH) remains a challenging diagnostic and treatment anatomical illness for clinicians. Pediatric pulmonologists, cardiothoracic and general surgeons and pediatric intensivists are confronted with these cases. CHD represents a group of congenital defects in the structural integrity of the diaphragm, affecting approximately 1 in 3000 births [1]. While it appears to be an anatomical malformation, CHD has a very complex pathophysiology. Despite the extensive research performed over past 4 decades and the advances in perinatal ultrasound, the early diagnosis is still not available and the mortality rate remains quite high, ranging from 30 to 50% [1]. When identified as a system illness, it is evident that CDH is not an isolated event, and not just a “hole in the diaphragm”, but indeed a complex syndrome that includes pulmonary hypoplasia, lung immaturity and left heart hypoplasia that leads to persistent pulmonary hypertension of the newborn [2]. This is particularly important for clinicians dealing with these patients in the acute and critical care settings. The economical impact of CDH can be significant in many patients. The pathophysiology of CDH has been studied thoroughly in animal models and yet, there are several areas that remain unclear. An exclusive mechanism causing the primary anatomical has not been found yet. In some rat studies, CDH has been noted to be more frequent in the offspring of rats fed with a vitamin A deficient diet [3]. In addition, specific gene deletions have been reported to cause diaphragmatic defects in mice [4]. Although initially CDH is a life-threatening condition in many patients but, those patients who survive, it can become a long-term clinical condition. CDH survivors experience ongoing medical morbidity, including pulmonary nutritional and developmental delays [5]. As the postnatal management of patients with CDH is often complicated by long primary hospitalizations, several authors have suggested that these patients have significant learning difficulties and low IQs that may interfere with their normal social life and employment status [6]. In this issue of Current Respiratory Medicine Reviews, Bourbon provides a historical perspective of the discovery of this elusive illness, as well as the pathophysiology and antenatal therapy currently available and an up-to-date information on clinical research [7]. The author identifies the needs for clinicians dealing with these complex patients. As noted by Bourbon and others, CDH is a genetic disease that still requires significant research in an attempt to identify and promptly stop the anomaly [4]. Recognizing the diaphragm's normal genetic pathways may lead to advanced therapeutic options. However, despite all these advances in diagnosis we “are not there yet!”. REFERENCES [1] Skari H, Bjornland K, Haugen G, et al. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg 2000; 35: 1187-97. [2] Thebaud B, Mercier JC, Din-Xuan AT. Congenital diaphragmatic hernia: a cause of persistent pulmonary hypertension of the newborn which lacks of an effective therapy. Biol Neonate 1998; 74: 323-36. [3] Clugston RD, Klatlig J, Englert C. Teratogen-induced, dietary and genetic models of congenital diaphragmatic hernia share a common mechanism of pathogenesis. Am J Pathol 2006; 169: 1541-49. [4] Pober BR. Genetic aspects of human congenital diaphragmatic hernia. Clin Gen 2008; 74: 1-15. [5] Chen C, Jeruss S, Terrin N, et al. Impact on family survivors of congenital diaphragmatic hernia repair: a pilot study J Pediatr Surg 2007; 42: 1845-52. [6] Koivusalo A, Pakarinen M, Vanamo K, et al. Health related quality of life in adults after repair of congenital diaphragmatic defects: a questionnaire study. J Pediatr Surg 2005; 40: 1376-81. [7] Bourbon J. New insights in congenital diaphragmatic hernia. Curr Respir Med Rev 2008; 4: 156-172.

Congenital diaphragmatic hernia (CDH) is a 1 out of 2500 live-born disease with a persistent 30-40% mortality rate, consecutively to severe pulmonary hypoplasia and hypertension. The etiology of CDH remains unknown, although recent studies have identified genes potentially involved. The classical view that unclosure of pleuroperitoneal canals is responsible for the occurrence of CDH has been challenged by recent work in transgenic mice. Recent studies on the pathophysiology of CDH provided a closer evaluation of formerly debated pulmonary consequences, especially for alveolarization and surfactant production. Recent advances in prenatal ultrasonography have largely improved the determination of prognosis, allowing reliable evaluation of pulmonary hypoplasia to be achieved through the simultaneous use of Lung-over-Head Ratio, liver position, and/or fetal lung volume measured by 3D ultrasound and MRI, although it remains difficult to predict the functionality of CDH lungs. Open fetal surgery to correct the diaphragmatic defect has been abandoned, but fetal tracheal occlusion used to force lung expansion and growth, after a number of pre-clinical studies in animals, has been applied to the human fetus with encouraging results. Last, post-natal care of CDH neonates was also improved with the use of high-frequency ventilation and vasodilators, particularly inhaled nitric oxide.

Pulmonary neuroendocrine cell (PNEC) system consists of solitary cells and innervated clusters, neuroepithelial bodies (NEB), widely distributed throughout the airway mucosa of mammalian lungs. These cells are numerous in fetal/ neonatal lungs and produce amine (serotonin, 5-HT) as well as a variety of neuropeptides (e.g. bombesin). The potential role and significance of these highly specialized lung cells in normal and diseased lung is only now beginning to be appreciated. The multifaceted role(s) of PNEC system include lung development, neonatal adaptation and during postnatal airway homeostasis as guardians of stem cell niche. Recent advances in cellular and molecular biology of PNEC system particularly their ontogeny and mechanisms of neuroendocrine differentiation in developing lung are reviewed. The evidence for the role of NEB as hypoxia-sensitive airway chemoreceptors is presented including identification and characterization of O2 sensor molecular complex that is activated by hypoxia leading to release of amine and peptide mediators acting locally or via NEB neural connections. Thus NEB are postulated to function as O2 sensitive airway sensors involved in respiratory control, especially during adaptation to extrauterine life. Hyperplasia of PNEC/NEB cells, suggesting altered function, has been identified in a number of perinatal/pediatric lung disorders including bronchopulmonary dysplasia, central hypoventilation syndrome, Sudden Infant Death Syndrome and Neuroendocrine Hyperplasia of Infancy as well as Cystic Fibrosis and pediatric asthma. In the adults, PNEC/NEB may be involved in the pathogenesis of tobacco induced airway disease, pulmonary fibrosis and lung carcinogenesis.

Sleep apnea syndrome is a disease of high prevalence and high morbidity, for which surgery used to be the only possible therapeutic approach. Uvulo-palatopharyngoplasty (UPPP) was the technique used until the nineteen eighties. However, surgery has largely been abandoned since the introduction of nasal continuous positive airway pressure (CPAP), which has become the main treatment option today. Surgery remains an alternative for patients who do not tolerate nasal CPAP. Since the range of surgical techniques available is wide, patients must be carefully evaluated with fiberoptic nasopharyngoscopy and lateral cephalometric radiograph to determine the level of the obstruction. In almost 98% of sleep apnea patients the soft tissue structures of the upper airway and the underlying maxillo-mandibular skeleton are disproportionate. Therefore, the choice of surgical procedure depends on the site of obstruction (nose, retropalatal or retrolingual region, or a combination). Here we review the various surgical procedures available and their efficacy when performed alone or in combination. These procedures are: classical uvulopalatopharyngoplasty and its modifications, genioglossus advancement techniques combined with UPPP, and retropalatal and maxillo-mandibular advancement, a highly aggressive technique which treats retropalatal and retrolingual regions simultaneously and is effective in 95% of cases, but has a high morbidity. We also discuss nasal surgical procedures (though they are unlikely to solve the problem), radiofrequency, and palatal implants. We assess the efficacy of these methods, bearing in mind; a) the differences in the criteria used for defining surgical success and b) the fact that they are often applied simultaneously or sequentially.

Asthma is a chronic inflammatory disorder of the respiratory system characterised by recurrent “reversible” obstruction of the airwflow in the airway. Various agents have been used in the treatment of asthma out of which inhaled beta-2 agonists have been mainstay of bronchodilator therapy of asthma for more than 40 years. Short-acting beta-2 agonists are still recommended for relieving the acute episode of bronchoconstriction. Long-acting beta-2 agonists (LABAs), alongwith inhaled corticosteroides are used as a first line anti-inflammatory therapy. The recent evidence suggested that the ability of short-acting and long-acting beta-2 agonists to protect the airways against bronchoconstrictor stimuli and to promote bronchodilatation may be partially lost with time following long-term use. The long-term use of beta-2 agonist is associated with an increased incidence of asthma exacerbations and other markers of morbidity and mortality. In this article, we try to address some of the current controversies as well as propose various mechanisms behind beta-2 agonist induced morbidity and mortality in asthmatic patients. On the basis of this article, we recommended that clinicians have to refine the use of beta-2 agonists in asthma management guidelines to avoid the beta-2 agonists induced asthma exacerbations.

Virtually all patients with a newly discovered pleural effusion should undergo thoracentesis to aid in diagnosis and management. Pleural fluid (PF) samples should be collected into heparinized tubes to prevent clot formation. The routine PF evaluation usually includes cell count and differential, protein, lactate dehydrogenase, glucose, adenosine deaminase, cytology and, if infection is a concern, pH as well as bacterial and mycobacterial cultures. Distinguishing transudates from exudates through Light's criteria is a pragmatic first step. If the effusion is an exudate, various PF tests have proven diagnostic utility: adenosine deaminase levels > 40 U/L usually indicate tuberculosis in lymphocytic-predominant PFs or empyema in neutrophilic-predominant PFs; pH < 7.2 and glucose < 60 mg/dL allow the clinician to identify complicated parapneumonic effusions and guides their initial management; and conventional cytology may demonstrate malignant cells in 60% of the patients with malignant effusions. A number of optional PF tests may complement the diagnostic approach to an undiagnosed pleural effusion. For example, natriuretic peptide assays significantly improve the accuracy of the diagnosis of cardiac pleural effusions; PF mesothelin levels greater than 20 nM are highly suggestive of mesothelioma; and new molecular techniques have improved the identification of the causative organisms in pleural infections.

Systemic sclerosis is a multisystem autoimmune disease with potential lung manifestations that include pulmonary vascular and interstitial disease. Not only is interstitial lung disease the most common pulmonary manifestation, it is a major cause of morbidity and mortality in patients with systemic sclerosis. The risk of systemic sclerosis patients developing progressive interstitial lung disease is strongly associated with the presence of certain autoantibodies The most common lung injury pattern observed in systemic sclerosis-related interstitial lung disease is the fibrotic variant of nonspecific interstitial pneumonia. Because scleroderma renal crisis can now be effectively treated, recently, focus has turned toward how best to treat systemic sclerosis-related interstitial lung disease. Therapy usually involves an immunomodulatory regimen consisting of a steroid-sparing agent with or without glucocorticoids, and response to therapy is variable.