Endobronchial ultrasound-guided transbronchial needle aspiration under conscious sedation with meperidine and midazolam.

Endobronchial Ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is usually performed under general anesthesia or deep sedation with drugs such as Propofol that, at least in Italy, can be administered only by an anesthesiologist. Aim of the study was to assess conscious sedation feasibility, safety and tolerability using Meperidine and Midazolam as administered by Pulmonologist and relevant impact on the efficiency of the sampling procedures.All patients undergoing EBUS-TBNA from February 2013 to July 2014 were examined retrospectively. Efficiency using Meperidine and Midazolam during EBUS-TBNA has been assessed: completion of lymph-nodal sampling, sampling adequacy, diagnostic yield, cough during endoscopic procedure complications and need for procedure repetition with Anesthesiology assistance. Patient satisfaction and cost/effectiveness were also evaluated. One hundred and thirty-four consecutive patients were considered; 97.7% completed the procedure. In 96.9% of cases the prefixed program of lymph-nodal sampling was accomplished. Sampling adequacy was 92,4%. Diagnostic yield was 55%. In 94.7% of cases cough was absent or did not interfere with EBUS-TBNA. The need to repeat the endoscopic procedure occurred in 6 cases but only in 2 the presence of an Anesthesiologist was required. Patient satisfaction was very high, with 95.9% of subjects reporting they would "definitely return". A 27% cost reduction was calculated. EBUS-TBNA under conscious sedation using Meperidine and Midazolam prescribed and administered by pulmonologist without the Anesthesiologist assistance, revealed to be a safe, well tolerated and cost saving procedure. The efficiency of sampling was good, apart from a relatively low diagnostic yield due to different expertise of operators.

Levels of circulating endothelial cells are low in idiopathic pulmonary fibrosis and are further reduced by anti-fibrotic treatments.

BACKGROUND: It has been suggested that circulating fibrocytes and endothelial cells actively participate in the intense remodelling of the pulmonary vasculature in patients with idiopathic pulmonary fibrosis (IPF). Indeed, fibrotic areas exist that have fewer blood vessels, whereas adjacent non-fibrotic tissue is highly vascularized. The number of circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) might reflect the balance between vascular injury and repair. Thus, fibrocytes as well as endothelial cells could potentially be used as biomarkers of disease progression and treatment outcome. METHODS: Peripheral blood samples were collected from 67 patients with a multidisciplinary diagnosis of IPF and from 45 age-matched and sex-matched healthy volunteers. Buffy coat was isolated according to standard procedures and at least 20 million cells were stained with different monoclonal antibodies for the detection of CEC, EPC and circulating fibrocytes. For the detection of CEC and EPC, cells were stained with anti-CD45, anti-CD34, anti-CD133, anti-CD14, anti-CD309 and with the viability probe Far-Red LIVE/DEAD. For the detection of circulating fibrocytes, cells were first stained with LIVE/DEAD and the following monoclonal antibodies: anti-CD3, anti-CD19, anti-CD45, anti-CD34 and anti-CD14, then cells were fixed, permeabilized and stained with fluorochrome-conjugated anti-collagen I monoclonal antibodies. RESULTS: Patients with IPF displayed almost undetectable levels of circulating fibrocytes, low levels of CEC, and normal levels of EPC. Patients treated with nintedanib displayed higher levels of CEC, but lower levels of endothelial cells expressing CD309 (the type II receptor for vascular endothelial growth factor). Treatment with both nintedanib and pirfenidone reduced the percentage of CEC and circulating fibrocytes. CONCLUSIONS: Levels of CEC were reduced in patients with IPF as compared to healthy individuals. The anti-fibrotic treatments nintedanib and pirfenidone further reduced CEC levels. These findings might help explain the mechanism of action of these drugs and should be explored as predictive biomarkers in IPF.

"Neurologist's contribution to the diagnosis of sine materia respiratory insufficiency: case report".

BACKGROUND: Right-to-left shunt (RLS) may be the cause of marked hypoxemia, a respiratory insufficiency which is usually difficult to diagnose by respiratory physicians as it develops in the absence of an intrinsic lung disease. CASE PRESENTATION: We report a case of RLS in a patient with a hepatopulmonary syndrome caused by chronic autoimmune cholangitis. RLS was suspected clinically by physical examination and by standard CT imaging and MIP reconstruction of the pulmonary vascular bed. Repeated previous transthoracic echocardiography (TTE) studies did not reveal shunts or any cardiac defect. The final diagnosis was made by means of a minimally invasive transcranial Doppler examination with the use of saline agitated with 0.5 ml of patient's blood as contrast solution. CONCLUSIONS: Transcranial Colour-Coded Duplex Sonography (TCCS) with saline contrast medium injection is described to have a higher sensitivity than TTE and comparable to transesophageal echocardiography (TEE) in RLS diagnosis. The collaboration of neurologists in diagnosing respiratory insufficiency is very important as the examination is simple, well tolerated in comparison with the discomfort associated with transesophageal echocardiography, and minimally invasive in comparison with angiography, which is the last diagnostic procedure in this clinical scenario. In order to confirm RLS, TCCS with blood-saline contrast medium injection should be performed for the diagnosis of chronic hypoxemia for which causes are not detected with routine clinical examinations.

Clinical audit on diagnostic accuracy and management of respiratory failure in COPD.

BACKGROUND: The aim of the study was to evaluate the adequacy of diagnosis and management of respiratory failure (RF) in COPD. METHODS: Retrospective analysis of the hospital discharge forms of COPD patients hospitalized for RF from January 2007 to June 2008. Using the clinical audit tool, the primary end point was the accuracy of RF diagnosis. The secondary end points were mortality, re-hospitalization rate, length of hospital stay, accuracy of long-term oxygen therapy (LTOT) prescription, and agreement of the treatments with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008 guidelines. Statistical analysis used Pearson and Spearman correlation test and the Cohen kappa for degree of agreement. Differences in demographics and clinical parameters were analyzed with the chi-square test, t test, or the Fisher test, as appropriate. RESULTS: We studied 130 patients, 81 males (62%), mean ± SD age 76.6 ± 9.1 years. Arterial blood gas analysis (ABG) was performed in 118 patients (90.8%), and in 77 (81%) a P(aO(2)) < 60 mm Hg was found at admission. Of these, 42 cases (54.5%) had no diagnosis of RF, despite a P(aO(2)) < 60 mm Hg. In 18 (19%) P(aO(2)) was ≥ 60 mm Hg; of these, 6 cases (33.3%) received an incorrect RF diagnosis. At discharge 8.1% of patients did not receive a diagnosis of RF, despite a compatible ABG. The highest mortality was found in the medicine departments (14.7%). The re-hospitalization rate at 90 days was 19.5%. Adherence of the treatment to the GOLD guidelines during hospitalization was confirmed in 75.8% of patients. In 41.1% of cases LTOT was prescribed at discharge; in 24 out of 27 cases P(aO(2)) values were < 55 mm Hg. CONCLUSIONS: Agreement between diagnosis of RF and ABG values was found to be insufficient in about half the cases. Among secondary end points, adherence of the treatment to guidelines and LTOT prescription were, however, found to be good. Data showed significant inaccuracies in the management of RF at our institution.

Long-term benefits of omalizumab in a patient with severe non-allergic asthma.

INTRODUCTION: Currently, omalizumab is indicated for the treatment of patients with severe allergic uncontrolled asthma despite optimal therapy. CASE PRESENTATION: We studied a 52-year-old man who has been suffering from severe non allergic steroid-resistant asthma with increased levels of total IgE and a lot of comorbidity. After a 3 years long treatment with omalizumab, he presented a significant improvement in disease control in terms of hospitalizations, exacerbation, quality of life and lung function with good safety profile. CONCLUSION: Our case shows, after a long follow-up, how omalizumab can be effective in a severe form of non-atopic asthma. It is therefore hoped that further studies can identify indicators that are able to give to clinicians information about patients who can be responsive to monoclonal anti-IgE antibody even if non allergic.

Real-life Efficacy of Omalizumab After 9 Years of Follow-up.

Omalizumab is frequently used as add-on treatment to inhaled corticosteroids (ICS) and long-acting ß2-agonists in patients with suboptimal control of severe asthma. Patients with severe asthma will typically require chronic treatment, although due to the limited amount of data available there are still some concerns about the safety and efficacy of long-term therapy with omalizumab. Herein, in an extension of a previous 4-year study, we report disease-related outcomes of 8 patients with severe persistent allergic asthma who have been followed for a total of 9 years in a real-life setting. Both quality of life (QoL) (evaluated using the Juniper Asthma-Related QoL Questionnaire [AQLQ]) and forced expiratory volume in 1 second (FEV1) showed sustained improvement at 9 years. The median values of AQLQ and FEV1 at 4 years were 5.5 and 82.0% compared to 5.9 and 85.5%, respectively, at 9 years, which were all significantly increased from baseline. After 9 years, the mean annual number of severe exacerbations was 0.63 compared to 5 at baseline. There also appeared to be a trend toward use of a lower dose of ICS at longer follow-up times. After 9 years, there were no safety concerns for continued use of omalizumab, and no asthma-related hospitalizations or emergency department visits were documented over the last 5 years. The present analysis is the longest reported clinical follow-up of omalizumab. Long-term maintenance treatment with omalizumab for up to 9 years is associated with continued benefits in reducing symptoms, exacerbations, and medication burden without any safety concerns.

Mepolizumab for severe refractory eosinophilic asthma: evidence to date and clinical potential.

Severe asthma is characterized by major impairment of quality of life, poor symptom control and frequent exacerbations. Inflammatory, clinical and causative factors identify different phenotypes and endotypes of asthma. In the last few years, new treatment options have allowed for targeted treatments according to the different phenotypes of the disease. To accurately select a specific treatment for each asthmatic variant, the identification of appropriate biomarkers is required. Eosinophilic asthma is a distinct phenotype characterized by thickening of the basement membrane and corticosteroid responsiveness. This review reports the latest evidence on an anti-IL-5 monoclonal antibody, mepolizumab, a new and promising biological agent recently approved by the FDA specifically for the treatment of severe eosinophilic refractory asthma.

The clinical profile of benralizumab in the management of severe eosinophilic asthma.

Despite several therapeutic choices, 10-20% of patients with severe uncontrolled asthma do not respond to maximal best standard treatments, leading to a healthcare expenditure of up to 80% of overall costs for asthma. Today, there are new important therapeutic strategies, both pharmacological and interventional, that can result in improvement of severe asthma management, such as omalizumab, bronchial thermoplasty and other biological drugs, for example, mepolizumab, reslizumab and benralizumab. The availability of these new treatments and the increasing knowledge of the different asthmatic phenotypes and endotypes makes correct patient selection increasingly complex and important. In this article, we discuss the features of benralizumab compared with other anti-interleukin-5 biologics and omalizumab, the identification of appropriate patients, the safety profile and future developments.

Clinical usefulness of mepolizumab in severe eosinophilic asthma.

Asthma is a chronic inflammatory disorder of the airways with variable clinical severity from very mild and occasional symptoms to recurrent critical exacerbations, at risk of fatal or near-fatal outcome, in a small percentage of patients. Within the different inflammatory cascades involved in asthma, eosinophils play a central role in the pathogenesis and largely influence disease severity. Interleukin-5 (IL-5) is the main cytokine controlling eosinophil activity and proliferation at the site of inflammation. Mepolizumab was the first biological humanized anti-IL-5 monoclonal antibody tested in randomized clinical trials on eosinophilic asthma and other eosinophilic diseases. On the basis of several positive clinical efficacy data, it has recently been approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. Unfortunately, high costs are at present a critical issue. Future studies will probably help in the correct selection of a potential "responder phenotype", allowing the prescription of this promising therapy to appropriate patients and best define cost-effectiveness issues.

Endobronchial Hamartoma Subtotally Occluding the Right Main Bronchus and Mimicking Bronchial Carcinoid Tumor.

Hamartomas are very rarely identified as an endobronchial lesion. Herein, we describe a peculiar case of a 55-year-old woman with persistent cough and increasing dyspnea and radiological detection of a solid lesion subtotally occluding the main right bronchus. Despite the radiological and radiometabolic (18-fluoro-2-deoxy-d-glucose positron emission tomography/computer tomography scan) features were highly suspected for bronchial carcinoid, the definitive diagnosis after endoscopic removal was indicative of an endobronchial hamartoma. When considering differential diagnosis of an endobronchial lesion, the physicians should take firmly in mind such rare entity and, accordingly, bronchoscopy and bronchoscopic biopsy should be done as first step in management of all cases presenting with endobronchial lesions.

Pulmonary involvement in an adult female affected by type B Niemann Pick disease.

We describe the case of a 33-year-old woman who presented with a pattern of diffuse micronodular opacities with centrolobular distribution at high resolution chest tomography (HRCT) performed after exposure to the smoke of a home fire. An abdominal CT scan showed the presence of 3 rounded hypodense lesions in the spleen parenchyma. A bronchoalveolar lavage (BAL) was performed, showing the presence of lipid laden cells in the aspirated fluid. A video-assisted thoracoscopic biopsy confirmed the presence of the foamy cells filling the alveolar spaces and showed a preserved background pulmonary architecture; the bronchiolar epithelium presented a cytoplasm with a particularly clear colour. Foam cells were present in the bone marrow aspirate too, that contained also sea-blue histiocytes. These data induced us to consider the diagnosis of a metabolic storage disorder, in the first instance Niemann-Pick type B, that was confirmed by low acid lysosomal sphingomyelinase activity on cultured fibroblasts: 5.22 nmol/mg prot/h (n.v. 92 +/- 18.2). Lung involvement is an important complication of Niemann-Pick disease, presenting with the clinical and radiological features of a diffuse lung disease.

Tailored therapy for severe asthma.

Patients with severe asthma or COPD have often a suboptimal symptom control due to inadequate treatment. A better understanding of pathogenetic mechanisms, phenotypes, endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen, or to open a way for new therapeutic target options. At the moment, the only biologic drug available in clinical practice is omalizumab. To overcome the limits of omalizumab, the research has focused on new monoclonal antibodies presenting higher avidity for IgE (e.g. ligelizumab and lumiximab) and ability to interact also with low affinity IgE receptor (FcϵRII). At present, many new biological drugs with different mechanisms of action and targets are matter of research. It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient. The most promising agents are targeted against cytokines of Th2 pattern and related receptors, such as IL-2 (daclizumab) and IL-13 (lebrikizumab) or IL-5 in patients with hypereosinophilia (mepolizumab, reslizumab and benralizumab). Other interesting drugs have as a target TNF-α or its soluble receptor (infliximab, golimumab and etanercept) or IL-1 (canakinumab), a cytokine with an important systemic proinflammatory action. Finally, the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody (eculizumab). Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient, such as IgE for omalizumab or periostin for lebrikizumab.

Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases.

Asthma is a complex disorder frequently associated with a poor symptom control, concomitant morbidity, mortality, and significant health care costs due to lack of compliance or inadequate therapeutic options. Interleukin-5 (IL-5) plays a key role in the pathogenesis of eosinophilic disorders, and in the latest years has become a definite target for treatment. Besides asthma, other hypereosinophilic disorders include the hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, sinonasal polyposis, COPD with eosinophilic airway inflammation, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis. The introduction of mepolizumab, a fully humanized monoclonal antibody that binds to IL-5, may represent a useful therapeutic option to control exacerbations and improve asthma-related quality of life in a subgroup of patients with persistent airway eosinophilia and moderate to severe asthma. Several studies carried out in recent years allow, at present, a careful patient selection for appropriate individualized treatment in severe asthma. Further research is anyway needed in order to better understand the pathogenetic mechanisms of asthma and to find new biomarkers. The high costs of biological agents as compared with standard drugs may be largely offset by increased clinical efficacy and good safety profile in selected patients.

Recurrent lung atelectasis from fibrin plugs as a very early complication of bronchial thermoplasty: a case report.

BACKGROUND: Bronchial thermoplasty (BT) is a new therapeutic option for severe refractory asthma not controlled despite high dose inhaled corticosteroids plus long-acting bronchodilators and omalizumab in selected cases. Risk of pulmonary atelectasis after BT in severe asthma has been described in literature, but no details have been reported on the possible mechanisms of the complication. CASE PRESENTATION: A 49-year-old male with severe uncontrolled asthma was referred to BT. One hour after the first procedure, acute respiratory failure occurred with PaO2/FiO2 < 300. A CT scan showed atelectasis of the right lower and middle lobes. A new bronchoscopy was performed under non-invasive ventilation; the right lower and middle lobe bronchus were occluded by bronchus-shaped plugs, that were very difficult to remove despite repeated saline washings and fragmentation with forceps. The patient had a rapid resolution of respiratory failure. Four weeks later, 6 hours after the second session of BT, severe bronchospasm occurred with respiratory failure. Chest X-Ray showed atelectasis of the left lower lobe, prompting to perform a new flexible bronchoscopy on non-invasive ventilation. The exam showed again a plug occluding the left lower lobar bronchus, removed with forceps and washings. The histological analysis of the plugs demonstrated the massive presence of fibrin with mucus debris, rare Charcot-Leyden crystals, scattered macrophages, neutrophils, eosinophils and bronchial epithelial cells. CONCLUSION: The originality of our case report is related to the recurrence of bronchial plugging with lobar atelectasis within one and five hours respectively, after two sequential BT procedures. At the histological evaluation the bronchial plugs appeared very different from the typical mucoid asthma plugs, being composed prevalently by fibrin. It can be hypothesized that intense thermal stimulation of the bronchial mucosa may represent a strong boost for inflammation in susceptible patients, with microvascular alteration induced directly by heat or through the release of mediators. Although in severe asthma a risk of atelectasis from the classical asthma mucoid plugs may be expected, the peculiarity of our case resides in the formation of fibrin plugs whose direct correlation with BT should be considered.

Lymphangioleiomyomatosis associated with pulmonary metastasis from an occult papillary carcinoma of the thyroid: report of a case occurring in a patient without tuberous sclerosis.

We report on 50-year-old woman without tuberous sclerosis, presenting with recurrent spontaneous pneumothorax. A CT-scan of the chest showed multiple, bilateral, thin-walled cysts, consistent with pulmonary lymphangioleiomyomatosis. A videothoracoscopic lung biopsy confirmed the diagnosis of lymphangioleiomyomatosis, but revealed also a micrometastasis from an occult papillary carcinoma of the thyroid gland. The main histologic differential diagnosis and the possible correlation between lymphangioleiomyomatosis and thyroid diseases are briefly discussed.

A budget impact analysis of bronchial thermoplasty for severe asthma in clinical practice.

INTRODUCTION: Fully 80% of asthma-related deaths occur in patients with uncontrolled disease and 50% of all costs are attributable to this subgroup. Although asthma is costly, direct costs and loss of productivity have only recently been extensively studied, partly as a result of the introduction of new and more costly treatment options. A 5-year population-based budget impact model in the perspective of the Emilia Romagna of Italy regional healthcare service compared the impact of adding adjuvant bronchial thermoplasty (BT) for a population of patients with severe, uncontrolled asthma treated with standard care (SC) with or without adjuvant omalizumab (OMAL). METHODS: The model compared the budget impact of two scenarios: the first examined a population treated either with SC alone or with administration of OMAL concurrent to SC; the second examined a population treated either with SC alone or with either the concurrent administration of OMAL or BT. RESULTS: The cost for treating asthmatics patients in Emilia Romagna with BT would require 17.7 million Euros during the initial year; these costs would be offset by savings of 1 million Euros, 10.5 million Euros, and up to 19.2 million Euros during third, fourth, and fifth years, respectively. CONCLUSION: Despite the increase in direct costs, the complementary treatment of patients with either BT or OMAL in addition to SC may not only help the clinician to meet the needs of a greater number of patients, but also decreases emergency room visits and hospitalizations, as well as generates economic savings in the longer term.

Clinical and pharmacoeconomic aspects of omalizumab: a 4-year follow-up.

OBJECTIVES: The aim of this study was to assess the stability of the effectiveness of omalizumab as add-on treatment in 11 patients with severe persistent allergic asthma followed for 4 years. Secondary outcomes were safety and economic impact, in terms of use of healthcare resources. METHODS: This retrospective study was designed to analyse a series of patients with severe allergic asthma treated with omalizumab. Patients were initially enrolled as part of the CIGE025A2425 international multicentre clinical trial. At the end (week 32), 11 responsive patients went on to complete the study and continued omalizumab treatment until June 2010. The monitoring visits coincided with the timescales planned for administering the drug and for the follow up. To estimate the economic impact, the PRE-POST treatment comparison was obtained by comparing the annual pretreatment costs with an annual average of the 4-year posttreatment period costs RESULTS: After 4 years, 81.8% of patients showed a good/excellent Global Evaluation of Treatment Effectiveness scale score and 81.2% showed an excellent increase (>1.5) in the Asthma Quality of Life Questionnaire score. The average forced expiratory volume in one second (FEV(1)) at 4 years was 75.3% compared with the predicted normal value for each patient, with a net increase (p = 0.009) compared with baseline FEV(1) values (58.6%). The frequency of serious exacerbations dropped by 94.7% compared with the pretreatment period, while mild-moderate exacerbations fell by 41.8%. A reduction in costs was observed for hospital admissions (97.3%), visits to emergency department (ED) (97.5%) and mild-moderate exacerbations (84%). The average cost reduction of concomitant drugs remained at 36%. CONCLUSIONS: This study confirms the effectiveness and reliability of omalizumab over the long term, while providing an excellent safety profile. The additional cost due the use of omalizumab was offset by the medium- and long-term savings associated with the reduction in hospital admissions and access to ED.

Eosinophilic infiltrate in a patient with severe Legionella pneumonia as a levofloxacin-related complication: a case report.

INTRODUCTION: Legionella pneumonia can appear with different levels of severity and it can often present with complications such as acute respiratory distress syndrome. CASE PRESENTATION: We report the case of a 44-year-old Caucasian man with Legionella pneumonia with successive development of severe acute respiratory distress syndrome. During his stay in intensive care the clinical and radiological situation of the previously observed acute respiratory distress syndrome unexpectedly worsened due to acute pulmonary eosinophilic infiltrate of iatrogenic origin. CONCLUSION: Levofloxacin treatment caused the occurrence of acute eosinophilic infiltrate. Diagnosis was possible following bronchoscopic examination using bronchoaspirate and transbronchial biopsy.

Síndrome de Bartter: relato de dois casos em crianças / Bartter's syndrome: two case report in childhood

Objetivo: Apresentar uma síndrome incomum em crianças e aleertar os pediatras para as tubulopatias - tais como a síndrome de Bartter - no diagnóstico diferencial dos distúrbios de crescimento e outras doenças comuns em crianças. Métodos: Dois pacientes säo apresentados. O primeiro, um menino com 3 anos e 2 meses, foi atendido ambulatorialmente para investigaçäo de retardo de crescimento que fora detectado ao redor do 9§ mês de vida. O segundo paciente, lactente com três meses de vida, foi internado em U.T.I. Pediátrica devido a graves distúrbios hidro-eletrolíticos e com suspeita diagnóstica de estenose hipertrófica de piloro. Resultados: Ambos os pacientes apresentavam retardo de crescimento, alcalose hipoclorêmica, hipocalemia e hipercalciúria. O primeiro paciente apresentava história de poli-hidrâmico, que é um achado freqüênte na forma neonatal. O tratamento consistiu na correçäo do potássio sangüíneo e na adminstraçäo de indometacina e espironolactona. Os dois pacientes apresentaram boa tolerâancia ao tratamento e, em pouco tempo, mostraram correçäo dos distúrbios ácido-básico e eletrolítico, com retomada gradual do ritmo de crescimento. Conclusöes: A síndrome de Bartter é uma tubulopatia infreqüente em crianças, mas que deve ser considerada como diagnóstico diferencial dos distúrbios do crescimento. A forma neonatal é rara e pode causar sérios distúrbios hidro-eletrolíticos, acarretando grandes dificuldades no diagnóstico. O tratamento é bem tolerado, mesmo por crianças muito pequenas, e deve ser instituído precocemente, no intuito de reduzir ao máximo os transtornos ao crescimento.