CHRONIC BRONCHOPULMONARY DISEASES

Department of pediatrics

BRONCHIECTASIS

Bronchiectasis is a chronic suppurative disease characterized by destruction of the bronchial and peribronchial tissues, dilatation of the bronchi and accumulation of infected material in the dependent bronchi.

Etiopathogenesis

• Most cases follow recurrent episods of respiratory infections such as bronchitis, bronchiolitis, post measles or post pertussis pulmonary infections, cystic fibrosis and pneumonitis in infancy and early childhood. Infections damage the bronchial wall and cause segmental areas of collapse, which exert a negative pressure on the damaged bronchi, causing them to dilate. The bronchial dilatation is widespread and patchy. The bronchi may show cylindrical, fusiform or saccular dilatation.

• Aspiration of foreign body, food, or mucus plug in the bronchus may occlude the bronchial lumen and cause segmental areas of collapse. The bronchi are dilated due to negative pressure by the collapsed segment. If the occlusion is relieved before the stagnant secretions are infected and the bronchial wall is damaged, the bronchiectasis is reversible. The bronchial dilatations are generally segmental or lobar. Extrinsic compression by the tuberculous lymph nodes often causes collapse of right middle lobe.

Etiopathogenesis

• Congenital disorders of bronchi such as bronchomalacia, communicating type of bronchial cyst or sequestrated lung may be the cause of bronchiectasis in some cases.

• Kartagener syndrome is characterized by bronchiectasis, situs inversus and sinusitis and is attributed to disorder of ciliary motility (immotile cilia syndrome)

• Cystic fibrosis is rare cause of bronchiectasis.• Immunodeficiency syndrome may be responsible for

recurrent pulmonary infections and bronchiectasis.• Young syndrome has sinusitis, bronchiectasis and

azoospermia (detected later in life).

Clinical manifestations• The onset is generally insidious. The respiratory infections tend to

persist longer and recur frequently with waxing and waning. Often the illness can be traced back to an episode of measles or whooping cough. A history of inhalation of foreign body is usually not forthcoming as it is often forgotten.

• The most prominent symptom is cough with copious mucopurulent expectoration. Cough is more marked in some postures because of irritation of the infected secretions draining into fresh areas of lung. Likewise the cough is more marked when the child wakes up in the morning due to a change of posture. Younger children may not expectorate out the sputum which they swallow. Infants and young children often have significant wheezing. In the course of illness, the sputum may become blood streaked or even frank hemoptysis may occur. In chronic cases clubbing of fingers is seen.

• The general health is poor, with recurrent infections. The patient complains of loss of appetite, irritability and poor weight gain.

Investigations

X-ray film of the chest shows honeycombing of the involved area indicating multiple small abscess cavities. Bronchography remains the mainstay for diagnosing bronchiectasis. Bronchoscopy is undertaken where there is a possibility of surgical intervention. Now-a-days CT of the chest has replaced bronchoscopy in following the evolution of disease and deciding the need of surgical intervention. Sputum should be sent for culture and sensitivity. Tuberculin reaction is done to exclude tuberculosis. Pilocarpine iontophoresis is done for estimating sweat chlorides in cases suspected to be suffering from cystic fibrosis.

Prevention

Most cases follow acute respiratory infections, which are inadequately treated. All pulmonary infections should be treated promptly and adequately till the chest is clear of all signs, long after the fever has subsided. Even in ordinary pulmonary infections, airway should be kept patent by encouraging postural coughing. Measles and whooping cough should be prevented by specific immunization. Prompt medical help should be sought if there is any suspicion of inhalation of a foreign body.

Management During acute exacerbation, bacterial infections should be controlled and

airway kept clear of secretions and exudates. This is facilitated by effective coughing at regular intervals and postural drainage. Assistance by a specially trained pulmonary physiotherapist may be useful. Surgical resection of the involved area should be undertaken only in children who have marked symptoms and in whom the disease is localized. Extrinsic compression of bronchi by mediastinal masses requires surgical intervention. Cases with significant bronchographic changes but minimal symptoms need not be operated upon. In young children with generalized disease associated with recurrent pulmonary infections, ill advised surgery may at times make the patient worse. If the child cannot cooperate in post surgery postural coughing, segmental or lobar collapse may occur in the postoperative period and new bronchiectatic lesions may appear. Children with generalized disease may improve significantly clinically with medical treatment alone during adolescence.

PRIMARY CILIARY DYSKINESIA (IMMOTILE CILIA SYNDROME, KARTAGENER SYNDROME)

The group of respiratory disorders making up primary ciliary dyskinesia (PCD) have in common the malfunction of airway cilia. The ciliary abnormality is a result of various inherited primary structural defects in the cilia that lead to repeated and chronic lung infections. However, the ciliary malfunction in these diseases is not a result of acquired repeated pulmonary infections.

Characteristic of cilia Location and structure. Airway cilia are located on epithelial surfaces in almost a

ubiquitous fashion. They are present in the nose, sinuses, ears, and airways. They are also present in places other than the respiratory epithelium, such as in the fallopian tubes and in sperm. The density of cilia varies, with the majority of cells (50-80%) in the large airways having cilia, far fewer cells in the lower airways having cilia, and no cells in air sacks and alveoli having cilia. The frequency of ciliary beating, or beatquency, is obout 1 – 20 Hz, with the higher beatquency occurring in the larger airways, correlating with the mucus velocity in various parts of the tracheobronchial tree.

Cilia are finger-like structures that extend from the surface of cells into the lumen of airways. They have a diameter of 0,25 μm and a length of 306 μm. Each cell usually has about 200 cilia on its surface. Each cilia has a trunk, a basal body (where the cilia attaches to the cell), and a crown, which is a specialized structure presumed to be important in cilia attachment to mucus. The trunk is made of an outer cell membrane and axonemes or cytoskeletal protein structures. The latter form a circular array of nine microtubules in pairs with an additional central pair. Each peripheral pair can attach to the other via bridges or dynein arms. Spokes are also cytoskeletal proteins that join peripheral and central microtubules.

Characteristic of cilia Function. Cilia beat and move by a sliding motion of microtubules. At the

outset of the beating cycle, they bend at the base and move backward, perpendicular to the surface. Subsequently, they extend (“slide”) as they are rotating in a forward motion. These bending and rotating movements, which are clockwise, three-dimensional rotations, are made possible by adenosine triphosphate hydrolysis and the dynein arms, which are adenosine triphosphates. When visualized under microscopy, airway cilia are seen to coordinate their activity regionally, and waves of ciliary movements (many cilia together) occur. How this is coordinated and how effective and important such coordination is to ciliary function is not well understood.

The main function of cilia is to transport, through its beating movements, mucus toward the mouth. The effectiveness of this function depends on the beatquency, the composition and thickness of the periciliary fluid and mucus layer above it, and the coordination of ciliary movements. In addition, there are a number of neurochemicals that modulate ciliary beating by increased beatquency such as β-adrenergic compounds, acetylcholine, bradykinins and serotonin. Alternatively, lowering airway humidity significantly lowers the frequency of ciliary beating. In addition, increasing bacterial loads decreases its beatquency.

Pathology The structural abnormalities of these disorders can be seen

with electron microscopy. Defects in both inner and outer dynein arms, radial spoke microtubular assembly, and central core cytoskeletal proteins have been described. It is estimated that there are more than 200 polypeptides in the ciliary structure, and primary ciliary dyskinesia is most likely based on the absence of one or several ciliary cytoskeletal proteins. All these structural defects result in ciliary malfunction characterized by either abnormal beating or immotility of cilia and defective mucociliary clearance of airway secretions. The most likely pathogenic sequence is airway mucus retention and failure to clear pathogenic organisms, followed by chronic or frequently recurring respiratory tract infections and, ultimately, injury to airway walls.

Genetics

PCD occurs in about 1/20.000 whites and has been reported in Japanese patients. It is probably the 3rd most common form of inherited chronic airway disease of white children, following cystic fibrosis (CF) and genetic immunodeficiency states. The inheritance pattern of PCD has not been established. There is conflictind evidence for autosomal recessive or autosomal dominant inheritance with the mother having a new mutation, mitochondrial inheritance, or an X-linked mutation.

Clinical manifestations• About 50% of patients with PCD have Kartagener’s syndrome: situs inversus, chronic

sinusitis and otitis, and airway disease leading to bronchiectasis. However, only about 25% of patients with situs inversus also have PCD. Situs inversus does not establish or exclude the presence of PCD. Investigations have hypothesized that normal rotation of viscera depends on the motion of ciliated gut cells early in development. The absence of ciliary motility allows random rotation; a dynein defect is at the basis of left-right asymmetry in the inversus viscerum mouse model.

• The course is variable. Individuals with PCD may have respiratory distress during the newborn period or may survive to adulthood without overt chronic sinusitis and airway disease symptoms. However, in one study of PCD, 100% of children had productive cough, sinusitis, and otitis. A feature that is helpful in differentiating PCD from CF is repeated bouts of acute otitis media or chronic serous otitis. Children diagnosed after several years of life often have been treated with tympanostomy tubes; conductive hearing loss is common. Nasal polyps or clubbing is present in about 20% of patients. Many children with PCD experience frequent wheezing and may have an initial diagnosis of asthma. The hallmark symptom is a chronic, often loose of productive cough. Pneumonia may supervene and lower respiratory tract disease can progress to weight loss, diminished exercise tolerance, and bronchiectasis. Respiratory failure in childhood is uncommon, as are lung complications such as pneumothorax and hemoptysis. Lobar atelectasis occurs frequently. Males are frequently infertile and display absent or poor sperm motility.

Diagnosis• PCD should be suspected in children with chronic or recurring upper and lower respiratory

tract symptoms, especially in the presence of substantial middle ear disease. Radiographic or computed tomographic imaging shows involvement of the paranasal sinuses. X-ray chest may demonstrate overinflation, bronchial wall thickening, and peribronchial infiltrates. Often, atelectasis and consolidation are present. Bronchiectasis is best detected by computed tomographic scanning. The presence of right-sided heart in a child with chronic respiratory tract symptoms is virtually diagnostic, but this configuration occurs in only 50% of these patients. Pulmonary function testing of older children yields a typical obstructive pattern.

• Mucociliary clearance can be assessed in cooperative children by ascertaining the time to taste perception of a saccharin particle placed on the inferior nasal turbinate. Scrapings or brushings of nasal mucosa can be examined directly by light or, preferably, by phase-contrast microscopy for evidence of motility. In most PCD tissue specimens, little or no ciliary motion is seen. However, because substantial motility has been documented in scrapings of several individuals with absent dynein arms, light microscopic examination of living tissue can be used as a screening tool only. The gold standard is quantitative documentation of abnormal structural elements, such as missing dynein arms or random orientation of cilia in nasal or bronchial biopsies or scrapings on electron microscopic esamination. Concordance of ultrastructural abnormalities in cilia and sperm is not complete. To avoid acquired ciliary changes, mucosal specimens should not be obtained until 2 wk after an acute respiratory tract infection. Ultrastructural evaluation should be reserved for highly suspicious cases. However, some of the reported structural abnormalities are also observed after injury to ciliated epithelial cells by viral infection or sulfur dioxide exposure. Therefore, definitive evidence that any structural alteration represents a discrete form of PCD awaits the identification of specific gene mutation.

Treatment

• Therapy is symptomatic. Cough should be encouraged. Chest physiotherapy assists the clearance of mucus. Antibiotics should be prescribed for evidence of infection of sinuses or lower airways. The choise of antibiotics is best dictated by identification and sensitivity testing of pathogenic organisms, often pneumococcus or untypable Haemophylus influenzae. Oral antibiotic administration is usually effective. Bronchodilators can be used for symptomatic wheezing or documentation of reversible airway obstruction. Children should be examined several times each year and followed by periodic chest radiographs and serial pulmonary function testing. Sinus and middle ear symptoms refractory to medical therapy deserve consultation with an otolaryngologist. Surgical intervention may be helpful in selected cases. Prevention of lung infection by measles, pertussis, influenza, and possibly pneumococcal vaccines is highly desirable. Additional preventive measures include avoidance of cigarette smoke and other airway irritants.

Prognosis

• Progression of lung disease appears to be much slower for patients with PCD than for those with CF. With proper treatment, disabling lung disease often can be avoided for long periods. A normal life span is possible.

BRONCHOMALACIA AND TRACHEOMALACIA• Chondromalacia of the trachea or of a main bronchus is a

common cause of persistent wheezing in infancy. In these disorders, there is insufficient cartilage to maintain the airway patency throughout the respiratory cycle. Tracheomalacia and bronchomalacia can be either primary or secondary. Although primary tracheomalacia and bronchomalacia are seen frequently in premature infants, most affected patients are born at term. Secondary tracheomalacia and bronchomalacia refers to the situation in which the central airway is compressed by adjacent structure (e.g., vascular ring) or deficient in cartilage due to tracheoesophagal fistula. Laryngomalacia may accompany primary bronchomalacia or tracheomalacia. Involvement of the entire central airway (laryngotracheobronchomalacia) is also seen.

Clinical manifestations

• Primary tracheo- and bronchomalacia are principally disorders of infants, with a male:female ratio of 2:1. The dominant finding, low pitched monophonic wheezing, is most prominent over the central airways. Parents often describe persistent respiratory congestion even in the absence of a viral respiratory infection. When the lesion involves only one main bronchus (more commonly the left), the wheezing is louder on that side. In case of tracheomalacia, the wheeze is loudest over the trachea. Hyperinflation and/or subcostal retractions do not occur unless the patient also has asthma or another cause of small airways obstruction. In the absence of asthma, patients with tracheomalacia and bronchomalacia are not helped by administration of a bronchodilator. Acquired tracheomalacia and bronchomalacia are seen in association with vascular rings (and may persist after surgical correction), tracheoesophageal fistula, and cardiomegaly, and after lung transplantation.

Diagnosis

• The definitive diagnosis of tracheomalacia and bronchomalacia is established by flexible or rigid bronchoscopy. The lesion is difficult to detect on plain radiographs, but fluoroscopy may demonstrate dynamic collapse and can avoid the need for invasive diagnostic techniques. Pulmonary function testing may show a pattern of decreased peak flow and flattening of the flow-volume loop. Other important diagnostic modalities include MRI and CT scanning. MRI is especially useful when there is a possibility of vascular ring and should be performed when a right aortic arch is seen on plain film radiography.

Treatment• Postural drainage may help with clearance of

secretions. Β-Adrenergic agents should be avoided in the absence of asthma. Nebulized ipratropium bromide may be useful. Endobronchial stents have been used in severely affected patients but have a high incidence of complications, ranging from airway obstruction from granulation tissue to erosion into adjacent vascular structures. Constant positive airway pressure (CPAP) via tracheostomy may be indicated for severe cases. Surgical approach (aorticopexy and bronchopexy) is rarely required and only for patients who have life-threatening apnea, cyanosis, and bradycardia (“cyanotic spells”) from airway obstruction.

Prognosis

• Primary bronchomalacia and tracheomalacia have excellent prognosis, because airflow improves as the airways grow. Wheezing at rest is usually gone by age 3 yr. Prognosis in secondary and acquired forms varies with cause. Patients with concurrent asthma need considerable supportive treatment.

INTERSTITIAL LUNG DISEASES

• The interstitial lung diseases (ILD) in infants and children include a group of uncommon, heterogeneous, familial, or sporadic diseases, that cause disruption of alveolar gas exchange and symptoms of reactive lung disease. Knowledge regarding pediatric ILD is limited because of its rare occurrence, varied spectrum of disease, and lack of controlled clinical trials investigating the disease process and treatment measures. The pathophysiologicy is believed to be more complex than adult disease because the injury occurs during the process of lung growth and differentiation. In ILD, the initial injury causes damage to the alveolar epithelium and capillary endothelium. Abnormal healing of injured tissue may be more prominent than inflammation in the initial steps of development of chronic ILD. Some familial cases, inherited as an autosomal dominant trait, may be due to mutations in surfactant protein genes, specifically surfactant protein C (SP-C). Some sporadic cases may also have similar SP-C gene mutations.

Classification and pathology• The classification of ILD in children is not standardized, but it is helpful to

separate diseases into those of known and unknown etiology. Respiratory infections caused by adenoviruses, influenza viruses, Chlamydia and Mycoplasma pneumoniae are usually self-limited illnesses but have been associated with prolonged and progressive lung damage, often in the form of bronchiolitis obliterans. Aspiration is a frequent cause of chronic lung disease in childhood. Children with developmental delay or neuromuscular weakness are at an increased risk for aspiration of food, saliva, of foreign matter secondary to swallowing dysfunction and/or gastroesophageal reflux. An undiagnosed tracheoesophageal fistula can also result in pulmonary complications related to aspiration of gastric contents and interstitial pneumonia. Children experiencing an exaggerated immunologic response to organic dust, molds, or bird antigens may develop hypersensitivity pneumonitis. Children with malignancies may develop ILD related to the primary malignancy, an opportunistic infection, or secondary to chemotherapy or radiation treatment. Unique forms of ILD have been described in infants presenting with chronic tachypnea, retractions, crackles, and hypoxemia. Defects in surfactant proteins may be associated with forms of familial and sporadic chronic lung disease. The prognosis in these diseases is variable.

Usual interstitial pneumonitis (UIP) It is the most common form of ILD in affected adults but is

rare in children. The pulmonary lesion is characterized by a mixed distribution of ongoing inflammation and progressive end-stage fibrosis that is patchy and heterogenous. The diagnosis is made by biopsy; there is no definitive clinical or radiologic feature. The diagnosis of desquamative interstitial pneumonitis (DIP) depends on biopsy that demonstrates a uniform, homogeneous process characterized by hyperplasia of alveolar epithelial cells with an accumulation of large macrophages within the air spaces. Fibrosis is usually not seen. Some infants with histology similar to DIP have been diagnosed with surfactant B deficiency. A familial form has been described in infants, which is unusually severe and often fatal.

Lymphocytic interstitial pneumonitis (LIP)

It is the most common form of ILD in children, is a form of pulmonary lymphoproliferative disease. LIP usually develops in association with conditions of impaired immunity, such as an autoimmune disease or immunodeficiency (HIV infection). The pulmonary interstitium is invaded by a diffuse infiltrate of mature lymphocytes. Fibrosis is rare. Infection with a virus such as Epstein-Barr virus is often a contributing factor in the development of pediatric LIP.

Acute interstitial pneumonitis

It is also known as rapidly progressive interstitial pneumonitis or Hamman-Rich syndrome is a distinct, rapidly progressive form of ILD. The alveolar damage progresses from an acute exudative process to severe fibrosis. An antecedent injury is often not identified, the fatality rate is more than 50%.

Clinical manifestations• A detailed history of needed to assess the severity of symptoms and

the possibility of an underlying systemic disease. Identification of precipitating factors such as exposure to molds or birds or a severe lower respiratory infection is important in establishing the diagnosis and instituting avoidance measures. A positive family history, especially in an affected infant, is suggestive of a genetic or familial disease, such as a surfactant protein B or C deficiency. Tachypnea, cough, dyspnea, and exercise intolerance are present in more than 65% of patients. The majority have a reduced arterial saturation. Hypercarbia is a late complication. Symptoms are usually insidious and occur in a continuous, not episodic pattern. Tachypnea and basilar crackles are present in >50% of the patients. Retractions, failure to thrive, clubbing and wheezing are common complaints. Cyanosis and a prominent 2nd heart sound are suggestive of severe disease. Anemia or hemoptysis suggests a pulmonary vascular disease or pulmonary hemosiderosis. Rashes or joint complaints are consistent with an underlying connective tissue disease.

Diagnosis

• Noninvasive tests are initially used to determine the extent and severity of the disease. Chest radiographic abnormalities can be classified as interstitial, reticular, nodular, reticulo-nodular, or honeycombed. The chest film may also be normal, with the extent of disease. High-resolution CT (HRCT) of the chest better defines the extent and distribution of disease and can provide specific information for selection of a biopsy site. Faster modalities such as helical, spiral, or ultra-fast CT may provide precise resolution of disease patterns in tachypneic infants. Serial HRCT images may be of benefit in monitoring disease progression and severity.

• Pulmonary function tests are important in defining the degree of restrictive lung disease and in following the response to treatment. In ILD, pulmonary function abnormalities demonstrate a restrictive ventilator deficit with decreased lung volumes. Functional residual capacity (FRC) is reduced but usually less than vital capacity (VC) and total lung capacity (TLC). The residual volume (RV) is usually maintained; therefore, ratios of FRC:TLC and RV:TLC are often increased. Diffusion of carbon monoxide (DLCO) is usually normal when corrected for the decreased alveolar volume. An impaired DLCO may suggest vascular disease. Bronchoalveolar lavage (BAL) may provide helpful information regarding secondary infection, bleeding, or aspiration but will not usually determine the exact diagnosis. BAL is diagnostic for pulmonary alveolar proteinosis. Transthoracic lung biopsy for histopathology is usually the final step and is necessary for a conclusive diagnosis. Conventional thoracotomy or video-assisted thoracoscopy is used to obtain tissue from children with suspected ILD. Evaluation for possible systemic disease may also be necessary.

Treatment• Supportive care is essential and includes supplemental oxygen for hypoxia

and adequate nutrition for growth failure. Antimicrobial treatment may be necessary for intercurrent infections. Some patients may be responsive to bronchodilators. Anti-inflammatory treatment with corticosteroids remains the initial treatment of choice. Controlled trials in children are lacking, and the clinical responses reported in case studies are variable. The usual dose of prednisone is 1 – 2 mg/kg/24hr for 6 – 8 wk with tapering dictated by clinical response. Alternative, but not adequately evaluated, therapy includes hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, methotrexate, intravenous immunoglobulin, and pulsed high-dose steroids. Hydroxychloroquine treatment is successful in some children with classic ILD, particularly those with histopathologic changes of DIP. Lung transplantation for progressive or end-stage ILD is successful in some infants and children. Appropiate treatment for underlying systemic disease is indicated. Preventive measures include avoidance of all inhalation irritants such as tobacco smoke and, when appropriate, molds and bird antigens. Supervised pulmonary rehabilitation programs may be helpful.

Prognosis and genetic counseling• Prognosis. The overall mortality of ILD is

dependent on specific diagnosis and is as high as 20% in infants and children. Prognosis is variable and poor in children with pulmonary hypertension, failure to thrive, and severe fibrosis.

• Genetic counseling. A high incidence of interstitial lung disease in some families suggests a genetic predisposition to either development of the disease or severity of the disorder. Genetic counseling may be beneficial if a familial history is obtained.

CYSTIC FIBROSIS• Cystic fibrosis (CF) is an inherited multisystem disorder of children

and adults, characterized by obstruction and infection of airways and by maldigestion and its consequences. It is the most common life-limiting recessive genetic trait in children. A dysfunction of epithelialized surfaces is the predominant pathogenetic feature and is responsible for a broad, variable, and sometimes confusing array of presenting manifestations and complications.

• CF is the major cause of severe chronic lung disease in children and is responsible for most exocrine pancreatic insufficiency in early life. It is also responsible for many cases of salt depletion, nasal polyposis, pansinusitis, rectal prolapse, pancreatitis, cholelithiasis, and insulin-dependent hyperglycemia. CF may present as failure to thrive and, occasionally, as cirrhosis or other forms of hepatic dysfunction. Therefore, this disorder enters into the differential diagnosis of many pediatric conditions.

Etiology

• The most common severe inherited disease in the Caucasian population (autosomal recessive in inheritance).

• Cystic fibrosis transmembrane regulator (CFTR): functions as a cyclic AMP-activated chloride channel, which allows for the transport of chloride out of the cell. It is accompanied by the passive passage of water, which keeps secretions well hydrated.

• In cystic fibrosis, an abnormality in CFTR blocks chloride transport and inadequate hydration of the cell surface results in thick secretions and organ damage.

• The CFTR gene is 250.000 base pairs long and located on the long arm of chromosome 7. The most common deletion is three base pairs, which results in the absence of phenylalanine at codon 508.

Epidemiology• Incidence of abnormalities in CFTR gene 1:25 individuals in Caucasian population;• Incidence of cystic fibrosis 1:2500 in Caucasian population 1:17.000 in African-American population

(rarely seen in African blacks and Asians)

Symptoms• Chronic cough, recurrent pneumonia, bronchorrhea,

nasal polyps, and chronic pansinusitis.• Pancreatic insufficiency: occurs in 85% of patients. Fat

malabsorption may lead to failure to thrive or pancreatitis.

• Rectal prolapsed: occurs in 2% of of the patients.• Meconium ileus: 15 – 20% of patients present with

this symptom.• Distal obstruction: of the large intestine may be seen

in older children.• Hypochloremic metabolic alkalosis.

Signs

• Cough (frequently productive of mucopurulent sputum), rhonchi, rales, hyperresonance to percussion, barrel-chest deformity of thorax in severe cases, nasal polyps, and cyanosis (in later stages).

• Digital clubbing, hepatosplenomegaly in patients with cirrhosis, growth retardation, hypertrophic osteoarthropathy, and delayed puberty, amenorrhea, irregular menstrual periods (in teenage patients).

Investigations Sweat test: “gold standard” for the diagnosis of cystic fibrosis.• Sweat chloride >60 mEq/L is considered abnormal. False positives are seen in

severe malnutrition, ectodermal dysplasia, adrenal insufficiency, nephrogenic diabetes insipidus, hypothyroidism, hypoparathyroidism, mucopolysaccharidoses. False negatives are seen in patients with edema and hypoproteinemia.

• Genetic testing: over 600 identified genotypes, but only 20-70 of the most common are tested: thus, the lack of a positive genotype reduces (but does not eliminate) the possibility that a CF sample can be obtained from blood or buccal cell scraping.

• Sputum cultures: frequent pathogens include Staphylococcus aureus, Pseudomonas aeruginosa (mucoid and nonmucoid), Burkholderia cepaica.

• Pulmonary function tests: usually reveal obstructive lung disease.• Pancreatic function tests: 72-hour fecal fat measurement, measurement of

serum para-aminobenzoic acid (PABA) levels, stool trypsin levels, serum immunoreactive trypsin(IRT).

• Chest radiography: typical features include hyperinflation, peribronchial thickening, atelectasis, cystic lesions filled with mucus, and bronchiectasis.

• Sinus radiography: typically shows pansinusitis.

Complications• Respiratory: recurrent bronchitis and pneumonia,

chronic sinusitis, pneumothorax, hemoptysis.• Gastrointestinal: include pancreatic insufficiency;

patients usually have steatorrhea; decreased levels of vitamins A, D, E andK; poor growth and failure th thrive; meconium ileus equivalent; rectal prolapsed; and clinically significant hepatobiliary disease (cirrhosis of the liver, esophageal varices and splenomegaly).

• Reproductive: include sterility in 98% males and 75% females.

• Endocrine: abnormal glucose tolerance; diabetes mellitus.

Differential diagnosis• Pulmonary: recurrent pneumonia, chronic

bronchitis, immotile cilia syndrome, severe asthma, aspiration pneumonia.

• Gastrointestinal: gastroesophageal reflux, celiac sprue, protein-losing enteropathy.

• Other: failure to thrive (secondary to neglect, poor caloric intake or feeding problems), immune deficiency syndromes, nasal polyposis, male infertility, hyponatremic dehydration.

Treatment aims

• To maintain good nutritional status (good nutrition is associated with better prognosis).

• To slow pulmonary deterioration as much as possible.

• To maintain a normal lifestyle.

Diet and lifestyle

• High calorie diet with nutritional supplements (given orally, via nasogastric tube feedings or through gastrostomy tube feeding).

• Vitamin supplements: multivitamins and fat soluble vitamin replacement (usually E and K).

• Pancreatic enzyme replacement therapy can be used in patients who are pancreatic insufficient. Dosage is adjusted for the frequency and character of the stools and for growth pattern.

• Stool softeners treat constipation or meconium ileus equivalent and include mineral oil, oral N-acetylcysteine, lactulose, enemas.

Pharmacologic treatment Antibiotic therapy (based on sputum culture results).• Oral antibiotics: cephalexin, cefaclor, trimethoprim-

sulfamethoxazole, chloramphenicol, ciprofloxacin. • Intravenous antibiotics (given for 2-3 week course)• For Staphylococcus aureus: oxacillin, nafcillin;• For Pseudomonas aeruginosa or Burkholderia cepacica:

semisynthetic penicillin (ticarcillin, piperacillin) or a cephalosporin (ceftazidime) plus an aminoglycoside (gentamycin, tobramycin, or amikacin) to obtain synergic action.

For aid in clearing pulmonary secretions:• Aerosolized bronchodilator therapy (to open airways): albuterol;• Mucolytic agents (to help break up viscous pulmonary

secretions): N-acetylcysteine, recombinant DNase.• Chest physiotherapy with postural drainage.

Prognosis

• Long-term prognosis is poor.• The course of the illness is variable; it is impossible

to predict the course of the disease in a specific person.

• The current mean life span is 29 years.• Due to new antibiotics, enzyme-replacement

therapy, and maintenance of good pulmonary toilet with chest physiotherapy and bronchodilators, the mean age of survival has been increasing for the past three decades.

Follow-up and management

• Routine care should be at Cystic Fibrosis Center.

• Frequency of visits is dependent on severity of illness: usually every 2-4 m.

• Usually lifelong nutritional support is required.• Duration of antibioticotherapy is controversial.

Chronic use is eventually required as the patient’s pulmonary function deteriorates.

• All siblings should have a sweat test.