CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

19. Respiratory Tract & Mediastinum

Monica J. Federico, MD

Christopher D. Baker, MD

Vivek Balasubramaniam, MD

Emily M. Deboer, MD

Robin R. Deterding, MD

Ann Halbower, MD

Oren Kupfer, MD

Stacey L. Martiniano, MD

Scott D. Sagel, MD

Paul Stillwell, MD

Edith T. Zemanick, MD

RESPIRATORY TRACT

Pediatric pulmonary diseases account for almost 50% of deaths in children younger than age 1 year and about 20% of all hospitalizations of children younger than age 15 years. Approximately 7% of children have a chronic disorder of the lower respiratory system. Understanding the pathophysiology of many pediatric pulmonary diseases requires an appreciation of the normal growth and development of the lung.

GROWTH & DEVELOPMENT

The lung has its origins from an outpouching of the foregut during the fourth week of gestation. The development of the lung is divided into five overlapping stages.

1. Embryonic stage (3–7 weeks’ gestation): During this stage, the primitive lung bud undergoes asymmetrical branching and then subsequent dichotomous branching, leading to the development of the conducting airways. This stage of lung development is dependent on a complex interaction of various growth factors originating in both the pulmonary epithelium and the splanchnic mesenchyme. It also sees the development of the large pulmonary arteries from the sixth aortic arch and the pulmonary veins as outgrowths of the left atrium. Abnormalities during this stage result in congenital abnormalities such as lung aplasia, tracheoesophageal fistula, and congenital pulmonary cysts.

2. Pseudoglandular stage (5–17 weeks’ gestation): During this stage, which overlaps with the embryonic stage, the lung has a glandular appearance. The conducting airways (bronchi and bronchioles) form over these 12 weeks. The respiratory epithelium of these airways begins to differentiate, and the presence of cartilage, smooth muscle cells, and mucus glands are first seen. In addition, the pleuroperitoneal cavity divides into two distinct compartments. Abnormalities during this stage lead to pulmonary sequestration, cystic adenomatoid malformation, and congenital diaphragmatic hernia.

3. Canalicular stage (16–26 weeks’ gestation): This stage witnesses the delineation of the pulmonary acinus. The alveolar type II cells differentiate into type I cells, the pulmonary capillary network develops, and the alveolar type I cells closely approximate with the developing capillary network. Abnormalities of development during this stage include neonatal respiratory distress syndrome and lung hypoplasia.

4. Saccular stage (26–36 weeks’ gestation): During this stage further branching of the terminal saccules takes place as well as a thinning of the interstitium and fusion of the type I cell and capillary basement membrane in preparation for the lungs’ function as a gas-exchange organ. This stage sees the beginning of an exponential increase in the epithelial surface area for gas exchange. During this stage of lung development the lung is able to fulfill its function, in terms of a gas-exchange organ.

5. Alveolar stage (36 weeks’ gestation to 3–8 years of age): Controversy surrounds the length of this stage of lung development. During this stage, secondary alveolar septa form to increase the surface area for gas exchange, the capillary network has a rapid phase of growth, and true alveoli develop. Abnormalities during this stage lead to lung hypoplasia and can result in the development of bronchopulmonary dysplasia (BPD).

At birth, the lung assumes the gas-exchanging function served by the placenta in utero, placing immediate stress on all components of the respiratory system. Any abnormality in the lung, respiratory muscles, chest wall, airway, central respiratory control, or pulmonary circulation may therefore lead to problems at birth. For example, infants who are homozygous for an abnormality in the surfactant protein B gene will develop lethal pulmonary disease. Persistent pulmonary hypertension of the newborn due to a failure of the normal transition to a low-resistance pulmonary circulation at birth can complicate neonatal respiratory diseases. There is also mounting evidence that abnormalities during fetal and neonatal growth and development of the lung have long-standing effects into adulthood, such as reduced gas exchange, exercise intolerance, asthma, and an increased risk of chronic obstructive pulmonary disease.

Bogue CW: Genetic and molecular basis of airway and lung development. In Haddad GG et al (eds): Basic Mechanisms of Pediatric Respiratory Disease. BC Decker; 2002.

Burri P: Structural aspects of prenatal and postnatal development and growth of the lung. In McDonald JA (ed): Lung Growth and Development. BC Decker; 1997.

Wharburton D et al: Molecular mechanisms of early lung specification and branching morphogenesis. Pediatr Res 2005;57(5 Pt 2): 26R [PMID: 15817505].

DIAGNOSTIC AIDS

The four components of a complete pulmonary examination include inspection, palpation, auscultation, and percussion. Inspection of respiratory rate, depth, ease, symmetry, and rhythm of respiration is critical to the detection of pulmonary disease. In young children, an elevated respiratory rate may be an initial indicator of pneumonia or hypoxemia. In a study of children with respiratory illnesses, abnormalities of attentiveness, inconsolability, respiratory effort, color, and movement had a good diagnostic accuracy in detecting hypoxemia. Palpation of tracheal position, symmetry of chest wall movement, and vibration with vocalization can help in identifying intrathoracic abnormalities. For example, a shift in tracheal position can suggest pneumothorax or significant atelectasis. Tactile fremitus may change with consolidation or air in the pleural space. Auscultation should assess the quality of breath sounds and detect the presence of abnormal sounds such as fine or coarse crackles, wheezing, or rhonchi. Wheezing or prolonged expiratory compared to inspiratory time suggests intrathoracic airways obstruction. Tachypnea with an equal inspiratory and expiratory time suggests decreased lung compliance. Transmitted voice sounds in egophony and whispered pectoriloquy change with lung consolidation. It is important to know the lung anatomy in order to identify the location of abnormal findings (Figure 19–1). In older patients, unilateral crackles are the most valuable examination finding in pneumonia. Percussion may identify tympanic or dull sounds that can help define an intrathoracic process. (This component of the examination can prove challenging in young children, who may not cooperate.) Although chest radiography has replaced the utility of these tests, they can be helpful when imaging is not available.

 Figure 19–1. Projections of the pulmonary lobes on the chest surface. The upper lobes are white, the right-middle lobe is the darker color, and the lower lobes are the lighter color.

Extrapulmonary manifestations of pulmonary disease include acute findings such as cyanosis and altered mental status and signs of chronic respiratory insufficiency such as growth failure, clubbing, and osteoarthropathy. Evidence of cor pulmonale (loud pulmonic component of the second heart sound, hepatomegaly, elevated neck veins, and rarely, peripheral edema) signifies pulmonary hypertension and may accompany advanced lung disease.

Respiratory disorders can be secondary to disease in other systems. It is therefore important to look for other conditions such as metabolic acidosis, congenital heart disease, neuromuscular disease, immunodeficiency, autoimmune disease, and occult malignancy (arthritis or hepatosplenomegaly). Children with an elevated body mass index are more likely to present with respiratory symptoms and need to be evaluated for pulmonary pathology versus deconditioning or dyspnea.

Wang WH et al: Joint effects of birth outcomes and childhood body mass index on respiratory symptoms. Eur Resp J 2012 May;39(5):1213-9. doi: 10.1183/09031936.00091311. Epub 2012 Mar 22.

Wipf JE et al: Diagnosing pneumonia by physical examination: Relevant or relic? Arch Intern Med 1999;159:1082 [PMID: 10335685].

Pulmonary function tests (PFTs) are objective measures of lung and airway physiology that can help differentiate obstructive from restrictive lung diseases, measure disease severity, measure disease progression, and evaluate response to therapy. Because the range of predicted normal values changes with growth, serial determinations of lung function are often more informative than a single determination. Patient cooperation and consistent effort is essential for almost all standard physiologic assessments. With a well-trained technician in a comfortable environment aided by visual incentives, and an interactive computer-animated system, most children age 3 years and older can produce satisfactory results. Lung function measurements in infants and toddlers are available at centers with specialized equipment and expertise. Despite these limitations, tests of lung function are valuable in the care of children. Children with cystic fibrosis perform pulmonary function testing routinely as early as they can cooperate. The Expert Panel Report (3) recommends pulmonary function testing be performed routinely for evaluation and management of asthmatic children age 5 and older. Current spirometers use a pneumotachograph to record flow over time and produce a volume-time tracing (spirogram) or a flow-volume curve. The patient inhales maximally, holds his or her breath for a short period, and then exhales as fast and hard as possible until they reach residual volume or for at least 3 seconds. The values reported include: the forced vital capacity (FVC), which is the total volume of air that is exhaled; the forced expiratory volume in the first second of the exhalation (FEV₁); the ratio of the FEV₁/FVC; the forced expiratory flow at the middle of the vital capacity (FEF_25–75); and the peak expiratory flow rate (PEFR). A suggested range of normal for these measurements are included in Table 19–1 and examples are shown in the figures. Obstructive processes include asthma, bronchopulmonary dysplasia (BPD), and cystic fibrosis (CF). Restrictive lung disease can be caused by chest wall deformities that limit lung expansion, muscle weakness, and interstitial lung diseases such as collagen-vascular diseases, hypersensitivity pneumonitis, and interstitial fibrosis. Confirmation of restrictive lung or chest wall physiology requires lung volume measurements (eg, total lung capacity, residual volume, and functional residual capacity) because poor effort can mimic restrictive physiology. Lung volume measurements are usually only available at specialized centers. (For examples of pulmonary function tests, see Figures 19–2 to 19–4.)

 Figure 19–2. Normal flow volume loop pre and post bronchodilator.

 Figure 19–3. Flow volume loops from a child with asthma (obstructive pattern).

 Figure 19–4. Flow volume loops from a child with scoliosis (restrictive pattern): lung volume studies are needed to confirm restriction).

The peak expiratory flow rate, the maximal flow recorded during an FVC maneuver, can be assessed by handheld devices. These devices are not as well calibrated as spirometers and the PEFR measurement can vary greatly with patient effort, so they are not good substitutes for actual spirometry. However, peak flow monitoring can be helpful in a patient with asthma that is difficult to control or for patients with poor perception of their airflow obstruction

Couriel JM, Child F: Applied physiology: lung function tests in children. Curr Paediatrics 2006;16:413–419.

Galant SP, Nickerson B: Lung function measurement in the assessment of childhood asthma: recent important developments. Curr Opin Allergy Clin Immunol 2010;10:149–154 [PMID: 20035221].

Arterial blood gas measurements define the acid-base balance between respiration at the tissue level and that in the lungs. Blood gas measurement is essential in critically ill children to evaluate hypoxemia, acidosis, and hypercarbia. Blood gas measurements can be used to categorize acid-base disturbances as respiratory, metabolic, or mixed. Blood gas measurements are affected by abnormalities of respiratory control, gas exchange, respiratory mechanics, and the circulation. In pediatrics, hypoxemia (low partial pressure of arterial oxygen [Pao₂]) most commonly results from ventilation (V’) and perfusion (Q’) mismatch. Common pediatric diseases that may be associated with

hypoxemia due to V’/Q’ mismatch include acute asthma, cystic fibrosis (CF), pneumonia, bronchiolitis, and bronchopulmonary dysplasia (BPD). Other causes of hypoxemia include hypoventilation, shunts, and diffusion barrier for oxygen. Hypercapnia (elevated partial pressure of arterial carbon dioxide [Paco₂]) results from inadequate alveolar ventilation (ie, inability to clear the CO₂ produced). This is termed hypoventilation. Causes include decreased central respiratory drive, respiratory muscle weakness, and low-tidal-volume breathing as seen in restrictive lung diseases, severe scoliosis, or chest wall trauma. Hypercapnea can also occur when severe V’/Q’ mismatch is present which may occur with severe CF or BPD. Table 19–2 gives normal values for arterial pH, Pao₂, and Paco₂ at sea level and at 5000 ft.

Venous blood gas analysis or capillary blood gas analysis can be useful for the assessment of Pco₂ and pH, but not Po₂ or saturation. Noninvasive assessment of oxygenation can be achieved with pulse oximetry (measuring light absorption by transilluminating the skin). Oxygenated hemoglobin absorbs light at different wavelengths than deoxygenated hemoglobin. Measurement during a systolic pulse allows estimation of arterial oxygen saturation. No heating of the skin is necessary. Values of oxygen saturation are reliable as low as 80%. The pulse oximeter has reduced reliability during conditions causing reduced arterial pulsation such as hypothermia, hypotension, or infusion of vasoconstrictor drugs. Carbon monoxide bound to hemoglobin results in falsely high oxygen saturation readings. Transcutaneous assessment of Pao₂ is not commonly utilized because of the multiple factors that can interfere with accurate measurements.

Exhaled or end-tidal CO₂ monitoring can be used to noninvasively estimate arterial CO₂ content. It is used to monitor alveolar ventilation and is most accurate in patients without significant lung disease, particularly those with a good match of ventilation and perfusion and without airway obstruction. Monitoring of exhaled or end-tidal CO₂ is commonly used during a polysomnogram and by anesthesia. Transcutaneous Pco₂ monitoring is also feasible but may be less reliable than transcutaneous Po₂ monitoring and should be used with caution if at all.

Ayers P, Warrington L: Diagnosis and treatment of simple acid-base disorders. Nutr Clin Pract 2008;23(2):122–127 [PMID: 18390779].

Fouzas S, Priftis KN, Anthracopoulos MB: Pulse oximetry in pediatric practice. Pediatrics 2011;128:740 [PMID: 21930554].

Kirk VG, Batuyong Ed, Bohn SG: Transcutaneous carbon dioxide monitoring and capnography during pediatric polysomnography. Sleep 2006;29(12):1601–168 [PMID: 17252891].

Salyer JW: Neonatal and pediatric pulse oximetry. Respir Care 2003 Apr;48(4):386–396 [PMID: 12667266].

Tobias JD: Transcutaneous carbon dioxide monitoring in infants and children. Paediatr Anaesth 2009 May;19(5):434–444 [PMID: 19236597].

Respiratory tract infections may be caused by bacteria, viruses, atypical bacteria (eg, Mycoplasma pneumonia and Chlamydia pneumoniae), Mycobacterium tuberculosis, nontuberculous mycobacterium, or fungi (eg, Aspergillus and Pneumocystis jiroveci). The type of infection suspected and appropriate diagnostic tests vary depending on host factors such as underlying lung disease, immune function, and geographic region. Sources of respiratory tract secretions for diagnostic testing include nasopharyngeal and oropharyngeal swabs; expectorated and induced sputum; tracheal aspirates; direct lung or pleural fluid sampling; bronchoalveolar lavage fluid; and gastric aspirates, specifically for M tuberculosis. Blood and urine samples may also be used for serologic and antigen testing. Spontaneously expectorated sputum is the least invasive way to collect a sample for diagnostics, though it is rarely available from patients younger than age 6 years. Sputum induction, performed by inhaling aerosolized hypertonic saline, is a relatively safe, noninvasive means of obtaining lower airway secretions. Sputum induction has been used in patients with CF and may be useful in patients with suspected M tuberculosis, P jiroveci pneumonia, or complicated community-acquired pneumonia. Tracheal aspirates can be obtained easily from patients with endotracheal or tracheostomy tubes. Culture of respiratory tract samples is the most commonly used approach to detect and identify airway pathogens. Molecular diagnostic tests, based on PCR amplification and detection of nucleic material from microbes, may offer more rapid and sensitive testing for microbes. Molecular assays are used for detection of viruses and atypical bacteria in many laboratories. PCR is also used as an adjunct to culture for identification of M tuberculosis,nontuberculous mycobacteria, and some fastidious bacteria. Molecular approaches to the diagnosis of M tuberculosis and P jiroveci are also available and their use is likely to become more widespread.

Hammitt Laura L et al: Specimen collection for the diagnosis of pediatric pneumonia. Clin Infect Dis 2012;54(S2):S132–S139 [PMID: 22403227].

Murboch DR et al: Laboratory methods for determining pneumonia etiology in children. Clin Infect Dis 2012 Apr;54(Suppl 2): S146–S152 [PMID: 22403229].

Zumla A et al: Tuberculosis. N Engl J Med 2013;368(8):745–755 [PMID: 23425167].

The plain chest radiograph remains the foundation for investigating the pediatric thorax. Both frontal (posterior-anterior) and lateral views should be obtained if feasible. The radiograph is useful for evaluating chest wall abnormalities, heart size and shape, mediastinum, diaphragm, and lung parenchyma. When pleural fluid is suspected, lateral decubitus radiographs may be helpful in determining the extent and mobility of the fluid. When a foreign body is suspected, forced expiratory radiographs may show focal air trapping and shift of the mediastinum to the contralateral side. Lateral neck radiographs can be useful in assessing the size of adenoids and tonsils and also in differentiating croup from epiglottitis, the latter being associated with the “thumbprint” sign.

Barium swallow is indicated for detection of swallowing dysfunction in patients with suspected aspiration, tracheoesophageal fistula, gastroesophageal reflux, vascular rings and slings, and achalasia. Airway fluoroscopy assesses both fixed airway obstruction (eg, tracheal stenosis, masses, or tracheal compression) and dynamic airway obstruction (eg, tracheomalacia). Fluoroscopy or ultrasound of the diaphragm can detect paralysis by demonstrating paradoxic movement of the involved hemidiaphragm.

Chest CT is useful in evaluation of congenital lung lesions, pleural disease (eg, effusion or recurrent pneumothorax), mediastinum (eg, lymphadenopathy), pulmonary nodules or masses. High-resolution CT is best for evaluating interstitial lung disease (ILD) or bronchiectasis while decreasing radiation exposure compared to a standard CT. Magnetic resonance imaging (MRI) is useful for defining vascular or bronchial anatomical abnormalities. Ventilation-perfusion scans can provide information about regional ventilation and perfusion and can help detect vascular malformations and pulmonary emboli. Pulmonary angiography is occasionally necessary to define the pulmonary vascular bed more precisely. Recent concerns about radiation exposure in children led to the Image Gently campaign, an initiative of The Alliance for Radiation Safety in Pediatric Imaging, dedicated to increasing awareness of the need for radiation protection for children. Identified challenges include the need for continued education particularly at adult-focused hospitals, increased emphasis on appropriateness of pediatric imaging and outcomes research to validate the use of CT, and establishing ranges of optimal CT technique when imaging children.

Goske MJ et al: Image Gently: progress and challenges in CT education and advocacy. Pediatr Radiol 2011 Sep;41(Suppl 2): 461–466 [PMID: 22988269].

Image Gently Campaign website: http://www.pedrad.org/associations/5364/ig/.

Schneebaum et al: Use and yield of chest computed tomography in the diagnostic evaluation of pediatric lung disease. Pediatrics 2009;124:472–479 [PMID: 19620200].

Direct visualization of the airways may be necessary to establish the etiology of the respiratory problem despite an extensive history and physical and sophisticated imaging. This can be achieved with rigid or flexible instrumentation. Indications for laryngoscopy include hoarseness, stridor, symptoms of obstructive sleep apnea, and laryngeal wheezing. Indications for bronchoscopy include wheezing, suspected foreign body, recurrent pneumonia, persistent atelectasis, chronic cough, and hemoptysis. A flexible bronchoscope can also be used to assess placement and patency of an endotracheal tube. In general, the more specific the indication, the higher the diagnostic yield. Each method, rigid or flexible, has advantages and for some patients both should be employed sequentially under the same anesthesia.

The rigid, open tube instruments have the best optics and allow surgical intervention to be easily achieved such as removal of a foreign body. Rigid bronchoscopy is done with general anesthesia. Flexible laryngoscopy may be done with topical anesthesia or light sedation and flexible bronchoscopy can be done with either conscious sedation or general anesthesia. The flexible bronchscopy is of a smaller caliber and allows more distal examination of the airways. Because it is smaller, the flexible bronchoscope does not stent the airway open during the procedure and often dynamic airway collapse is more easily documented by the flexible procedure. Bronchoalveolar lavage is useful to sample the alveolar space for infection, inflammation, hemorrhage, or aspiration. Although removal of foreign bodies has been achieved with the flexible bronchoscope in larger children, the standard of care in most institutions is to remove foreign bodies via the rigid bronchoscope.

Transbronchial biopsy in children is limited to evaluation of infection and rejection in lung transplant patients. There is low diagnostic yield in most conditions. Transbronchial biopsy may have a role in sarcoidosis. Video-assisted thoracoscopic lung biopsy (VATS) provides a more substantial specimen for pathologic assessment.

Nicholai T: The role of rigid and flexible bronchoscopy in children. Paediatr Respir Rev 2011;12:190–195 [PMID: 21722848].

GENERAL THERAPY OF PEDIATRIC LUNG DISEASES

The goal of supplemental oxygen (O₂) therapy is to relieve hypoxemia. Supplemental oxygen can reduce the work of breathing, resulting in fewer respiratory symptoms; relax the pulmonary vasculature, lessening the potential for pulmonary hypertension and congestive heart failure; and improve feeding. Patients breathing spontaneously can be treated by nasal cannula, head hood, or mask (including simple, rebreathing, nonrebreathing, or Venturi masks). The goal of O₂ therapy is to achieve an arterial oxygen tension of 65–90 mm Hg or an oxygen saturation above 92%, although lower Pao₂ or Spo₂ levels may be acceptable in certain situations. The actual O₂ concentration achieved by nasal cannula or mask depends on the flow rate, the type of mask used, and the patient’s age. Small changes in flow rate during oxygen administration by nasal cannula can lead to substantial changes in inspired oxygen concentration in young infants. The amount of oxygen required to correct hypoxemia may vary according to the child’s activity. It is not unusual, for example, for an infant with chronic lung disease to require 0.75 L/min while awake but 1 L/min while asleep or feeding.

Although the head hood is an efficient device for delivery of oxygen in young infants, the nasal cannula is used more often because it allows greater mobility. The cannula has nasal prongs that are inserted in the nares. Flow through the cannula should generally not exceed 3 L/min to avoid excessive drying of the mucosa. Even at high flow rates, oxygen by nasal cannula rarely delivers inspired oxygen concentrations greater than 40%–45%. In contrast, partial rebreathing and nonrebreathing masks or head hoods achieve inspired oxygen concentrations as high as 90%–100%. Heated high-flow nasal cannulas have been developed recently to deliver a high flow rate without a high Fio₂.

Physical findings of hypoxemia are subtle. Adequate oxygenation should be measured by the arterial oxygen tension or pulse oximetry. The advantages of the latter noninvasive method include the ability to obtain continuous measurements during normal activities and to avoid artifacts caused by crying or breath-holding during arterial puncture. For children with cardiopulmonary disorders that require chronic supplemental oxygen therapy (eg, bronchopulmonary dysplasia or cystic fibrosis), frequent noninvasive assessments are essential to ensure the safety and adequacy of O₂ treatment.

AARC Clinical Practice Guidelines: selection of an oxygen delivery device for neonatal and pediatric patients-2002 revision and update. Respir Care 2002;47:707–716 [PMID: 12078654].

Ralston M et al (eds): Pediatric Advanced Life Support Provider Manual. American Heart Association and American Academy of Pediatrics; 2006.

Inhalation of medications is a mainstay of therapy for pediatric respiratory conditions and are routinely used in patients with chronic diseases such as cystic fibrosis (CF), bronchopulmonary dysplasia (BPD), and asthma, as well as in acute illnesses such as infectious laryngotracheobronchitis and bronchiolitis (Table 19–3). Short-acting β-agonists and anticholinergics provide acute bronchodilitation (relievers), whereas inhaled corticosteroids and cromones provide anti-inflammatory effects (controllers). Nebulized antibiotics have documented benefit in CF and nebulized mucolytic medications are used in CF and other conditions with impaired secretion control such as non-CF bronchiectasis.

The medications can be delivered by pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), or compressed air-driven wet nebulization. Careful attention to delivery technique is critical to optimize medication delivery to the airways. A valved holding chamber or similar spacer should be used with pMDI use, and this technique has been shown to be effective in infants as young as 4 months of age. A face-mask interface is recommended for both pMDI and wet nebulization in infants and toddlers; a simple mouth piece suffices for older children who can form a seal around the mouth piece. Delivery technique should be assessed and reviewed at each clinical visit.

Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL et al: Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest 2005;127:335–371 [PMID: 15654001].

Janssens HM, Tiddens HA: Aerosol therapy: the special needs of young children. Paediatr Respir Rev 2006;7(Suppl 1) [PMID: 16798606].

Chest physical therapy, with postural drainage, percussion, and forced expiratory maneuvers, has been widely used to improve the clearance of lower airway secretions in children with CF, bronchiectasis, and neuromuscular disorders. Currently available airway clearance techniques include: chest physiotherapy, autogenic drainage, blowing therapies (bubbles, pinwheels), active coughing, positive expiratory pressure (PEP) with handheld devices, intrapulmonary percussive ventilation, or high-frequency chest compression. The decision about which technique to use should be based on the patient’s age and preference after trying different approaches. Daily exercise is an important adjunctive therapy for airway clearance and overall lung health. Cough assist devices (eg, mechanical insufflator-exsufflators) are useful for children with a weak cough. For example, they are useful for children with neuromuscular disorders such as muscular dystrophy and spinal muscular atrophy. Bronchodilators or mucolytic medications may be given prior to or during airway clearance therapy. Inhaled corticosteroids and inhaled antibiotics should be given after airway clearance therapy so that the airways are first cleared of secretions, allowing the medications to maximally penetrate into the lung. Airway clearance has not been shown to be beneficial for patients with acute respiratory illnesses such as pneumonia, bronchiolitis, and asthma.

De Boeck K et al: Airway clearance techniques to treat acute respiratory disorders in previously healthy children: where is the evidence? Eur J Pediatr 2008;167;607–612 [PMID: 18322699].

Kravitz RM: Airway clearance in Duchenne muscular dystrophy. Pediatrics 2009;123:S231–S235 [PMID: 19420150].

Lester MK et al: Airway-clearance therapy guidelines and implementation. Resp Care 2009;54(6):733–750 [PMID: 19467161].

Environmental insults can aggravate existing lung diseases and impair pulmonary function, and probably cause lung disease in children. Outdoor air pollution (ozone and particulates), indoor pollution, diesel exhaust, and household fungi are examples. Environmental tobacco poisoning, either second or third hand, dramatically increases childhood pulmonary morbidity. Many adolescents personally abuse tobacco and become addicted. Public health policies that limit smoke exposure and reduce advertising to children have had a positive impact. Smoking family members should be admonished to quit smoking and do everything possible to minimize environmental smoke exposure to the children around them. Homes with mold should have remediation, particularly if children with lung disease are in residence. Ozone exposure can be limited by avoiding outdoor activities during the height of daily ozone levels, but additional public policy changes will be required to further reduce ozone pollutants in the air.

For children with asthma, family pets may be a significant trigger as can household cockroach infestation. Despite the known risk, many families are reluctant to eliminate risk of exposure to the pet. Families should also be counseled about risks of foreign body aspiration in curious toddlers.

Anderson ME, Bogdan GM: Environments, indoor air quality, and children. Pediatr Clin N Am 2007;54:295–307 [PMID: 17448361].

State of the Air Report 2012: Report by the American Lung Association: http://www.stateoftheair.org/. Accessed March 13, 2013.

Tzivian L: Outdoor air pollution and asthma in children. J Asthma 2011;48:470 [PMID: 21486196].

The conducting airways include the nose, mouth, pharynx, larynx, trachea, bronchi, and terminal bronchioles. These airways direct inspired air to the gas-exchange units of the lung but do not participate in gas exchange. Airflow obstruction in the conducting airways can occur at extrathoracic sites (eg, above the thoracic inlet) or at intrathoracic sites (eg, below the thoracic inlet). Extrathoracic or upper airway obstruction disrupts the inspiratory phase of respiration and is often manifest by stridor or “noisy breathing.” Intrathoracic obstruction disrupts the expiratory phase of respiration and is often manifest by wheezing and prolongation of the expiratory phase. After assessing whether the obstruction is extrathoracic or intrathoracic the next challenge is to determine if the obstruction is fixed or variable. Fixed obstructions disrupt each breath and the abnormal sounds are consistently heard. Fixed obstructions can be intrinsic to the airway or due to airway compression (extrinsic). They are often associated with anatomic abnormalities that may be amenable to surgical correction (Table 19–4).

Variable obstruction leads to abnormal sounds with breathing that are softer or absent with normal quiet breathing and may sound different with every breath. Variable obstructions are often due to dynamic changes in airway caliber that occurs with laryngomalacia, tracheomalacia, or bronchomalacia. The onset and progression of the obstruction can provide important clues as to the etiology and help determine the urgency of evaluation and management. Obstructions due to dynamic airway collapse often improve with age, whereas fixed obstructions typically progress or fail to improve with age. Acute onset extrathoracic obstruction is often infectious. Clinical indications that the obstruction is severe include high-pitched stridor or wheezing, biphasic stridor, drooling or dysphagia, poor-intensity breath sounds, severe retractions, and poor color or cyanosis.

Helpful diagnostic studies in the evaluation of extrathoracic obstruction include chest and lateral neck radiographs, airway fluoroscopy, and barium swallow. Patients who have symptoms of severe chronic obstruction should have an electrocardiogram and/or ECHO to evaluate for right ventricular hypertrophy and pulmonary hypertension. Patients suspected to have obstructive sleep apnea should have polysomnography (see section on Sleep Disordered Breathing). Diagnostic studies for intrathoracic obstruction include two-view chest radiographs, a sweat test, and pulmonary function tests. Other diagnostic studies are dictated by the history and physical findings. If asthma is suspected, a trial of bronchodilators and/or anti-inflammatories should be considered. If noninvasive studies are unable to establish the cause of airway obstruction, laryngoscopy and bronchoscopy remaim the procedures of choice to establish the precise diagnosis. In older children, pulmonary function tests can differentiate fixed from variable airflow obstruction and may identify the site of obstruction. Treatment should be directed at relieving airway obstruction and correcting the underlying condition if possible.

LARYNGOMALACIA & CONGENITAL DISORDERS OF THE EXTRATHORACIC AIRWAY

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Presentation from birth or within the first few months of life.

 Intermittent, high-pitched, inspiratory stridor.

 Moderate to severe symptoms require visualization of the airway.

Laryngomalacia is a benign congenital disorder in which the cartilaginous support for the supraglottic structures is underdeveloped. It is the most common cause of variable extrathoracic airway obstruction and manifests as intermittent stridor in infants and usually is seen in the first 6 weeks of life. Stridor has been reported to be worse in the supine position, with increased activity, with upper respiratory infections, and during feeding; however, the clinical presentation can be variable. Patients may have slight oxygen desaturation during sleep. The condition usually improves with age and resolves by the time the child is 2 years old, but in some cases symptoms persist for years. The diagnosis is established by direct laryngoscopy, which shows inspiratory collapse of an omega-shaped epiglottis (with or without long, redundant arytenoids). In mildly affected patients with no stridor at rest and no retractions, treatment is not usually needed. Patients with either severe symptoms of airway obstruction such as stridor with each breath, retractions, and increased work of breathing or more chronic signs such as feeding difficulties, failure to thrive, obstructive sleep apnea, hypoxemia, or severe dyspnea may benefit from surgical epiglottoplasty.

Meier JD et al: Improved growth curve measurements after supraglottoplasty. The Laryngoscope 2011;121(7):1574 [PMID: 21647914].

Thompson DM et al: Laryngomalacia: factors that influence disease severity and outcomes of management. Curr Opin Otolaryngol Head Neck Surg 2010;18(6):564 [PMID: 20962644].

Other congenital lesions of the larynx such as laryngeal atresia, laryngeal web, laryngocele and cyst of the larynx, subglottic hemangioma, and laryngeal cleft usually present as fixed extrathoracic obstruction and are best evaluated by direct laryngoscopy.

Laryngeal atresia presents at birth with severe respiratory distress and is usually fatal. Laryngeal web, representing fusion of the anterior portion of the true vocal cords, is associated with hoarseness, aphonia, and stridor. Surgical correction is usually necessary. Laryngeal cysts and lanryngocoeles present with stridor and significant airway obstruction. Laryngeal cysts are superficial and are generally fluid filled. Laryngoceles communicate with the interior of the larynx and may be either air- or fluid-filled. Both require surgery or laser therapy.

Subglottic hemangiomas are a rare cause of upper airway obstruction in infants and are associated with cutaneous vascular lesions of the skin in 50%–60% of patients. Although vascular malformations regress spontaneously, airway obstruction usually necessitates intervention. Medical management options include propranolol, systemic steroids, or intralesional steroids. Surgical intervention with laser ablation is usually successful, but rarely tracheostomy is required. Laryngeal cleft is an uncommon condition resulting from failure of posterior cricoid fusion. Patients present with stridor, dysphagia, or silent aspiration. A type 1 laryngeal cleft (above the vocal cords) may not show aspiration on a modified barium swallow while more severe type 2 and 3 laryngeal clefts almost always do. All types of clefts may result in recurrent or chronic pneumonia and failure to thrive. The diagnosis is made by direct laryngoscopy with attention to spreading the glottis structures apart and assessing for the absence of tissue above the vocal folds. The decision to correct type 1 clefts should be made after multidisciplinary consideration of the pulmonary complications and other comorbidities. Repair of type 1 clefts may be addressed surgically or with an injection laryngoplasty. More severe clefts require surgical repair and may require tracheostomy. Normal swallow function without aspiration may take months to occur, even after repair.

Ahmad SM, Soliman AM: Congenital anomalies of the larynx. Otolaryngol Clin North Am 2007 Feb;40(1):177–191 [PMID: 17346567].

Cohen M et al: Injection laryngoplasty for type 1 laryngeal cleft in children. Otolaryngol Head Neck Surg 2011;144(5):789 [PMID: 21493369].

Starkey E et al: Propranolol for infantile haemangiomas: a review. Arch Dis Child 2011;96(9):890 [PMID: 21622997].

ACQUIRED DISORDERS OF THE EXTRATHORACIC AIRWAY

Acquired disorders of the extrathoracic airway can present acutely or with recurrent symptoms of upper airway obstruction. Children with acquired disorders of the extrathoracic airway present with inspiratory sounds consistent with stridor. The pitch of the sound varies depending on the diagnosis. Upper airway obstruction can progress quickly and may be life-threatening, requiring close observation.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Sudden onset of coughing or respiratory distress.

 Difficulty vocalizing.

Aspiration of a foreign body into the respiratory tract is a significant cause of accidental death each year.

The foreign body can lodge anywhere along the respiratory tract. Foreign bodies that lodge in the esophagus may compress the airway and cause respiratory distress. More typically, the foreign body lodges in the supraglottic airway, triggering protective reflexes that result in laryngospasm. Small objects such as coins may pass through the glottis and obstruct the trachea. Objects that pass into the lower airway cause coughing but more variable respiratory distress (see section Acquired Causes of Intrathoracic Airway Obstruction).

Foreign body aspiration is commonly seen with small, round foods such as nuts and seeds, berries, corn/popcorn, hot dogs, and beans. Children 6 months to 4 years are at highest risk. Homes and child care centers in which an older sibling or child feeds age-inappropriate foods (eg, peanuts, hard candy, or carrot slices) to the younger child are typical. Without treatment, progressive cyanosis, loss of consciousness, seizures, bradycardia, and cardiopulmonary arrest can follow.

 Clinical Findings

Signs at the time of ingestion can include coughing, choking, or wheezing. Onset is generally abrupt, with a history of the child running with food in the mouth or playing with seeds, small coins, or toys.

The diagnosis is established by acute onset of choking along with inability to vocalize or cough and cyanosis with marked distress (complete obstruction), or with drooling, stridor, and ability to vocalize (partial obstruction). Chest x-rays and other imaging studies have been used to evaluate for foreign body ingestion. However, rigid bronchoscopy is the gold standard for diagnosis.

 Treatment

The emergency treatment of upper airway obstruction due to foreign body aspiration has changed over the last few years. If complete obstruction is present, then one must intervene immediately. If partial obstruction is present, then the choking subject should be allowed to use his or her own cough reflex to remove the foreign body. If, after a brief observation period, the obstruction increases or the airway becomes completely obstructed, acute intervention is required. The American Academy of Pediatrics and the American Heart Association distinguish between children younger than and older than 1 year of age. In an awake child younger than 1 year of age with a complete obstruction, the child should be placed face down over the rescuer’s arm. Five measured back blows are delivered rapidly followed by rolling the infant over and delivering 5 rapid chest thrusts. This sequence is repeated until the obstruction is relieved. In a choking child older than 1 year of age, abdominal thrusts (Heimlich maneuver) should be performed, with special care in younger children because of concern about possible intra-abdominal organ injury. If the child of any age becomes unresponsive, cardiopulmonary resuscitation is recommended. Chest compressions may help to dislodge the foreign body.

Blind finger sweeps should not be performed in infants or children because the finger may push the foreign body further into the airway causing worse obstruction. The airway may be opened by jaw thrust, and if the foreign body can be directly visualized, careful removal with the fingers or instruments should be attempted. Patients with persistent apnea and inability to achieve adequate ventilation may require emergency intubation, tracheotomy, or needle cricothyrotomy, depending on the setting and the rescuer’s skills. Foreign body removal is most successfully performed using a rigid bronchoscopy under general anaesthesia.

Berg MD et al: Pediatric basic life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Pediatrics 2010 Nov;126(5):e1345-60. doi: 10.1542/peds.2010-2972C. Epub 2010 Oct 18 [PMID:20956430].

Fiedkowski CW, Zheng H, Firth PG: The anesthetic considerations of tracheobronchial foreign bodies in children: a literature review of 12,979 cases. Anesth Analg 2010;111(4):1016–1025 [PMID: 20802055].

Croup describes acute inflammatory diseases of the larynx, including viral croup (laryngotracheobronchitis), epiglottitis (supraglottitis), and bacterial tracheitis. These are the main entities in the differential diagnosis for patients presenting with acute stridor, although spasmodic croup, angioedema, laryngeal or esophageal foreign body, and retropharyngeal or peritonsillar abscess should be considered as well.

1. Viral croup

Viral croup generally affects young children 6 months to 5 years of age in the fall and early winter months and is most often caused by parainfluenza virus serotypes. Other organisms causing croup include respiratory syncytial virus (RSV), human coronavirus NL63, rhinovirus, human metapneumovirus, influenza virus A&B, rubeola virus, adenovirus, and M pneumoniae. Although inflammation of the entire airway is usually present, edema formation in the subglottic space accounts for the predominant signs of upper airway obstruction.

 Clinical Findings

A. Symptoms and Signs

Usually a prodrome of upper respiratory tract symptoms is followed by a barking cough and stridor. Fever is usually absent or low-grade but may on occasion be high-grade. Patients with mild disease may have stridor when agitated. As obstruction worsens, stridor occurs at rest, accompanied in severe cases by retractions, air hunger, and cyanosis. On examination, the presence of cough and the absence of drooling favor the diagnosis of viral croup over epiglottitis.

B. Imaging

Anteroposterior and lateral neck radiographs in patients with classic presentations are not required but can be diagnostically supportive if the x-ray shows subglottic narrowing (the steeple sign) without the irregularities seen in tracheitis and a normal epiglottis. However, a severely ill patient should never be left unattended in the imaging suite.

 Treatment

Treatment of viral croup is based on the symptoms. Mild croup, signified by a barking cough and no stridor at rest, requires supportive therapy with oral hydration and minimal handling. Mist therapy has historically been used but clinical studies do not demonstrate effectiveness. Conversely, patients with stridor at rest require active intervention. Oxygen should be administered to patients with oxygen desaturation. Nebulized racemic epinephrine (0.5 mL of 2.25% solution diluted in sterile saline) is commonly used because it has a rapid onset of action within 10–30 minutes. Both racemic epinephrine and epinephrine hydrochloride (l-epinephrine, an isomer) are effective in alleviating symptoms and decreasing the need for intubation.

The efficacy of glucocorticoids in croup is now firmly established. Dexamethasone, 0.6 mg/kg intramuscularly as one dose, improves symptoms, reduces the duration of hospitalizations and frequency of intubations, and permits earlier discharge from the emergency department. Oral dexamethasone (0.15 mg/kg) may be equally effective for mild to moderate croup. Inhaled budesonide (2–4 mg) also improves symptoms and decreases hospital stay and may be as effective as dexamethasone. Dexamethasone has also been shown to be more effective than prednisolone in equivalent doses.

If symptoms resolve within 3 hours of glucocorticoids and nebulized epinephrine, patients can safely be discharged without fear of a sudden rebound in symptoms. If, however, recurrent nebulized epinephrine treatments are required or if respiratory distress persists, patients require hospitalization for close observation, supportive care, and nebulization treatments as needed. In patients with impending respiratory failure, an airway must be established. Intubation with an endotracheal tube of slightly smaller diameter than would ordinarily be used is reasonably safe. Extubation should be accomplished within 2–3 days to minimize the risk of laryngeal injury. If the patient fails extubation, tracheostomy may be required. Other underlying causes should be considered in hospitalized patients with persistent symptoms over 3–4 days despite treatment.

 Prognosis

Most children with viral croup have an uneventful course and improve within a few days. Some evidence suggests that patients with a history of croup associated with wheezing may have airway hyperreactivity. It is not always clear if the hyperreactivity was present prior to the croup episode or if the viral infection causing croup altered airway function.

Bjornson CL, Johnson DW: Croup. The Lancet 2008;371(9609):329 [PMID: 18295000].

2. Epiglottitis

With the introduction of the Haemophilus influenzae conjugate vaccine, the incidence of epiglottitis has dramatically decreased and epiglottitis is rare in countries with immunization programs. If disease occurs, it is likely to be associated with H influenzae in unimmunized children, or another organism such as nontypeable H influenzae, Neisseria meningitides, or Streptococcus species in immunized populations.

 Clinical Findings

A. Symptoms and Signs

The classic presentation is a sudden onset of high fever, dysphagia, drooling, muffled voice, inspiratory retractions, cyanosis, and soft stridor. Patients often sit in the so-called sniffing dog position, with the neck hyperextended and the chin stretched forward, which gives them the best airway possible under the circumstances. Progression to total airway obstruction may occur and result in respiratory arrest. The definitive diagnosis is made by direct inspection of the epiglottis, a procedure that should be done by an experienced airway specialist under controlled conditions (typically in the operating room during intubation). The typical findings are a cherry-red and swollen epiglottis and swollen arytenoids.

B. Imaging

Diagnostically, lateral neck radiographs may be helpful in demonstrating a classic “thumbprint” sign caused by the swollen epiglottis. Obtaining radiographs, however, may delay important airway intervention.

 Treatment

Once the diagnosis of epiglottitis is made, endotracheal intubation must be performed immediately in children but not necessarily in adult populations. Most anesthesiologists prefer general anesthesia (but not muscle relaxants) to facilitate intubation. After an airway is established, cultures of the blood and epiglottis should be obtained and the patient should be started on appropriate intravenous antibiotics to cover H influenzae and Streptococcus species (ceftriaxone sodium or an equivalent cephalosporin). Extubation can usually be accomplished in 24–48 hours, when direct inspection shows significant reduction in the size of the epiglottis. Intravenous antibiotics should be continued for 2–3 days, followed by oral antibiotics to complete a 10-day course.

 Prognosis

Prompt recognition and appropriate treatment usually results in rapid resolution of swelling and inflammation. Recurrence is unusual.

Guardiani E et al: Supraglottitis in the era following widespread immunization against Haemophilus influenzae type B: evolving principles in diagnosis and management. The Laryngoscope 2010;120(11):2183 [PMID: 20925091].

Tibballs J et al: Symptoms and signs differentiating croup and epiglottitis. J Paediatr Child Health 2011;47(3):77 [PMID: 21091577].

3. Bacterial Tracheitis

Bacterial tracheitis (pseudomembranous croup) is a severe life-threatening form of laryngotracheobronchitis. As the management of severe viral croup has been improved with the use of dexamethasone and vaccination has decreased the incidence of epiglottitis, tracheitis is a more common cause of a pediatric airway emergency requiring admission to the pediatric intensive care unit. This diagnosis must be high in the differential when a patient presents with severe upper airway obstruction and fever. The organism most often isolated is Staphylococcus aureus, but organisms such as H influenzae, group A Streptococcus pyogenes, Neisseria species, Moraxella catarrhalis, and others have been reported. A viral prodrome is common. Viral coinfections are described and should be treated especially in Influenza A and H1N1. The disease probably represents localized mucosal invasion of bacteria in patients with primary viral croup, resulting in inflammatory edema, purulent secretions, and pseudomembranes. Although cultures of the tracheal secretions are frequently positive, blood cultures are almost always negative.

 Clinical Findings

A. Symptoms and Signs

The early clinical picture is similar to that of viral croup. However, instead of gradual improvement, patients develop higher fever, toxicity, and progressive or intermittent severe upper airway obstruction that is unresponsive to standard croup therapy. The incidence of sudden respiratory arrest or progressive respiratory failure is high; in such instances, airway intervention is required. Findings of toxic shock and the acute respiratory distress syndrome may also be seen. Recently, subsets of patients with tracheal membranes have been reported with a less severe initial clinical presentation. Nevertheless, these patients are still at risk for life-threatening airway obstruction. Aggressive medical treatment and debridement still must occur in these patients.

B. Laboratory Findings and Imaging

The white cell count is usually elevated with a left shift. Cultures of tracheal secretions usually demonstrate one of the causative organisms. Lateral neck radiographs show a normal epiglottis but severe subglottic and tracheal narrowing. Irregularity of the contour of the proximal tracheal mucosa can frequently be seen radiographically and should elicit concern for tracheitis. Bronchoscopy showing a normal epiglottis and the presence of copious purulent tracheal secretions and membranes confirms the diagnosis.

 Treatment

Patients with suspected bacterial tracheitis will require direct visualization of the airway in a controlled environment and debridement of the airway. Most patients will be intubated because the incidence of respiratory arrest or progressive respiratory failure and respiratory arrest is high. Patients may also require further debridement, humidification, frequent suctioning, and intensive care monitoring to prevent endotracheal tube obstruction by purulent tracheal secretions. Intravenous antibiotics to cover S aureus, H influenzae, and the other organisms are indicated. Thick secretions persist for several days, usually resulting in longer periods of intubation for bacterial tracheitis than for epiglottitis or croup. Despite the severity of this illness, the reported mortality rate is very low if it is recognized and treated promptly.

Hopkins BS et al: H1N1 influenza A presenting as bacterial tracheitis. Otolaryngol Head Neck Surg 2010;142(4):612 [PMID: 20304287].

Tebruegge M et al: Bacterial tracheitis: a multi-centre perspective. Scand J Infect Dis 2009;41(8):548-557. [PMID: 19401934].

Unilateral or bilateral vocal cord paralysis may be congenital, or more commonly may result from injury to the recurrent laryngeal nerves. Risk factors for acquired paralysis include difficult delivery (especially face presentation), neck and thoracic surgery (eg, ductal ligation or repair of tracheoesophageal fistula), trauma, mediastinal masses, and central nervous system disease (eg, Arnold-Chiari malformation). Patients may present with varying degrees of hoarseness, aspiration, or high-pitched stridor. Unilateral cord paralysis is more likely to occur on the left because of the longer course of the left recurrent laryngeal nerve and its proximity to major thoracic structures. Patients with unilateral paralysis are usually hoarse but rarely have stridor. With bilateral cord paralysis, the closer to midline the cords are positioned, the greater the airway obstruction; the more lateral the cords are positioned, the greater the tendency to aspirate and experience hoarseness or aphonia. If partial function is preserved (paresis), the adductor muscles tend to operate better than the abductors, with a resultant high-pitched inspiratory stridor and normal voice.

Airway intervention (tracheostomy) is rarely indicated in unilateral paralysis but is often necessary for bilateral paralysis. Clinically, paralysis can be assessed by direct visualization of vocal cord function with laryngoscopy or more invasively by recording the electrical activity of the muscles (electromyography). Electromyogram recordings can differentiate vocal fold paralysis from arytenoid dislocation, which has prognostic value. Recovery is related to the severity of nerve injury and the potential for healing.

Khariwala SS et al: Laryngotracheal consequences of pediatric cardiac surgery. Arch Otolaryngol Head Neck Surg 2005;131:336 [PMID: 15837903].

Subglottic stenosis may be congenital, or more commonly may result from endotracheal intubation. Neonates and infants are particularly vulnerable to subglottic injury from intubation. The subglottis is the narrowest part of an infant’s airway, and the cricoid cartilage, which supports the subglottis, is the only cartilage that completely encircles the airway. This area is therefore susceptible to injury while patients have an endotracheal tube inserted. The clinical presentation may vary from totally asymptomatic to the typical picture of severe upper airway obstruction. Patients with signs of stridor who repeatedly fail extubation are likely to have subglottic stenosis. Subglottic stenosis should also be suspected in children with multiple, prolonged, or severe episodes of croup. Diagnosis is made by direct visualization of the subglottic space with bronchoscopy and maneuvers to size the airway. Tracheostomy is often required when airway compromise is severe. Surgical intervention is ultimately required to correct the stenosis. Laryngotracheal reconstruction in which a cartilage graft from another source (eg, rib) is used to expand the airway has become the standard procedure for symptomatic subglottic stenosis in children.

O’Connor Tony E et al: Laryngotracheoplasty to avoid tracheostomy in neonatal and infant subglottic stenosis. Otolaryngol Head Neck Surg 2011;144(3):435 [PMID: 21493209].

Quesnel Alicia M et al: Minimally invasive endoscopic management of subglottic stenosis in children: success and failure. Int J Pediatr Otorhinolaryngol 2011;75(5):652 [PMID: 21377219].

CONGENITAL CAUSES OF INTRATHORACIC AIRWAY OBSTRUCTION

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Chronic monophonic wheeze with or without a barking cough.

 Respiratory symptoms do not respond to bronchodilators.

 Pathogenesis

Tracheomalacia or bronchomalacia exists when the cartilaginous framework of the airway is inadequate to maintain airway patency. Airway collapse is dynamic and can lead to airway obstruction. Because the cartilage of the infant airway is normally soft, all infants may have some degree of dynamic collapse of the central airway when pressure outside the airway exceeds intraluminal pressure.

Tracheomalacia and bronchomalacia can be congenital or acquired. Congenital tracheomalacia and bronchomalacia are associated with developmental abnormalities such as tracheoesophageal fistula, vascular ring, or cardiac anomalies causing extrinsic airway compression during development. Tracheomalacia is also associated with various syndromes. Congenital tracheomalacia may be localized to part of the trachea, but can also involve the entire trachea as well as the remainder of the conducting airways (bronchomalacia). Acquired tracheomalacia has been associated with long-term ventilation of premature newborns, severe tracheobronchitis, surgical repair of airways anomalies such as tracheoesophageal fistula and complete tracheal rings, and airway compression due to tumors, abscess or infection, and cysts.

 Clinical Findings

Coarse wheezing, cough, stridor, recurrent illnesses, recurrent wheezing that does not respond to bronchodilators, or radiographic changes are common findings. Symptoms classically present insidiously over the first few months of life and can increase with agitation, excitement, activity, or upper respiratory tract infections. Diagnosis can be made by airway fluoroscopy or bronchoscopy.

 Treatment

Conservative treatment is usually indicated for the isolated condition, which generally improves over time with growth. Coexisting lesions such as tracheoesophageal fistulas and vascular rings need primary repair. In severe cases of tracheomalacia, intubation or tracheostomy may be necessary. Unfortunately, tracheostomy alone is seldom satisfactory because airway collapse continues to exist below the tip of the artificial airway. Positive pressure ventilation may be required to stent the collapsing airway. Surgical approaches to the problem (tracheopexy or aortopexy) may be considered as alternatives prior to or in an effort to wean off ventilatory support.

Carden KA et al: Tracheomalacia and tracheobronchomalacia in children and adults: an in-depth review. Chest 2005;127:984 [PMID: 15764786].

Goyal V, Masters IB, Chang AB: Interventions for primary (intrinsic) tracheomalacia in children. Cochrane Database Syst Rev 2012; CD005304 [PMID: 23076914].

The most common vascular anomaly to compress the trachea or esophagus is a vascular ring. A vascular ring can be formed by a double aortic arch or a right aortic arch with left ligamentum arteriosum or a patent ductus arteriosus. The pulmonary sling is created when the left pulmonary artery branches off the right pulmonary artery. Other common vascular anomalies include an anomalous innominate artery, a left carotid artery, and an aberrant right subclavian artery. All but the right subclavian artery can cause tracheal compression. The pulmonary sling may compress the trachea but can also compress the right upper lobe bronchus or the right mainstem takeoff. Of note, a pulmonary sling is associated with long segment tracheal stenosis 50% of the time.

 Clinical Findings

A. Symptoms and Signs

Symptoms of chronic airway obstruction (stridor, coarse wheezing, and croupy cough) are often worse in the supine position. Respiratory compromise is most severe with double aortic arch and may lead to apnea, respiratory arrest, or even death. Esophageal compression, present in all but anomalous innominate or carotid artery, may result in feeding difficulties. Barium swallow showing esophageal compression is the mainstay of diagnosis. Chest radiographs and echocardiograms may miss abnormalities. Anatomy can be further defined by angiography, chest CT with contrast, MRI or magnetic resonance angiography, or bronchoscopy.

 Treatment

Patients with significant symptoms require surgical correction, especially those with double aortic arch. Patients usually improve following correction but may have persistent but milder symptoms of airway obstruction due to associated tracheomalacia.

Humphrey C et al: Decade of experience with vascular rings at a single institution. Pediatrics 2006;117:e903 [PMID: 16585275].

McLaren CA, Elliott MJ, Roebuck DJ: Vascular compression of the airway in children. Paediatr Respir Rev 2008;9(2):85–94 [PMID: 18513668].

Bronchogenic cysts generally occur in the middle mediastinum (see section Mediastinal Masses) near the carina and adjacent to the major bronchi but can be found elsewhere in the lung. They range in size from 2 to 10 cm. Cyst walls are thin and may contain air, pus, mucus, or blood. Cysts develop from abnormal lung budding of the primitive foregut. They can be seen in conjunction with other congenital pulmonary malformations such as pulmonary sequestration or lobar emphysema.

 Clinical Findings

Bronchogenic cysts can present acutely with respiratory distress in early childhood due to airway compression or with symptoms of infection. Other patients present with chronic symptoms such as chronic wheezing, cough, intermittent tachypnea, recurrent pneumonia, or recurrent stridor, depending on the location and size of the cysts and the degree of airway compression. Still other patients remain asymptomatic until adulthood. However, all asymptomatic cysts will eventually become symptomatic with chest pain being the most common presenting complaint. The physical examination is often normal. Positive examination findings might include tracheal deviation from the midline and decreased breath sounds; percussion over involved lobes may be hyperresonant due to air trapping.

A. Laboratory Findings and Imaging Studies

The choice of diagnostic studies for bronchogenic cysts is controversial. Chest radiographs can show air trapping and hyperinflation of the affected lobes or may show a spherical lesion with or without an air-fluid level. However, smaller lesions may not be seen on chest radiographs. CT scan is the preferred imaging study and can differentiate solid versus cystic mediastinal masses and define the cyst’s relationship to the airways and the rest of the lung. A barium swallow can help determine whether the lesion communicates with the gastrointestinal tract. MRI and ultrasound are other imaging modalities used.

 Treatment

Treatment is surgical resection. Resection should be performed as soon as the cyst is detected to avoid future complications including infection. Postoperatively, vigorous pulmonary physiotherapy is required to prevent complications (atelectasis or infection of the lung distal to the site of resection of the cyst).

Eber E: Antenatal diagnosis of congenital thoracic malformations: early surgery, late surgery, or no surgery? Semin Respir Crit Care Med 2007;28(3)355–366 [PMID: 17562505].

Fievet L et al: Bronchogenic cyst: best time for surgery? Ann Thorac Surg 2012;94(5):1695–1699 [PMID: 22884598].

ACQUIRED CAUSES OF INTRATHORACIC AIRWAY OBSTRUCTION

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Sudden onset of coughing, wheezing, or respiratory distress.

 Asymmetrical physical findings of decreased breath sounds or localized wheezing.

 Asymmetrical radiographic findings, especially with forced expiratory view.

 Clinical Findings

A. Symptoms and Signs

Respiratory symptoms and signs vary depending on the site of obstruction and the duration following the acute episode. (See section Foreign Body Aspiration in the Intrathoracic Airway.) For example, a large or central airway obstruction may cause marked distress. The acute cough or wheezing caused by a foreign body in the lower respiratory tract may diminish over time only to recur later as chronic cough or persistent wheezing, monophonic wheezing, asymmetrical breath sounds on chest examination, or recurrent pneumonia in one location. Foreign body aspiration should be suspected in children with chronic cough, persistent wheezing, or recurrent pneumonia. Long-standing foreign bodies may lead to bronchiectasis or lung abscess. Hearing asymmetrical breath sounds or localized wheezing also suggests a foreign body.

B. Laboratory Findings and Imaging Studies

Inspiratory and forced expiratory (obtained by manually compressing the abdomen during expiration) chest radiographs should be obtained if foreign body aspiration is suspected. Chest radiographs may be normal up to 17% of the time. A positive forced expiratory study shows unilateral hyperinflation and there may be a mediastinal shift away from the affected side. If airway obstruction is complete, atelectasis and related volume loss will be the major radiologic findings. Virtual broncscopy and computerized tomography are alternative approaches for detecting a foreign body.

 Treatment

When a foreign body is highly suspected, a normal chest radiograph should not rule out the possibility of an airway foreign body. If clinical suspicion persists based on two of three findings—history of possible aspiration, focal abnormal lung examination, or an abnormal chest radiograph—then a bronchoscopy is indicated. Rigid bronchoscopy under general anesthesia is recommended. Flexible bronchoscopy may be helpful for follow-up evaluations (after the foreign object has been removed).

Children with suspected acute foreign body aspiration should be admitted to the hospital for evaluation and treatment. Chest postural drainage is no longer recommended because the foreign body may become dislodged and obstruct a major central airway. Bronchoscopy should not be delayed in children with respiratory distress but should be performed as soon as the diagnosis is made—even in children with more chronic symptoms. Following the removal of the foreign body, β-adrenergic nebulization treatments followed by chest physiotherapy are recommended to help clear related mucus or treat bronchospasm. Failure to identify a foreign body in the lower respiratory tract can result in bronchiectasis or lung abscess. This risk justifies an aggressive approach to suspected foreign bodies in suspicious cases.

Chiu CY et al: Factors predicting early diagnosis of foreign body aspiration in children. Pediatr Emerg Care 2005;21:161 [PMID: 15744193].

Cohen S, Avital A, Godfrey S, Gross M, Kerem E, Springer C: Suspected foreign body inhalation in children: what are the indications for bronchoscopy? J Pediatr 2009 Aug;155(2): 276–280 [Epub 2009 May 15] [PMID: 19446848].

Fiedkowski CW, Zheng H, Firth PG: The anesthetic considerations of tracheobronchial foreign bodies in children: a literature review of 12,979 cases. Anesth Analg 2010;111(4):1016–1025 [PMID: 20802055].

DISORDERS OF MUCOCILIARY CLEARANCE

Mucociliary clearance is the primary defense mechanism for the lung. Inhaled particles including microbial pathogens are also entrapped in mucus on the airway surface, then cleared by the coordinated action of cilia. The volume and composition of airway surface liquid influence the efficiency of ciliary function and mucus clearance. Mucous that cannot be cleared normally can obstruct the airways. If mucociliary clearance is not normal, bacteria that are not cleared can lead to a vicious cycle of infection and inflammation and increased mucous production. The two main genetic diseases of mucociliary clearance involve disorders of ion transport (cystic fibrosis [CF]) and disorders in ciliary function (primary ciliary dyskinesia [PCD]).

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Greasy, bulky, malodorous stools; failure to thrive.

 Recurrent respiratory infections.

 Digital clubbing on examination.

 Bronchiectasis on chest imaging.

 Sweat chloride > 60 mmol/L.

 Pathogenesis

Cystic fibrosis (CF), an autosomal recessive disease, results in a syndrome of chronic sinopulmonary infections, malabsorption, and nutritional abnormalities. It is one of the most common lethal genetic diseases in the United States, with an incidence of approximately 1:3000 among Caucasians and 1:9200 in the US Hispanic population. Although abnormalities occur in the hepatic, gastrointestinal, and male reproductive systems, lung disease is the major cause of morbidity and mortality. Most individuals with CF develop obstructive lung disease associated with chronic infection that leads to progressive loss of pulmonary function.

The cause of CF is a defect in a single gene on chromosome 7 that encodes an epithelial chloride channel called the CF transmembrane conductance regulator (CFTR) protein. The most common mutation is ΔF508, although approximately 1500 other disease-causing mutations in the CF gene have been identified. Gene mutations lead to defects or deficiencies in CFTR, causing problems in salt and water movement across cell membranes, resulting in abnormally thick secretions in various organ systems and critically altering host defense in the lung.

 Clinical Findings

A. Symptoms and Signs

All states in the United States and many other countries now perform newborn screening for CF by measuring immunoreactive trypsin (IRT), a pancreatic enzyme, in blood with or without concurrent DNA testing. Most infants with CF have elevated IRT in the newborn period, although false negative results are possible. In newborns with positive newborn screen, the diagnosis of CF must be confirmed by sweat testing, mutation analysis, or both (http://www.cff.org/AboutCF/Testing/NewbornScreening/).

Approximately 15% of newborns with CF present at birth with meconium ileus, a severe intestinal obstruction resulting from inspissation of tenacious meconium in the terminal ileum. Meconium ileus is virtually diagnostic of CF, so the infant should be treated presumptively as having CF until a sweat test or genotyping can be obtained.

During infancy and beyond, a common presentation of CF is failure to thrive due to malabsorption from exocrine pancreatic insufficiency. These children fail to gain weight despite good appetite and typically have frequent, bulky, foul-smelling, oily stools. These symptoms are the result of severe exocrine pancreatic insufficiency, the failure of the pancreas to produce sufficient digestive enzymes to allow breakdown and absorption of fats and protein. Pancreatic insufficiency occurs in more than 85% of persons with CF. (Chapter 22 describes gastrointestinal and hepatobiliary manifestations of CF; see also Table 22–12.) Infants with undiagnosed CF may also present with hypoproteinemia with or without edema, anemia, and deficiency of the fat-soluble vitamins A, D, E, and K, because of ongoing steatorrhea.

CF should also be considered in infants and children who present with severe dehydration and hypochloremic alkalosis. Other findings that should prompt a diagnostic evaluation for CF include unexplained bronchiectasis, rectal prolapse, nasal polyps, chronic sinusitis, and unexplained pancreatitis or cirrhosis. From a respiratory standpoint, clinical manifestations include productive cough, wheezing, recurrent pneumonias, progressive obstructive airways disease, exercise intolerance, dyspnea, and hemoptysis. Chronic airway infection with bacteria, including S aureus and H influenzae, often begins in the first few months of life, even in asymptomatic infants. Eventually, Pseudomonas aeruginosa and other gram-negative opportunistic bacteria becomes the predominant pathogen. Chronic infection leads to airflow obstruction and progressive airway and lung destruction resulting in bronchiectasis. There is increasing appreciation that bacterial communities (or microbiota) in CF airways are diverse and that these communities may also contribute to lung health and disease.

An acute change in respiratory signs and symptoms from the subject’s baseline is generically termed a pulmonary exacerbation. Clinically, an exacerbation is typically manifested by increased cough and sputum production, decreased exercise tolerance, malaise, and anorexia. These symptoms are usually associated with decreased measures of lung function. Treatment for pulmonary exacerbations generally consists of antibiotics and augmented airway clearance.

CF should also be considered in infants and children who present with severe dehydration and hypochloremic alkalosis. Other findings that should prompt a diagnostic evaluation for CF include unexplained bronchiectasis, rectal prolapse, nasal polyps, chronic sinusitis, and unexplained pancreatitis or cirrhosis.

B. Laboratory Findings and Imaging Studies

The diagnosis of CF is made by a sweat chloride concentration greater than 60 mmol/L in the presence of one or more typical clinical features (chronic sinopulmonary disease, pancreatic insufficiency, salt loss syndromes) or an appropriate family history (sibling or first cousin who has CF). Sweat tests should be performed at a CF Foundation–accredited laboratory. A diagnosis can also be confirmed by genotyping that reveals two disease-causing mutations. Intermediate sweat chloride values of 30–60 may be associated with mild CFTR mutations or CFTR-related metabolic syndrome (CFRM). Patients with mild CFTR mutations typically have adequate pancreatic exocrine function, but are still at risk for severe lung disease. CFRM patients appear to have even milder disease phenotypes, but the natural history of this condition is still being defined.

 Treatment

It is strongly recommended that individuals with CF be followed at a CF Foundation–accredited CF care center (http://www.cff.org).

The cornerstone of gastrointestinal treatment is pancreatic enzyme supplementation combined with a high calorie, high protein, and high fat diet. Persons with CF are required to take pancreatic enzyme capsules immediately prior to each meal and with snacks. Individuals should also take daily multivitamins that contain vitamins A, D, E, and K. Caloric supplements are often added to the patient’s diet to optimize growth. Daily salt supplementation also is recommended to prevent hyponatremia, especially during hot weather

Airway clearance therapy and aggressive antibiotic use form the mainstays of treatment for CF lung disease. Antibiotic therapy appears to be one of the primary reasons for the increased life expectancy of persons with CF. Respiratory treatments typically include recombinant human DNAse (Pulmozyme), inhaled hypertonic saline, and for those with chronic Pseudomonas infection, inhaled tobramycin (TOBI) or inhaled aztreonam, and chronic oral azithromycin. These therapies have been shown to maintain lung function and reduce the need for hospitalizations and intravenous antibiotics. Early detection of P aeruginosa and treatment with inhaled tobramycin can often eradicate the bacteria and delay chronic infection. Bronchodilators and anti-inflammatory therapies are also frequently used. Recent clinical trials using protein-rescue therapies to improve CFTR function have shown encouraging results, and the first small-molecule drug that directly addresses the underlying defect in CF was approved by the FDA in 2012. This drug, ivacaftor, is currently approved for use in patients with the G551D CFTR mutation which affects about 4% of CF patients. Ongoing trials of this drug with others in combination regimens may extend its use to patients who are F508del homozygous or have other mutations.

 Prognosis

A few decades ago, CF was fatal in early childhood. Now the median life expectancy is around 35 years of age. The rate of lung disease progression usually determines survival. Lung transplantation may be performed in those with end-stage lung disease. In addition, new treatments, including gene therapy trials and agents that modulate CFTR protein function, are being developed based on improved understanding of the disease at the cellular and molecular levels.

Cohen-Cymberknow M et al: Managing cystic fibrosis: Strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med 2011;183(11):1463–1471 [PMID: 21330455].

Farrell PM et al: Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4–S14 [PMID: 18639722].

Ramsey BW et al: A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011;365(18): 1663–1672 [PMID: 22047557].

Ratjen F et al: Update in cystic fibrosis 2011. Am J Respir Crit Care Med 2012;185(9):933–936 [PMID: 22550209].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Chronic cough, sinusitis, and otitis.

 Unexplained respiratory distress in the newborn period.

 Situs inversus in approximately 50% of cases

 Diagnosis confirmed by identifying a ciliary ultrastructural abnormality on electron microscopy or mutations in PCD genes.

Primary ciliary dyskinesia (PCD), also known as immotile cilia syndrome, is a rare, inherited, usually autosomal recessive disorder with impaired ciliary function leading to progressive sinopulmonary disease. It is believed to occur in approximately 1 in 15,000 births. Almost half of patients with PCD have situs abnormalities, and men are usually infertile. The triad of situs inversus totalis, bronchiectasis, and chronic sinusitis is known as Kartagener syndrome.

 Clinical Findings

A. Symptoms and Signs

Situs inversus totalis occurs in approximately 50% of patients with PCD. Conversely, 20% of children with situs inversus totalis have PCD. Upper and lower respiratory tract manifestations are cardinal features of PCD. The majority of children with PCD present in the immediate newborn period with respiratory distress (commonly diagnosed as neonatal pneumonia or transient tachypnea of the newborn). Upper respiratory tract problems include chronic year-around nasal drainage that may begin in the first weeks of life, chronic sinusitis, nasal polyps, and chronic serous otitis media. Conductive hearing loss with chronic middle ear effusion is common. If myringotomy tubes are placed, chronic otorrhea often ensues. Lower respiratory tract features include chronic productive cough, chronic and recurrent bronchitis, and recurrent pneumonia. They are at risk to develop obstructive lung disease and bronchiectasis.

Nonrespiratory ciliopathies have been associated with PCD and include heterotaxy, asplenia, polysplenia, congenital heart disease, autosomal dominant polycystic kidney disease, retinitis pigmentosa, biliary atresia, and hydrocephalus.

B. Laboratory Findings and Imaging Studies

The diagnosis of PCD currently requires a compatible clinical phenotype and identification of ultrastructural and/or functional defects of the cilia. Examination of ciliary ultra-structure by transmission electron microscopy remains the cornerstone test for PCD. Cilia samples may be obtained from either the upper airways (nasal passage) or lower airways (trachea). Semen collection from older male patients can also be obtained to analyze sperm tails, which have the same ultrastructure as cilia. Significant expertise is required to produce high-quality transmission electron micrographs of cilia, and to distinguish primary (genetic) defects from secondary (acquired) defects in ciliary ultrastructure. Ciliary beat frequency or airway epithelium cultures are also used in some settings. In patients with a compatible clinical history but without visible ultrastructural defects, measurement of nasal nitric oxide has proven to be a useful screening and adjunctive diagnostic test in children ages 5 and older based on very low levels in PCD. Genetic testing is emerging for PCD and demonstrates extensive genetic heterogeneity. Some genes and gene mutations involved in PCD have been defined. Approximately 60% PCD cases have identifiable gene mutations in one of 14 known PCD genes.

 Treatment

At present, no specific therapies are available to correct the ciliary dysfunction in PCD. Treatment is not evidence-based and recommendations are largely extrapolated from CF and other suppurative lung diseases. Respiratory management includes routine pulmonary monitoring (lung function testing, respiratory cultures, chest imaging), airway clearance by combinations of physiotherapy and physical exercise, and aggressive treatment of upper and lower airways infections.

 Prognosis

The progression of lung disease in PCD is quite variable. Importantly, persons with PCD are at risk for chronic obstructive lung disease with bronchiectasis. With monitoring and aggressive treatment during times of illness, most individuals with PCD should experience a normal or near-normal life span.

Bush A, Hogg C: Primary ciliary dyskinesia: recent advances in epidemiology, diagnosis, management and relationship with the expanding spectrum of ciliopathy. Expert Rev Respir Med 2012;6(6):663–682 [PMID: 23234452].

Sagel SD et al: Update of respiratory tract disease in children with primary ciliary dyskinesia. Proc Am Thorac Soc 2011;8(5): 438–443 [PMID: 21926396].

Stillwell PC, Wartchow EP, Sagel SD: Primary ciliary dyskinesia in children: a review for pediatricians, allergists, and pediatric pulmonologists. Pediatr Allergy Immunol Pulmonol 2011;24(4):191–196 [PMID: 22276227].

Bronchiolitis obliterans is a rare chronic obstructive lung disease characterized by complete obliteration of the small airways following a severe insult. The most common form in children is post-infectious, following a lower airway tract infection with adenovirus, although influenza, rubeola, Bordetella, and Mycoplasma are also implicated. Other causes include connective tissue diseases, chronic aspiration, Stevens-Johnson syndrome, post-transplantation (lung or bone marrow) and inhalational injury. Many cases of bronchiolitis obliterans are idiopathic. Adenovirus-induced bronchiolitis obliterans occurs more frequently in the Native American population. Mechanical ventilation for severe adenoviral respiratory infection is a strong risk factor for development of bronchiolitis obliterans.

 Clinical Findings

A. Symptoms and Signs

Persons with bronchiolitis obliterans usually experience dyspnea, coughing, and exercise intolerance. This diagnosis should be considered in children with persistent cough, wheezing, crackles, or hypoxemia persisting longer than 60 days following a lower respiratory tract infection.

B. Laboratory Findings and Imaging Studies

Chest radiograph abnormalities include evidence of heterogeneous air trapping and airway wall thickening. Traction bronchiectasis can occur as the disease progresses. Classic findings on chest high-resolution CT include a mosaic perfusion pattern, vascular attenuation, and central bronchiectasis. This finding along with pulmonary function testing showing airway obstruction unresponsive to bronchodilators may be diagnostic in some patients with the appropriate clinical history. Although not typically required for diagnosis, ventilation-perfusion scans may show a pattern of ventilation and perfusion mismatch. Pulmonary angiograms reveal decreased vasculature in involved lung, and bronchograms show marked pruning of the bronchial tree.

 Differential Diagnosis

Poorly treated asthma, CF, and BPD must be considered in children with persistent airway obstruction. A trial of medications (including bronchodilators and corticosteroids) may help to determine the reversibility of the process when the primary differential is between asthma and bronchiolitis obliterans. Others without classic findings on CT scan and lung function testing may require a lung biopsy.

 Complications

Sequelae of bronchiolitis obliterans include persistent airway obstruction, recurrent wheezing, bronchiectasis, chronic atelectasis, recurrent pneumonia, and unilateral hyperlucent lung syndrome.

 Treatment

Supportive care including supplemental oxygen for hypoxemia, routine vaccination, avoidance of environmental irritant exposure, exercise and nutritional support should be provided. Ongoing airway damage due to problems such as aspiration should be prevented. Inhaled bronchodilators may reverse airway obstruction if the disease has a reactive component. Corticosteroids (inhaled, daily, or pulse dosing) may help reverse the obstruction or prevent ongoing damage. Antibiotics should be used as indicated for pneumonia. Azithromycin has been shown to have therapeutic properties for airway injury in CF, diffuse panbronchiolitis, and in bronchiolitis obliterans syndrome (BOS) after lung transplantation, providing some rationale for a trial of this medication for bronchiolitis obliterans. Lung transplant may be an option for patients with severe, progressive disease. Early research in animal models suggests that TNF-α blockers may be useful in prevention progression of bronchiolitis obliterans.

 Prognosis

Prognosis depends in part on the underlying cause as well as the age of onset. Postinfectious bronchiolitis obliterans tends to be nonprogressive with low mortality and the possibility of slow improvement with time. Conversely, posttransplantation or Stevens-Johnson Syndrome related bronchiolitis obliterans may have a rapidly progressive course leading to death or need for lung transplantation.

Fischer GB et al: Post infectious bronchiolitis obliterans in children. Pediatr Respiratory Reviews 2010;11:233–239 [PMID: 21109182].

Moonnumakal SP et al: Bronchiolitis obliterans in children. Curr Opin Pediatr 2008;20(3):272–278 [PMID: 18475095].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Chronic cough with sputum production.

 Rhonchi or wheezes (or both) on chest auscultation.

 Diagnosis is confirmed by high-resolution CT scan.

 Pathogenesis

Bronchiectasis is the permanent dilation of bronchi resulting from airway obstruction by retained mucus secretions or inflammation in response to chronic or repeated infection. It occurs either as a consequence of a preceding illness (severe pneumonia or foreign body aspiration) or as a manifestation of an underlying systemic disorder (CF, PCD, chronic aspiration or immunodeficiency).

 Clinical Findings

A. Symptoms and Signs

Persons with bronchiectasis will typically have chronic cough, purulent sputum, fever, and weight loss. Recurrent respiratory infections and dyspnea on exertion are also common. Hemoptysis occurs less frequently in children than in adults with bronchiectasis. On physical examination, finger clubbing may be seen. Rales, rhonchi, and decreased air entry are often noted over the bronchiectatic areas.

B. Laboratory Findings and Imaging Studies

The most common bacteria detected in cultures from the lower respiratory tract include S pneumoniae, S aureus, nontypeable H influenzae, and P aeruginosa. Nontuberculous mycobacterial species may also be detected in patients with bronchiectasis.

Chest radiographs may be mildly abnormal with slightly increased bronchovascular markings or areas of atelectasis, or they may demonstrate cystic changes in one or more areas of the lung. The extent of bronchiectasis is best defined by high-resolution CT scan of the lung, which often reveals far wider involvement of lung than expected from the chest radiograph. Airflow obstruction and air trapping often is seen on pulmonary function testing. Evaluation of lung function after use of a bronchodilator is helpful in assessing the benefit a patient may have from bronchodilators. Serial assessments of lung function help define the progression or resolution of the disease.

 Differential Diagnosis

Bronchiectasis has numerous causes. It can occur following severe respiratory tract infections by bacteria (S aureus, Bordetella pertussis), viruses (adenovirus), or other organisms (M tuberculosis). Bronchiectasis can also be due to persistent inflammation and is commonly seen in persons with recurrent aspiration pneumonia, CF, PCD, immunodeficiency, surfactant deficiencies, and collagen-vascular conditions. Other diagnostic considerations include foreign body aspiration and allergic bronchopulmonary aspergillosis.

 Treatment

Aggressive antibiotic therapy during pulmonary exacerbations and routine airway clearance are mainstays of treatment. Inhaled hyperosmolar agents (hypertonic saline) were shown in small clinical trials to improve lung function and secretion clearance in non-CF bronchiectasis. Chronic antibiotic use, anti-inflammatory therapy, hyperosmolar agents (hypertonic saline), and bronchodilators have not been proven effective in non-CF bronchiectasis, although individual patients may benefit. Chronic azithromycin was recently shown to reduce exacerbations in adults with non-CF bronchiectasis. Conversely, a large study in adults with idiopathic bronchiectasis concluded that those who received dornase alpha twice a day had more frequent exacerbations, hospitalizations, and lower lung function compared to placebo; thus, dornase alpha is not indicated in adult idiopathic bronchiectasis. Whether these results translate to children with idiopathic bronchiectasis is not known.

Surgical removal of an area of lung affected with severe bronchiectasis is considered when the response to medical therapy is poor. Other indications for operation include severe localized disease, repeated hemoptysis, and recurrent pneumonia in one area of lung. If bronchiectasis is widespread, surgical resection offers little advantage.

 Prognosis

The prognosis depends on the underlying cause and severity of bronchiectasis, the extent of lung involvement, and the response to medical management. Good pulmonary hygiene and avoidance of infectious complications in the involved areas of lung may reverse cylindric bronchiectasis.

Redding GJ: Bronchiectasis in children. Pediatr Clin North Am 2009;56:157–171, xi [PMID: 19135586].

Salerno T et al: Bronchiectasis and severe respiratory insufficiency associated with a new surfactant protein C mutation. Acta Paediatr 2013 Jan;102(1):e1–e2 [PMID: 23025826].

Wong C et al: Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012 Aug 18;380(9842):660–667 [PMID: 22901887].

CONGENITAL MALFORMATIONS OF THE LUNG PARENCHYMA

What follows is a brief description of selected congenital pulmonary malformations.

In unilateral pulmonary agenesis (complete absence of one lung), the trachea continues into a main bronchus and often has complete tracheal rings. The left lung is affected more often than the right. With compensatory postnatal growth, the remaining lung often herniates into the contralateral chest. Chest radiographs show a mediastinal shift toward the affected side, and vertebral abnormalities may be present. Absent or incomplete lung development may be associated with other congenital abnormalities, such as absence of one or both kidneys or fusion of ribs, and the outcome is primarily related to the severity of associated lesions. About 50% of patients survive; the mortality rate is higher with agenesis of the right lung than of the left lung. This difference is probably not related to the higher incidence of associated anomalies but rather to a greater shift in the mediastinum that leads to tracheal compression and distortion of vascular structures.

Pulmonary hypoplasia is incomplete development of one or both lungs, characterized by a reduction in alveolar number and a reduction in airway branches. Pulmonary hypoplasia is present in up to 10%–15% of perinatal autopsies. The hypoplasia can be a result of an intrathoracic mass, resulting in lack of space for the lungs to grow; decreased size of the thorax; decreased fetal breathing movements; decreased blood flow to the lungs; or possibly a primary mesodermal defect affecting multiple organ systems. Congenital diaphragmatic hernia is the most common cause, with an incidence of 1:2200 births. Other causes include extralobar sequestration, diaphragmatic eventration or hypoplasia, thoracic neuroblastoma, fetal hydrops, and fetal hydrochylothorax. Chest cage abnormalities, diaphragmatic elevation, oligohydramnios, chromosomal abnormalities, severe musculoskeletal disorders, and cardiac lesions may also result in hypoplastic lungs. Postnatal factors may play important roles. For example, infants with advanced BPD can have pulmonary hypoplasia.

 Clinical Findings

A. Symptoms and Signs

The clinical presentation is highly variable and is related to the severity of hypoplasia as well as associated abnormalities. Lung hypoplasia is often associated with pneumothorax in newborns. Some newborns present with perinatal stress, severe acute respiratory distress, and persistent pulmonary hypertension of the newborn secondary to primary pulmonary hypoplasia (without associated anomalies). Children with lesser degrees of hypoplasia may present with chronic cough, tachypnea, wheezing, and recurrent pneumonia.

B. Laboratory Findings and Imaging Studies

Chest radiographic findings include variable degrees of volume loss in a small hemithorax with mediastinal shift. Pulmonary agenesis should be suspected if tracheal deviation is evident on the chest radiograph. The chest CT scan is the optimal diagnostic imaging procedure if the chest radiograph is not definitive. Ventilation-perfusion scans, angiography, and bronchoscopy are often helpful in the evaluation, demonstrating decreased pulmonary vascularity or premature blunting of airways associated with the maldeveloped lung tissue. The degree of respiratory impairment is defined by analysis of arterial blood gases.

 Treatment & Prognosis

Treatment is supportive. The outcome is determined by the severity of underlying medical problems, the extent of the hypoplasia, and the degree of pulmonary hypertension.

Berrocal T et al: Congenital anomalies of the tracheobronchial tree, lung and mediastinum: Embryology, radiology, and pathology. Radiographics 2004:24(1):e17 [PMID: 14610245].

Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK: Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics 2010;30(6):1721–1738. doi:10.1148/rg.306105508 [PMID: 21071385].

Winn HN et al: Neonatal pulmonary hypoplasia and perinatal mortality in patients with midtrimester rupture of amniotic membranes—a critical analysis. Am J Obstet Gynecol 2000;182:1638 [PMID: 10871491].

Pulmonary sequestration is nonfunctional pulmonary tissue that does not communicate with the tracheobronchial tree and receives its blood supply from one or more anomalous systemic arteries. This abnormality originates during the embryonic period of lung development. It is classified as either extralobar or intralobar. Extralobar sequestration is a mass of pulmonary parenchyma anatomically separate from the normal lung, with a distinct pleural investment. Its blood supply derives from the systemic circulation (more typical), from pulmonary vessels, or from both. Rarely, it communicates with the esophagus or stomach. Pathologically, extralobar sequestration appears as a solitary thoracic lesion near the diaphragm. Abdominal sites are rare. Size varies from 0.5 to 12 cm. The left side is involved in more than 90% of cases. In contrast to intralobar sequestrations, venous drainage is usually through the systemic or portal venous system.

Histologic findings include uniformly dilated bronchioles, alveolar ducts, and alveoli. Occasionally the bronchial structure appears normal; however, often the cartilage in the wall is deficient, or no cartilage-containing structures can be found. Lymphangiectasia is sometimes found within the lesion. Extralobar sequestration can be associated with other anomalies, including bronchogenic cysts, heart defects, and diaphragmatic hernia, the latter occurring in over half of cases.

Intralobar sequestration is an isolated segment of lung within the normal pleural investment that often receives blood from one or more arteries arising from the aorta or its branches. Intralobar sequestration is usually found within the lower lobes (98%), two-thirds are found on the left side, and it is rarely associated with other congenital anomalies (< 2% vs 50% with extralobar sequestration). It rarely presents in the newborn period (unlike extralobar sequestration). Some researchers have hypothesized that intralobar sequestration is an acquired lesion secondary to chronic infection. Clinical presentation includes chronic cough, wheezing, or recurrent pneumonias. Rarely, patients with intralobar sequestration can present with hemoptysis. Diagnosis is often made by angiography, which shows large systemic arteries perfusing the lesion. Recently spiral CT scans with contrast or magnetic resonance angiography have proved useful in identifying anomalous systemic arterial supply to the lung. Treatment is usually by surgical resection.

Berrocal T et al: Congenital anomalies of the tracheobronchial tree, lung and mediastinum: embryology, radiology, and pathology. Radiographics 2004 Jan–Feb;24(1):e17 [PMID: 14610245].

Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK: Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics 2010;30(6):1721–1738. doi:10.1148/rg.306105508 [PMID: 21071385].

Patients with congenital lobar emphysema—also known as infantile lobar emphysema, congenital localized emphysema, unilobar obstructive emphysema, congenital hypertrophic lobar emphysema, or congenital lobar overinflation—present most commonly with severe neonatal respiratory distress or progressive respiratory impairment during the first year of life. Rarely the mild or intermittent nature of the symptoms in older children or young adults results in delayed diagnosis. Most patients are white males. Although the cause of congenital lobar emphysema is not well understood, some lesions show bronchial cartilaginous dysplasia due to abnormal orientation or distribution of the bronchial cartilage. This leads to expiratory collapse, producing obstruction and the symptoms outlined in the following discussion.

 Clinical Findings

A. Symptoms and Signs

Clinical features include respiratory distress, tachypnea, cyanosis, wheezing, retractions, and cough. Breath sounds are reduced on the affected side, perhaps with hyperresonance to percussion, mediastinal displacement, and bulging of the chest wall on the affected side.

B. Imaging Studies

Radiologic findings include overdistention of the affected lobe (usually an upper or middle lobe; > 99%), with wide separation of bronchovascular markings, collapse of adjacent lung, shift of the mediastinum away from the affected side, and a depressed diaphragm on the affected side. The radiographic diagnosis may be confusing in the newborn because of retention of alveolar fluid in the affected lobe causing the appearance of a homogeneous density. Other diagnostic studies include chest radiograph with fluoroscopy, ventilation-perfusion study, and chest CT scan followed by bronchoscopy, angiography, and exploratory thoracotomy.

 Differential Diagnosis

The differential diagnosis of congenital lobar emphysema includes pneumothorax, pneumatocele, atelectasis with compensatory hyperinflation, diaphragmatic hernia, and congenital cystic adenomatoid malformation. The most common site of involvement is the left upper lobe (42%) or right middle lobe (35%). Evaluation must differentiate regional obstructive emphysema from lobar hyperinflation secondary to an uncomplicated ball-valve mechanism due to extrinsic compression from a mass (ie, bronchogenic cyst, tumor, lymphadenopathy, foreign body, pseudotumor or plasma cell granuloma, or vascular compression) or intrinsic obstruction from a mucus plug due to infection and inflammation from various causes.

 Treatment

When respiratory distress is marked, a segmental or complete lobectomy is usually required. Less symptomatic older children may do equally well with or without lobectomy.

Berrocal T et al: Congenital anomalies of the tracheobronchial tree, lung and mediastinum: embryology, radiology, and pathology. Radiographics 2004 Jan–Feb;24(1):e17 [PMID: 14610245].

Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK: Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics 2010;30(6):1721–1738. doi:10.1148/rg.306105508 [PMID: 21071385].

Congenital pulmonary adenomatoid malformations (CPAMs; previously known as congenital cystic adenomatoid malformations) are unilateral hamartomatous lesions which generally present with marked respiratory distress within the first days of life. This disorder accounts for 95% of cases of congenital cystic lung disease.

Right and left lungs are involved with equal frequency. These lesions originate in the first 5–22 weeks of gestation during the embryonic period of lung development. They appear as glandlike, space-occupying masses or have an increase in terminal respiratory structures, forming intercommunicating cysts of various sizes, lined by cuboidal or ciliated pseudostratified columnar epithelium. The lesions may have polypoid formations of mucosa, with focally increased elastic tissue in the cyst wall beneath the bronchial type of epithelium. Air passages appear malformed and tend to lack cartilage.

There are five types of such malformations.

1. Type 0, also known as acinar dysplasia or agenesis istracheal or bronchial in origin and is rare and incompatible with life. The lungs are small, firm and microscopically are made up entirely of irregular bronchial type structures.

2. Type 1, a large cyst lesion (bronchial or bronchiolar origin), is most common (50%–65%) and consists of single or multiple large cysts (> 2 cm in diameter) with features of mature lung tissue, including a pseudostratified epithelium. Type 1 is amenable to surgical resection. A mediastinal shift is evident on examination or chest radiograph in 80% of patients and can mimic infantile lobar emphysema. Approximately 75% of type 1 lesions are on the right side. A survival rate of 90% is generally reported. There are some reports of bronchioloalveolar carcinoma in patients with type 1 CPAM although this does not necessitate urgent resection.

3. Type 2 lesions, small cyst lesions (bronchiolar origin) and (10%–40% of cases), consist of multiple small cysts (< 2 cm) resembling dilated simple bronchioles and are often (60%) associated with other anomalies, especially renal agenesis or dysgenesis, cardiac malformations, extralobar sequestration and intestinal atresia. Approximately 60% of type 2 lesions are on the left side. Mediastinal shift is evident less often (10%) than in type 1, and the survival rate is worse (40%). Microscopically the lesion is composed of dilated bronchioles lined by cuboidal to low columnar epithelium and separated by alveolar duct-like structures.

4. Type 3 lesions, adenomatoid lesion (bronchiolar/alveolar duct origin) and (5%–10% of cases), consist of small cysts (< 0.5 cm). These are the “classic” CPAM (or CCAM). They appear as bulky, firm masses with mediastinal shift and carry the risk of hydrops from mass shift resulting in caval obstruction and cardiac compression (80% of cases). The lesion will often involve the entire lobe and microscopically random bronchiolar/alveolar duct-like structures are seen. There is a striking absence of any small, medium or large pulmonary arteries within the lesion. Often the adjacent or uninvolved lung is hypoplastic. The reported survival rate is 50%.

5. Type 4 lesions, “unlined” cyst (distal acinar origin) and (10%–15% of cases), appear to be a hamartomatous malformation of the distal acinus. The cysts are large thin walled and found at the periphery of the lung. The cysts are lined by flattened epithelial (type I) cells.

 Clinical Findings

A. Symptoms and Signs

Clinically, respiratory distress is noted soon after birth. Expansion of the cysts occurs with the onset of breathing and produces compression of normal lung areas with mediastinal herniation. Breath sounds are decreased. With type 3 lesions, dullness to percussion may be present. Older patients can present with a spontaneous pneumothorax or with pneumonia-like symptoms. Recently more patients are diagnosed with these lesions on prenatal ultrasound

B. Laboratory Findings and Imaging Studies

With type 1 lesions, chest radiographs show an intrapulmonary mass of soft tissue density with scattered radiolucent areas of varying sizes and shapes, usually with a mediastinal shift and pulmonary herniation. Placement of a radiopaque feeding tube into the stomach helps in the differentiation from diaphragmatic hernia. Type 2 lesions appear similar except that the cysts are smaller. Type 3 lesions may appear as a solid homogeneous mass filling the hemithorax and causing a marked mediastinal shift. Type 4 lesions are large air-filled cysts localized to one lobe. Differentiation from sequestration is not difficult because congenital CPAM have no systemic blood supply.

 Treatment

In cases of prenatal diagnosis, the treatment of these lesions is variable and does not need antenatal intervention. Up to 6%–10% of these have regressed spontaneously and thus they need to be followed serially, prenatally. Attention must be paid to the development of hydrops as a complication of these lesions. Postnatal treatment of types 1 and 3 lesions involves surgical removal of the affected lobe. Resection is often indicated because of the risk of infection and air trapping, since the malformation communicates with the tracheobronchial tree but mucous clearance is compromised. Because type 2 lesions are often associated with other severe anomalies, management may be more complex. Segmental resection is not feasible because smaller cysts may expand after removal of the more obviously affected area. CPAM have been reported to have malignant potential; therefore, expectant management with observation alone should proceed with caution. Recent development of intrauterine surgery for congenital malformations has led to promising results.

Biyyam DR, Chapman T, Ferguson MR, Deutsch G, Dighe MK: Congenital lung abnormalities: embryologic features, prenatal diagnosis, and postnatal radiologic-pathologic correlation. Radiographics 2010;30(6):1721–1738. doi:10.1148/rg. 306105508 [PMID: 21071385].

Lakhoo K: Management of congenital cystic adenomatous malformations of the lung. Arch Dis Child - Fetal Neonatal Ed 2009;94(1):F73–F76. doi:10.1136/adc.2007.130542 [PMID: 18708416].

Stocker JT: Cystic lung disease in infants and children. Fetal Pediatr Pathol 2009;28(4):155–184 [PMID: 19842869].

ACQUIRED ABNORMALITIES OF THE LUNG PARENCHYMA

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Acute respiratory distress in the first week of life.

 Required oxygen therapy or mechanical ventilation, with persistent oxygen requirement at 36 weeks’ gestational age or 28 days of life.

 Persistent respiratory abnormalities, including physical signs and radiographic findings.

Bronchopulmonary dysplasia (BPD) remains one of the most significant sequelae of acute respiratory distress in the neonatal intensive care unit, with an incidence of about 30% for infants with a birth weight of less than 1000 g. This disease was first characterized in 1967 when Northway reported the clinical, radiologic, and pathologic findings in a group of preterm newborns that required prolonged mechanical ventilation and oxygen therapy to treat hyaline membrane disease (HMD). The progression from acute HMD to chronic lung disease was divided into four stages: acute respiratory distress shortly after birth, (stage I); clinical and radiographic worsening of the acute lung disease, often due to increased pulmonary blood flow secondary to a patent ductus arteriosus (stage II); and progressive signs of chronic lung disease (stages III and IV).

The pathologic findings and clinical course of BPD in recent years have changed due to a combination of new therapies (artificial surfactants, prenatal glucocorticoids, and protective ventilatory strategies) and increased survival of infants born at earlier gestational ages. Although the incidence of BPD has not changed, the severity of the lung disease has decreased. Pathologically this “new” BPD is a developmental disorder of the lung characterized by decreased surface area for gas exchange, reduced inflammation, and a dysmorphic vascular structure.

 Pathogenesis

The precise mechanism that results in the development of BPD is unclear. Current studies indicate that these babies have abnormal lung mechanics due to structural immaturity of the alveolar-capillary network, surfactant deficiency, atelectasis, and pulmonary edema. Furthermore, mechanical ventilation causes barotrauma and supplemental oxygen may lead to toxic oxygen metabolites in a child whose antioxidant defense mechanisms are not sufficiently mature. The ongoing injuries may lead to a vicious cycle of ventilator and oxygen dependence. As a result, the lungs of extremely preterm newborns with BPD show simplified histology with fewer alveoli, early inflammation, and hypercellularity followed by healing with fibrosis. Excessive fluid administration, patent ductus arteriosus, pulmonary interstitial emphysema, pneumothorax, infection, pulmonary hypertension, and inflammatory stimuli secondary to lung injury or infection also play important roles in the pathogenesis of the disease.

 Clinical Findings

A recent summary of a National Institutes of Health workshop on BPD proposed a definition of the disease that includes oxygen requirement for more than 28 days, a history of positive pressure ventilation or continuous positive airway pressure, and gestational age. The new definition accommodates several key observations regarding the disease, as follows: (1) although most of these children were born preterm and had hyaline membrane disease, full-term newborns with such disorders as meconium aspiration, diaphragmatic hernia, or persistent pulmonary hypertension also can develop BPD; (2) some extremely preterm newborns require minimal ventilator support yet subsequently develop a prolonged oxygen requirement despite the absence of severe acute manifestations of respiratory failure; (3) newborns dying within the first weeks of life can already have the aggressive, fibroproliferative pathologic lesions that resemble BPD; and (4) physiologic abnormalities (increased airway resistance) and biochemical markers of lung injury (altered protease-antiprotease ratios and increased inflammatory cells and mediators) which may be predictive of BPD are already present in the first week of life.

The clinical course of infants with BPD ranges from an oxygen requirement that gradually resolves over a few months to more severe disease requiring chronic tracheostomy and mechanical ventilation for the first few years of life. In general, patients show slow, steady improvements in oxygen or ventilator requirements but can have respiratory exacerbations leading to frequent and prolonged hospitalizations. Clinical management generally includes careful attention to growth, nutrition (infants with oxygen dependence and respiratory have high caloric requirements), metabolic status, developmental and neurologic status, along with the associated cardiopulmonary abnormalities.

 Treatment

A. Medical Therapy

Early use of surfactant therapy with adequate lung recruitment increases the chance for survival without BPD, reduces the need for mechanical ventlaton, and can decrease the overall mortality. Short courses of postnatal glucocorticoid therapy have been helpful in increasing the success of weaning from the ventilator. Longer courses of postnatal glucocorticoids have been linked to an increased incidence of cerebral palsy. Inhaled corticosteroids together with occasional use of β-adrenergic agonists are commonly part of the treatment plan but the overall effect on the course of BPD is not clear.

Salt and water retention secondary to chronic hypoxemia, hypercapnia, or other stimuli may be present. Chronic or intermittent diuretic therapy is commonly used if rales or signs of persistent pulmonary edema are present; clinical studies show acute improvement in lung function with this therapy. Unfortunately, diuretics often have adverse effects, including volume contraction, hypokalemia, alkalosis, hyponatremia, and nephrocalcinosis. Potassium and arginine chloride supplements may be required.

B. Airway Evaluation

Children with significant stridor, sleep apnea, chronic wheezing, or excessive respiratory distress need diagnostic bronchoscopy to evaluate for structural lesions (eg, subglottic stenosis, vocal cord paralysis, tracheal or bronchial stenosis, tracheobronchomalacia, or airway granulomas). The contribution of gastroesophageal reflux and aspiration should be considered in the face of worsening chronic lung disease.

C. Management of Pulmonary Hypertension

Infants with BPD are at risk of developing pulmonary hypertension. In many of these children even mild hypoxemia can cause significant elevations of pulmonary arterial pressure. To minimize the harmful effects of hypoxemia, the arterial oxygen saturation should be kept above 93% in children with pulmonary hypertension, with care to avoid hyperoxia during retinal vascular development. Electrocardiographic and echocardiographic studies should be performed to monitor for the development of right ventricular hypertrophy. Management of neonatal pulmonary hypertension should involve expert consultation with a pulmonary hypertension specialist. If right ventricular hypertrophy persists or if it develops when it was not previously present, intermittent hypoxemia should be considered and further assessments of oxygenation pursued, especially while the infant sleeps. Cardiac catheterization may be necessary to diagnose unsuspected cardiac or pulmonary lesions and to measure the response of the pulmonary vasculature to vasodilators such as nitric oxide before chronic therapy is initiated. Infants with a history of intubation can develop obstructive sleep apnea secondary to a high-arched palate or subglottic narrowing. Barium esophagram, esophageal pH/impedence studies, and bronchoscopy may aid in diagnosing gastroesophageal reflux, aspiration, and airway abnormalities that contribute to the underlying pathophysiology. In infants with severe BPD, prophylactic fundoplication at the tme of gastrostomy tube placement may prevent catastrophic aspiration events that could be life threatening. Long-term care also should include monitoring for systemic hypertension and the development of left ventricular hypertrophy.

D. Nutrition and Immunizations

Nutritional problems in infants with BPD may be due to increased oxygen consumption, feeding difficulties, gastroesophageal reflux, and chronic hypoxemia. Hypercaloric formulas and gastrostomy tubes are often required to ensure adequate intake while avoiding overhydration. Routine vaccinations including the influenza vaccine are recommended. With the onset of acute wheezing secondary to suspected viral infection, rapid diagnostic testing for RSV infection may facilitate early treatment. Immune prophylaxis of RSV reduces the morbidity of bronchiolitis in infants with BPD. In children older than 2 years of age with severe BPD, pneumococcal polysaccharide 23-valent vaccine should be considered in addition to standard pneumococcal vaccination.

E. Ventilation

For children with BPD who remain ventilator-dependent, attempts should be made to maintain Paco₂ below 60 mm Hg—even when pH is normal—because of the potential adverse effects of hypercapnia on salt and water retention, cardiac function, and perhaps pulmonary vascular tone. Changes in ventilator settings in children with severe lung disease should be slow, because the effects of many of the changes may not be apparent for days.

 Differential Diagnosis

The differential diagnosis of BPD includes meconium aspiration syndrome, congenital infection (eg, with cytomegalovirus or Ureaplasma), cystic adenomatoid malformation, recurrent aspiration, pulmonary lymphangiectasia, total anomalous pulmonary venous return, overhydration, and idiopathic pulmonary fibrosis.

 Prognosis

Surfactant replacement therapy has had a significantly and markedly beneficial effect on reducing morbidity and mortality from BPD. Infants of younger gestational age are surviving in greater numbers. Surprisingly, the effect of neonatal care has not significantly decreased the incidence of BPD. The disorder typically develops in the most immature infants. The long-term outlook for most survivors is favorable. Follow-up studies suggest that lung function may be altered for life. Hyperinflation and damage to small airways has been reported in children 10 years after the first signs of BPD. In addition, these infants are at a risk for developing such sequelae as hypoxemia, airway hyperreactivity, exercise intolerance, pulmonary hypertension, chronic obstructive pulmonary disease, and abnormal lung growth. As smaller, more immature infants survive, abnormal neurodevelopmental outcomes become more likely. The incidence of cerebral palsy, hearing/visual impairment, and developmental delays is increased. Feeding abnormalities, behavior difficulties, and increased irritability have also been reported. A focus on good nutrition and prophylaxis against respiratory pathogens and airway hyperreactivity provide the best outcomes. Family support, developmental therapies (physical, occupational, and speech), and attention to cognitive function and learning issues help to improve the long-term outlook.

Baraldi E, Filippone M: Chronic lung disease after premature birth. N Engl J Med 2007;357:1946 [PMID: 17989387].

Chess PR et al: Pathogenesis of bronchopulmonary dysplasia. Semin Perinatol 2006;30:171 [PMID: 16860156].

Higgins RD et al: Executive summary of the workshop on oxygen in neonatal therapies: Controversies and opportunities for research. Pediatrics 2007;119:790 [PMID: 17403851].

Northway WH et al: Pulmonary disease following respiratory therapy of hyaline membrane disease: bronchopulmonary dysplasia. N Engl J Med 1967;276:357 [PMID: 5334613].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Fever, cough, dyspnea.

 Abnormal chest examination (crackles or decreased breath sounds).

 Abnormal chest radiograph (infiltrates, hilar adenopathy, pleural effusion).

Lower respiratory tract infections (LRTIs) are a major cause of childhood mortality in disadvantaged areas of the world. The infectious etiologies vary widely by geographic region and by the age of the child. In developed countries the majority of pneumonias are caused by viral agents and bacterial pneumonia is a less common cause. Discrimination between viral and bacterial pneumonia is challenging as neither the white blood cell count nor differential nor the chest radiograph are strong predictors. In areas where the technology is readily available chest radiography is recommended to establish with certainty the presence of pneumonia. The most common cause of bacterial pneumonia in children of all ages is S pneumoniae. Bacterial pneumonia usually follows a viral lower respiratory tract infection. Children at high risk for bacterial pneumonia are those with compromised pulmonary defense systems. For example, children with abnormal mucociliary clearance, immunocompromised children, children who aspirate their own secretions or who aspirate while eating, and malnourished children are at increased risk for bacterial pneumonia.

 Clinical Findings

A. Symptoms and Signs

The pathogen, severity of the infection, and age of the patient may cause substantial variations in the presentation of community-acquired pneumonia (CAP). Fevers (over 39°C), tachypnea, and cough are hallmarks of CAP. Chest auscultation may reveal crackles or decreased breath sounds in the setting of consolidation or an associated pleural effusion. Some patients may have additional extrapulmonary findings, such as meningismus or abdominal pain, due to pneumonia itself. Others may have evidence of infection at other sites due to the same organism causing their pneumonia: meningitis, otitis media, sinusitis, pericarditis, epiglottitis, or abscesses.

B. Laboratory Findings and Imaging Studies

An elevated peripheral white blood cell count with a left shift may be a marker of bacterial pneumonia. A low white blood count (< 5000/μL) can be an ominous finding in this disease. Blood cultures should be obtained in children admitted to the hospital with pneumonia, although approximately 10% or less will be positive, even with known bacterial pneumonia. Sputum cultures may be helpful in older children capable of providing a satisfactory sample. Invasive diagnostic procedures (bronchial brushing or washing, lung puncture, or open or thoracoscopic lung biopsy) should be undertaken in critically ill patients when other means do not adequately identify the cause (see section Diagnosis of Respiratory Tract Infections).

The spectrum of potential pathogens to be considered includes aerobic, anaerobic, and acid-fast bacteria as well as Chlamydia trachomatis, C Pneumoniae, C psittaci, Coxiella burnetii (Q fever), P jiroveci, B pertussis, M pneumoniae, Legionella pneumophila, and respiratory viruses. S pneumoniae is the most prevalent bacterial pathogen. Viral antigen immunofluorescent staining (DFA) and polymerase chain reactivity (PCR) technology has improved the ability to detect a wide variety of viral infections.

Air space disease or consolidation in a lobar distribution on chest x-ray suggests bacterial pneumonia; interstitial or peribronchial infiltrates suggest a viral infection. Severity of the infection may not correlate with radiographic findings and clinical improvement precedes radiographic resolution. If a pleural effusion is suspected, radiographs should be taken in the lateral decubitus position. A diagnostic (and possibly therapeutic) thoracocentesis should also be performed in a child with a pleural effusion.

 Differential Diagnosis

Noninfectious pulmonary disease (including gastric aspiration, foreign body aspiration, atelectasis, congenital malformations, congestive heart failure, malignancy, tumors such as plasma cell granuloma, chronic ILD, and pulmonary hemosiderosis) should be considered in the differential diagnosis of localized or diffuse infiltrates. When effusions are present, additional noninfectious disorders such as collagen diseases, neoplasm, and pulmonary infarction should also be considered.

 Complications

Empyema can occur frequently with staphylococcal, pneumococcal, and group A β-hemolytic streptococcal pneumonia. Distal sites of infection—meningitis, otitis media, sinusitis (especially of the ethmoids), and septicemia—may be present, particularly with disease due to S pneumoniae or H influenzae. Certain immunocompromised patients, such as those who have undergone splenectomy or who have hemoglobin SS or SC disease or thalassemia, are especially prone to overwhelming sepsis with these organisms.

 Treatment

If a bacterial pneumonia is suspected, empiric antibiotic therapy should be considered. Children less than 4 weeks of age should be treated with ampicillin and an aminoglycoside. Infants 4–12 weeks of age should be treated with IV ampicillin for 7–10 days. Children 3 months to 5 years of age should be treated with oral amoxicillin (50–90 mg/kg/dose) for 7–10 days. Children older than 5 years should be treated with a macrolide antibiotic or amoxicillin or penicillin G depending on the suspected etiology. When possible, therapy can be guided by the antibiotic sensitivity pattern of the organisms isolated. (For further discussion, see Chapter 39.) An appropriate antiviral (eg, amantadine, rimantidine, osetamivir, zanamivir) should be considered for the child with pneumonia due to Influenza. Whether a child should be hospitalized depends on his or her age, the severity of illness, the suspected organism, and the anticipated reliability of adherence to the treatment regimen at home. All children younger than 3 months of age should be admitted for treatment. Moderate to severe respiratory distress, apnea, hypoxemia, poor feeding, clinical deterioration on treatment, or associated complications (large effusions, empyema, or abscess) indicate the need for immediate hospitalization in older children. Careful outpatient follow-up within 12 hours to 5 days is often indicated in those not admitted.

Additional therapeutic considerations include oxygen, humidification of inspired gases, hydration and electrolyte supplementation, and nutrition. Removal of pleural fluid for diagnostic purposes is indicated initially to guide antimicrobial therapy. Removal of pleural fluid for therapeutic purposes may also be indicated.

 Prognosis

In developed countries, for the immunocompetent host in whom bacterial pneumonia is adequately recognized and treated, the survival rate is high. For example, the mortality rate from uncomplicated pneumococcal pneumonia is less than 1%. If the patient survives the initial illness, persistently abnormal pulmonary function following empyema is surprisingly uncommon, even when treatment has been delayed or inappropriate.

Durbin WJ, Stille C: Pneumonia. Pediatr Rev 2008;29(5):147–158 [PMID: 18450836].

Esposito S: Antiobiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? Pediatr Infect Dis 2012;31(6):e78–e85 [PMID: 22466326].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Respiratory distress and chest pain.

 Fever.

 Chest x-ray showing a meniscus or layering fluid on a lateral decubitus film.

Bacterial pneumonia is often accompanied by pleural effusion. Some of these effusions harbor infection, and others are inflammatory reactions to pneumonia. The nomenclature in this area is somewhat confusing. Some authors use the term empyema for grossly purulent fluid and parapneumonic effusion for nonpurulent fluid. It is clear, however, that some nonpurulent effusions will also contain organisms and represent either partially treated or early empyema. It is probably best to refer to all effusions associated with pneumonia as parapneumonic effusions, some of which are infected and some not.

The most common organism associated with empyema is S pneumoniae. Other common organisms include H influenzae and S aureus. Less common causes are group A streptococci, gram-negative organisms, anaerobic organisms, and M pneumoniae. Effusions associated with tuberculosis are almost always sterile and constitute an inflammatory reaction.

 Clinical Findings

A. Symptoms and Signs

Patients usually present with typical signs of pneumonia, including fever, tachypnea, and cough. They may have chest pain, decreased breath sounds, and dullness to percussion on the affected side and may prefer to lie on the affected side. With large effusions, there may be tracheal deviation to the contralateral side. According to a study in Canada, empyema is more likely to occur in children less than 5 years.

B. Diagnostic Studies

The white blood cell count is often elevated, with left shift. Blood cultures are sometimes positive. The tuberculin skin test is positive in most cases of tuberculosis. Thoracentesis reveals findings consistent with an exudate. Cells in the pleural fluid are usually neutrophils in bacterial disease and lymphocytes in tuberculous effusions. In bacterial disease, pleural fluid pH and glucose are often low. A pH less than 7.2 suggests active bacterial infection. The pH of the specimen should be determined in a blood gas syringe sent to the laboratory on ice. Extra heparin should not be used in the syringe as it can falsely lower the pH. Although in adults the presence of low pH and glucose indicates the need for aggressive and thorough drainage procedures, the prognostic significance of these findings in children is unknown. Gram stain, cultures, and counterimmunoelectrophoresis are often positive for the offending organism.

The presence of pleural fluid is suggested by a homogeneous density that obscures the underlying lung on chest radiograph. Large effusions may cause a shift of the mediastinum to the contralateral side. Small effusions may only blunt the costophrenic angle. Lateral decubitus radiographs may help to detect freely movable fluid by demonstrating a layering-out effect. If the fluid is loculated, no such effect is perceived. Ultrasonography can be extremely valuable in localizing the fluid and detecting loculations, especially when thoracentesis is contemplated, but availability may be limited. Chest CT scan can help determine whether the fluid is intraparenchymal or extraparenchymal and can direct further care of complicated pneumonias.

 Treatment

After initial thoracentesis and identification of the organism, appropriate intravenous antibiotics and adequate drainage of the fluid remain the mainstay of therapy, but the approach is debated. Although there is a trend toward managing smaller pneumococcal empyemas without a chest tube, larger effusions require chest tube drainage. Evidence of early interventions using thoracoscopic techniques such as VATS may reduce morbidity and has been shown to shorten length of hospital stay when done by an experienced surgeon. While there is growing use of VATS as first-line therapy, it is not standard of care. Studies in adults show that aggressive management with drainage of pleural cavity fluid and release of adhesions with fibrinolytics is cost effective and decreases the length of stay. There are limited studies of fibrinolytics in children. The therapeutic choice will vary depending on the resources available and the preferences of the clinician.

 Prognosis

The prognosis is related to the severity of disease but is generally excellent, with complete or nearly complete recovery expected in most instances.

Cohen E et al: The long-term outcomes of pediatric pleural empyema: a prospective study. Arch Pediatr Adolesc Med 2012;166(11):999–1004 [PMID: 22945017].

Jaffe A, Balfour-Lynn IM: Management of empyema in children. Pediatr Pulmonol 2005;40:148–156 [PMID: 15965900].

Langle JM et al: Empyema associated with community acquired pneumonia: a Pediatric Investigator’s Collaborative Network on Infections in Canada (PICNIC) study. BMC Infect Dis 2008;8:129 [PMID: 18816409].

ATYPICAL PNEUMONIAS

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Upper respiratory infection prodrome (fever, coryza, cough, hoarseness).

 Wheezing or rales.

 Myalgia, malaise, headache (older children).

Viral infection is a common cause of community-acquired pneumonia in children. Viral pneumonia is most common in children younger than 2 years of age. RSV, parainfluenza (1, 2, and 3) viruses, influenza (A and B) viruses, and human metapneumovirus are responsible for the large majority of cases. Severity of disease, severity of fever, radiographic findings, and the characteristics of cough or lung sounds do not reliably differentiate viral from bacterial pneumonias. Furthermore, such infections may coexist. However, substantial pleural effusions, pneumatoceles, abscesses, lobar consolidation with lobar volume expansion, and “round” pneumonias are generally inconsistent with viral disease.

 Clinical Findings

A. Symptoms and Signs

An upper respiratory infection frequently precedes the onset of lower respiratory disease due to viruses. Although wheezing or stridor may be prominent in viral disease, cough, signs of respiratory distress (tachypnea, retractions, grunting, and nasal flaring), and physical findings (rales and decreased breath sounds) may not be distinguishable from those in bacterial pneumonia.

B. Laboratory Findings

The peripheral white blood cell count can be normal or slightly elevated and is not useful in distinguishing viral from bacterial disease.

Rapid viral diagnostic methods such as fluorescent antibody tests or enzyme-linked immunosorbent assay and/or polymerase chain reaction (PCR) should be performed on nasopharyngeal secretions to confirm this diagnosis in high-risk patients and for epidemiology or infection control. Rapid diagnosis of RSV infection does not preclude the possibility of concomitant infection with other pathogens.

C. Imaging Studies

Chest radiographs frequently show perihilar streaking, increased interstitial markings, peribronchial cuffing, or patchy bronchopneumonia. Lobar consolidation or atelectasis may occur, however. Hyperinflation of the lungs may occur when involvement of the small airways is prominent.

 Differential Diagnosis

The differential diagnosis of viral pneumonia is the same as for bacterial pneumonia. Patients with prominent wheezing may have asthma, airway obstruction caused by foreign body aspiration, acute bacterial or viral tracheitis, or parasitic disease.

 Complications

Viral pneumonia or laryngotracheobronchitis may predispose the patient to subsequent bacterial tracheitis or pneumonia as immediate sequelae. Bronchiolitis obliterans or severe chronic respiratory failure may follow adenovirus pneumonia. The results of studies evaluating the development of asthma after a viral pneumonia are variable. Bronchiectasis, chronic ILD, and unilateral hyperlucent lung (Sawyer-James syndrome) may follow measles, adenovirus, and influenza pneumonias.

 Treatment

General supportive care for viral pneumonia does not differ from that for bacterial pneumonia. Patients can be quite ill and should be hospitalized according to the level of their illness. Because bacterial disease often cannot be definitively excluded, antibiotics may be indicated.

Patients at risk for life-threatening RSV infections (eg, those with BPD or other severe pulmonary conditions, congenital heart disease, or significant immunocompromise) should be hospitalized and ribavirin should be considered. Rapid viral diagnostic tests may be a useful guide for such therapy.

All children with influenza should be treated with the appropriate therapy for the specific type of influenza (A, B, H1N1). When available epidemiologic data indicate an active influenza infection in the community, rimantadine, amantadine hydrochloride, or oseltamivir phosphate should be considered early for high-risk infants and children who appear to be infected. Children with suspected viral pneumonia should be placed in respiratory isolation.

 Prognosis

Although most children with viral pneumonia recover uneventfully, worsening asthma, abnormal pulmonary function or chest radiographs, persistent respiratory insufficiency, and even death may occur in high-risk patients such as newborns or those with underlying lung, cardiac, or immunodeficiency disease. Patients with adenovirus infection or those concomitantly infected with RSV and second pathogens such as influenza, adenovirus, cytomegalovirus, or P jiroveci also have a worse prognosis.

Don M, Caniani M, Korppi M: Community-acquired pneumonia in children: what’s old? what’s new? Acta Paediatrica 2010;99:1602–1608 [PMID: 20573146].

Esposito S: Antiobiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? Pediatr Infect Dis 2012;31(6):e78–e85 [PMID: 22466326].

Ruuskanen O, Lahti E, Jennings LC, Murdoch DR: Viral pneumonia. Lancet 2011;377:1364–1375 [PMID: 21435708].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Clinical syndrome characterized by one or more of the following findings: coughing, tachypnea, labored breathing, and hypoxia.

 Irritability, poor feeding, vomiting.

 Wheezing and crackles on chest auscultation.

Bronchiolitis is the most common serious acute respiratory illness in infants and young children. The diagnosis of bronchiolitis is based upon clinical findings including an upper respiratory infection that has progressed to cough, tachypnea, respiratory distress, and crackles or wheeze by physical examination. In most literature from the United States, this definition of bronchiolitis specifically applies to children younger than 2 years old. One to 3% of infants with bronchiolitis will require hospitalization, especially during the winter months. RSV is by far the most common viral cause of acute bronchiolitis. Parainfluenza, human metapneumovirus, influenza, adenovirus, Mycoplasma, Chlamydia, Ureaplasma, Bocavirus, and Pneumocystis are less common causes of bronchiolitis during early infancy.

 Prevention

The most effective preventions against RSV infection are proper handwashing techniques and reducing exposure to potential environmental risk factors. Major challenges have impeded the development of an RSV vaccine, but a licensed product may be expected in the near future. Prophylaxis with a monoclonal antibody (palivizumab) has proven effective in reducing the rate of hospitalization and associated morbidities in high-risk premature infants and those with chronic cardiopulmonary conditions.

 Clinical Findings

A. Symptoms and Signs

The usual course of RSV bronchiolitis is 1–2 days of fever, rhinorrhea, and cough, followed by wheezing, tachypnea, and respiratory distress. Typically the breathing pattern is shallow, with rapid respirations. Nasal flaring, cyanosis, retractions, and rales may be present, along with prolongation of the expiratory phase and wheezing, depending on the severity of illness. Some young infants present with apnea and few findings on auscultation but may subsequently develop rales, rhonchi, and expiratory wheezing.

B. Laboratory Findings and Imaging Studies

A viral nasal wash may be performed to identify the causative pathogen but is not necessary to make the diagnosis of bronchiolitis. The peripheral white blood cell count may be normal or may show a mild lymphocytosis. Chest radiographs are not indicated in children who have bilateral, symmetrical findings on examination, who are not in significant respiratory distress, and who do not have elevated temperature for the child’s age. If obtained, chest radiograph findings are generally nonspecific and typically include hyperinflation, peribronchial cuffing, increased interstitial markings, and subsegmental atelectasis.

 Complications

The most common complication of bronchiolitis is superinfection with a bacterial pathogen such as Streptococcus pneumoniae leading to pneumonia. The results of studies investigating the risk for the subsequent development of chronic airway hyperreactivity (asthma) are variable. Bronchiolitis due to RSV infection contributes substantially to morbidity and mortality in children with underlying medical disorders, including chronic lung disease of prematurity, CF, congenital heart disease, and immunodeficiency.

 Treatment

Although most children with RSV bronchiolitis are readily treated as outpatients, hospitalization is required in infected children with hypoxemia on room air, a history of apnea, moderate tachypnea with feeding difficulties, and marked respiratory distress with retractions. Children at high risk for hospitalization include infants (younger than 6 months of age), especially with any history of prematurity, and those with underlying chronic cardiopulmonary disorders. While in the hospital, treatment should include supportive strategies such as frequent suctioning and providing adequate fluids to maintain hydration. If hypoxemia is present, supplemental oxygen should be administered. There is no evidence to support the use of antibiotics in children with bronchiolitis unless there is evidence of an associated bacterial pneumonia. Bronchodilators and corticosteroids have not been shown to change the severity or the length of the illness in bronchiolitis and therefore are not recommended. Studies evaluating the effectiveness of hypertonic saline and the combination of oral dexamethasone and inhaled epinephrine in children with bronchiolitis seen in the emergency department and inpatient setting are ongoing.

Patients at risk for life-threatening RSV infections (eg, children younger than 24 months of age whose gestational age is less than 35 weeks, children younger than 24 months of age with other severe pulmonary conditions, congenital heart disease, neuromuscular disease, or significant immunocompromise) should be considered for RSV prophylaxis therapy. For more detail, refer to the American Academy of Pediatrics 2009 guidelines. High-risk patients with RSV bronchiolitis may need to be hospitalized and treated with ribavirin.

 Prognosis

The prognosis for the majority of infants with acute bronchiolitis is very good. With improved supportive care and prophylaxis with palivizumab, the mortality rate among high-risk infants has decreased substantially.

American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis: Diagnosis and management of bronchiolitis. Pediatrics 2006;118:1774 [PMID: 17015575].

Committee in Infectious Disease: From the American Academy of Pediatrics: policy statements—modified recommendations for the use of palivizumab for prevention of respiratory syncitial virus infections. Pediatrics 2009;124(6):1694–1701 [PMID: 19736258].

Guilbert TW, Bacharier LB: Controversies in the treatment of the acutely wheezing infant. AJRCCM 2011;183(10):1284–1285 [PMID: 21596826].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Fever.

 Cough.

 Most common in children older than 5 years of age.

M pneumoniae is a common cause of symptomatic pneumonia in older children although it may be seen in children younger than 5 years of age. Endemic and epidemic infection can occur. The incubation period is long (2–3 weeks), and the onset of symptoms is slow. Although the lung is the primary infection site, extrapulmonary complications sometimes occur.

 Clinical Findings

A. Symptoms and Signs

Fever, cough, headache, and malaise are common symptoms as the illness evolves. Although cough is usually dry at the onset, sputum production may develop as the illness progresses. Sore throat, otitis media, otitis externa, and bullous myringitis may occur. Rales and chest pain are frequently present on chest examination; decreased breath sounds or dullness to percussion over the involved area may be present.

B. Laboratory Findings and Imaging Studies

The total and differential white blood cell counts are usually normal. Enzyme immunoassay (EIA) and complement fixation are sensitive and specific for M pneumoniae. The cold hemagglutinin titer may be elevated during the acute presentation. A titer of 1:64 or higher supports the diagnosis. Acute and convalescent titers for M pneumoniae demonstrating a fourfold or greater rise in specific antibodies confirm the diagnosis. Diagnosis of mycoplasmal pneumonia by polymerase chain reaction is also available.

Chest radiographs usually demonstrate interstitial or bronchopneumonic infiltrates, frequently in the middle or lower lobes. Pleural effusions are extremely uncommon.

 Complications

Extrapulmonary involvement of the blood, central nervous system, skin, heart, or joints can occur. Direct Coombs–positive autoimmune hemolytic anemia, occasionally a life-threatening disorder, is the most common hematologic abnormality that can accompany M pneumoniae infection. Coagulation defects and thrombocytopenia can also occur. Cerebral infarction, meningoencephalitis, Guillain-Barré syndrome, cranial nerve involvement, and psychosis all have been described. A wide variety of skin rashes, including erythema multiforme and Stevens-Johnson syndrome, can occur. Myocarditis, pericarditis, and a rheumatic fever–like illness can also occur.

 Treatment

Antibiotic therapy with a macrolide for 7–10 days may shorten the course of illness. Ciprofloxacin is a possible alternative. Supportive measures, including hydration, antipyretics, and bed rest, are helpful.

 Prognosis

In the absence of the less common extrapulmonary complications, the outlook for recovery is excellent. The extent to which M pneumoniae can initiate or exacerbate chronic lung disease is not well understood.

Don M, Canciani M, Korppi M: Community acquired pneumonia in children: what’s old? what’s new? Acta Paediatr 2010;99(11):1602–1608 [PMID: 20573146].

Mulholland S et al: Antibiotics for community-acquired lowere respiratory tract infections secondary to Mycoplasma pneumonia in children. Cochrane Database Syst Rev 2012:CD004875 [PMID: 20614439].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Positive tuberculin skin test or anergic host.

 Positive culture for M tuberculosis.

 Symptoms of active disease (if present): chronic cough, anorexia, weight loss or poor weight gain, fever, night sweats.

Tuberculosis is a widespread and deadly disease resulting from infection with M tuberculosis. The clinical spectrum of disease includes asymptomatic primary infection, calcified nodules, pleural effusions, progressive primary cavitating lesions, contiguous spread into adjacent thoracic structures, acute miliary tuberculosis, and acute respiratory distress syndrome, overwhelming reactivation infection in the immunocompromised host, occult lymphohematogenous spread, and metastatic extrapulmonary involvement at almost any site. Because transmission is usually through respiratory droplets, isolated pulmonary parenchymal tuberculosis constitutes more than 85% of presenting cases. Pulmonary tuberculosis is the focus of discussion here; additional manifestations of tuberculosis are discussed in Chapter 42.

Following resurgence in the 1980s and early 1990s, tuberculosis has declined among all age groups in the United States, including children. This trend has continued through 2006, the most recent year for which data are available. However, the disease remains a significant cause of morbidity and mortality worldwide.

 Clinical Findings

A. Symptoms and Signs

Most children with tuberculosis are asymptomatic and present with a positive tuberculin skin test. Symptoms of active disease, if present, might include chronic cough, anorexia, weight loss or poor weight gain, fever, and night sweats. Children can also present with symptoms of airway obstruction, with secondary bacterial pneumonia or airway collapse resulting from hilar adenopathy.

Because most children infected with tuberculosis are asymptomatic, a clue to infection may be contact with an individual with tuberculosis—often an elderly relative, a caregiver, or a person previously residing in a region where tuberculosis is endemic—or a history of travel to or residence in such an area. Homeless and extremely impoverished children are also at high risk, as are those in contact with high-risk adults (patients with AIDS, residents or employees of correctional institutions or nursing homes, drug users, and healthcare workers). Once exposed, pediatric patients at risk for developing active disease include infants and those with malnutrition, AIDS, diabetes mellitus, or immunosuppression (cancer chemotherapy or corticosteroids).

The symptoms of active disease listed previously most often occur during the first year of infection. Thereafter, infection remains quiescent until adolescence, when reactivation of pulmonary tuberculosis is common. At any stage, chronic cough, anorexia, weight loss or poor weight gain, and fever are useful clinical signs of reactivation. Of note, except in patients with complications or advanced disease, physical findings are few.

B. Laboratory Findings and Imaging Studies

A positive tuberculin skin test is defined by the size of induration as measured by a medical provider 48–72 hours after intradermal injection of 5 tuberculin units of purified protein derivative (PPD). A positive test is defined as an induration greater than or equal to 5 mm in patients who are at high risk for developing active disease (ie, immunocompromised, those with a history of a positive test or radiograph, children younger than 4 years, and those known to have close contact with someone with active disease); greater than 10 mm in patients from or exposed to high-risk populations (ie, born in countries with a high prevalence, users of injected drugs, having poor access to health care, or living in facilities such as jails, homeless shelters, or nursing homes); and greater than 15 mm in those who are at low risk. Tine tests should not be used. Appropriate control skin tests, such as those for hypersensitivity to diphtheria-tetanus, mumps, or Candida albicans, should be applied in patients with suspected or proven immunosuppression or in those with possible severe disseminated disease. If the patient fails to respond to PPD, the possibility of tuberculosis is not excluded. In suspected cases, the patient, immediate family, and suspected carriers should also be tuberculin-tested. Because healing—rather than progression—is the usual course in the uncompromised host, a positive tuberculin test may be the only manifestation. The primary focus (usually single) and associated nodal involvement may not be seen radiographically. For patients born outside the United States or those who have received a previous bacillus Calmette-Guérin immunization, induration greater than 5 mm should be considered positive and further evaluated.

There are new serum immunological tests that are currently being studied in adults and children. For example, T-spot. TB (Oxford Immunotec, UK) and Quantiferon-TB Gold (Cellestis, Australia) are now being used in adults. Guidelines for interpretation of the tests in pediatrics are not available. In addition, it is not clear how to distinguish new infection from latent infections using these immunological assays.

C. Imaging Studies

Anteroposterior and lateral chest radiographs should be obtained in all suspected cases. Culture for M tuberculosis is critical for proving the diagnosis and for defining drug susceptibility. Early morning gastric lavage following an overnight fast should be performed on three occasions in infants and children with suspected active pulmonary tuberculosis before treatment is started, when the severity of illness allows. Although stains for acid-fast bacilli on this material are of little value, this is the ideal culture site. Despite the increasing importance of isolating organisms because of multiple drug resistance, only 40% of children will yield positive cultures.

D. Special Tests

Sputum cultures from older children and adolescents can also be useful. Stains and cultures of bronchial secretions can be obtained using bronchoscopy. When pleural effusions are present, pleural biopsy for cultures and histopathologic examination for granulomas or organisms provide diagnostic information. Meningeal involvement is also possible in young children, and lumbar puncture should be considered in their initial evaluation.

 Differential Diagnosis

Fungal diseases that affect mainly the lungs, such as histoplasmosis, coccidioidomycosis, cryptococcosis, and North American blastomycosis, may resemble tuberculosis and in cases where the diagnosis is unclear, should be excluded by biopsy or appropriate serologic studies. Atypical tuberculous organisms may involve the lungs, especially in the immunocompromised patient. Depending on the presentation, diagnoses such as lymphoreticular and other malignancies, collagen-vascular disorders, or other pulmonary infections may be considered.

 Complications

In addition to those complications listed in the sections on general considerations and clinical findings, lymphadenitis, meningitis, osteomyelitis, arthritis, enteritis, peritonitis, and renal, ocular, middle ear, and cutaneous disease may occur. Infants born to parents infected with M tuberculosis are at great risk for developing illness. The possibility of life-threatening airway compromise must always be considered in patients with large mediastinal or hilar lesions.

 Treatment

Because the risk of hepatitis due to isoniazid is extremely low in children, this drug is indicated in those with a positive tuberculin skin test. This greatly reduces the risk of subsequent active disease and complications with minimal morbidity. Isoniazid plus rifampin treatment for 6 months, plus pyrazinamide during the first 2 months, is indicated when the chest radiograph is abnormal or when extrapulmonary disease is present. Without pyrazinamide, isoniazid plus rifampin must be given for 9 months. In general, the more severe tuberculous complications are treated with a larger number of drugs (see Chapter 42). Enforced, directly observed therapy (twice or three times weekly) is indicated when nonadherence is suspected. Recommendations for antituberculosis chemotherapy based on disease stage are continuously being updated. The most current edition of the American Academy of Pediatrics Red Book is a reliable source for these protocols.

Corticosteroids are used to control inflammation in selected patients with potentially life-threatening airway compression by lymph nodes, acute pericardial effusion, massive pleural effusion with mediastinal shift, or miliary tuberculosis with respiratory failure.

 Prognosis

In patients with an intact immune system, modern antituberculous therapy offers good potential for recovery. The outlook for patients with immunodeficiencies, organisms resistant to multiple drugs, poor drug adherence, or advanced complications is guarded. Organisms resistant to multiple drugs are increasingly common. Resistance emerges either because the physician prescribes an inadequate regimen or because the patient discontinues medications. When resistance to or intolerance of isoniazid and rifampin prevents their use, cure rates are 50% or less.

Newton S et al: Paediatric tuberculosis. Lancet Infect Dis 2008;8: 498–510 [PMID: 18652996].

Powell DA, Hunt WG: Tuberculosis in children: an update. Adv Pediatr 2006;53:279 [PMID: 17089872].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 History of recurrent aspiration or an aspiration event.

 New-onset respiratory distress, oxygen requirement, or in some children, fever, after the aspiration or in a child with known aspiration.

 Focal findings on physical examination (usually in the side).

Patients whose anatomic defense mechanisms are impaired are at risk of aspiration pneumonia (Table 19–5). Acute disease is commonly caused by bacteria present in the mouth (especially gram-negative anaerobes). Chronic aspiration often causes recurrent bouts of acute febrile pneumonia. It may also lead to chronic focal infiltrates, atelectasis, an illness resembling asthma or ILD, bronchiectasis, or failure to thrive.

 Clinical Findings

A. Symptoms and Signs

Acute onset of fever, cough, respiratory distress, or hypoxemia in a patient at risk suggests aspiration pneumonia. Chest physical findings, such as rales, rhonchi, or decreased breath sounds, may initially be limited to the lung region into which aspiration occurred. Although any region may be affected, the right side—especially the right upper lobe in the supine patient—is commonly affected. In patients with chronic aspiration, diffuse wheezing may occur. Generalized rales may also be present. Such patients may not develop acute febrile pneumonias.

B. Laboratory Findings and Imaging Studies

Chest radiographs may reveal lobar consolidation or atelectasis and focal or generalized alveolar or interstitial infiltrates. In some patients with chronic aspiration, perihilar infiltrates with or without bilateral air trapping may be seen.

In severely ill patients with acute febrile illnesses, and especially when the pneumonia is complicated by a pleural effusion, a bacteriologic diagnosis should be made. In addition to blood cultures and cultures of the pleural fluid, cultures of tracheobronchial secretions and bronchoalveolar lavage specimens may be considered (see section Diagnosis of Respiratory Tract Infections).

In patients with chronic aspiration pneumonitis, documentation of aspiration as the cause of illness may be elusive. Barium contrast studies using liquids of increasing consistency may provide evidence of suck-swallow dysfunction or laryngeal cleft. Bolus barium swallow studies with good distention of the esophagus may help to identify an occult tracheoesophageal fistula. Gastroesophageal reflux may be a risk factor for aspiration while the child is sleeping, and an overnight or 24-hour esophageal pH probe studies may also help establish the diagnosis of gastroesophageal reflux. Although radionuclide scans are commonly used, the yield from such studies is disappointingly low. Rigid bronchoscopy in infants or flexible bronchoscopy in older children can be used to identify anatomic abnormalities such as tracheal cleft and tracheoesophageal fistula. Flexible bronchoscopy and bronchoalveolar lavage specimens to search for lipid-laden macrophages can also suggest chronic aspiration.

 Differential Diagnosis

In the acutely ill patient, bacterial and viral pneumonias should be considered. In the chronically ill patient, the differential diagnosis may include disorders causing recurrent pneumonia (eg, immunodeficiencies, ciliary dysfunction, or foreign body), chronic wheezing, or interstitial lung disorders (see next section), depending on the presentation.

 Complications

Empyema or lung abscess may complicate acute aspiration pneumonia. Chronic aspiration may also result in bronchiectasis.

 Treatment

Aspiration pneumonia leads to a chemical pneumonitis and, in some cases, supportive treatment is the only recommended therapy. Antimicrobial therapy for patients who are acutely ill from aspiration pneumonia includes coverage for gram-negative anaerobic organisms. In general, clindamycin is appropriate initial coverage. However, in some hospital-acquired infections, additional coverage for multiple resistant P aeruginosa, streptococci, and other organisms may be required

Treatment of recurrent and chronic aspiration pneumonia may include the following: surgical correction of anatomic abnormalities; improved oral hygiene; improved hydration; and inhaled bronchodilators, chest physical therapy, and suctioning. In patients with compromise of the central nervous system, exclusive feeding by gastrostomy and (in some) tracheostomy may be required to control airway secretions. Gastroesophageal reflux, if present in these patients, also often requires surgical correction.

 Prognosis

The outlook is directly related to the disorder causing aspiration.

Boesch RP et al: Advances in the diagnosis and management of chronic pulmonary aspiration in children. Eur Respir J 2006; 28(4):847–861 [PMID: 17012631].

An immunocompromised state must be considered in patients following solid organ or hematopoietic stem cell transplants, those with congenital or acquired immune deficits or autoimmune disorders, and those on chemotherapy or immunosuppressant therapy. Pulmonary infection is the most common form of infection in these hosts and can present with focal pneumonia or ILD. The underlying cause of the immunocompromised state often determines the spectrum of infectious agents responsible for disease (see also Chapter 33). Pneumonia in an immunocompromised host may be due to any common bacteria (streptococci, staphylococci, or M pneumoniae) or less common pathogens such as Toxoplasma gondii, P jiroveci, Aspergillus species, Mucor species, Candida species, Cryptococcus neoformans, gram-negative enteric and anaerobic bacteria, Nocardia species, L pneumophila, mycobacteria, and viruses (cytomegalovirus, varicella-zoster, herpes simplex, influenza virus, respiratory syncytial virus, human metapneumovirus, or adenovirus). Multiple organisms are common and disseminated disease is possible.

 Clinical Findings

A. Symptoms and Signs

Patients often present with subtle signs such as mild cough, tachypnea, or low-grade fever that can rapidly progress to high fever, respiratory distress, and hypoxemia or chILD syndrome. An obvious portal of infection, such as an intravascular catheter, may predispose to bacterial or fungal infection.

B. Laboratory Findings and Imaging Studies

Fungal, parasitic, or bacterial infection, especially with antibiotic-resistant bacteria, should be suspected in the neutropenic child. Cultures of peripheral blood, sputum, tracheobronchial secretions, urine, nasopharynx or sinuses, bone marrow, pleural fluid, biopsied lymph nodes, or skin lesions or cultures through intravascular catheters should be obtained as soon as infection is suspected. Currently, serum and bronchoalveolar lavage (BAL) galactomannan assays for invasive pulmonary aspergillosis are being used in some centers to help guide therapy.

Invasive methods are commonly required to make a diagnosis. Appropriate samples should be obtained soon after a patient with pneumonia fails to respond to initial treatment. The results of these procedures usually lead to important changes in empiric therapy. Sputum is often unavailable. Bronchoalveolar lavage frequently provides the diagnosis of one or more organisms and should be done early in evaluation. The combined use of a wash, brushing, and lavage has a high yield. In patients with rapidly advancing, or more peripheraldisease, lung biopsy becomes more urgent. The morbidity and mortality of this procedure can be reduced by a surgeon skilled in video-assisted thoracoscopic surgical (VATS) techniques. Because of the multiplicity of organisms that may cause disease, a comprehensive set of studies should be done on lavage and biopsy material. These consist of rapid diagnostic studies, including fluorescent antibody studies for Legionella; rapid culture and antigen detection for viruses; Gram, acid-fast, and fungal stains; cytologic examination for viral inclusions; cultures for viruses, anaerobic and aerobic bacteria, fungi, mycobacteria, and Legionella; and rapid immunofluorescent studies for P jiroveci.

Chest radiographs and increasingly high-resolution CT scans may be useful in identifying the pattern and extent of disease. In P jiroveci pneumonia, dyspnea and hypoxemia may be marked despite minimal radiographic abnormalities.

 Differential Diagnosis

The organisms causing disease vary with the type of immunocompromise present. For example, the splenectomized or sickle cell disease patient may be overwhelmed by infection with encapsulated bacteria. The child with HIV/AIDS or receiving immunosuppressant therapy or chemotherapy is more likely to have P jiroveci infection. The febrile neutropenic child who has been receiving adequate doses of intravenous broad-spectrum antibiotics or systemic steroid therapy may have fungal disease. The key to diagnosis is to consider all possibilities of infection.

Depending on the form of immunocompromise, perhaps only half to two-thirds of new pulmonary infiltrates in such patients represent infection. The remainder are caused by pulmonary toxicity of radiation, chemotherapy, or other drugs; pulmonary disorders, including hemorrhage, embolism, atelectasis, or aspiration; idiopathic pneumonia syndrome or acute respiratory distress syndrome in bone marrow transplant patients; recurrence or extension of primary malignant growths or immunologic disorders; transfusion reactions, leukostasis, or tumor cell lysis; or ILD, such as lymphocytic interstitial pneumonitis with HIV infection.

 Complications

Necrotizing pneumonia, lung abscesses, and parapneumonic effusions can develop. Progressive respiratory failure, shock, multiple organ damage, disseminated infection, and death commonly occur in the infected immunocompromised host if the primary etiology is not treated effectively.

 Treatment

Early use of broad-spectrum intravenous antibiotics is indicated early in febrile, neutropenic, or immunocompromised children. Trimethoprim-sulfamethoxazole (for Pneumocystis) and macrolides (for Legionella) are also indicated early in the treatment of immunocompromised children before an organism is identified. Further therapy should be based on studies of specimens obtained from bronchoalveolar lavage or lung biopsy. Recent data suggest that use of noninvasive ventilation strategies early in the course of pulmonary insufficiency or respiratory failure may decrease mortality.

 Prognosis

Prognosis is based on the severity of the underlying immunocompromise, appropriate early diagnosis and treatment, and the infecting organisms. Intubation and mechanical ventilation have been associated with high mortality rates, especially in hematopoietic stem cell transplant patients.

Collaco J, Michael et al: Pulmonary dysfunction in pediatric hematopoietic stem cell transplant patients: overview, diagnostic considerations, and infectious complications. Pediatr Blood Cancer 2007;49(2):117 [PMID: 17029246].

Nouér Simone A et al: Earlier response assessment in invasive aspergillosis based on the kinetics of serum Aspergillus galactomannan: proposal for a new definition. Clin Infect Dis 2011;53(7):671 [PMID: 21846834].

 Pathogensis

Lung abscesses are thick-walled cavities that form from inflammation and central necrosis following an initial pulmonary infection. A primary lung abscess occurs in a previously well child or one prone to aspiration, while secondary lung abscesses develop in children with immunosuppression, underlying lung or systemic disease. Lung abscesses may also occur via embolic spread. Although organisms such as S aureus, S pneumoniae, and other staphylococci and streptococci more commonly affect the healthy host, anaerobic and gram-negative organisms as well as Nocardia, Legionella species, and fungi (Candida and Aspergillus) should also be considered in the immunocompromised host or in patients not responding to treatment.

 Clinical Findings

A. Symptoms and Signs

Symptoms and signs referable to the chest may or may not be present. High fever, malaise, and weight loss are often present. In infants, evidence of respiratory distress can be present.

B. Laboratory Findings and Imaging Studies

Elevated peripheral white blood cell count with a neutrophil predominance or an elevated erythrocyte sedimentation rate or C-reactive protein may be present. Blood cultures are rarely positive except in the overwhelmed host.

Chest radiographs usually reveal single or multiple thick-walled lung cavities. Air-fluid levels can be present. Local compressive atelectasis, pleural thickening, or adenopathy may also occur. Chest CT scan may provide better localization and understanding of the lesions.

In patients producing sputum, stains, and cultures may provide the diagnosis. Direct percutaneous aspiration of material for stains and cultures guided by fluoroscopy or ultrasonography or CT imaging should be considered in the severely compromised or ill.

 Differential Diagnosis

Loculated pyopneumothorax, an Echinococcus cyst, neoplasms, plasma cell granuloma, and infected congenital cysts and sequestrations should be considered. Pneumatoceles, non–fluid-filled cysts, are common in children with empyema and usually resolve over time.

 Complications

Although complications due to abscesses are now rare, mediastinal shift, tension pneumothorax, and spontaneous rupture can occur. Diagnostic maneuvers such as radiology-guided lung puncture to drain and culture the abscess may also cause a pneumothorax or a bronchopulmonary fistula.

 Treatment

Because of the risks of lung puncture, uncomplicated abscesses are frequently conservatively treated in the uncompromised host with appropriate broad-spectrum intravenous antibiotics directed at S aureus, S pneumonia, and other staphylococci and streptococci. Additional coverage for anaerobic gram-negative organisms and fungi should be provided for others. Prolonged therapy with 2–3 weeks of intravenous antibiotics followed by oral therapy may be required. Attempts to drain abscesses via bronchoscopy have caused life-threatening airway compromise. Surgical drainage or lobectomy is occasionally required, primarily in immunocompromised patients. However, such procedures may themselves cause life-threatening complications.

 Prognosis

Although radiographic resolution may be very slow (6 weeks–5 years), resolution occurs in most patients without risk factors for lower respiratory tract infections or loss of pulmonary function. In the immunocompromised or medically complex host, the outlook depends on the underlying disorder.

Chan PC et al: Clinical management and outcome of childhood lung abscess: a 16-year experience. J Microbiol Immunol Infect 2005;38:183 [PMID: 15986068].

Patradoon-Ho P et al: Lung abscess in children. Paediatr Respir Rev 2007;8(1):77–84 [PMID: 17419981].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Occurs acutely in the neonatal period or subacutely in infancy or childhood.

 Infants and young children have different diagnoses than adolescents and adults.

 Presence of three to five of the following criteria in the absence of any identified primary etiology is suggestive of an interstitial lung disease (ILD) syndrome:

 Symptoms of impaired respiratory function (cough, tachypnea, retractions, exercise intolerance).

 Evidence of impaired gas exchange (resting hypoxemia or hypercarbia, desaturation with exercise).

 Diffuse infiltrates on imaging.

 Presence of adventitious sounds (crackles, wheezing).

 Abnormal spirometry, lung volumes, or carbon monoxide diffusing capacity.

 History of exposure (eg, birds, organic dusts, drug therapy, hot tubs, molds), previous lung disease, immunosuppression, symptoms of connective tissue disease; family history of familial lung disease (especially ILD) or early infant death from lung disease.

Children’s Interstitial Lung Disease (chILD) syndrome is a constellation of signs and symptoms and not a specific diagnosis. Once recognized, chILD syndrome should elicit a search for a more specific diagnosis. Known disorders can present as chILD syndrome and must be excluded as the primary cause of symptoms. These disorders include CF, cardiac disease, asthma, acute infection, immunodeficiency, neuromuscular disease, scoliosis, thoracic cage abnormality, typical BPD or premature respiratory distress syndrome, and confirmed significant aspiration on a swallow study. However, if patients present with symptoms out of proportion to the diagnosis, consideration should be given to other ILD disorders.

 Clinical Findings

A. Symptoms and Signs

chILD syndrome may present acutely in the newborn period with respiratory failure or gradually over time with a chronic dry cough or a history of dyspnea on exertion. The child with more advanced disease may have dyspnea, resting tachypnea, retractions, hypoxemia, cyanosis, barrel chest, clubbing, failure to thrive, or weight loss.

B. Laboratory Findings

Initial evaluations should be directed at ruling out known conditions. Depending on the age and presentation, this should include the following: chest radiographs, modified barium swallow, pulmonary function tests, and skin tests (see section Tuberculosis); complete blood count and erythrocyte sedimentation rate; sweat chloride test for CF; electrocardiogram or echocardiogram; serum immunoglobulins and other immunologic evaluations; sputum studies (see section Pneumonia in the Immunocompromised Host); and possibly studies for Epstein-Barr virus, cytomegalovirus, M pneumoniae, Chlamydia, Pneumocystis, and Ureaplasma urealyticum.

C. Imaging Studies

Chest radiographs are normal in up to 10%–15% of patients. Frequently, specific chILD disorders can be suspected by findings on controlled volume inspiratory and expiratory high-resolution CT. Diagnoses of bronchiolitis obliterans (BO) and neuroendocrine cell hyperplasia of infancy (NEHI) can be made using CT findings in the right clinical context. Infants and children younger than age 5 years require sedation, which allows either infant pulmonary function testing or bronchoscopy to be completed at the same time. The lowest possible dose of radiation should always be used and this point should be emphasized at centers not specialized in pediatric care.

D. Special Tests

Depending on the specific ILD, pulmonary function tests may show (1) a restrictive pattern of decreased lung volumes, compliance, and carbon monoxide diffusing capacity, (2) an obstructive pattern with hyperinflation, or (3) a mixed obstructive-restrictive pattern. Exercise-induced or nocturnal hypoxemia is often the earliest detectable abnormality of lung function in children.

During the second evaluation phase, bronchoscopy is performed to exclude anatomic abnormalities, and obtain bronchoalveolar lavage for microbiologic and cytologic testing. Nasal brushings to evaluate for primary ciliary dyskinesia (see section Primary Ciliary Dyskinesia) may be obtained if this diagnosis is suspected.

In patients with static or slowly progressing disease, one can then await results of bronchoscopic studies. In patients with acute, rapidly progressive disease, this stage should be combined with video-assisted thoracoscopic lung biopsy. Lung biopsy is the most reliable method for definitive diagnosis when analyzed by pathologists experienced in chILD disorders. A new chILD histology classification has been proposed to improve diagnostic yields. Tissue should be processed in a standard manner for special stains and cultures, electron microscopy, and immunofluorescence for immune complexes if indicated. Although transbronchial biopsy may be useful in diagnosing a few diffuse disorders and graft rejection in transplantation (eg, sarcoidosis), its overall usefulness in chILD is limited at this time.

E. Special Examinations: Genetic Testing

Genomic mutational analysis of tissue or blood for surfactant proteins B and C (SP-B, SP-C) and ABCA3 is now offered in clinical laboratories and should be considered in children with diffuse lung disease or a strong family history of ILD. Recently other genetic mutations have been reported for rare chILD that offer diagnostic information. A newly recognized disorder associated with the thyroid transcription factor–1 protein (NKX2.1 gene) can result in variable phenotypes of brain, thyroid, and lung syndrome. Children with unexplained lung disease and hypotonia or developmental delays with or without hypothyroidism and newborns with severe RDS and congenital hypothyroidism should be screened for this disorder. Other genetic disorders that cause ILD include alveolar capillary dysplasia (FOXF1 found in 30% of patients), pulmonary alveolar proteinosis (GCSF [granulocyte colony-stimulating factor] receptor mutations or autoantibodies), pulmonary alveolar microlithiasis (SLC34A2), and lysinuric protein intolerance (SLC7A7).

 Differential Diagnosis

chILD syndrome is composed of a group of diverse conditions that differ from adult ILD conditions. Common adult causes of ILD such as idiopathic pulmonary fibrosis, which is associated with a high mortality rate, and respiratory bronchiolitis, associated with smoking, have not been found in children. Conversely, newly identified conditions unique to infancy such as neuroendocrine cell hyperplasia of infancy (NEHI) or pulmonary interstitial glycogenosis (PIG), have not been described in adults. Other chILD conditions include the genetically recognized surfactant dysfunction mutations SP-B, SP-C, ABCA3, and NKX2.1; developmental abnormalities; and growth disorders, especially in younger children. Older children are more likely to have SP-C or ABCA3 surfactant mutations, hypersensitivity pneumonitis, or collagen-vascular disease. Other known conditions must also be ruled out.

 Complications

Respiratory failure or pulmonary hypertension may occur. Somatic growth deficiencies often require nutritional supplementation. Mortality and morbidity can be significant in and vary by specific diagnosis.

 Treatment

Therapy for known causes of ILD such as infection, aspiration, or cardiac disorders should be directed toward the primary disorder. It must be recognized that treatment for chILD conditions is anecdotal and based on case reports and small case series. In noninflammatory chILD syndrome conditions such as NEHI or developmental or growth abnormalities, treatment is supportive and may not require corticosteroids. For surfactant dysfunction mutations, PIG, hypersensitivity pneumonitis, and systemic collagen-vascular disease, patients are frequently treated initially with glucocorticoids. Other conditions may require oral glucocorticoids (2 mg/kg/d for 6 weeks) or monthly pulse glucocorticoids (IV doses of 10–30 mg/kg for 1–3 days). Many patients require even more protracted therapy with alternate-day prednisone. Chloroquine (5–10 mg/kg/d) may be useful in selected disorders such as desquamative interstitial pneumonitis, surfactant dysfunction mutations, or refractory disease. Cyclophosphamide is used in severe cases of diffuse alveolar hemorrhage associated with pulmonary capillaritis. In refractory cases, immunomodulatory therapies (plasmapheresis, intravenous immunoglobulin, azathioprine, cyclophosphamide, and rituximab) have been used. Finally, some patients with severe disease may require long-term mechanical ventilation or lung transplantation for survival. Children with ILD should be evaluated and cared for by an experienced multidisciplinary team. The chILD Family Foundation can provide further supportive resources for families (http://www.childfoundation.us).

 Prognosis

Prognosis is guarded in children with ILD due to collagen-vascular disease, surfactant dysfunction mutations, and lung development disorders. Mortality has been reported in PIG, usually in association with a concurrent lung growth abnormality. Deaths have not been reported in NEHI.

Das S et al: Insterstitial lung disease in children. Curr Opin Pediatr 2011;23(3):325–331 [PMID: 21572385].

Hamvas A et al: Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 2013 Sep;144(3):794-804 [PMID: 23430038].

Kurland G et al: Recommendation for evaluation and diagnosis of the neonate, infant and young child with suspected interstitial lung disease: an official ATS consensus statement. Am J Respir Crit Care Med 2013 Aug 1;188(3):376-94. doi: 10.1164/rccm.201305-0923ST. Review. [PMID: 23905526].

Hypersensitivity pneumonitis, or extrinsic allergic alveolitis, is a T-cell–mediated disease involving the peripheral airways, interstitium, and alveoli and presents as a distinct form of chILD. Both acute and chronic forms may occur. In children, the most common forms are brought on by exposure to domestic and occasionally wild birds or bird droppings (eg, pigeons, parakeets, parrots, or doves) also known as bird fanciers lung. Intensity, duration, and genetic predisposition are all important factors. However, inhalation of almost any organic dust (moldy hay, compost, logs or tree bark, sawdust, or aerosols from humidifiers or hot tubs) can cause disease. Methotrexate-induced hypersensitivity has also been described in a child with juvenile rheumatoid arthritis. Hot tub lung can be caused by exposure to aerosolized Mycobacterium avium complex. A high level of suspicion and a thorough history with attention to environmental exposures are required for diagnosis.

 Clinical Findings

A. Symptoms and Signs

Episodic cough and fever can occur with acute exposures. Chronic exposure results in weight loss, fatigue, dyspnea, cyanosis, and, ultimately, respiratory failure.

B. Laboratory Findings

Acute exposure may be followed by polymorphonuclear leukocytosis with eosinophilia and evidence of airway obstruction on pulmonary function testing. Chronic disease results in a restrictive picture on lung function tests.

The serologic key to diagnosis is the finding of precipitins (precipitating IgG antibodies) to the organic materials that contain avian proteins or fungal or bacterial antigens. Ideally, to identify avian proteins, the patient’s sera should be tested with antigens from droppings of the suspected species of bird. However, exposure may invoke precipitins without causing disease.

When serologic investigations are not diagnostic, lung biopsy may be necessary. Histopathology is characterized by lymphocyte predominant interstitial infiltrates, cellular bronchiolitis, and peribronchiolar noncaseating granulomas.

Chest x-ray findings are variable and may include normal lung fields, air-space consolidation, nodular, or reticulonodular patterns. High-resolution CT of the chest is more sensitive, with classic findings of centrilobular nodules, ground-glass opacities, and air-trapping. Pulmonary fibrosis is seen in chronic disease. Lymphocytosis or M avium complex on bronchoalveolar lavage may be suggestive.

 Differential Diagnosis

Patients with mainly acute symptoms must be differentiated from those with atopic asthma. Patients with chronic symptoms must be distinguished from those with collagen-vascular, immunologic, or primary interstitial lung disease.

 Complications

Prolonged exposure to offending antigens may result in pulmonary hypertension due to chronic hypoxemia, irreversible restrictive lung disease due to pulmonary fibrosis, or respiratory failure.

 Treatment & Prognosis

Complete elimination of exposure to the offending antigens is required. If drug-induced hypersensitivity pneumonitis is suspected, discontinuation is required. Corticosteroids may hasten recovery. With appropriate early diagnosis and identification and avoidance of offending antigens, the prognosis is excellent.

Venkatesh P, Wild L: Hypersensitivity pneumonitis in children: clinical features, diagnosis, and treatment. Paediatr Drugs 2005; 7(4):235–244 [PMID: 16117560].

DISEASES OF THE PULMONARY CIRCULATION

Pulmonary hemorrhage can be caused by a spectrum of disorders affecting the large and small airways and alveoli. It can occur as an acute or chronic process. If pulmonary hemorrhage is subacute or chronic, hemosiderin-laden macrophages can be found in the sputum and tracheal or gastric aspirate 48–72 hours after the bleeding begins. Many cases are secondary to bacterial, mycobacterial, parasitic, viral, or fungal infections (such as the toxigenic mold Stachybotrys chartarum. Lung abscess, bronchiectasis (CF or other causes), foreign body, coagulopathy (often with overwhelming sepsis), or elevated pulmonary venous pressure (secondary to congestive heart failure, anatomic heart lesions, or ascent to high altitude) may also cause pulmonary hemorrhage. Other causes include lung contusion from trauma, pulmonary embolus with infarction, arteriovenous fistula or telangiectasias, autoimmune vasculitis, hypersensitivity pneumonitis pulmonary sequestration, agenesis of a single pulmonary artery, and esophageal duplication or bronchogenic cyst. In children, pulmonary hemorrhage due to airway tumors (eg, bronchial adenoma or left atrial myxoma) is quite rare.

Hemorrhage involving the alveoli is termed diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage may be idiopathic or drug-related or may occur in Goodpasture syndrome, rapidly progressive glomerulonephritis, and systemic vasculitides (often associated with such collagen-vascular diseases as systemic lupus erythematosus, rheumatoid arthritis, Wegener granulomatosis, polyarteritis nodosa, Henoch-Schönlein purpura, and Behçet disease). Idiopathic pulmonary hemosiderosis refers to the accumulation of hemosiderin in the lung, especially the alveolar macrophage, as a result of chronic or recurrent hemorrhage (usually from pulmonary capillaries) that is not associated with the previously listed causes. Children and young adults are mainly affected, with the age at onset ranging from 6 months to 20 years.

 Clinical Findings

A. Symptoms and Signs

Large airway hemorrhage presents with hemoptysis and symptoms of the underlying cause, such as infection, foreign body, or bronchiectasis in CF. Hemoptysis from larger airways is often bright red or contains clots. Children with diffuse alveolar hemorrhage may present with massive hemoptysis, marked respiratory distress, stridor, or a pneumonia-like syndrome. However, most patients with diffuse alveolar hemorrhage and idiopathic pulmonary hemosiderosis present with nonspecific respiratory symptoms (cough, tachypnea, and retractions) with or without hemoptysis, poor growth, and fatigue. Fever, abdominal pain, digital clubbing, and chest pain may also be reported. Jaundice and hepatosplenomegaly may be present with chronic bleeding. Physical examination often reveals decreased breath sounds, rales, rhonchi, or wheezing.

B. Laboratory Findings and Imaging Studies

Laboratory studies depend on the cause of hemorrhage. When gross hemoptysis is present, large airway bronchiectasis, epistaxis, foreign body, and arteriovenous malformations should be considered. Flexible bronchoscopy and imaging (MRI or CT-assisted angiography) can be used to localize the site of bleeding. Alveolar bleeding with hemoptysis is often frothy and pink. Long-standing idiopathic pulmonary hemorrhage may cause iron deficiency anemia and heme-positive sputum. Nonspecific findings may include lymphocytosis and an elevated erythrocyte sedimentation rate. Peripheral eosinophilia is present in up to 25% of patients. Chest radiographs may demonstrate perihilar infiltrates, fluffy alveolar infiltrates with or without atelectasis, and mediastinal adenopathy. Pulmonary function testing generally reveals restrictive impairment, with low lung volumes, poor compliance, and an increased diffusion capacity. Hemosiderin-laden macrophages are found in tracheal or gastric aspirates. The diagnostic usefulness of lung biopsy is controversial.

Patients with diffuse alveolar hemorrhage with an underlying systemic disease may need a lung biopsy. In patients with systemic lupus erythematosus, Wegener granulomatosis, and occasionally Goodpasture syndrome diffuse alveolar hemorrhage can occur with the histologic entity known as necrotizing pulmonary capillaritis. Lung biopsy reveals alveolar septa infiltrated with neutrophils, edema, or necrosis in addition to alveolar hemorrhage. In idiopathic pulmonary hemosiderosis, a mild form of capillaritis is associated with focal or diffuse alveolar hemorrhage. An immune-mediated process may cause idiopathic pulmonary hemosiderosis and capillaritis by biopsy in the absence of an identifiable serologic marker. Although capillaritis has been described without evidence of underlying systemic disease, the search for collagen-vascular disease, vasculitis, or pulmonary fibrosis should be exhaustive.

Serologic studies such as circulating antineutrophilic cytoplasmic autoantibodies for Wegener granulomatosis, perinuclear antineutrophilic cytoplasmic autoantibodies for microscopic polyangiitis, antinuclear antibodies for systemic lupus erythematosus, and anti–basement membrane antibodies for Goodpasture syndrome should be obtained. α₁-Antitrypsin deficiency should also be considered.

Cow’s milk–induced pulmonary hemosiderosis (Heiner syndrome) can be confirmed by high titers of serum precipitins to multiple constituents of cow’s milk and positive intradermal skin tests to cow’s milk proteins. Improvement after elminating cow’s milk also supports the diagnosis.

 Differential Diagnosis

Bleeding from the nose or mouth can present as hemoptysis. Therefore, a complete examination of the nose and mouth is required before confirming the diagnosis of intrapulmonary bleeding. Hematemesis can also be confused with hemoptysis; confirming that the blood was produced after coughing and not with emesis should also be part of the initial evaluations. A complete past medical history including underlying systemic illness and cardiovascular anomalies may direct the search for the site of respiratory bleeding.

 Treatment

Therapy should be aimed at direct treatment of the underlying disease. In severe bleeding, intubation with application of positive pressure during mechanical ventilation and/or endotracheal administration of epinephrine may help attenuate bleeding. Patients with cystic fibrosis or bronchiectasis from other causes who develop massive (> 240 mL) or recurrent hemoptysis, bronchial artery embolization may be necessary. An experienced interventional radiologist should be consulted immediately. Although its use requires anticoagulation, extracorporal life support has resulted in the survival of children with severe pulmonary hemorrhage. For more chronic bleeding, supportive measures, including iron therapy, supplemental oxygen, and blood transfusions, may be needed. A diet free of cow’s milk should be tried in infants. Systemic corticosteroids have been used for various causes of diffuse alveolar hemorrhage and have been particularly successful in those secondary to collagen-vascular disorders and vasculitis. Case reports have been published describing the variable effectiveness of steroids, chloroquine, cyclophosphamide, and azathioprine for idiopathic pulmonary hemosiderosis.

 Prognosis

The outcome of pulmonary hemorrhage depends on the cause of the bleeding and how much blood has been lost. The course of idiopathic pulmonary hemosiderosis is variable, characterized by a waxing and waning course of intermittent intrapulmonary bleeds and the gradual development of pulmonary fibrosis over time. The severity of the underlying renal disease contributes to the mortality rates associated with Goodpasture syndrome and Wegener granulomatosis. Diffuse alveolar hemorrhage is considered a lethal pulmonary complication of systemic lupus erythematosus.

Bull TM et al: Pulmonary vascular manifestations of mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:451 [PMID: 16084318].

Flume PA et al: Cystic Fibrosis Pulmonary Guidelines–Pulmonary Complications: Hemoptysis and Pneumothorax. Am J Respir Crit Care Med 2010;182(3):298 [PMID: 20675678].

Godfrey S: Pulmonary hemorrhage/hemoptysis in children. Pediatr Pulmonol 2004;37:476 [PMID: 15114547].

Sherman J et al: Time course of Hemosiderin production and clearance by human pulmonary macrophages. Chest 1984;86:409 [PMID: 6468000].

Pulmonary embolism is a rare, but severe cause of respiratory distress in children. It is commonly caused by sickle cell anemia as part of the acute chest syndrome, malignancy, rheumatic fever, infective endocarditis, schistosomiasis, bone fracture, dehydration, polycythemia, nephrotic syndrome, atrial fibrillation, and other conditions. A majority of children with pulmonary emboli referred for hematology evaluation have coagulation regulatory protein abnormalities and antiphospholipid antibodies. Emboli may result in clinical signs and symptoms dependent on the severity of pulmonary vascular obstruction. In children, tumor emboli are a more common cause of massive pulmonary embolism than embolization from a lower extremity deep venous thrombosis.

 Clinical Findings

A. Symptoms and Signs

Pulmonary embolism usually presents as an acute onset of dyspnea and tachypnea. Heart palpitations, pleuritic chest pain, and a sense of impending doom may be reported.

Hemoptysis is rare, but may occur along with splinting, cyanosis, and tachycardia. Massive emboli may be present with syncope and cardiac arrhythmias. Physical examination is usually normal (except for tachycardia and tachypnea) unless the embolism is associated with an underlying disorder. Mild hypoxemia, rales, focal wheezing, or a pleural friction rub may be found.

B. Laboratory Findings and Imaging Studies

Radiographic findings may be normal, but a peripheral infiltrate, small pleural effusion, or elevated hemidiaphragm can be present. If the emboli are massive, differential blood flow and pulmonary artery enlargement may be appreciated. The electrocardiogram is usually normal unless the pulmonary embolus is massive. Echocardiography is useful in detecting the presence of a large proximal embolus. A negative D-dimer has a more than 95% negative predictive value for an embolus. Ventilation-perfusion scans show localized areas of ventilation without perfusion.

Spiral CT with contrast may be helpful, but pulmonary angiography is the gold standard. A recent case series suggests that bedside chest ultrasound may aid in diagnosing pulmonary emboli, particularly in critically ill children. Further evaluation may include Doppler ultrasound studies of the legs to search for deep venous thrombosis. Coagulation studies, including assessments of antithrombin III, fibrinogen, antiphospholipid antibodies, homocystine, coagulation regulatory proteins (proteins C and S, and factor V Leiden), and the prothrombin G20210A mutation are abnormal in up to 70% of pediatric patients with pulmonary embolism.

 Treatment

Acute treatment includes supplemental oxygen, and anticoagulation. Current recommendations include heparin therapy to maintain an activated partial thromboplastin time of greater than 1.5 times the control value for the first 24 hours. Urokinase or tissue plasminogen activator can be used to help dissolve the embolus. These therapies should be followed by warfarin therapy for at least 6 weeks with an international normalized ratio (INR) greater than 2.

Baird JS et al: Massive Pulmonary Embolism in Children. J Pediatr 2010;156:148 [PMID: 20006766].

Konstantinides S et al: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143 [PMID: 12374874].

 Pathogenesis

Pulmonary edema is excessive accumulation of extravascular fluid in the lung. This occurs when fluid is filtered into the lungs faster than it can be removed, leading to changes in lung mechanics such as decreased lung compliance, worsening hypoxemia from ventilation-perfusion mismatch, bronchial compression, and if advanced, decreased surfactant function. There are two basic types of pulmonary edema: increased pressure (cardiogenic or hydrostatic) and increased permeability (noncardiogenic or primary). Hydrostatic pulmonary edema is usually due to excessive increases in pulmonary venous pressure, which is most commonly due to congestive heart failure from multiple causes. Postobstructive pulmonary edema occurs when airway occlusion (or its sudden relief) causes a sudden drop in airway pressure which leads to increased venous return and decreased left heart blood flow. These changes result in elevated hydrostatic pressures and transudation of fluid from the pulmonary capillaries to the alveolar space.

In contrast, many lung diseases, especially acute respiratory distress syndrome, are characterized by the development of pulmonary edema secondary to changes in permeability due to injury to the alveolocapillary barrier. In these settings, pulmonary edema occurs independently of the elevations of pulmonary venous pressure.

 Clinical Findings

A. Symptoms and Signs

Cyanosis, tachypnea, tachycardia, and respiratory distress are commonly present. Physical findings include rales, diminished breath sounds, and (in young infants) expiratory wheezing. More severe disease is characterized by progressive respiratory distress with marked retractions, dyspnea, and severe hypoxemia.

B. Imaging Studies

Chest radiographic findings depend on the cause of the edema. Pulmonary vessels are prominent, often with diffuse interstitial or alveolar infiltrates. Heart size is usually normal in permeability edema but enlarged in hydrostatic edema.

 Treatment

Although specific therapy depends on the underlying cause, supplemental oxygen therapy, and ventilator support may be indicated. Diuretics, digoxin, and vasodilators may be indicated for congestive heart failure along with restriction of salt and water. Loop diuretics, such as furosemide, are primarily beneficial because they increase systemic venous capacitance, not because they induce diuresis. Improvement can even be seen in anuric patients. Recommended interventions for permeability edema are reduction of vascular volume and maintenance of the lowest central venous or pulmonary arterial wedge pressure possible without sacrificing cardiac output or causing hypotension (see following discussion). β-Adrenergic agonists such as terbutaline have been shown to increase alveolar clearance of lung water, perhaps through the action of a sodium-potassium channel pump. Maintaining normal albumin levels and a hematocrit concentration above 30 maintains the filtration of lung liquid toward the capillaries, avoiding low oncotic pressure.

High-altitude pulmonary edema (HAPE) occurs when susceptible individuals develop noncardiogenic edema after rapid ascent to altitudes above 3000 m. Children may develop HAPE with variation in severity. Oxygen therapy and prompt descent are the cornerstones of therapy for this illness.

Bartsch P et al: Physiologic aspects of high-altitude pulmonary edema. J Appl Physiol 2005;98:1101 [PMID: 15703168].

O’Brodovich H: Pulmonary edema in infants and children. Curr Opin Pediatr 2005;17:381 [PMID: 15891430].

Udeshi A et al: Postobstructive pulmonary edema. J Crit Care 2010; 25:508 [PMID: 20413250].

Structurally, congenital pulmonary lymphangiectasia appears as dilated subpleural and interlobular lymphatic channels and may present as part of a generalized lymphangiectasis (in association with obstructive cardiovascular lesions—especially total anomalous pulmonary venous return) or as an isolated idiopathic lesion. Pathologically, the lung appears firm, bulky, and noncompressible, with prominent cystic lymphatics visible beneath the pleura. On cut section, dilated lymphatics are present near the hilum, along interlobular septa, around bronchovascular bundles, and beneath the pleura. Histologically, dilated lymphatics have a thin endothelial cell lining overlying a delicate network of elastin and collagen.

 Clinical Findings

Congenital pulmonary lymphangiectasia is a rare, usually fatal disease that generally presents as acute or persistent respiratory distress at birth. Although most patients do not survive the newborn period, some survive longer, and there are case reports of its diagnosis later in childhood. Congenital pulmonary lymphangiectasia may be associated with Noonan syndrome, asplenia, total anomalous pulmonary venous return, septal defects, atrioventricular canal, hypoplastic left heart, aortic arch malformations, and renal malformations. Chylothorax has been reported. Chest radiographic findings include a ground-glass appearance, prominent interstitial markings suggesting lymphatic distention, diffuse hyperlucency of the pulmonary parenchyma, and hyperinflation with depression of the diaphragm.

 Prognosis

Although the onset of symptoms may be delayed for as long as the first few months of life, prolonged survival is rare. Most deaths occur within weeks after birth. However, more recent studies have shown that respiratory symptoms do improve after the first year of life suggesting that maximal medical treatment remains warranted. In those with the most severe disease, rapid diagnosis is essential in order to expedite the option of lung transplantation.

Barker PM et al: Primary pulmonary lymphangiectasia in infancy and childhood. Eur Respir J 2004;24(3):413 [PMID: 15358700].

Esther CR et al: Pulmonary lymphangiectasia: diagnosis and clinical course. Pediatr Pulmonol 2004;38:308 [PMID: 15334508].

Mettauer N et al: Outcome of children with pulmonary lymphangiectasis. Pediatr Pulmonol 2009;44:351 [PMID: 19330773].

DISORDERS OF THE CHEST WALL & DIAPHRAGM

Scoliosis is defined as lateral curvature of the spine and is commonly categorized as idiopathic, congenital, or neuromuscular. No pulmonary impairment is typically seen with a Cobb angle showing thoracic curvature of less than 35 degrees. Most cases of idiopathic scoliosis occur in adolescent girls and are corrected before significant pulmonary impairment occurs. Congenital scoliosis of severe degree or with other major abnormalities carries a more guarded prognosis. Patients with progressive neuromuscular disease, such as Duchenne muscular dystrophy, can be at risk for respiratory failure due to severe scoliosis and restrictive lung disease. Severe scoliosis can also lead to impaired lung function and, if uncorrected, possible death from cor pulmonale. (See also Chapter 26.) Small studies indicate that surgical correction of neuromuscular scoliosis may lead to improved quality of life, although pulmonary function may not improve.

Gill I: Correction of neuromuscular scoliosis in patients with preexisting respiratory failure. Spine 2006;31(21):2478–2483 [PMID: 17023858].

Greiner KA: Adolescent idiopathic scoliosis: Radiologic decision-making. Am Fam Physician 2002;65:1817 [PMID: 12018804].

Johnston CE et al: Correlation of preoperative deformity magnitude and pulmonary function tests in adolescent idiopathic scoliosis. Spine 2011;36:1096–1102 [PMID: 21270699].

Pectus carinatum is a protrusion of the upper or lower (more common) portion of the sternum, more commonly seen in males. Impedance of cardiopulmonary function due to pectus carinatum is debated. The decision to repair this deformity is often based upon cosmetic concerns. Research has shown that those with reduced endurance or dyspnea with mild exercise experienced marked improvement within 6 months following repair, suggesting possible physiologic indications. Pectus carinatum may be associated with systemic diseases such as the mucopolysaccharidoses and congenital heart disease.

Lawson ML et al: Impact of pectus excavatum on pulmonary function before and after repair with the Nuss procedure. J Pediatr Surg 2005;40:174 [PMID: 15868581].

Malek MH et al: Ventilatory and cardiovascular responses to exercise in patients with pectus excavatum. Chest 2003;124:870 [PMID: 12970011].

Pectus excavatum is anterior depression of the chest wall that may be symmetrical or asymmetrical with respect to the midline. Its presence can be psychologically difficult for the patient. Whether or not it is cause for cardiopulmonary limitations is controversial. While subjective exertional dyspnea can be reported and may improve with repair, objective cardiopulmonary function may not change postoperatively. Therefore, the decision to repair the deformity may be based on cosmetic or physiologic considerations. Surgical literature provides more information regarding long-term outcomes following repair. Timing of repair is critical in light of growth plate maturation. Pectus excavatum may be associated with congenital heart disease.

Fonkalsrud EW, Anselmo DM: Less extensive techniques for repair of pectus carinatum: the undertreated chest deformity. J Am Coll Surg 2004;198:898 [PMID: 15194071].

Williams AM, Crabbe DC: Pectus deformities of the anterior chest wall. Paediatr Respir Rev 2003;4:237 [PMID: 12880759].

NEUROMUSCULAR DISORDERS

Neuromuscular disorders are discussed in detail in Chapter 25. Weakness of the respiratory and pharyngeal muscles leads to chronic or recurrent pneumonia secondary to weak cough and poor mucous clearance, aspiration and infection, persistent atelectasis, hypoventilation, and respiratory failure in severe cases. Scoliosis, which frequently accompanies longstanding neuromuscular disorders, may further compromise respiratory function. Children born with significant neuromuscular weakness may present with signs and symptoms of respiratory compromise early in life. The time to presentation for children with progressive or acquired neuromuscular disease will depend upon the progression of their disease. Typical examination findings in children at increased risk for pulmonary disease are a weak cough, decreased air exchange, crackles, wheezing, and dullness to percussion. The child also may have symptoms of obstructive sleep apnea and decreased lung function by spirometry and/or lung volume analysis. Signs of cor pulmonale (loud pulmonary component to the second heart sound, hepatomegaly, and elevated neck veins) may be evident in advanced cases. Chest radiographs generally show small lung volumes. If chronic aspiration is present, increased interstitial infiltrates and areas of atelectasis or consolidation may be present. Arterial blood gases demonstrate hypoxemia in the early stages and compensated respiratory acidosis in the late stages. Typical pulmonary function abnormalities include low lung volumes and decreased inspiratory force generated against an occluded airway.

Treatment is supportive and includes vigorous pulmonary toilet, antibiotics with infection, and oxygen to correct hypoxemia. Consideration of bilevel positive airway pressure and mechanical airway clearance support, like mechanical inexsufflation, should be introduced before respiratory failure is present. Unfortunately, despite aggressive medical therapy, many neuromuscular conditions progress to respiratory failure and death. The decision to intubate and ventilate is a difficult one; it should be made only when there is real hope that deterioration, though acute, is potentially reversible or when chronic ventilation is wanted. Chronic mechanical ventilation using either noninvasive or invasive techniques is being used more frequently in patients with chronic respiratory insufficiency.

Danov Z: Respiratory management of pediatric patients with neuromuscular disease. Pediatr Ann 2010;39(12):769–776 [PMID: 21162485].

Panitch HB: The pathophysiology of respiratory impairment in pediatric neuromuscular diseases. Pediatric 2009;123(Suppl 4): S215–S218 [PMID: 19420146].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Respiratory distress in a newborn.

 Recurrent pneumonia.

 Persistent elevation of the diaphragm by chest x-ray.

Eventration of the diaphragm occurs when striated muscle is replaced with connective tissue and is demonstrated on radiograph by elevation of a part or whole of the diaphragm. There are two types: congenital and acquired. The congenital type is thought to represent incomplete formation of the diaphragm in utero. The acquired type is related to atrophy of diaphragm muscles secondary to prenatal or postnatal phrenic nerve injury. The differential diagnosis of eventration includes phrenic nerve injury and partial diaphragmatic hernia.

 Clinical Findings

A. Symptoms and Signs

The degree of respiratory distress depends on the amount of paradoxical motion of the diaphragm. When the diaphragm moves upward during inspiration, instability of the inferior border of the chest wall increases the work of breathing and can lead to respiratory muscle fatigue and potential failure when stressed. Symptoms include persistent increased work of breathing, particularly with feeding or failure to extubate.

B. Laboratory Findings and Imaging Studies

Small eventrations may be an incidental finding on a chest radiograph, commonly seen on the right side. Ultra-sound provides useful information to further define a suspected eventration. When defects are small, there is no paradoxical movement of the diaphragm and little symptomatology. When defects are large, paradoxical movement of the diaphragm may be present.

 Treatment

Treatment is based on severity of symptoms. If symptoms persist for 2–4 weeks, the diaphragm is surgically plicated, which stabilizes it. Function returns to the diaphragm in about 50% of cases of phrenic nerve injury whether or not plication was performed. Recovery periods of up to 100 days have been reported in these cases.

Clements BS: Congenital malformations of the lungs and airways. In Taussig LM, Landau LI (eds): Pediatric Respiratory Medicine. Mosby; 1999.

Eren S et al: Congenital diaphragmatic eventration as a cause of anterior mediastinal mass in children: imaging modalities and literature review. Eur J Radiol 2004;51:85 [PMID: 15186890].

DISORDERS OF THE PLEURA & PLEURAL CAVITY

The parietal pleura covers the inner surface of the chest wall. The visceral pleura covers the outer surface of the lungs. Disease processes can lead to accumulation of air or fluid or both in the pleural space. Pleural effusions are classified as transudates or exudates. Transudates occur when there is imbalance between hydrostatic and oncotic pressure, so that fluid filtration exceeds reabsorption (eg, congestive heart failure). Exudates form as a result of inflammation of the pleural surface leading to increased capillary permeability (eg, parapneumonic effusions). Other pleural effusions include chylothorax and hemothorax.

Thoracentesis is helpful in characterizing the fluid and providing definitive diagnosis. Recovered fluid is considered an exudate (as opposed to a transudate) if any of the following are found: a pleural fluid–serum protein ratio greater than 0.5, a pleural fluid–serum lactate dehydrogenase ratio greater than 0.6, or a pleural fluid lactate dehydrogenase level greater than 200 U/L. Important additional studies on pleural fluid include cell count; pH and glucose; Gram stain, acid-fast and fungal stains; aerobic and anaerobic cultures; counterimmunoelectrophoresis for specific organisms; and occasionally, amylase concentration. Cytologic examination of pleural fluid should be performed to rule out leukemia or other neoplasm.

Hilliard TN et al: Management of parapneumonic effusion and empyema. Arch Dis Child 2003;88:915 [PMID: 14500314].

Accumulation of blood in the pleural space can be caused by surgical or accidental trauma, coagulation defects, and pleural or pulmonary tumors. A parapneumonic effusion is defined as a hemothorax when the hematocrit of the fluid is more than 50% of the peripheral blood. With blunt trauma, hemopneumothorax may be present. Symptoms are related to blood loss and compression of underlying lung parenchyma. There is some risk of secondary infection, resulting in empyema.

 Treatment

Drainage of a hemothorax is required when significant compromise of pulmonary function is present, as with hemopneumothorax. In uncomplicated cases, observation is indicated because blood is readily absorbed spontaneously from the pleural space.

VATS has been used successfully in the management of hemothorax. Chest CT scan is helpful to select patients who may require surgery, as identification of blood and the volume of blood may be more predictive by this method than by chest radiograph.

Muzumdar H, Arens R: Pleural fluid. Pediatr Rev 2007; 28(12):462–464 [PMID: 18055645].

Accumulation of chyle, fluid of intestinal origin containing fat digestion products (mostly lipids), in the pleural space usually results from accidental or surgical trauma to the thoracic duct. The most common cause of a pleural effusion in the first few days of life is a chylothorax. In a newborn, chylothorax can be due to congenital abnormalities of the lymph vessels or secondary to birth trauma. In an older child, chylothoracies can be due to: laceration or obstruction of the thoracic duct due to trauma or any surgery involving the chest wall (cardiac surgery, scoliosis repair etc); obstruction of the vessels due to a benign or malignant mass or lymphadenopathy; or increased venous pressure due to obstruction or left ventricular failure. Symptoms of chylothorax are related to the amount of fluid accumulation and the degree of compromise of underlying pulmonary parenchyma. Thoracentesis reveals typical milky fluid (unless the patient has been fasting) containing chiefly T lymphocytes.

 Treatment

Treatment should be conservative because many chylothoraces resolve spontaneously. Oral feedings with medium-chain triglycerides reduce lymphatic flow through the thoracic duct. Recent literature has shown somatostatin or the long-acting somatostain analogue, octreotide, as viable therapeutic options. Drainage of chylous effusions should be performed only for respiratory compromised because the fluid often rapidly reaccumulates. Repeated or continuous drainage may lead to protein malnutrition and T-cell depletion, rendering the patient relatively immunocompromised. If reaccumulation of fluid persists, surgical ligation of the thoracic duct or sclerosis of the pleural space can be attempted, although the results may be less than satisfactory.

Helin RD, Angeles ST, Bhat R: Octreotide therapy for chylothorax in infants and children: a brief review. Pediatr Crit Care Med 2006 Nov;7(6):576–579 [PMID: 16878051].

Soto-Martinez M, Massie J: Chylothorax: diagnosis and management in children. Paediatr Respir Rev 2009;10(4):199–207 [PMID: 19879510].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Sudden onset shortness of breath.

 Focal area of absent breath sounds on chest auscultation.

 Shift of the trachea away from the area with absent breath sounds.

Pneumothorax can occur spontaneously in newborns and in older children, or more commonly, as a result of birth trauma, positive pressure ventilation, underlying obstructive or restrictive lung disease, or rupture of a congenital or acquired lung cyst. Pneumothorax can also occur as an acute complication of tracheostomy. Air usually dissects from the alveolar spaces into the interstitial spaces of the lung. Migration to the visceral pleura ultimately leads to rupture into the pleural space. Associated conditions include pneumomediastinum, pneumopericardium, pneumoperitoneum, and subcutaneous emphysema. These conditions are more commonly associated with dissection of air into the interstitial spaces of the lung with retrograde dissection along the bronchovascular bundles toward the hilum.

 Clinical Findings

A. Symptoms and Signs

The clinical spectrum can vary from asymptomatic to severe respiratory distress. Associated symptoms include cyanosis, chest pain, and dyspnea. Physical examination may reveal decreased breath sounds and hyperresonance to percussion on the affected side with tracheal deviation to the opposite side. When pneumothorax is under tension, cardiac function may be compromised, resulting in hypotension or narrowing of the pulse pressure. Pneumopericardium is a life-threatening condition that presents with muffled heart tones and shock. Pneumomediastinum rarely causes other than chest pain symptoms by itself.

B. Diagnostic Studies

Chest radiographs usually demonstrate the presence of free air in the pleural space. If the pneumothorax is large and under tension, compressive atelectasis of the underlying lung and shift of the mediastinum to the opposite side may be demonstrated. Cross-table lateral and lateral decubitus radiographs can aid in the diagnosis of free air. Pneumopericardium is identified by the presence of air completely surrounding the heart, whereas in patients with pneumomediastinum, the heart and mediastinal structures may be outlined with air, but the air does not involve the diaphragmatic cardiac border. Chest CT scan may be helpful with recurrent spontaneous pneumothoraces to look for subtle pulmonary disease not seen on chest radiograph, but this is debated.

 Differential Diagnosis

Acute deterioration of a patient on a ventilator can be caused by tension pneumothorax, obstruction or dislodgment of the endotracheal tube, or ventilator failure. Radiographically, pneumothorax must be distinguished from diaphragmatic hernia, lung cysts, congenital lobar emphysema, and cystic adenomatoid malformation, but this task is usually not difficult.

 Treatment

Small (< 15%) or asymptomatic pneumothoraces usually do not require treatment and can be managed with close observation. Larger or symptomatic pneumothoraces require drainage, although inhalation of 100% oxygen to wash out blood nitrogen can be tried. Needle aspiration should be used to relieve tension acutely, followed by chest tube or pigtail catheter placement. Pneumopericardium requires immediate identification, and if clinically symptomatic, needle aspiration to prevent death, followed by pericardial tube placement.

 Prognosis

In older patients with spontaneous pneumothorax, recurrences are common; sclerosing and surgical procedures are often required.

Baumann MH et al: Management of spontaneous pneumothorax: an American College of Chest Physicians Delphi Consensus Statement. ACCP Pneumothorax Consensus Group. Chest 2001;119:590 [PMID: 11171742].

Johnson NN, Toledo A, Endom EE: Pnuemothorax, pneumomediastinum, and pulmonary embolism. Pediatri Clin North Am 2010;57(6):1357–1383 [PMID: 21111122].

MEDIASTINUM

Children with mediastinal masses may present because of symptoms produced by pressure on the esophagus, airways, nerves, or vessels within the mediastinum, or the masses may be discovered on a routine chest radiograph. Once the mass is identified, localization to one of four mediastinal compartments aids in the differential diagnosis. The superior mediastinum is the area above the pericardium that is bordered inferiorly by an imaginary line from the manubrium to the fourth thoracic vertebra. The anterior mediastinum is bordered by the sternum anteriorly and the pericardium posteriorly, and the posterior mediastinum is defined by the pericardium and diaphragm anteriorly and the lower eight thoracic vertebrae posteriorly. The middle mediastinum is surrounded by these three compartments.

 Clinical Findings

A. Symptoms and Signs

Respiratory symptoms, when present, are due to pressure on an airway (cough or wheezing) or an infection (unresolving pneumonia in one area of lung). Hemoptysis can also occur but is an unusual presenting symptom. Dysphagia may occur secondary to compression of the esophagus. Pressure on the recurrent laryngeal nerve can cause hoarseness due to paralysis of the left vocal cord. Superior vena caval syndrome presents with dilation of neck vessels and other signs and symptoms of venous obstruction from the head and neck: superior mediastinal syndrome presents similarly but includes tracheal compression.

B. Laboratory Findings and Imaging

The mass is initially defined by frontal and lateral chest radiographs together with thoracic CT scans or MRI. A barium esophagram may also help define the extent of a mass. Other studies that may be required include angiography (to define the blood supply to large tumors), electrocardiography, echocardiography, ultrasound of the thorax, fungal and mycobacterial skin tests, and urinary catecholamine assays. MRI or myelography may be necessary in children suspected of having a neurogenic tumor in the posterior mediastinum. Mediastinal masses, particularly anterior masses, can cause life-threatening airway compromise during sedation even in patients with mild symptoms; thus, any sedation or anesthesia should be avoided if possible and performed cautiously if absolutely necessary.

 Differential Diagnosis

The differential diagnosis of mediastinal masses is determined by their location. Within the superior mediastinum, one may find cystic hygromas, vascular or neurogenic tumors, thymic masses, teratomas, intrathoracic thyroid tissue, mediastinal abscess, and esophageal lesions. Within the anterior mediastinum, thymic tissue (thymomas, hyperplasia, cysts and intrathoracic thyroid) and teratomas, vascular tumors, and lymphatic tissue (lymphomas, leukemia, or reactive lymphadenopathy) give rise to masses. Within the middle mediastinum one may again find lymphomas and hypertrophic lymph nodes, granulomas, bronchogenic or enterogenous cysts, metastases, and pericardial cysts. Abnormalities of the great vessels and aortic aneurysms may also present as masses in this compartment. Within the posterior mediastinum, neurogenic tumors, enterogenous cysts, thoracic meningoceles, or aortic aneurysms may be present.

In some series, more than 50% of mediastinal tumors occur in the posterior mediastinum and are mainly neurogenic tumors or enterogenous cysts. Most neurogenic tumors in children younger than age 4 years are malignant (neuroblastoma or neuroganglioblastoma), whereas a benign ganglioneuroma is the most common histologic type in older children. In the middle and anterior mediastinum, lymphoma and leukemia are the primary concern. Definitive diagnosis in most instances relies on surgery to obtain the mass or a part of the mass for histologic examination.

 Treatment & Prognosis

The appropriate therapy and the response to therapy depend on the cause of the mediastinal mass.

Franco A et al: Imaging evaluation of pediatric mediastinal masses. Radiol Clin North Am 2005;43:325 [PMID: 15737372].

Garey CL et al: Management of anterior mediastinal masses in children. Eur J Pediatr Surg 2011 July 12 (e-published).

SLEEP-DISORDERED BREATHING

Sleep apnea is recognized as a major public health problem in adults, with the risk of excessive daytime sleepiness, driving accidents, poor work performance, and effects on mental health. Pediatric sleep disorders are less commonly recognized because of a lack of training in sleep problem recognition and the presentation, risks, and outcome all differ from those in adults. The spectrum of sleep-disordered breathing includes obstructive sleep apnea, upper airway resistance disorder, and primary snoring. Sleep apnea is defined as cessation of breathing and can be classified as obstructive (the attempt to breathe through an obstructed airway) or central (the lack of effort to breathe). Snoring, mouth breathing, and upper airway obstruction are discussed in Chapter 18.

 Clinical Findings and Differential Diagnosis

Obstructive sleep apnea (OSA) occurs in normal children with an incidence of about 2%, increasing in children with craniofacial abnormalities, neuropathies, or other medical problems. The incidence also increases when children are medicated with hypnotics, sedatives, or anticonvulsants. While not all children who snore have sleep apnea, there is evidence that that snoring without gas exchange abnormalities has neurobehavioral consequences. Obstructive sleep apnea should be suspected whenever a child presents with frequent or habitual snoring, witnessed apnea, labored breathing, frequent nighttime arousals, failure to thrive, oxygen desaturations, life-threatening events, behavior abnormalities, obesity, or craniofacial abnormalities. Upper airway resistance syndrome is characterized by daytime fatigue or sleepiness in the presence of a snoring without gas exchange abnormalities on the polysomnogram. Symptoms are similar to obstructive sleep apnea, including snoring, change in appetite, poor performance in school, and problems with behavior. This chronic flow limitation often improves with treatment. In children, airway obstruction is often associated with adenotonsillar hypertrophy. Tonsillar hypertrophy is most common between the ages of two and seven years. Obesity is widely recognized as an etiologic component in adult OSA and has been similarly cited in children. In children, consequences of sleep apnea include failure to thrive, pulmonary hypertension, deficits of cognition, poor school performance, and psychiatric or behavioral problems. Central apneas are seen in infants and children. These are pauses in breathing without concomitant effort. Clinical significance is uncertain, but they may be relevant if they occur frequently or gas exchange problems or sleep fragmentation occur. Healthy children have been shown to have central apneas lasting 25 seconds without clear consequences. In comparison, central hypoventilation syndrome patients have intact voluntary control of ventilation, but lack automatic control. During sleep, they will hypoventilate to the point at which they need ventilatory support that may require treatment with positive airway pressure and a rated tidal volume via a noninvasive mask or tracheostomy. Central hypoventilation may occur with low tidal volume breathing and not discreet central apneas, and requires treatment of gas exchange problems.

 Diagnostic Studies

Several studies have shown that clinical history and physical examination alone are not enough to identify children with OSA and that polysomnography should be performed in all suspected cases. This test measures sleep state with electroencephalogram leads and electromyography, airflow at the nose, chest and abdominal muscle movement, heart rate and rhythm, gas exchange (CO₂ and oxygenation), and leg movements, along with other potential data including body position, vibrations representing snoring, and esophageal pH/impedence. Polysomnography allows diagnosis of various forms of apnea, sleep fragmentation, periodic limb movement disorder, or other sleep disorders of children. Overnight oximetry is not an ideal study to diagnose obstructive sleep apnea. While it may identify subjects with severe obstructive sleep apnea, its sensitivity is low. Literature has shown normal oximetry studies in half a population of subjects with polysomnographically confirmed obstructive sleep apnea.

 Treatment

First-line therapy for obstructive sleep apnea in children is adenotonsillectomy, which improves the clinical status for most children with normal craniofacial structure. Even children with craniofacial anomalies or neuromuscular disorders may benefit, although additional treatment with continuous positive airway pressure may be indicated (Roland et al: S1–15). Down syndrome presents unique challenges: up to half of these children can still have obstructive sleep apnea despite adenotonsillectomy. Treatment of young or developmentally delayed children with apnea also presents several challenges. (See Chapter 18 for additional discussion.) Other therapies, such as, nasal steroids, leukotriene modifiers (Goldbart et al: 364–370), oral appliances, rapid maxillary expanders, and weight loss have their roles in select patient populations.

Because the presentation of sleep apnea is quite varied among children, pediatric sleep disorder centers are the referral of choice for testing and initiation of therapy.

Aurora RN et al: American Academy of Sleep Medicine. Practice parameters for the respiratory indications for polysomnography in children. Sleep 2011 Mar 1;34(3):379–388 [PMID: 21359087].

Capdevila OS et al: Pediatric obstructive sleep apnea: complications, management, and long-term outcomes. Proc Am Thorac Soc 2008;5(2):274–282 [PMID: 18250221].

Goldbart AD, Greenberg-Dotan S, Tal A. Monteleukast for children with obstructive sleep apnea: a double-blind placebo-controlled study. Pediatrics 2012;130(3):e575-580 [PMID: 22869829].

Owens JA: Neurocognitive and behavioral impact of sleep disordered breathing in children. Pediatr Pulmonol 2009 May;44(5):417–422 [PMID: 19382210].

Roland PS et al: Clinical practice guideline: polysomnography for sleep-disordered breathing prior to tonsillectomy in children. Otolarnygol Head Neck Surg. 2011;145(1 Suppl):S1-15 [PMID: 21676944].

Sateia MJ (ed): The International Classification of Sleep Disorders, 2nd ed. American Academy of Sleep Medicine; 2005.

APPARENT LIFE-THREATENING EVENTS

Apparent life-threatening events (ALTEs) are characterized as being frightening to the observer and commonly include some combination of apnea, color change (usually cyanosis or pallor), a marked change in muscle tone (usually extreme limpness), choking, or gagging. The observer sometimes fears the infant has died. The most frequent problems associated with an ALTE are gastrointestinal (~50%), neurologic (30%), respiratory (20%), cardiovascular (5%), metabolic and endocrine (< 5%), or diverse other problems, including child abuse. Up to 50% of ALTEs remain unexplained and are referred to as apnea of infancy. The relationship between ALTE and future risk of sudden infant death syndrome (SIDS) is not clear, as ALTE infants tend to be slightly younger and found more often while the caretaker is awake. The term apparent life-threatening event replaced “near-miss SIDS” in order to distance the event from a direct association with SIDS. Literature has reported an increased risk when extreme cardiopulmonary events were present at the time of the ALTE. About 12%–15% of both SIDS victims and infants dying unexpectedly of a known cause (SUDI) have had a prior history of ALTE, but most do not.

The mechanism for ALTEs is unknown, but because they do not occur after infancy, immaturity is felt to play a major role. Classic studies on the nervous system, reflexes, or responses to apnea or gastroesophageal reflux during sleep in infants and immature animals show profound cardiovascular changes during stimulation of the vagus nerve where adults would not be affected. More recently, an association of endogenous opioids and opioid-induced respiratory depression has been implicated as an association with ALTE in infants, and is an area of exciting research. The following section describes an approach to the patient who has undergone an ALTE, taking note of the very broad differential diagnosis and uncertainties in both evaluation and treatment.

 Clinical Findings and Differential Diagnosis

A. Symptoms and Signs

Table 19–6 classifies disorders associated with ALTEs. As seen from the outset, the causes of ALTEs are multifactorial, but it is the response to the trigger that creates a symptom cluster unique to infants. A careful history is often the most helpful part of the evaluation. In a large epidemiological study of infants who later died of SIDS or SUDI, a careful history using a “baby check” score was useful in identifying infants who were seriously ill. It is useful to determine whether the infant has been ill or essentially well. A history of several days of poor feeding, temperature instability, or respiratory or gastrointestinal symptoms suggests an infectious process. Reports of “struggling to breathe” or “trying to breathe” imply airway obstruction. Association of the episodes with feeding implies discoordinated swallowing, gastroesophageal reflux, or delayed gastric emptying, or may imply an airway abnormality, but these awake episodes may lead to very different diagnoses than those episodes occurring during sleep. Episodes that typically follow crying may be related to breath-holding. Association of episodes with sleeping may also suggest seizure, gastroesophageal reflux, apnea of infancy, or sleep-disordered breathing. Attempts should be made to determine the duration of the episode, but this is often difficult. It is helpful to role-play the episode with the family. Details regarding the measures taken to resuscitate the infant and the infant’s recovery from the episode may be useful in determining severity.

The physical examination provides further direction in pursuing the diagnosis. Fever or hypothermia suggests infection. An altered state of consciousness implies a postictal state or drug overdose. Respiratory distress implies cardiac or pulmonary lesions.

Apneic episodes have been linked to child abuse in several ways. Head injury following nonaccidental trauma may be first brought to medical attention because of apnea. Other signs of abuse are usually immediately apparent in such cases. Drug overdose, either accidental or intentional, may also present with apnea. Several series document that apneic episodes may be falsely reported by parents seeking attention (ie, Munchausen syndrome by proxy). Parents may physically interfere with a child’s respiratory efforts, in which case pinch marks on the nares are sometimes found.

B. Laboratory Findings

Most patients are hospitalized for observation in order to reduce stress on the family and allow prompt completion of the evaluation. Laboratory evaluation includes a complete blood count for evidence of infection. Diagnostic testing should be based very heavily on the history and physical examination. Laboratory evaluation might include a complete blood count, blood culture with urinalysis and urine culture for evidence of infection, especially in the face of fever, hypothermia, or an abnormal physical examination. Serum electrolytes might be considered as elevations in serum bicarbonate suggest chronic hypoventilation, whereas decreases suggest acute acidosis, perhaps due to hypoxia during the episode. Chronic acidosis suggests an inherited metabolic disorder. Arterial blood gas studies provide an initial assessment of oxygenation and acid-base status, and low Pao₂ or elevated PaCO₂ (or both) implies cardiorespiratory disease. A significant base deficit suggests that the episode was accompanied by hypoxia or circulatory impairment. Oxygen saturation measurements in the hospital assess oxygenation status during different activities and are more comprehensive than a single blood gas sample. Because apnea has been associated with respiratory infections, diagnostic studies for RSV and other viruses, pertussis, and Chlamydia may help with diagnosis. Apnea occurring with infection often precedes other physical findings.

C. Imaging Studies

The chest radiograph is examined for infiltrates suggesting acute infection or chronic aspiration and for cardiac size as a clue to intrinsic cardiac disease. If the episode might have involved airway obstruction, the airway should be examined either directly by fiberoptic bronchoscopy or radiographically by CT or barium swallow. Barium swallow is a useful tool to rule out the possibility of anatomic abnormalities such as vascular ring and tracheoesophageal fistula. Esophageal pH monitoring is only helpful if the infant has sufficiently acidified the stomach, and can underestimate the degree of reflux for nonacid events. Impedence monitors improve this interpretation. Gastroesophageal reflux is one of the most common findings in infants with ALTE; however, it may be a marker of autonomic immaturity as opposed to a diagnosis for the event. Most infants with reflux and apnea can be given medical antireflux treatment. Infants with reflux and repeated episodes of apnea may benefit from a surgical antireflux procedure.

D. Special Tests: Polysomnography and Other Studies

ALTEs occur in the same age group as infants who die of sudden death (2–4 months is the peak age). Sleep-disordered breathing has been implicated as a possible cause of ALTEs and perhaps sudden death. Depending on the discretion of the clinician in appropriate scenarios, polysomnograms can be useful to determine abnormalities of cardiorespiratory function, sleep state, oxygen saturation, CO₂ retention, and seizure activity. They can be used in conjunction with pH monitoring to determine the contribution of reflux to apnea. Esophageal pressure manometry can be useful to detect subtle changes in respiratory effort related to partial obstructive breathing (hypopnea). Infants may be at more risk of adverse events from sleep-disordered breathing due to their immature nervous system.

There are several neurologic causes of ALTEs, and seizure disorder has been found to be a cause of ALTE in a significant number of cases. Apnea as the sole manifestation of a seizure disorder is unusual but may occur. In cases of repeated episodes, 24-hour electroencephalographic monitoring may be helpful in detecting a seizure disorder.

 Treatment

Therapy is directed at the underlying cause if one is found. After blood cultures are taken, antibiotics should be given to infants who appear toxic. Seizure disorders are treated with anticonvulsants. Gastroesophageal reflux should be treated, but may not prevent future episodes of ALTE. Vascular rings and pulmonary slings must be corrected surgically because of severe morbidity and high mortality rates when untreated.

The approach to care of infants with ALTEs where no definable cause can be ascertained is controversial. Home monitoring has been used in the past as treatment, but the efficacy of monitoring has not been demonstrated in controlled trials. With more than 30 years of home monitoring, the sudden infant death rate did not change due to this intervention. Although monitors can detect central apnea or bradycardia, they do not predict which children will have future ALTEs, and they do not detect obstructive forms of breathing a common form of apnea in infants. Apnea monitors are prone to frequent false alarms, and it must be noted that many parents cannot handle the stress associated with having a monitor in the home. Parents should be taught cardiopulmonary resuscitation prior to discharge and should prevent modifiable risk factors for infant death discussed below. The decision to monitor these infants involves the participation of the family. Infants with severe initial episodes or repeated severe episodes are now thought to be at significantly increased risk. A monitor with an oxygen saturation detection capability may identify episodes earlier. The caregiver responsible for prescribing a monitor should have a plan for the data acquisition, and the discontinuation of the monitor so that the parents can be prepared. Oxygen has been used as therapy for ALTEs for several reasons. Oxygen reduces periodic breathing of infancy, an immature pattern of breathing that can cause some degree of oxygen desaturation. Second, infants have small chest capacities with increased chest wall compliance that reduces lung volume. Oxygen can increase the baseline saturation, reducing the severity of desaturation with short apneas. Respiratory stimulants such as caffeine and aminophylline have been used in specific cases of central apnea or periodic breathing.

Any infant younger than 1 year of age should be evaluated for the presence of modifiable SIDS risk factors by a caregiver. Parents should be educated on how to avoid these risk factors, especially in infants at increased risk such as former preterm infants, children exposed to cigarette smoke environmentally or prior to birth, African American or Native American infants, and infants in poor socioeconomic areas. Updates on recommendations for the prevention of unexpected death in infants was recently published by the American Academy of Pediatrics (SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment: 1030–1039) and especially applies to infants after an ALTE. The reference should be read in full, but new recommendations include:

• Always place a baby on its back to sleep (this includes a baby with reflux).

• A baby should always sleep in its own space such as a crib, bassinette, or pack & play. A baby should not sleep on an adult bed, couch, armchair, futon, or other soft surface. Use a firm mattress designed for the crib, bassinet, or pack & play with a tight fitting sheet. The mattress should be flat, not elevated, and with no soft bedding underneath or on top.

• Share a room, but not a bed, with a baby.

• There should be nothing in a baby’s sleep space, other than the baby. Avoid overheating, overwrapping, and covering the face and head; use appropriate baby sleep clothing or sleep sack.

• Breast-feeding a baby is recommended.

• Consider offering a pacifier to a baby at nap and sleep time.

• Avoid or limit a baby’s exposure to cigarette smoke.

• Car seats, swings, and baby slings should NOT be used for sleep.

• Avoid the use of adult beds, bed rails, and in-bed co-sleepers, which increase the risk of suffocation and entrapment.

SIDS is defined as the sudden death of an infant younger than age 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history. The postmortem examination is an important feature of the definition because approximately 20% of cases of sudden death can be explained by autopsy findings. The incidence of SIDS in the United States has declined to less than 1 in 1000 live births over the last 15 years; however, it has leveled off. Reduction of prone sleeping after the “Back to Sleep” campaign was in large part responsible for the reduction of SIDS from a high of 2 infants per 1000 births, but new evidence shows the increase of sudden unexpected deaths of infants (SUDI) due to accidental suffocation and unsafe sleep surfaces.

 Epidemiology and Pathogenesis

Epidemiologic and pathologic data constitute most of what is known about SIDS. The number of deaths peaks between ages 2 and 4 months. Most deaths occur between midnight and 8 AM, while the infant and often the caregiver are sleeping. In fact, the only unifying features of all SIDS cases are age and sleep. SIDS is more common among ethnic and racial minorities and socioeconomically disadvantaged populations. Racial disparity in the prevalence of prone positioning or especially in cosleeping (Fu, Moon, and Hauck: 376–382) may also be contributing to the continued disparity in SIDS rates between black and white infants. There is a 3:2 male predominance in most series. Other risk factors include low birth weight, teenage or drug-addicted mothers, multiparity, crowded living conditions, maternal smoking, and a family history of SIDS. Most of these risk factors are associated with a two- to threefold elevation of incidence but are not specific enough to be useful in predicting which infants will die unexpectedly. Recent immunization is not a risk factor.

The most consistent pathologic findings are intrathoracic petechiae and mild inflammation and congestion of the respiratory tract. More subtle pathologic findings include brainstem gliosis, extramedullary hematopoiesis, and increases in peri-adrenal brown fat. These latter findings suggest that infants who succumb to SIDS have had intermittent or chronic hypoxia before death.

The mechanism or mechanisms of death in SIDS are unknown. For example, it is unknown whether the initiating event at the time of death is cessation of breathing, cardiac arrhythmia, or asystole. Hypotheses have included upper airway obstruction, catecholamine excess, and increased fetal hemoglobin. However, maldevelopment or delay in maturation of the brainstem, which is responsible for arousal, remains the predominant theory. A history of mild symptoms of upper respiratory infection before death is not uncommon, and SIDS victims are sometimes seen by physicians a day or so before death. The postmortem examination is essential for the diagnosis of SIDS and may help the family by excluding other possible causes of death. A death scene investigation is also important in determining the cause of sudden unexpected deaths in infancy.

Families must be supported following the death of an infant. The National SIDS Resource Center (http://www.sidscenter.org) provides information about psychosocial support groups and counseling for families of SIDS victims.

 Prevention

Since 1990, SIDS rates have declined more than 60% worldwide. Population studies in New Zealand and Europe identified risk factors, which when changed had a major effect on the incidence of SIDS. Since 1994 the American Academy of Pediatrics’ “Back-to-Sleep” campaign has promoted education about SIDS risk factors in the United States. The new updated recommendations are printed above and are available on line (SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment: 1030–1039). Modifiable risk factors include sleeping position, bottle feeding, maternal smoking, and infant overheating. The prone sleep position could contribute to SIDS through decreased arousal or rebreathing of exhaled gases. The side position, often used in hospitals and then mimicked at home, increases risk of SIDS compared with the supine position. Maternal smoking, especially prenatal maternal smoking, increases the risk of SIDS. Investigations of tobacco effects on the autonomic nervous system of the developing fetus, pulmonary growth and function of the newborn, or its combination with viral infection all point to differences in SIDS compared with control subjects. New data demonstrates decreased risk of SIDS with the use of pacifiers and breast feeding.

The healthcare provider is instrumental in parental education regarding the modifiable risk factors for SIDS (Table 19–7). The healthcare provider should screen all infants for SIDS risk factors, and include awareness of the child care setting, as many parents rely on others to watch their children, where the importance of risk factors may not be recognized. Hospitals should set an example by placing infants in the supine position with no blankets in the bed prior to discharge. At present, the data shows that the environment is key to the safety of the infant, and unsafe sleep environments are responsible for the recent increase in accidental suffocation, asphyxia, and entrapment.

“Back-to-sleep” (supine sleeping position)

Firm sleep surface designed for infant sleep

Pillows/loose bedding, loose blankets should be out of the crib

Share a room, not a bed with the infant

Do not smoke during pregnancy, and smoke-free environment after birth

Consider offering a pacifier at nap and bed time

Avoid overheating, overwrapping, and head covering

Avoid commercial devices marketed to reduce the risk of SIDS

Do not use home monitors as a strategy to reduce the risk of SIDS

Encourage tummy time while awake

American Academy of Pediatrics: SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics 2011;128(5):1030–1039 [PMID: 22007004].

Aurora RN et al: Practice parameters for the respiratory indications for polysomnography in children. Sleep 2011;34(3): 379–388 [PMID: 21359087].

Fu LY, Moon LY, Hauck FR. Bed sharing among black infants and sudden death syndrome: interactions with other known risk factors. Acad Pediatr 2010;10(6):376-382 [PMID: 21075317].

Platt MW et al: A clinical comparison of SIDS and explained sudden infant deaths: how healthy and how normal? CESDI SUDI Research Group. Confidential Inquiry into Stillbirths and Deaths in Infancy study. Arch Dis Child 2000;82(2):98–106 [PMID: 10648361].