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Congenital lung diseases by Dr. Wael Abd El-fattah Lecturer of Chest Diseases Faculty of Medicine Ain shams University Immotile cilia syndrome (1ry ciliary dyskinesia) 1. Kartagener’s syndrome 2. Young’s syndrome 3. Cystic Fibrosis Alpha 1-Antitrypsin deffeciency Infant RDS Kartagener’s syndrome • (> one gene responsible for defect in cilia structure) by failure of coordinated sliding and binding of cilia either due to absence of dynein arms or presence of special transposition of microtubules abnormal mucus transport from bronchial tree to the mouth impaired defenses): • Ccc: • Recurrent frontal sinusitis ± chronic rhinorrhea and otitis media (mild deafness) • LRTI (recurrent diffuse pneumonias) chronic cough and acquired bronchiectasis. • Male infertility (immotile live sperms) • Dextrocardia (situs inversus totalis in 1/2 cases) • Diagnosed by: • History of repeated infections and previous ccc • Nasal mucosal biopsy ultra-structural defect by high speed digital video photography. • Saccharine test abnormal mucociliary movement (place a small particle of saccharin approximately 1 cm behind the anterior end of the inferior turbinate. In the presence of normal mucociliary action, the saccharin will be swept backwards to the nasopharynx and a sweet taste perceived normally from 10-15mins, >28 mins means permanent damage. • E.M. for sperm tails and ciliary movement. Young’s syndrome • (defect in ciliary function with unknown mechanism): • Ccc: • Recurrent LRTI and bronchiectasis (1/5 cases). • Recurrent sinusitis. • Azospermia (due to obstruction in vas deferens),Poorly motile sperms in epididymis (not in ejaculate) Cystic Fibrosis • Definition: • Heritable disorder demonstrating an autosomal recessive pattern in which there is a wide spread dysfunction of exocrine glands in the form of: • Chronic pulmonary disease (more presented in adolescents). • Pancreatic insufficiency (more presented in infants). • Malabsorption (thick sticky secretions in intestine; mucoviscidosis). • Abnormally high levels of electrolytes in sweat (diagnostic test). • -Etiology: – Autosomal recessive mutation in CFTR gene (cystic fibrosis trans-membrane conductance regulator) which is found in all tissues affected- in the middle part of the long arm of chromosome 7. – 66% of that mutation is in the form of deletion of phenylalanine from position 508 of CFTR, • destroying chloride channels which are anchored to the outer membrane of cells in sweat glands, and other increased trapping of Cl ions outside those cells attracting Na ions followed by H2O as well dehydrated thick secretions with higher incidence of repeated infections. Incidence: One every 2000-2500 births/year in Europe and North America but very rare in Asia and Africa • Clinical Picture: • Symptoms: – Respiratory: • Upper airways: sinusitis, nasal polyps & otitis media ↑ dyspnea. • Lower airways: – Early: coughing of copious due to bacteria out of control. – Late: Chronic dyspnea, hemoptysis (50%), P++, Corpulmonale,Rt.sided HF, RF, Pneumothorax . GIT: • Pancreas: • Early: pancreatic auto-destruction pancreatitis malabsorption steatorrhea and osteoporosis (low vitamin D absorption) retarded growth and failure to thrive. • Late: fibrosis obliteration in islets of langerhans ± D.M. (12% in adulthood) • Intestine: • Abnormal mucins ↓transit time of intestine + maldigestion fecal impaction distal meconium ileus in newly born (50%) or intestinal obstruction • Gall bladder and Liver: • Inspissated bile syndrome in new born prolonged neonatal Jaundice 2-8wks). • Focal biliary cirrhosis in adolescents. • Chronic calcular cholecystitis and cirrhosis – Reproductive system: • ♂: Vas deference is absent or atretic no sperms infertility. • ♀: ↑↑ Viscosity & abnormal midcycle cervical mucus only can sometimes cause infertility. – Sweat glands: no histological changes but abnormal function. • Signs: – General: • Loss of weight with mal-absorption and digestion • Fever (in infective exacerbation) • Clubbing ± osteoarthropathy (15% in adults) • Jaundice in new born • Cyanosis with RF • Pallor with repeated hemoptysis • Congested neck veins in corpulmonale • Bilateral lower limb edema in corpulmonale • Working ala nasi if distressed child. – Local: • Tachypnea • Hyper inflated chest later in the course of the disease • Polyphonic wheezes in 50% • Inspiratory crepitations (more in the upper lobe) • Investigations and Diagnosis: • Depends on: clinical background, +ve sweat test and F.H. • Sweat test: (The Gold Standard Diagnostic Test for Cystic Fibrosis) • Pilocarpine iontophoresis technique: – Mechanism: Pilocarpine of 100 mg is put in 2 electrodes on the skin (on right arm or thigh or sometimes forearm if older child) with weak electric current to aid its penetration for 10 mins sweat is collected by a sweat patch in 30-45 mins & analyzed for Na and Cl (no creams is put on skin before testing) – Results: +ve result when Cl > 60 (2 tests are done to confirm) Borderline when 30-60 (to be repeated) Normal <30 mmol/liter • • • • • • • • • • Laboratory investigations: WBCs: leucocytosis in exacerbations. Serum Igs due to infections. Liver functions: AST and ALT might be elevated but ALP and bilirubin are more likely to elevate. Glucose level: for diabetes mellitus. Amylase: for pancreatitis. PT: in liver affection and mal-absorption. Serum trypsinogen: screening test. Stool analysis: for trypsin, chymotrypsin & secretin stimulation test. Semen analysis: for infertility (azospermia >97%). Radiological investigations: • Conventional CXR: • Early: – Mild hyper-inflation. – Minimal peri-bronchial thickening. • Late: • • • • • • • Thickening increase in upper lobe then becoming diffuse. Bronchiectatic picture (see bronchiectasis). Atelectasis. Increase in proximal arteries size. Enlarged right ventricle. Pneumothorax. Pneumomediastinum. • HRCT: (more sensitive) – Ground glass opacities – Early bronchiectatic changes Functional investigations: (for monitoring progression only) Microbiological investigations: • Sputum collection • Gram stain and culture ± specific culture media • Organisms: – Staphylococcus aureus (in young more) – H. influenza (in young more) – Pseudomonas (late & most severe, mucoid cepasium form): – Aspergillus fumigates (5-15%) – Mycobacterium (TB) – Legionella pneumophilia Early detection of CF Pre-natal diagnosis: in the 17th wk searching for: • It's important for good prognosis (early detection) and gene therapy. • Families with CF one parent can be assessed first if a carrier then examine the other because 2 copies of the gene must be affected for a disease to develop • ↑ level of intestinal iso-enzymes of ALP in amniotic fluid (marker) • DNA probes are used to localize defective genes using a sample of chorionic villi. Screening tests: (for newborn) • Immuno-reactive trypsinogen measurement (IRT): elevated if CF, a blood sample taken from foot of a baby or his arm on filter paper then left to dry then sent to the lab. • Mutation assessment of the gene: one or two mutations in DNA detected in 10-21 days. Treatment: • [A] General measures: • Proper nourishment by high caloric diet (double normal) with high proteins and carbohydrates due to increased need due to high energy expenditure due to increased work of breathing with chronic infection clear secretions and eradicate infections. • Exercise program to improve PFT. • [B] Drainage: (90% of patients die of complications) • Physiotherapy every 12 hrs in stable stages and more in exacerbations (same as bronchiectasis). • Bronchodilator (B2 agonist or ipratropium may help). • Corticosteroids reverse airflow obstruction when unresponsive to BD, in aspergillosis and in severe bronchiolitis in infants. • Mucolytics • [C] Antibiotics: for 2 weeks even after improvement to decrease relapse rate and increase intervals between exacerbations mainly anti-staphylococcal and anti-pseudomonal • [D] Psychological support • Early prenatally detected cases: –Gene therapy (trials are done). –U.T.P (uridine triphosphate aerosol activates Cl- channel) • Others aspects of management: • Chest complications: – – – – Pneumothorax: Corpulmonale: O2 up to BiPAP or IPPV and diuretics. Nasal inflammation: fluticazone nasal spray. End stage lung: cardio-pulmonary transplantation (difficult to select patients because it's a systemic disease). • Reproductive problems: – ♂ Intra-cytoplasmic sperm injection. – ♀ Assisted reproduction techniques. • GIT problems: – Meconium ileus: gastric aspiration, IV fluids, enemas and surgical ttt for DU & gall stones. – Pancreatic insufficiency: extract of pancreatin and H2 blockers to prevent its inactivation with gastric acid. – D.M.: insulin. – Liver disease: vitamin K (especially if high PT). – Mal-absorption: correct defects (supplementations). • Osteoporosis: Vitamin D and Ca intake ± bisphosphonates. Alpha 1-Antitrypsin deffeciency • Aggregation of COPD in families have established a role for genetic predisposition to COPD. The occurrence of reduced maximal expiratory airflow among nonsmoking first-degree relatives of individuals with early onset COPD provides further support. • However,dissecting specific genetic factors that increase the risk of COPD has proven difficult. • α1-AT deficiency illustrates this difficulty. Even among individuals with this clearly identified genetic risk factor, there is wide, unexplained, variability in the occurrence of COPD. • α1-Antitrypsin (a1-AT) or a1-protease inhibitor (α 1-Pi) is a polymorphic glycoprotein responsible for the majority of the antiprotease activity in the serum.It is synthesized in the liver, and most of the lung α 1-AT is derived from the plasma, although monocytes and macrophages can also manufacture the protein. • Chromosome 14 contains a gene that encodes the a1-AT protein. The gene for a1-AT is polymorphic, with over 70 known alleles, resulting from changes in the amino acid sequence, none of which alter protein structure, function or expression. Alpha1-AT deficiency caused by: 1- An increase in the proteinase burden, due to either the presence of increased numbers of inflammatory leucocytes in the airspaces or the release of excess protease . 2- Functional deficiency of protease inhibitors; 3- Combination of 1 and 2; 4 -Abnormality in the repair mechanisms for lung connective tissue. • The most important heterozygous type is PiSZ, where basal levels are 35–50% of normal values ,the homozygous PiZZ deficiency, in which serum levels are 10–20% of the average normal value, is the strongest genetic risk factor for the development of emphysema and the associated airflow obstruction. • The incidence of α1-Pi deficiency in a population study of patients presenting with COPD was 1–2% but rises to greater than 50% in patients with severe disease who are less than 40 years of age. The onset of dyspnoea and death occur at a younger age in smokers with α1-Pi deficiency. • In a study of deficient subjects in New Zealand, dyspnoea began on average at age 32 years in smokers compared with 51 years in non-smokers. The mean age at death in this group was 48 years for smokers and 67 years for non-smokers Table: Serum a1-proteinase inhibitor concentrations and the frequency of the more common phenotypes and the risk for emphysema. Phenotype Average concentration (g/L) Risk factor for emphysema MM 2.0 NO MS 1.6 NO MZ 1.2 NO SS 1.2 NO SZ 0.8 YES ZZ 0.4 YES Infant respiratory distress syndrome • Infant respiratory distress syndrome (IRDS), also called neonatal respiratory distress syndrome or respiratory distress syndrome of newborn, previously called hyaline membrane disease. • It is a syndrome in premature infants caused by developmental insufficiency of surfactant production and structural immaturity in the lungs. It can also result from a genetic problem with the production of surfactant associated proteins. • RDS affects about 1% of newborn infants and is the leading cause of death in preterm infants. • The incidence decreases with advancing gestational age, from about 50% in babies born at 26–28 weeks, to about 25% at 30–31 weeks. Histopathology • The characteristic histopathology seen in babies who die from RDS was the source of the name "hyaline membrane disease". These waxy-appearing layers line the collapsed alveoli of the lung. In addition, the lungs show bleeding, over-distention of airways and damage to the lining cells. Clinical course • IRDS begins shortly after birth and is manifest by tachypnea, tachycardia, chest wall retractions (recession), expiratory grunting, nasal flaring and cyanosis during breathing efforts. • As the disease progresses, the baby may develop ventilatory failure (rising carbon dioxide concentrations in the blood), and prolonged cessations of breathing ("apnea"). Whether treated or not, the clinical course for the acute disease lasts about 2 to 3 days. • Complications include metabolic disorders (acidosis, low blood sugar), patent ductus arteriosus, low blood pressure, chronic lung changes, and intracranial hemorrhage. The disease is frequently complicated by prematurity and its additional defects in other organ function. Prevention • The fetal lung maturity may be tested by sampling the amount of surfactant in the amniotic fluid,these include the lecithinsphingomyelin ratio ("L/S ratio"), and more recently, the surfactant/albumin (S/A) ratio. • For the L/S ratio, if the result is less than 2:1, the fetal lungs may be surfactant deficient. The presence of PG usually indicates fetal lung maturity. For the S/A ratio, the result is given as mg of surfactant per gm of protein. An S/A ratio <35 indicates immature lungs, between 35-55 is indeterminate, and >55 indicates mature surfactant production • Most cases of infant respiratory distress syndrome can be ameliorated or prevented if mothers who are about to deliver prematurely can be given glucocorticoids, antenatal glucocorticoid treatment for women at risk for preterm delivery prior to 34 weeks of gestation. Treatment • Oxygen is given with a small amount of continuous positive airway pressure ("CPAP"), and intravenous fluids are administered to stabilize the blood sugar, blood salts, and blood pressure. If the baby's condition worsens, an endotracheal tube (breathing tube) is inserted into the trachea and intermittent breaths are given by a mechanical device. • An exogenous preparation of surfactant, either synthetic or extracted from animal lungs, is given through the breathing tube into the lungs. One of the most commonly used surfactants is Survanta, derived from cow lungs, which can decrease the risk of death in hospitalized very-low-birthweight infants by 30%. • Extracorporeal membrane oxygenation (ECMO) is a potential treatment, providing oxygenation through an apparatus that imitates the gas exchange process of the lungs. However, newborns cannot be placed on ECMO if they are under 4.5 pounds (2 kg), because they have extremely small vessels for cannulation, thus hindering adequate flow because of limitations from cannula size and subsequent higher resistance to blood flow. • Furthermore, in infants aged less than 34 weeks of gestation several physiologic systems are not well-developed, specially the cerebral vasculature and germinal matrix, resulting in high sensitivity to slight changes in pH, PaO2, and intracranial pressure. Subsequently, preterm infants are at unacceptably high risk for intraventricular hemorrhage. • Therefore, the device cannot be used for most premature newborns. Thank you