Likurgos Kolilekas

Sleep oxygen desaturation predicts survival in idiopathic pulmonary fibrosis.

BACKGROUND Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fibrosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. METHODS In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). RESULTS Sleep oxygen desaturation exceeded significantly that of maximal exercise (p < 0.001). Maxdiff SpO2 was inversely related to survival, DLCO%, and SpO2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT distance, SpO2 after 6MWT, peak oxygen consumption/kg, SpO2 at peak exercise), while an inverse association with dyspnea score, AHI, and RVSP was observed. CONCLUSIONS Our findings provide evidence that intermittent sleep oxygen desaturation significantly exceeds that of maximal exercise and is associated with survival in IPF patients. Furthermore, they imply the existence of a link between lung damage and apnea events resulting to the induction and severity of intermittent sleep oxygen desaturation that aggravate pulmonary arterial hypertension and influence IPF survival.

Combined pulmonary fibrosis and emphysema

The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Emphysema is usually encountered in the upper lobes preceding fibrosis of the lower lobes, and patients are smokers, predominantly male, with distinct physiologic profile characterized by preserved lung volumes and markedly reduced diffusion capacity. Actually, the term CPFE is reserved for the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia computed tomography pattern as well as any pathologically confirmed case. CPFE is complicated by pulmonary hypertension, lung cancer and acute lung injury and may present different outcome than that of its components.

Acute severe asthma: new approaches to assessment and treatment.

The precise definition of a severe asthmatic exacerbation is an issue that presents difficulties. The term ‘status asthmaticus’ relates severity to outcome and has been used to define a severe asthmatic exacerbation that does not respond to and/or perilously delays the repetitive or continuous administration of short-acting inhaled β2-adrenergic receptor agonists (SABA) in the emergency setting. However, a number of limitations exist concerning the quantification of unresponsiveness. Therefore, the term ‘acute severe asthma’ is widely used, relating severity mostly to a combination of the presenting signs and symptoms and the severity of the cardiorespiratory abnormalities observed, although it is well known that presentation does not foretell outcome.In an acute severe asthma episode, close observation plus aggressive administration of bronchodilators (SABAs plus ipratropium bromide via a nebulizer driven by oxygen) and oral or intravenous corticosteroids are necessary to arrest the progression to severe hypercapnic respiratory failure leading to a decrease in consciousness that requires intensive care unit (ICU) admission and, eventually, ventilatory support. Adjunctive therapies (intravenous magnesium sulfate and/or others) should be considered in order to avoid intubation. Management after admission to the hospital ward because of an incomplete response is similar.The decision to intubate is essentially based on clinical judgement. Although cardiac or respiratory arrest represents an absolute indication for intubation, the usual picture is that of a conscious patient struggling to breathe. Factors associated with the increased likelihood of intubation include exhaustion and fatigue despite maximal therapy, deteriorating mental status, refractory hypoxaemia, increasing hypercapnia, haemodynamic instability and impending coma or apnoea. To intubate, sedation is indicated in order to improve comfort, safety and patient-ventilator synchrony, while at the same time decrease oxygen consumption and carbon dioxide production. Benzodiazepines can be safely used for sedation of the asthmatic patient, but time to awakening after discontinuation is prolonged and difficult to predict. The most common alternative is propofol, which is attractive in patients with sudden-onset (near-fatal) asthma who may be eligible for extubation within a few hours, because it can be titrated rapidly to a deep sedation level and has rapid reversal after discontinuation; in addition, it possesses bronchodilatory properties. The addition of an opioid (fentanyl or remifentanil) administered by continuous infusion to benzodiazepines or propofol is often desirable in order to provide amnesia, sedation, analgesia and respiratory drive suppression.Acute severe asthma is characterized by severe pulmonary hyperinflation due to marked limitation of the expiratory flow. Therefore, the main objective of the initial ventilator management is 2-fold: to ensure adequate gas exchange and to prevent further hyperinflation and ventilator-associated lung injury. This may require hypoventilation of the patient and higher arterial carbon dioxide (PaCO2) levels and a more acidic pH. This does not apply to asthmatic patients intubated for cardiac or respiratory arrest. In this setting the post-anoxic brain oedema might demand more careful management of PaCO2 levels to prevent further elevation of intracranial pressure and subsequent complications. Monitoring lung mechanics is of paramount importance for the safe ventilation of patients with status asthmaticus.The first line of specific pharmacological therapy in ventilated asthmatic patients remains bronchodilation with a SABA, typically salbutamol (albuterol). Administration techniques include nebulizers or metered-dose inhalers with spacers. Systemic corticosteroids are critical components of therapy and should be administered to all ventilated patients, although the dose of systemic corticosteroids in mechanically ventilated asthmatic patients remains controversial. Anticholinergics, inhaled corticosteroids, leukotriene receptor antagonists and methylxanthines offer little benefit, and clinical data favouring their use are lacking.In conclusion, expertise, perseverance, judicious decisions and practice of evidence-based medicine are of paramount importance for successful outcomes for patients with acute severe asthma.

Pulmonary alveolar proteinosis: time to shift?

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive ‘occupation’ of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells’ immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF ‘as needed’.

The many faces of sarcoidosis: asymptomatic muscle mass mimicking giant-cell tumor

Sarcoidosis is a chronic, multisystem granulomatous disease of unknown etiology. Muscle involvement is frequent, but often asymptomatic. There are three forms of muscular sarcoidosis: only the nodular type can be recognized by imaging. MRI and 18F-FDG PET–CT are the best methods to attempt the diagnosis of nodular muscular sarcoidosis; nevertheless, the lesion can mimic a malignant tumor. In this case, biopsy is the only tool to identify the disease.

High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations

Introduction Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF‐AEs). According to one hypothesis IPF‐AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro‐inflammatory and pro‐fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. Methods Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF‐AE were based on international guidelines and consensus criteria. The interleukins (IL)‐4, IL‐6, IL‐8, IL‐10, and IL‐13 as well as active transforming growth factor‐beta (TGF‐&bgr;) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12 months. Mann‐Whitney test as well as Tobit and logistic regression analyses were applied. Results Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL‐6 and IL‐8 levels were significantly higher in exacerbated patients (p = 0.002 and p = 0.046, respectively). An increase in either IL‐6 or IL‐8 by 1 pg/ml increases the odds of death by 5.6% (p = 0.021) and 6.7% (p = 0.013), respectively, in all patients. No differences were detected for the other cytokines. Conclusion High levels of IL‐6 and IL‐8 characterize early‐on IPF‐AEs and an increase in the levels of IL‐6 and IL‐8 associates with worse outcome in all patients. However, as the most representative pro‐fibrotic cytokines, TGF‐&bgr;, IL‐10, IL‐4 and IL‐13 were not increased and given the dualistic nature, both pro‐inflammatory and pro‐fibrotic of IL‐6 further studies are necessary to clarify the enigma of IPF‐AEs etiopathogenesis. HighlightsControversy exists about the pathogenesis of IPF‐AEs.Early in the development of an IPF‐AE, IL‐6 and IL‐8 blood levels are significantly increased.While TGF‐&bgr;, IL‐4, IL‐10, and IL‐13 levels show no difference compared stable IPF patients.Increased IL‐6 and IL‐8 levels are related to a higher risk of death in all IPF patients.Further studies are necessary to clarify the enigma of IPF‐AEs etiopathogenesis.

Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract

Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5 years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the disease.

Idiopathic pulmonary fibrosis acute exacerbations: where are we now?

Considerable controversy is haunting the treatment of IPF ‘acute exacerbation’, its most devastating complication. The consensus coined term ‘acute exacerbation’ implies that on an unknown etiology disease such as IPF, an unknown etiology superimposed acute lung injury/acute respiratory distress syndrome (ALI/ARDS) represents the end-life event in a consistent proportion of patients and are treated by high dose steroids despite unproven benefit. Inversely, ALI/ARDS treatment recommendations are based on the provision of excellent supportive care plus an extensive search and appropriate treatment of the etiologic precipitant and all intensive care clinicians in the absence of an obvious etiology, considering that occult infection is the most probable and also the most treatable underlying condition, universally administer extensive spectrum antimicrobials. Viewing the persistent high mortality in IPF ‘acute exacerbations’ treated with steroids we strongly believe that a study comparing the two arms of the steroid and non-steroid approach is greatly awaited by scientists and owed to the patients.

Bronchiolitis: adopting a unifying definition and a comprehensive etiological classification

Bronchiolitis is an inflammatory and potentially fibrosing condition affecting mainly the intralobular conducting and transitional small airways. Secondary bronchiolitis participates in disease process of the airways and/or the surrounding lobular structures in the setting of several already defined clinical entities, mostly of known etiology, and occurs commonly. Primary or idiopathic bronchiolitis dominates and characterizes distinct clinical entities, all of unknown etiology, and occurs rarely. Secondary bronchiolitis regards infections, hypersensitivity disorders, the whole spectrum of smoking-related disorders, toxic fumes and gas inhalation, chronic aspiration, particle inhalation, drug-induced bronchiolar toxicities, sarcoidosis and neoplasms. Idiopathic or primary bronchiolitis defines clinicopathologic entities sufficiently different to be designated as separate disease entities and include cryptogenic constrictive bronchiolitis, diffuse panbronchiolitis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, neuroendocrine hyperplasia in infants, bronchiolitis obliterans syndrome in lung and allogeneic hematopoietic cell transplantation, connective tissue disorders, inflammatory bowel disease and bronchiolitis obliterans organizing pneumonia. Most of the above are pathological descriptions used as clinical diagnosis. Acute bronchiolitis, though potentially life threatening, usually regresses. Any etiology chronic bronchiolitis contributes to morbidity and/or mortality if it persists and/or progresses to diffuse airway narrowing and distortion or complete obliteration. Bronchiolitis in specific settings leads to bronchiolectasis, resulting in bronchiectasis.

Medical Research Council dyspnea scale does not relate to fibroblast foci profusion in IPF.

BackgroundIn Idiopathic pulmonary fibrosis (IPF) irreversibly progressive fibrosing parenchymal damage, leads to defects in mechanics and gas exchange, manifesting with disabling exertional dyspnea. Previous studies have shown a relationship between fibroblast foci (FF) profusion and severity and survival and a relationship between dyspnea grade and severity and outcome. We hypothesized a relationship between Medical Research Council (MRC) dyspnea scale with FF, and a relationship between FF and functional parameters and survival.MethodsWe retrospectively reviewed 24 histologically documented IPF patients. Profusion of FF was semiquantitatively evaluated by two scores, Brompton and Michigan. Survival analysis was performed by fitting Cox regression models to examine the relationship of the two scores with survival and the non-parametric Spearman correlation coefficient was calculated to describe the relationships of FF scores with dyspnea scores and functional parameters.ResultsNo statistically significant correlation between FF scores and the MRC scores was observed (p = 0.96 and p = 0.508 respectively). No significant correlation between FF scores and survival (p = 0.438 and p = 0.861 respectively) or any functional parameter was observed.ConclusionsThe lack of relationship between the MRC dyspnea scale and the FF might relate to the fact that dyspnea in IPF better reflects the overall of lung damage and its related consequences on mechanics and gas exchange whereas FF, one of its histological hallmarks, may not reflect its entire histology derangement also constrained by the geographically limited sampled tissue. This might be also valid for the observed lack of association between FF and survival or functional parameters.