Chapter 47 Pneumonitis and Interstitial Disease

Jeffrey C. Benson, Daiva Parakininkas, Tom B. Rice

• Most pediatric pulmonary parenchymal disease occurs as the result of an infectious agent.

• Clinical evaluation for parenchymal lung disease in the pediatric patient should include a search for symptoms and signs associated with pulmonary disease, such as difficulty with feeding, exercise intolerance, chest pain, cough, tachypnea, dyspnea, cyanosis, orthopnea, clubbing of the nail beds, weight loss, and lethargy.

• Factors predisposing a child to bacterial pneumonia include having numerous siblings, having parents who smoke, preterm delivery, living in an urban environment, poor socioeconomic status, presence of an airway foreign body, impaired immune response, congenital and anatomic lung defects, abnormalities of the tracheobronchial tree, cystic fibrosis, and congestive heart failure.

• Viral agents are the leading cause of lower respiratory tract infection in infants and children.

• Three major clinical syndromes are associated with lower respiratory tract viral illness are (1) bronchitis, (2) bronchiolitis, and (3) pneumonia.

• Fungal infections are important in the differential diagnosis of pulmonary infections, particularly in children whose immunity is compromised and in healthy children who are exposed to pathogens in a particular geographic or environmental setting.

• Three forms of disease patterns in pneumocystosis are (1) childhood/adult, (2) infantile, and (3) chronic fibrosing observed in some patients infected with the human immunodeficiency virus.

• Chemical pneumonitis and/or pneumonia may be acquired by (1) aspiration, (2) inhalation, (3) ingestion, or (4) injection.

• Pulmonary hemorrhage is a potentially life-threatening event that can occur at any age. Clinical presentation varies from massive fatal hemoptysis to silent bleeding with respiratory distress and anemia.

Pneumonitis, or inflammation of the lung parenchyma, is perhaps the most common cause of life-threatening lower respiratory tract disease in pediatric patients. Although pneumonitis may result from noninfectious processes (Box 47-1), most pediatric pulmonary parenchymal disease occurs as the result of an infectious agent. Pneumonitis may involve the pleura, interstitium, and airways; pneumonia by definition must include alveolar consolidation. Whereas early parenchymal lung injury is associated with increased cellularity with minimal fibrosis, advanced disease is characterized by extensive fibrosis and destruction of gas exchange units. Physiologic changes may include the following: low lung volumes, diminished lung compliance, impaired gas exchange, and airflow limitation. This chapter addresses the principal potential causes of pediatric pulmonary parenchymal disease, including alveolar and interstitial disorders.

Box 47–1 Etiology of Pediatric Interstitial Lung Disease

Infectious

Pathophysiology

Changes in lung volumes in pulmonary parenchymal disease depend primarily on the intensity of the alveolitis and stage of the disease process. Acute severe pneumonitis with an intense alveolitis is characterized by moderate to severe reduction in both vital capacity (VC) and total lung capacity. It also is associated with a reduction in pulmonary compliance. In the early stages, patients with chronic interstitial diseases involving the lung parenchyma often have normal VC and total lung capacity. Subsequent reduction in lung volumes and pulmonary compliance occurs as the disease progresses and pulmonary fibrosis ensues.¹ Expiratory flow rates usually are preserved in persons with pneumonitis involving the lung parenchyma, and major obstructive defects, although reported, are rare. The carbon monoxide diffusing capacity, one of the earliest and most sensitive tests of parenchymal inflammation, is diminished in persons with interstitial lung disease (ILD). A reduction in the carbon monoxide diffusing capacity is not specific and may be found with other parenchymal disorders. Early in the course of parenchymal disease, resting arterial oxygen tension may be normal, but there is often mild alveolar hyperventilation with reduction in alveolar carbon dioxide tension and widening of the alveolar-arterial oxygen gradients (PAO₂ – PaO₂). With exercise, hypoxemia and an increased PAO₂ – PaO₂ become exaggerated because of ventilation/perfusion (V/Q) imbalance. V/Q mismatch is attributed to regional alterations of flow, altered parenchymal compliance, and increased obstruction to pulmonary airflow. Progressive alveolitis and subsequent derangement of gas exchange lead to deterioration of ventilatory efficiency and markedly increased work of breathing. Adequate oxygenation may become impossible even with the use of high-flow supplemental oxygen. Resting hypercapnia, pulmonary hypertension, and eventual right ventricular dysfunction with heart failure are common sequelae.²^–⁴

Diagnosis

Diagnosing parenchymal lung disease in the pediatric patient may be quite challenging because of extreme variability in the presentation of disease. Clinical evaluation of the child should include a search for symptoms and signs associated with pulmonary disease, such as difficulty with feeding, exercise intolerance, chest pain, cough, tachypnea, dyspnea, cyanosis, orthopnea, clubbing of the nail beds, weight loss, and lethargy. In the child with diffuse alveolar disease, auscultative findings may be normal unless significant consolidation or small airway involvement is present. Fine crackles that may be heard throughout the chest late in inspiration are a characteristic finding of small airway disease. These rales are produced by the opening of occluded small peripheral airways.

Laboratory Diagnosis

The chest radiograph is critical in the diagnosis and management of pulmonary parenchymal disease. In children with ILD the classic radiographic features that are present in adults may be absent. Computed tomography scanning,⁵^–⁷ gallium lung scanning, and bronchoalveolar lavage (BAL)⁸^–¹⁰ are useful techniques in the diagnosis and management of diseases involving the lung parenchyma. Pulmonary function testing is important and usually can be performed reliably in children who are older than 4 years.^1,¹¹

Bacterial Pneumonitis

Bacterial infections of the lower respiratory tract continue to account for a significant number of hospital admissions. The frequency of bacteria as etiologic agents of lower respiratory tract infection varies from 10% to 50%, depending on the study population and the methods of evaluation used.^12,¹³ In a large study of pediatric patients with lower respiratory tract infection, an etiologic agent was identified in nearly 50% of the patients. Bacteria accounted for 10% to 15% of the causative agents identified.

Factors predisposing to bacterial pneumonia include having numerous siblings, having parents who smoke, preterm delivery, living in an urban environment, and poor socioeconomic status. Hospitalization also increases the risk of contracting bacterial pneumonia because of the clustering of ill patients in confined areas, administration of immunosuppressive therapy, and various medical and surgical interventions that enhance the opportunity for colonization and infection. Additional factors that increase susceptibility to bacterial pneumonia include the presence of an airway foreign body,¹⁴ impaired immune response,¹⁵^–¹⁹ congenital and anatomic lung defects, abnormalities of the tracheobronchial tree, cystic fibrosis,²⁰ and congestive heart failure.

Definition

Bacterial pneumonia is an inflammatory process of the lungs that may involve interstitial tissue and pleura in its evolution but always progresses to alveolar consolidation.

Pathophysiology

Pneumonia occurs when pulmonary defense mechanisms are disrupted and bacteria invade the respiratory system by aspiration or hematogenous spread. In most instances pneumonia appears to be a consequence of aspiration of a high inoculum of pathogenic bacteria. Viruses often are responsible for enhancing the susceptibility of the respiratory tract to bacterial infection. Less frequently, bacterial pneumonia may be the result of defects in host immunity because of young age, underlying immune dysfunction, or immunosuppressive therapy. Pneumonia also may occur when host defenses are mechanically disrupted because of tracheostomy or endotracheal intubation. The presence of respiratory pathogens in the terminal bronchioles and alveoli induces an outpouring of edema fluid and large numbers of leukocytes into the alveoli.^2,²¹ Macrophages subsequently remove cellular and bacterial debris. The infectious process may extend further within the lung segment, or it may disseminate through infected bronchial fluid to other areas of the lung. The pulmonary lymphatic system enables bacteria to reach the bloodstream or visceral pleura.

With consolidation of lung tissue, VC and lung compliance markedly decrease and intrapulmonary right-to-left shunt and V/Q mismatch occur, resulting in hypoxia. Subsequently, pulmonary hypertension may occur because of significant oxygen desaturation and hypercapnia, often leading to cardiac overload.

Clinical Features

Signs and symptoms of bacterial pneumonia vary with the individual pathogen, the age and immunologic condition of the patient, and the severity of the illness. Clinical manifestations, especially in newborns and infants, may be absent. General or nonspecific complaints include fever, chills, headache, irritability, and restlessness. Individual patients may have gastrointestinal complaints including nausea, vomiting, diarrhea, abdominal distension, or pain. Specific pulmonary signs include nasal flaring, retractions, tachypnea, dyspnea, and occasionally apnea.

Tachypnea is the most sensitive index of disease severity. The sleeping respiratory rate is often a valuable guide to diagnosis. On auscultation, diminished breath sounds are frequently noted. Fine crackles that may be heard in children and older patients are commonly absent in infants. Because of the relatively small size of the child’s thorax and the thin chest wall, broad transmission of the breath sounds occurs, and the classic findings of consolidation are often obscured. Pleural inflammation may be accompanied by chest pain at the site of inflammation. This pleuritic pain may cause “splinting,” which restricts chest wall movement during inspiration and reduces lung volume.

Extrapulmonary infections that may be present in some children include abscesses of the skin or soft tissue (Staphylococcus aureus); conjunctivitis, sinusitis, otitis media, and meningitis (Streptococcus pneumoniae or Haemophilus influenzae); and epiglottitis (H. influenzae).

Radiographic Features

Bacterial pneumonia typically is characterized by defined areas of consolidation with either segmental or lobar involvement. Lobar consolidation is the most characteristic, but multilobed disease is not unusual. The findings of pleural effusion, pneumatocele, or abscess are also strongly indicative of a bacterial infection. Staphylococcal pneumonia is suggested by rapid clinical and radiographic progression of disease, particularly in a young infant. Evidence of an abscess or pneumatocele further suggests a diagnosis of staphylococcal or gram-negative pneumonia such as Klebsiella. Group A streptococcal pneumonia may initially present with a diffuse interstitial pattern prior to the development of consolidation. Except for Pseudomonas, which may have a diffuse nodular appearance in the lower lobes, pneumonias caused by gram-negative organisms have no specific radiographic pattern. Anaerobic pulmonary infection is also associated with lung abscesses or air fluid levels.

Diagnosis

Bacterial pneumonia is suggested by fever, leukocytosis (>15,000 white blood cells), and increased band forms on the peripheral blood smear. Examination of the sputum may be helpful in establishing the diagnosis of bacterial pneumonia; however, it often is difficult to obtain a satisfactory sputum sample in pediatric patients unless transtracheal aspiration or bronchoscopy is used. Transtracheal aspiration, although useful in adolescents and adults, is associated with significant complications in infants and young children. If a sputum sample is obtained (an adequate specimen must have >25 polymorpho-nuclear cells and <25 epithelial cells per high-power field), the Gram stain should be examined for a predominant bacterial pathogen, and cultures should be performed with the appropriate antibiotic susceptibility studies. Counterimmune electrophoresis (CIE) performed on sputum specimens has proved helpful in establishing the diagnosis in both adults and children. Bacterial pneumonia is accompanied by bacteremia in a significant number of cases; hence blood cultures should be obtained prior to initiation of antibiotic therapy. Circulating antigens in S. pneumoniae and H. influenzae may be detected in the blood with CIE,²² polymerase chain reaction (PCR),²³^–²⁵ or latex agglutination.^26,²⁷

If a significant pleural effusion is present, a diagnostic thoracentesis should be performed for the purposes of Gram stain and culture. Culturing pleural fluid has a relatively high yield in patients who have not received previous antibiotic therapy. If the Gram stain of pleural fluid is negative, CIE or latex agglutination should be performed because bacterial antigen may be detected in the fluid even after the initiation of antibiotics.

BAL should be considered in the management of a severely ill child in order to make a prompt diagnosis.^9,¹⁰ Making a prompt diagnosis is essential for the patient with progressive disease that has responded poorly to initial therapy or for the child with underlying immunodeficiency for whom empirical antibiotic treatment may be hazardous. In such instances, if the BAL is nondiagnostic, then lung aspiration or biopsy should be considered.²⁸ Material may be obtained through closed-needle biopsy, percutaneous needle aspiration, or an open lung biopsy. Positive results for such procedures in carefully selected cases identify an etiologic agent in 30% to 75% of cases, with open lung biopsy having the highest yield.^18,²⁹

Specific Pathogens

Group B Streptococci

Group B streptococci can cause infection in people of any age; however, these organisms are common pathogens in infants younger than 3 months.³⁰ Early-onset illness often is associated with maternal fever at the time of delivery, prolonged rupture of membranes, amnionitis, prematurity, and low birth weight.

Infected neonates usually manifest clinical symptoms within the first 6 to 12 hours of life. Symptoms include fever, respiratory distress, apnea, tachypnea, and hypoxemia. By 12 to 24 hours of age, signs of cardiovascular collapse often are apparent. Frequently, the syndrome of pulmonary hypertension of the newborn is present, and pulmonary or intracranial hemorrhage may become the terminal event.

Isolation of the organism establishes the diagnosis. Cultures from blood and cerebrospinal fluids must be obtained in all instances of suspected group B streptococcal pneumonia. Rapid diagnostic techniques have been helpful in providing early diagnoses. The radiographic findings in neonates with group B streptococcal pneumonia can be either a lobar (40%) or a diffuse reticulonodular pattern with bronchograms similar to findings of respiratory distress syndrome.

Aggressive cardiovascular and ventilatory support is usually required, particularly in the early stages of the disease. Antibiotic therapy should include a combination of ampicillin or penicillin and an aminoglycoside agent.

Although in the past the mortality rate of patients with group B streptococcal pneumonia could be as high as 50% to 60%, recent studies suggest improvement with prompt initiation of therapy and even better outcomes with maternal prophylaxis.³¹ Some infants experience a second episode of infection 1 to 2 weeks after discontinuation of antibiotic therapy. Infants with group B streptococcal pneumonia and meningeal involvement (30%) may demonstrate significant neurologic deficits (20% to 50%).

Streptococcus Pneumoniae

S. pneumoniae is a gram-positive diplococcus with at least 84 sera types; however, 80% of the serious infections are caused by only 12 sera types. Streptococci are a major cause of pneumonia in the United States. Victims are usually infants younger than 2 years, with a peak age between 3 and 5 months. Patients with asplenia, functional hyposplenia, or malignancy or those receiving immunosuppressive drugs are at special risk of the development of invasive disease.³²

The radiographic finding in infants often is a patchy bronchopneumonia. Lobar consolidation is not uncommon. Penicillin is the drug of choice in the treatment of persons with streptococcal pneumonia. However, organisms relatively resistant to penicillin occur in 3% to 40% of culture-positive patients recorded in studies from different parts of the United States.³³ In such instances, pneumonias have been effectively treated with vancomycin or high-dose β-lactam cephalosporin agents such as cefuroxime, ceftriaxone, or cefotaxime. Disease resulting from penicillin-resistant pneumococci should be considered in patients who received therapy with β-lactam antibiotics.³³^–³⁵

The heptavalent pneumococcal conjugate vaccine is recommended for all children aged 2 to 23 months. It also is recommended for certain children aged 24 to 59 months. Pneumococcal polysaccharide vaccine is recommended in addition to pneumococcal conjugate vaccine for certain high-risk groups.³⁶

Haemophilus Influenzae

Haemophilus organisms are small, nonmotile, gram-negative rods that occur in both encapsulated and nonencapsulated forms. Approximately 90% to 95% of invasive disease is caused by the encapsulated sera type B. A pleural effusion or empyema is detected in nearly 40% of patients with H. influenzae pneumonia. There is an extremely high incidence of bacteremia in this disease. Serious complications such as epiglottitis, meningitis, and pericarditis can be diagnosed in 15% to 20% of patients. Cellulitis, anemia, and septic arthritis occur infrequently.

In a hospitalized patient, administration of the combination of ampicillin and chloramphenicol or a single cephalosporin such as cefuroxime, cefotaxime, or ceftriaxone generally is effective therapy.^33,³⁷ The mortality rate in appropriately treated patients is generally considered less than 5% and often is related to associated meningitis, epiglottitis, or pericarditis rather than the pneumonic process itself. Hib conjugate vaccine is an important measure in reducing the incidence of Haemophilus-related disease and should be administered to all children.^33,^38,³⁹

Staphylococcal Pneumonia

Primary S. aureus pneumonia has decreased in frequency in recent years but still accounts for approximately 25% of cases in young infants. The incidence of secondary or metastatic dissemination has increased since 1972. Patients with primary pneumonia present with fever and respiratory symptoms, whereas those with metastatic disease often present with fever, generalized toxicity, and musculoskeletal symptoms. In patients presenting with primary staphylococcal pneumonia, the disease often is preceded by an upper respiratory tract infection.^40,⁴¹ Pleural effusion or empyema develops in nearly 80% of the patients with primary staphylococcal pneumonia and is extremely common in patients with metastatic disease. It is not unusual for patients with staphylococcal pneumonia to remain bacteremic long after the initiation of appropriate antibiotic therapy.

Radiographic findings of S. aureus pneumonia differ according to the stage of disease. They vary from minimal changes to consolidation (most common) and are associated with pleural effusion (50% to 60%) or pneumothorax (21%). Pneumatoceles usually appear during the convalescent stage and may persist for prolonged periods in asymptomatic patients. Antibiotic therapy should be administered intravenously and include a drug that is resistant to inactivation. Strong consideration should be given to providing antibiotic coverage for methicillin-resistant S. aureus, which can account for 1% to 30% of isolates, depending on the prevalence in the area.⁴² The duration of therapy usually is lengthier in patients with staphylococcal disease than for patients with other bacterial pneumonias and consists of 21 days or more of treatment. The mortality rate of staphylococcal pneumonia varies from 23% to 33%. An increased incidence of mortality usually is associated with younger age, inappropriate initial antimicrobial therapy, or failure to drain an empyema appropriately.

Mycoplasma Pneumonia

Mycoplasma organisms are the smallest free-living microorganisms. They lack a cell wall and are pleomorphic. Mycoplasma is an uncommon cause of pneumonia in children younger than 5 years but is the leading cause of pneumonia in school-aged children and young adults. Illness can range from a mild upper respiratory tract infection to tracheobronchitis to pneumonia. Symptoms include malaise, low-grade fevers, and headache. In 10% of children a rash develops that usually is maculopapular. Cough, if it develops, usually occurs within a few days and may continue for 3 to 4 weeks. Initially the cough is nonproductive but then it may become productive and usually is associated with widespread rales on physical examination. Roentgenographic abnormalities vary but usually are bilateral and diffuse.³³

Isolation of Mycoplasma by culture is complicated by the requirement for special enriched broth or agar media, which are not widely available; it is successful in only 40% to 90% of cases and requires 7 to 21 days. A fourfold increase in antibody titer between acute and convalescent sera is diagnostic but the time involved is lengthy, providing only a retrospective diagnosis. Complement fixation and immunofluorescent and several enzyme immunoassay antibody tests have been developed but have been of limited diagnostic value.³³ Serum cold agglutinins with titers of 1:32 or greater are present in more than 50% of patients with pneumonia by the beginning of the second week of illness. A PCR test has been developed but is not widely available. Where available, the PCR test has become an important means of diagnosing M. pneumoniae infections in clinical practice and allows for institution of therapy directed at the causative pathogen.⁴³ Treatment of upper respiratory tract infections or acute bronchitis is rarely indicated, but treatment with erythromycin or another macrolide such as azithromycin is indicated for persons with pneumonia or otitis media.

Miscellaneous Etiologic Agents

Pneumonia resulting from group A streptococcus accounts for less than 1% of all bacterial pneumonias. This disease is found in older children (median age 5 to 6 years), and nearly all patients are bacteremic and toxic at the time of diagnosis. Associated findings may include anemia, hyponatremia, and respiratory distress often accompanied by pleural effusion or empyema. Often a positive history of a preceding viral infection is noted.

Gram-Negative Bacteria

Pneumonia caused by gram-negative enteric bacteria, especially Pseudomonas, almost always is found in patients with underlying pulmonary disease, compromised immune status, or those receiving prolonged respiratory therapy.^44,⁴⁵ Gram-negative enteric bacteria are a frequent cause of nosocomial infection in critical care units. These organisms can produce a severe necrotizing pneumonia that is associated with an increase in morbidity.⁴⁶

Legionella Pneumophila

Pneumonia that occurs as a result of Legionella pneumophila has been reported infrequently in the pediatric age group.⁴⁷^–⁵⁰ The onset of this disease is characterized by high unremitting fever, chills, and a nonproductive cough.⁴⁸ Extrapulmonary manifestations include gastrointestinal symptoms such as diarrhea, liver involvement, and confusion. Chest radiographs typically consist of peripheral nodular infiltrates and pleural effusions. Cavitation occurs only in immunosuppressed individuals. Death in the normal host is unusual if prompt therapy with azithromycin or erythromycin is initiated.

Anaerobic Bacteria

Pneumonia resulting from anaerobic upper respiratory flora is uncommon in healthy children. When it does occur, it is frequently associated with risk factors such as underlying pulmonary disease, a central nervous system disorder (including seizures), a postanesthetic state, and aspiration of a foreign body. Lung abscess and empyema are frequent complications in persons with anaerobic bacterial pneumonias.

Complications

The mortality rate in persons with uncomplicated bacterial pneumonia is less than 1%. Death is more common in children with complicated disease or an underlying disorder. The most frequent complications of bacterial pneumonia are pleural effusion and empyema (Table 47-1). Thoracentesis should always be performed if fluid is present to facilitate an etiologic diagnosis and to establish the character of the fluid. Tube thoracostomy is indicated if a large amount of fluid is present and is producing respiratory compromise or if purulent fluid is obtained by thoracentesis. Empyema may extend locally to involve the pericardium, mediastinum, or chest wall. Evidence of empyema extension should be considered in the child who is unresponsive to antibiotic therapy.²⁸

Table 47–1 Major Sequelae/Life-Threatening Complications Associated with Bacterial Infections

Complication/Sequelae	Organism
Necrotizing pneumonia	Anaerobic, GNB
Respiratory failure	GBS
Shock	GBS, SP, H. flu, GNB
Apnea	GBS
Pneumothorax	H. flu
Pneumatoceles	H. flu, anaerobic, staph, SP, GAS
Abscess (lung)	Staph, SP, anaerobic
Pleural effusion	H. flu, GAS, SP, staph
Empyema	H. flu, staph, SP
Epiglottitis	H. flu, GAS
Meningitis	H. flu, GBS, SP
Encephalopathy	Legionella
Pericarditis	H. flu
Bone/joint	H. flu, staph
Kidneys	Staph

GAS, Group A streptococcus; GBS, group B streptococcus; GNB, gram-negative bacteria; H. flu, Haemophilus influenzae; SP, Streptococcus pneumoniae; Staph, Staphylococcus aureus.

When tube thoracostomy/surgical drainage is required, it should be discontinued as soon as drainage has substantially decreased. For patients with staphylococcal empyema, streptococcal pneumonia, or H. influenzae empyema, 3 to 7 days of drainage usually is sufficient. Patients with empyema require prolonged antimicrobial therapy and careful follow-up.

Pneumothorax and pneumatoceles can be seen with almost any bacterial pneumonia but are especially common with staphylococcal disease.⁴⁰ Such pneumatoceles require no special therapy and usually resolve. Lung abscess is an infrequent complication of H. influenzae and pneumococcal pneumonia and is most often encountered with staphylococcal disease or anaerobic bacteria.

Prognosis usually is excellent even in persons with severe bacterial pneumonia complicated by empyema. Long-term follow-up of children with empyema has demonstrated remarkably few, if any, residual pulmonary function abnormalities and remarkable clearing of chest roentgenograms. In contrast to adults with empyema, children seldom require surgical procedures such as decortication. However, follow-up chest radiographs should be obtained on all patients with bacterial pneumonia to document complete resolution. Such radiographic follow-up studies probably are not indicated until at least 6 to 8 weeks following the initiation of antibiotic therapy.

Therapy

Therapy for persons with bacterial pneumonia should include appropriate intravenous antibiotic treatment directed toward the specific pathogen, if it is known (Table 47-2). Localized or compartmental complications such as empyema, lung abscess, pericarditis, or septic joints require appropriate surgical drainage and antibiotic therapy. Prevention via immunization or chemoprophylaxis has changed the incidence and epidemiology of pneumonitides significantly. Options for immunization, active or passive, and chemoprophylaxis for various etiologic agents are listed in Table 47-3.

Table 47–2 Bacterial Pneumonia Therapy

Disease/Organism	Therapy
UNDETERMINED ORGANISMS
Serious, life-threatening pneumonia, nonsuppressed host	Cefotaxime or ceftriaxone + azithromycin
	Bronchial lavage or needle aspiration of lung may be necessary to establish diagnosis
Suppressed neutropenic host	Imipenem/meropenem or Piperacillin or ceftazidime + aminoglycoside ± clindamycin
	Vancomycin not included in initial therapy unless high suspicion, ampho not used unless still febrile after 3 days/high suspicion. Bronchial lavage, needle/open biopsy may be necessary to establish diagnosis
Lung abscess	Clindamycin or Ticarcillin/clavulanate or Piperacillin/tazobactam
SPECIFIC ORGANISMS
*Pneumonia with Empyema*
Streptococcus pneumoniae, group A strep
Penicillin susceptible	Cefotaxime or ceftriaxone + chest tube drainage
Penicillin resistant	Vancomycin ± rifampin + chest tube drainage
Staphylococcus
Methicillin sensitive	Nafcillin or oxacillin + chest tube drainage
Methicillin resistant	Vancomycin ± chest tube drainage
*Pneumonia without Empyema*
Haemophilus influenzae	Ampicillin or cefotaxime or ceftriaxone + chloramphenicol
Klebsiella pneumonia	Cefotaxime or ceftriaxone
Escherichia coli, Enterobacter	Aminoglycoside or cephalosporin
Legionella	Azithromycin or erythromycin ± rifampin
Pseudomonas	Aminoglycoside + anti-Pseudomonas penicillin or Aminoglycoside + ceftazidime
Mycoplasma pneumoniae	Erythromycin or azithromycin or Clarithromycin

Table 47–3 Preventive Measures

Organism	Immunization	Chemoprophylaxis
Cytomegalovirus	IVIG: prophylaxis in seronegative transplant recipients	Ganciclovir or valganciclovir
Haemophilus influenzae type b	Capsular polysaccaride vaccine or Conjugate vaccine	Rifampin in the face of incomplete immunization and exposure
Influenza	Inactivated virus produced in chicken embryos	Oseltamivir (A or B) or Amantadine/rimantadine (A)
Measels	Live virus vaccine or IVIG for immunocompromised patients	None
Streptococcus pneumonia	Purified capsular polysaccharide antigens of 23 pneumococcal serotypes vaccine or Multivalent protein conjugate vaccine	Penicillin VK for functional or anatomic aspleia until age 5 years
Pneumocystitis carinii	None	Trimethoprim-sulfamethoxazole or Pentamidine or dapsone
RSV	RSV-IVIG or Palivizumab (monoclonal antibody)	None
Group B strep	None	Intrapartum antibiotics

IVIG, Intravenous immunoglobulin; RSV, respiratory syncytial virus.

Viral Pneumonitis

Infection is the most common cause of pulmonary interstitial disease in children, and viral agents are the leading cause of lower respiratory tract infection in infants and children. The viral agents listed in Table 47-4 account for the greatest percentage of pediatric pulmonary disease. Nearly 85% of all hospitalizations of children younger than 15 years occur during outbreaks of respiratory syncytial, parainfluenza, or influenza virus.

Table 47–4 Viral Agents Associated with Pediatric Interstitial Lung Disease

Agent	Frequency
Respiratory syncytial virus	+++++
Parainfluenza virus	++++
Adenovirus	+++
Influenza virus	+++
Cytomegalovirus	+
Enterovirus	+
Rhinovirus	+
Measles	+

The diagnosis of a viral pneumonia in children is frequently based on the clinical presentation, epidemiologic setting, and exclusion of bacterial pathogens by negative cultures. A specific agent is identified in only approximately 50% of cases of presumed viral pneumonia. Pediatric viral respiratory tract infections occur most commonly during the winter, with distinct peaks during midwinter and early spring in temperate climates. Closed population groups provide for greater spread of respiratory viruses and increased recognition of viral pneumonias.

Pathophysiology

The mechanism of infection for most respiratory viruses appears to be a progressive spread from the larger airways to the alveoli. The respiratory epithelial cell is the major target of cytopathic effect. The normal ciliated columnar epithelium may become markedly dysplastic with loss of the overlying cilia.^51,⁵² Areas of ulceration then occur as segments of the mucosal surface desquamate into the bronchial lumen. Impaired mucociliary clearance occurs and altered stimulation of nerves mediating bronchial smooth muscle tone leads to increased airway resistance.⁵³ Enhanced mucus formation along with mucosal debris may lead to obstruction of the bronchioles, luminal narrowing, distal air trapping, and hyperinflation of various lung segments. In advanced disease with complete small airway obstruction, atelectasis results, causing hypoxemia as a result of intrapulmonary shunting and V/Q imbalance.

In persons with severe viral pneumonia, widespread parenchymal injury caused by a necrotizing alveolitis may occur. Alveolar round cell infiltrates occur often, with subsequent hyaline membrane formation and intraalveolar hemorrhage, which produces extensive parenchymal destruction and diminished lung compliance, decreased lung volumes, and intrapulmonary shunting.⁵⁴

Diagnosis

Although the clinical presentations of illness by respiratory viruses overlap, presumptive diagnosis of the specific etiology is based on clinical presentation, setting, and, most importantly, epidemiologic information. In the past, virus isolation or seroconversion was necessary for a definitive diagnosis. Today many respiratory viral infections can be diagnosed through the use of new techniques.

Viral specimens should be obtained as early as possible during the period of greatest viral excretion. Nasopharyngeal washings or swabs of the throat are most widely used. Cultures may be negative in up to 40% of patients during acute viral respiratory tract disease; failure to isolate a virus is not definitive evidence against the diagnosis of viral pneumonia. Serologic tests including complement fixation, hemagglutination inhibition, enzyme-linked solid-phase assays (enzyme-linked immunosorbent assays), and antibody assays have been used in the diagnosis of viral infection. Histologic evidence of infection in biopsy or postmortem specimens may be helpful, particularly when intranuclear inclusions are documented. Rapid diagnostic techniques focus on detection of the virus or its components in the sample. These new techniques include refinements in the use of immunofluorescence, enzyme immunoassay, time-resolved fluoroimmunoassay, latex agglutination assays, and use of nucleic acid hybridization methods, such as deoxyribonucleic acid (DNA) probes and PCR.⁵⁵^–⁵⁸

Three major clinical syndromes are associated with lower respiratory tract viral illness:

1. Bronchitis: Acute bronchitis is a febrile illness associated with a new productive cough. Symptoms of upper respiratory tract infection may be present. Acute bronchitis can adversely affect respiratory function, particularly in patients with chronic pulmonary impairment, leading to hospitalization of persons with marginal lung function.

2. Bronchiolitis: Symptoms result from airflow obstruction caused by localized inflammation of the terminal respiratory bronchioles. The development of cough, tachypnea with intercostal retractions, fine, moist, inspiratory crackles, and expiratory wheezes are characteristic. Hypoxemia and cyanosis are often present.⁵⁹

3. Pneumonia: Primary viral pneumonia is frequently a mild illness characterized by a mild cough and one or more segmental infiltrates on chest radiograph. Although it is usually a self-limited process, in some persons the pneumonic process may progress with extensive parenchymal injury, diffuse interstitial alveolar infiltrates, and severe hypoxemia. Bacterial superinfection is heralded by increased temperature, change in sputum, and signs of localized consolidation several days after the initial onset of symptoms.

Radiographic Findings

Differentiation of bacteria from viral pneumonia cannot be made solely on the radiographic appearance. Children with presumed viral pneumonia, however, may have several radiographic findings, including the following:

1. Peribronchial thickening and perihilar linear densities

2. Partial lobar or patchy involvement in multiple areas of the lung

3. Shifting regional infiltrates

4. Areas of hyperinflation and atelectasis

Hilar adenopathy is usually absent. Diffuse bilateral infiltrates similar to those reported in acute respiratory distress syndrome (ARDS) have been found in persons with severe influenza, adenovirus, and respiratory syncytial virus (RSV) pneumonias.⁶⁰ Pleural effusions can occur in both adenovirus and parainfluenza pneumonias. Pulmonary calcifications/nodules have been described in the convalescent phase of varicella and measles.

Specific Pathogens

We will review the most common viral pathogens that cause pneumonitis in children but have elected to exclude such viruses as Hantavirus that are beyond the scope of this chapter. Please refer to more up-to-date journal articles for specific pathogens of interest (see also Chapter 102: Neuroendrocrine-Immune Mediator Cooordination and Disarray in Critical Illness.).^25,⁶¹

Respiratory Syncytial Virus

RSV is the most common cause of bronchiolitis and pneumonia in the United States in children between the ages of 6 months and 3 years. The disease produced by RSV varies from upper respiratory tract infection to severe bronchiolitis and pneumonia with wheezing and respiratory failure.⁵⁹ Higher mortality rates and greater severity with prolonged symptoms occur in infants and children younger than 6 weeks of age and in those who have a history of prematurity, chronic lung disease, cardiopulmonary disease, congenital heart disease, pulmonary hypertension, or neuromuscular impairment and in those receiving chemotherapy or immunosuppressive therapy. ^16,⁶²^–⁷⁰ Signs of RSV pneumonia include wheezing, dyspnea, pulmonary infiltrates, and areas of atelectasis and hyperinflation on the chest radiograph. RSV infection may result in increased airway reactivity and airway resistance that persists for months. Significant respiratory tract shedding of virus continues for up to 21 days from the onset of illness. Nosocomial spread of RSV infection is common, and early diagnosis and appropriate isolation techniques are critical in hospitalized patients.

Methods for diagnosis of RSV include viral isolation in cell culture, immunofluorescence of exfoliated nasopharyngeal epithelial cells for detection of RSV antigens, and enzyme immunoassay for detection of RSV antigens in nasal secretions.^71,⁷² PCR technology is now available for diagnosis of RSV illness.

All hospitalized patients with bronchiolitis and RSV pneumonia should be monitored for hypoxia, hypercarbia, and the need for ventilatory assistance. Supportive care includes the use of humidified oxygen, secretion clearance, and hydration.^73,⁷⁴ Mechanical ventilation for respiratory failure usually is well tolerated. Extracorporeal membrane oxygenation has been used successfully in infants who do not respond to conventional ventilation.^75,⁷⁶ The routine administration of bronchodilators and corticosteroids is not warranted; use should be individualized based on clinical reponse.^74,⁷⁷ Ribavirin, an antiviral agent, has been used to treat children with severe RSV pneumonitis, but its clinical effectiveness remains controversial.^66,⁷⁸^–⁸⁹ Passive immunoprophylaxis has proved useful in high-risk populations in preventing RSV infection, as has palivizumab, a humanized mouse monoclonal antibody. ^33,⁹⁰^–⁹⁴ The incidence of bacterial superinfection in persons with RSV disease is low; therefore prophylactic antibiotics are not recommended for RSV disease.^63,^95,⁹⁶ It is not unusual for an infant with RSV to require hospitalization for 7 to 10 days following the onset of illness. Long-term complications of RSV infection may include persistent bronchial reactivity, with lower respiratory tract symptoms in more than 70% of infants in the year following hospitalization.⁸⁸ Whether moderately severe RSV infection predisposes a person to asthma later in life remains controversial.⁹⁷^–¹⁰¹

Parainfluenza Virus

Parainfluenza virus (types 1 and 2) is more often associated with laryngotracheobronchitis and croup than with pneumonia (usually type 3). Parainfluenza is second only to RSV as an etiology of lower respiratory tract disease responsible for the hospitalization of children.¹⁰²^–¹⁰⁷ The pneumonia associated with parainfluenza is typically mild; however, fatal cases with prolonged viral shedding have been reported in patients with severe combined immunodeficiency disease.¹⁰⁸^–¹¹¹ Conferred immunity following infection is low; repeat infection occurs in nearly 50% of patients by age 30 months, although they result in progressively milder illness. Parainfluenza virus, like RSV, has demonstrated ability to elicit an immunoglobulin IgE-specific antibody response.¹⁰⁴ Rapid identification of parainfluenza virus by either fluorescent and enzyme-linked immunologic techniques is possible, but results are variable depending on the viral type and antisera used. Viral culture may take up to a week. PCR methods are available for detection and differentiation, with high sensitivity and specificity. Treatment is supportive.

Adenovirus

Adenoviruses are responsible for approximately 3% of the pneumonias occurring in children. Clinical features are similar to other viral pneumonias except that the onset of illness is often gradual, occurring over several days. Of the 51 serotypes, types 3, 4, and 7 are the most common causes of lower respiratory tract disease in children. Adenovirus type 7 is most commonly associated with severe pneumonitis in infants and children and has a significant incidence of mortality and morbidity.^41,¹¹²^–¹¹⁶ In 2007, a new strain of adenovirus 14 was isolated in previously healthy infants and young adults in the United States in whom fatal pneumonia developed.¹¹⁷ A clinical presentation similar to that of bacterial pneumonia, with massive pleural effusion, rhabdomyolysis, and myoglobinuria, has been reported with adenovirus type 21.¹¹⁸ In many infants with documented adenovirus respiratory tract infection, chronic pulmonary disease develops that manifests as persistent atelectasis, bronchiectasis, and recurrent pneumonitis with areas of hyperinflation and interstitial fibrosis. Bronchiectasis and restrictive lung disease have been documented in children following acute adenovirus infection. Adenovirus pneumonia is the most common cause of bronchiolitis obliterans in children, and unilateral hyperlucent lung syndrome has been reported.¹¹⁹^–¹²⁴ Disseminated adenovirus occurs and usually is associated with infection by serotype 3, 7, or 21. It occurs most frequently in infants younger than 18 months and usually involves the heart, pericardium, liver, pancreas, kidneys, central nervous system, and skin.¹²⁵ Fatal cases of adenovirus and pneumonia can occur in previously healthy young individuals. Diagnosis is made by cell culture, and antigen and DNA detection by PCR. Adenovirus typing is available from some reference and research laboratories. Treatment is supportive.

Influenza

Three antigenically distinct influenza viruses exist—types A, B, and C. All three have hemagglutinin surface antigen, but only types A and B have neuraminidase surface antigen. Antigenic drift for types A and B produce minor changes in the surface antigens, resulting in endemic illness. Antigenic shift only occurs with influenza type A, resulting in a major change or new surface antigen, for which there may be low or no immunity in the population. Influenza type A is subtyped by its surface antigens, and currently three influenza strains are circulating world wide, including influenza A/H1N1, H1N2, and H3N2.^33,¹²⁶

Clinical signs of uncomplicated influenza pneumonia include coryzal symptoms followed by dyspnea, fever, cyanosis, cough, and wheezing. Children with influenza typically have a more sudden onset of “toxic” signs than do those with other viral diseases. Infection is associated with myalgia, encephalopathy, and cardiac involvement. Pathologically, influenza virus infection is similar to RSV in that the virus destroys ciliated respiratory epithelial cells with subsequent edema and an acute inflammatory response. Influenza has been associated with Reye syndrome and with significant bacterial suprainfections.¹²⁷ In patients in whom bacterial infection develops, there often is a period of apparent improvement before a sudden worsening that is heralded by the production of purulent sputum, return of fever, and development of pulmonary consolidation.¹²⁸ Fatal outcomes have been reported in previously healthy children as well as in high-risk groups.

Prevention of influenza disease is possible with either administration of multivalent influenza vaccine (influenza A/H1N1, A/H3N2, and B) or chemoprophylaxis with Oseltamivir and Zanamivir (influenza A, B, and A/H1N1) or amantadine hydrochloride and its closely related analogue rimantadine (influenza A). One study showed efficacy of aerosolized ribavirin in the treatment of persons with influenza B.^129,¹³⁰ Diagnosis of influenza pneumonia may be made by a culture of the virus from respiratory secretions or with serologic techniques. Rapid diagnosis by means of immunofluorescence of exfoliated nasopharyngeal cells may be helpful, as well as by PCR, which may be available at some institutions. Treatment includes supportive care, monitoring of respiratory status, and administration of antiviral medications.

Measles

Measles is a highly contagious disease that is preventable by vaccine; the incidence fell below the endemic threshold in the United States in 2000.¹³¹ Endemic outbreaks continue in developing countries and when international travelers import measles to nonimmunized persons in the United States.^33,¹³¹ Typical disease manifests as high fever, cough, runny nose, and generalized rash. Respiratory symptoms are nearly universal in this illness, making the prevalence of measles pneumonia difficult to determine. Moist crackles develop in most children, and approximately 20% have expiratory wheezes and hypoxia. In cases in which radiographs have been obtained, a fine reticular infiltrate was present, compared with the nodular infiltrates in children with atypical measles. Although the clinical syndrome usually resolves over 1 to 2 weeks, both radiographic and pulmonary function abnormalities may persist for months. Severe life-threatening tracheitis may occur during the course of measles or bacterial suprainfection.¹³²^–¹³⁴ In fatal cases, severe respiratory and nervous system disease is manifested, and lung tissue demonstrating interstitial pneumonitis with diffuse endothelial cells, pneumatocyte degeneration, and presence of multinucleated giant cells has been reported.¹³⁵

Diagnosis is made by isolation of the virus, standard serology, or identification of viral ribonucleic acid by reverse transcription-PCR. All suspected cases should be reported to local and state health departments. No antiviral agent is available; treatment is supportive. Two doses of vitamin A (200,000 International Units) on consecutive days) has been shown to reduce pulmonary-specific and overall mortality rates in patients up to 2 years of age.¹³⁶ Administration of intravenous immunoglobulin may be of benefit to high-risk or immunosuppressed patients when it is started within 6 days of exposure.³³

Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) infection in children most commonly presents with recurrent bacterial infections. The major morbidity and mortality in pediatric acquired immune deficiency syndrome (AIDS) is associated with lung disease, ranging from opportunistic infections such as Pneumocystis carinii pneumonia to entities such as chronic interstitial pneumonitis.^137,¹³⁸ Treatment for specific pulmonary pathogens are discussed throughout this chapter, but specific guidelines for HIV/AIDS treatment are lengthy, rapidly changing, and beyond the scope of this chapter. More specific and current information regarding HIV/AIDS are available at www.aidsinfo.nih.gov/guidelines. This Web site provides the most current information regarding HIV/AIDS clinical research, HIV treatment and prevention, and medical practice guidelines. This information also can be obtained by phone at 1-800-HIV-0440 within the United States or at 1-301-519-0459 outside the United States or by mail at AIDS Info, P.O. Box 6303, Rockville, MD 20849-6303.

Complications

The actual mechanisms by which viruses predispose the lung to secondary bacterial infection are not precisely understood. Viruses are capable of altering both cellular and noncellular defenses of the respiratory tract.^52,^53,¹³⁹ Viral infection of the epithelial cells appears to predispose the upper respiratory tract mucosa to bacterial colonization by allowing bacterial pathogens to adhere to injured cells.^51,⁵² Viral infection may cause significant impairment of both intracellular killing and ingestion of bacteria by the pulmonary macrophage. Significant defects in polymorphonuclear leukocyte chemotaxis and phagolysosome fusion occur during acute viral infection. The greatest impairment of macrophage function occurs 1 week after the onset of viral infection, which correlates with the peak incidence of bacterial suprainfection. Thus suprainfection during the course of viral lower respiratory tract disease appears to be the result of a combination of the cytopathic effects of the virus on the respiratory mucosa and various alterations in host immune response.

Significant life-threatening complications of viral lower respiratory tract disease are noted in Box 47-2. Respiratory failure with viral pneumonitis resembling ARDS is frequently seen in patients in the pediatric critical care unit. It often is associated with influenza or adenovirus but can occur with varicella, cytomegalovirus, and RSV.⁶⁰

Box 47–2 Major Sequelae/Life-Threatening Complications Associated with Viral Pneumonitis

• Subacute sclerosing panencephalitis: measles

• Guillain-Barré syndrome: influenza, varicella

• Reye syndrome: influenza, VZV

• Encephalitis: adenovirus, measles, RSV, CMV

• Seizures: influenza

• Bacterial superinfection: influenza, VZV, Epstein-Barr virus, measles

• Asthma: RSV, parainfluenza, rhinovirus

• Apnea: RSV, influenza

• Bronchiolitis obliterans: influenza, adenovirus, measles

• Chronic obstructive pulmonary disease: RSV

• Fatal pneumonitis: influenza, measles, adenovirus, RSV, parainfluenza, CMV