Chapter 40: Lower Respiratory Tract Infections in Children

Respiratory infections in children, particularly community-acquired bacterial pneumonias, are among the most important worldwide public health issues. Pneumonia is the most common cause of death in children <5 years of age and is particularly important in developing countries. It is estimated that 4-5 million children die annually of bacterial pneumonias, with the large majority of those deaths occurring in developing countries. In the United States, about 6 in 1,000 children over the age of 9 years develop pneumonia, while the incidence in children <5 years old is more than 5 times this rate. In less affluent countries, the incidence of pneumonia is an order of greater magnitude, primarily owing to other factors including malnutrition, environmental and indoor air pollution, immunization status, crowding, and coinfection with HIV or measles. Although bacterial pneumonias are an important cause of morbidity and mortality throughout the world, nonbacterial pneumonias and viral lower respiratory tract infections (such as bronchiolitis) are more prevalent in newborns and children. Terms such as viral pneumonia, atypical pneumonia, and interstitial pneumonia are used to describe the clinical presentations and radiographic images of patients presenting with these latter illnesses. This chapter addresses respiratory infections—both "atypical" and bacterial—in newborns and children.

Etiology and Age-Specific Considerations

In determining the possible etiology of pneumonia in a specific child, it is useful to appreciate that certain infectious causes are more or less unique to particular age groups. The most important of these by age cohort are shown in Table 40.1. In the first month of life, most cases of pneumonia are caused by either group B Streptococcus or gram-negative pathogens such as E. coli. This chapter will not specifically review pneumonias in neonates, but instead will focus on children beyond the newborn period. Viruses as a group are the most common causes of pneumonia in younger children. The specific viral pathogens causing such pneumonia, as well as their relative frequencies and usual severities, are depicted in Table 40.2.

Infections with bacterial pathogens become more prevalent in school-aged children and adolescents (though bacterial infections can occur at any age). Organisms such as C. pneumoniae and M. pneumoniae occur more frequently in adolescents and, to a lesser extent, among children in their elementary school years. It is worth emphasizing that the most common bacterial pathogen causing pneumonia in all children is Streptococcus pneumoniae. This is true despite universal administration of the pneumococcal conjugate vaccine which protects against seven serotypes. There is considerable evidence, however, that a number of serotypes not contained in the 7-valent vaccine can cause pneumococcal disease in children. It is unclear at this time as to the impact of the newest pneumococcal conjugate vaccine, which protects against 13 serotypes, on the incidence of bacterial pneumonia due to S. pneumoniae.

The lower respiratory tract is generally sterile as a result of an abundant set of pulmonary host defense mechanisms including mucociliary transport, cough reflexes, components of the complement system, immunoglobulins (particularly secretory IgA), and alveolar macrophages (Chap. 10). Most viral pathogens that cause pneumonia first inoculate and proliferate in the upper respiratory tract. In a subset of patients, viral infection spreads directly to involve more distal portions of the respiratory tract, leading to illnesses such as bronchiolitis and pneumonia. In the course of the illness, the infected respiratory epithelial cells lose their cilia and are sloughed into the respiratory passages resulting in stasis of mucus and accumulation of cellular debris. An inflammatory response at the sites of tissue damage results in mononuclear cell infiltration, and causes swelling of the submucosa and interstitial structures that further contributes to narrowing of the airways. These pathologic changes are particularly problematic in younger children whose airways are already of a small caliber. Various degrees of obstruction of the airways may lead to areas of atelectasis, interstitial edema, and hyperinflation. The resulting imbalance in V̇_A/ Q̇ further contributes to underlying alveolar hypoxia. A direct consequence of these multiple airway abnormalities is an enhanced risk of superinfection with bacterial pathogens.

The pathogenesis of bacterial infection in the lungs often varies according to the etiological agent. For example, S. pneumoniae produces local airway edema allowing proliferation and spread of the organism into adjacent areas of the pulmonary parenchyma. This leads to the typical lobar involvement observed in pneumococcal pneumonia. On the other hand, M. pneumoniae organisms adhere to the ciliated epithelium and paralyze ciliary function, leading to an intense inflammatory response and cellular necrosis. Much like viral respiratory infections, Mycoplasma infection spreads along the bronchial tree. Staphylococcus aureus pneumonia is often a unilateral process that is characterized by areas of bronchopneumonia, hemorrhagic necrosis, pneumatocele formation, and complicated pleural effusions.

In children with either viral or bacterial pneumonia, nonspecific upper respiratory tract findings such as rhinitis or cough may be initial symptoms. Tachypnea is the most common feature of pneumonia at all ages; this finding along with cough, fever, respiratory distress, and an abnormal chest exam (crackles or wheezes on auscultation) are often present in children with pneumonia. In infants, severe viral or bacterial infections may be accompanied by cyanosis and signs of impending respiratory failure. In older children and adolescents with bacterial pneumonia, symptoms may include shaking chills, high fever, cough, chest pain, and splinting (defined here as reduced inspiratory effort due to pleuritic pain). Some children with bacterial pneumonia may present only with fever and chest or abdominal pain, but with cough either absent or a minor feature. Fever is usually present in children with viral pneumonias, although it is often lower than in children with bacterial pneumonia. In reality, there are no sensitive clinical, radiographic, or laboratory findings that reliably distinguish between viral and bacterial pneumonias. In general, x-rays in viral pneumonia show bilateral interstitial infiltrates, hyperinflation, and peribronchial thickening (Fig. 40.1). In contrast, evidence of lobar consolidation is typical of bacterial pneumonias such as those caused by S. pneumoniae (Fig. 40.2). The peripheral blood leukocyte count in viral pneumonia may be normal, or slightly elevated with a predominance of lymphocytes, while the leukocyte count in bacterial pneumonia tends to be higher with a larger proportion of neutrophils and band forms. Notably, the presence of lobar disease, a large pleural effusion, and high fever are generally and collectively indicative of a bacterial etiology (Fig. 40.3).

The chest x-ray confirms the clinical suspicion of pneumonia based on symptoms reported, while demonstrating potential complications such as the presence of a pleural effusion. Determining the etiologic agent in instances of viral pneumonia generally takes the form of samples of nasopharyngeal secretions and subjecting them to widely available and accurate DNA or RNA tests for RSV, influenza, parainfluenza, and others. Serologic studies are also available for viral pathogens and M. pneumoniae, particularly when acute and convalescent phase samples are obtained. For bacterial pathogens, diagnosis may be achieved with samples of blood, pleural fluid, sputum, or bronchoalveolar lavage. However, sputum samples are generally unreliable in most children with pneumonia.

Viral Pathogens

Respiratory syncytial virus (RSV) is the most frequent cause of pneumonias in children with lower respiratory tract involvement (~50% cases) and is a particular problem in infants and young toddlers. RSV usually occurs in epidemics during the winter and early spring months, and infects virtually all children during the first 3 years of life. RSV is spread by direct or close contact with contaminated secretions or large infectious droplets in the air. Clinical features in RSV bronchiolitis include copious nasal discharge, cough, irritability, fever, and anorexia. Symptoms may progress over 3-7 days with worsening cough, dyspnea, and respiratory distress. Patients may develop significant tachypnea, nasal flaring, and sternal retractions. Wheezing is often a prominent feature that is accompanied by a prolonged expiratory phase. Underlying conditions that increase the risk of severe disease from RSV include children with congenital heart disease, immune deficiencies, or pulmonary disorders such as bronchopulmonary dysplasia (BPD).

RSV antigens in clinical specimens such as nasopharyngeal swabs are best detected using any of several rapid diagnostic tests that utilize immunofluorescent and enzyme immunoassay techniques. As with other viral causes of lower respiratory tract infection, treatment for RSV bronchiolitis includes adequate hydration, fever control, palliative measures, and supplemental oxygen in children who show hypoxemia. More aggressive therapeutic approaches have been proposed for RSV bronchiolitis, but lack evidence at present of their benefit in altering disease course, notably bronchodilators (albuterol, epinephrine), corticosteroids, and the antiviral agent ribavirin. Clinicians have found that a patient's response to bronchodilators may change as the illness progresses, particularly in atopic children (eg, those with eczema) or in those with a strong family history of allergic disease. Prophylaxis against RSV infection in those infants at highest risk of severe disease is available in the form of a humanized monoclonal antibody that is directed against an RSV surface protein. Thus, palivizumab is approved for children <24 months of age who have BPD or a history of prematurity (<32 weeks' gestation). It is administered once monthly as an intramuscular injection during the high risk months of RSV disease (in North America, those being November through March).

In addition to RSV, other viruses and atypical organisms are capable of causing lower respiratory tract infections such as bronchiolitis or pneumonia. Parainfluenza viruses are second in frequency to RSV and cause ~25% of viral lower respiratory disease in this population, with type 3 the most likely to cause severe pneumonia. Parainfluenza infections can occur at any time of the year. Types 1 and 2 cause about one-third of all parainfluenza disease and are generally endemic in late summer and fall; type 3 tends to peak in the late spring and accounts for two-thirds of all parainfluenza cases. The parainfluenza viruses more typically cause upper respiratory tract disease, accounting for over half of the cases of laryngotracheitis (croup).

Adenoviruses cause 5%-7% of viral respiratory disease in children, often with a variety of syndromes that also affect the eyes, heart, bladder, and gastrointestinal tract. Adenoviral types 3, 4, 7, and 21 are associated with respiratory illnesses in children. Types 3, 7, and 21 have been identified in patients with severe adenoviral pneumonias and are linked to case fatality rates as high as 5%-10%. Residual adenovirus-caused morbidities can occur, notably bronchiectasis, unilateral hyperlucent lung syndrome, bronchiolitis obliterans, or rarely, pulmonary fibrosis. Among the many viral etiologies of lower respiratory tract infections in children, adenoviral infections most often have features that are more usually identified with bacterial infections, such as lobar consolidations, pleural effusions, and high fevers.

Infections with influenza virus type A or type B cause another 5% of childhood respiratory illnesses. These are often accompanied by a variety of systemic symptoms including fever, headache, anorexia, malaise, myalgia, sore throat, vomiting, and abdominal pain. Respiratory complications from influenza may be limited to upper respiratory tract symptoms (croup, rhinitis), or the patient may present with pneumonia or a bronchiolitis-like illness. More so than in other viral infections, influenza infection is associated with an increased risk of secondary bacterial infections, particularly pneumonias due to S. aureus or S. pneumoniae. In this setting, the patient may improve clinically from the initial influenza illness but then have renewed fever, chills, cough, and respiratory distress, reflecting the bacterial superinfection. Treatment for routine influenza infections is supportive. In cases where more severe disease is a concern, antiviral agents can be administered provided this therapy is begun within 48 hours of the onset of symptoms.

Metapneumovirus is a recently described pathogen (2001) which causes ~5% of lower respiratory tract disease, primarily in infants, but is reported in all age groups. Outbreaks occur in late winter and early spring in temperate climates and often coincide with the RSV season. Transmission probably occurs by direct contact with infected individuals, and nosocomial outbreaks have been described. Epidemiological studies point to metapneumovirus being the second leading cause of bronchiolitis in infants, after RSV. It causes pneumonia and croup in all age groups and is thought to be a major trigger of asthma exacerbations in children and adults. Clinical manifestations of metapneumovirus infection are similar to RSV disease with cough, wheeze, and respiratory distress being prominent features. More severe disease occurs in patients with congenital or acquired immune deficiencies, and likely those with underlying cardiopulmonary disorders and premature birth. Treatment for metapneumovirus, as with most viral lower respiratory tract infections, is supportive.

Mycoplasma pneumoniae is included with the discussion of viral pathogens since it is a frequent cause of "atypical" pneumonia, accounting for 5%-10% of respiratory tract infections in the pediatric population. Mycoplasmata are the smallest free-living microorganisms, lacking a cell wall. Pneumonia caused by M. pneumoniae is the prototype of the primary atypical pneumonia syndrome, although a variety of pathogens may be associated with this syndrome, including many described above. M. pneumoniae is the most common infectious agent causing pneumonia in older children and adolescents. It is a highly transmissible organism, with human to human spread by symptomatic individuals being a common cause of propagation within a family, school, military, or prison setting.

Initial symptoms in children with Mycoplasma pneumonia include malaise and fever. Cough may be an early symptom but typically arises or worsens later. Within a few days of the onset of illness a nonproductive cough develops with diffuse crackles often found on lung exam. Cough may become productive later in the illness and last up to four or more weeks. About 10% of children develop a maculopapular rash in the course of the illness. Radiographically, the typical pattern is bilateral diffuse infiltrates that may be particularly pronounced in the lower lobes. Definitive diagnosis of Mycoplasma disease relies on acute and convalescent sera utilizing complement fixation or immunofluorescent assays. A fourfold or greater increase in titer or the presence of specific IgM antibodies confirms recent infection. By the second week of illness, cold agglutinin titers of 1:32 or greater are present in half of patients with pneumonia. However, this test lacks specificity. Treatment with tetracyclines, or with macrolides such as erythromycin or newer derivatives (clarithromycin, azithromycin) are effective in shortening the clinical manifestations of the disease.

Bacterial Pathogens

Streptococcus pneumoniae

S. pneumoniae (formerly Pneumococcus pneumoniae) is frequently detected in the upper respiratory tract of children. There it can cause disease including sinusitis or otitis media, or more invasively pneumonia, meningitis, or bacteremic sepsis. It is a common cause of community-acquired pneumonia in children, responsible for more than 50% of patients requiring hospital admission. The near-universal use of the heptavalent pneumococcal conjugate vaccine in the United States has had a substantial impact on the epidemiology of invasive pneumococcal disease. The incidence of invasive disease has dropped among vaccinated children, and upper respiratory tract colonization with this organism has fallen, but there has been a notable shift in pneumococcal serotypes causing disease in those not covered by the vaccine. As noted, the introduction of a conjugate vaccine protecting against 13 serotypes may have a broader impact on the incidence of pneumococcal disease (see Clinical Correlation 40.1). High-risk groups for invasive disease include Native American and African-American children, children with sickle cell disease, children with acquired or congenital splenic disorders, and children with HIV infection or other immune deficiencies.

Clinical manifestations of pneumococcal disease are protean, with most children presenting with spiking fevers, cough, an elevated leukocyte count, and lobar or segmental consolidation on chest radiographs. Notably, up to one-fourth of children may have no signs or symptoms attributable to respiratory tract disease and instead present with fever, abdominal pain, or diarrhea. Further, many different radiographic patterns have been described in pneumococcal pneumonia, above and beyond the typical lobar abnormalities (Fig. 40.2). Complications arising from pneumococcal pneumonia are not uncommon in hospitalized children and include parapneumonic effusions, empyema, abscess formation, and necrotizing pneumonia. Although antibiotic-resistant isolates are not predictive of these morbidities, patients with complicated pneumonias tend to be older, are more likely to be Caucasian, and more likely to present with chest pain. Provided that empiric antibiotic choices are correct, most patients will improve within 2-4 days. Ongoing fever, chills, chest or abdominal pain, or the lack of an improvement in the overall clinical picture should raise concerns for one of the above complications.

Pleural effusions accompanying pneumococcal chest infections are the result of a complicated pathophysiologic process (Chap. 29). Parenchymal lung injury causes an inflammatory response of the pleural surfaces and a subsequent increase in regional capillary permeability. This pleural inflammation also reduces the dynamic process of pleural fluid reabsorption by the parietal pleura. When this is combined with the change in capillary permeability, considerable amounts of fluid can accumulate. Initially, pleural effusions are sterile, free flowing, and contain fluid with few leukocytes. This exudative phase (or stage 1) may last for 3-5 days before giving way to the fibrinopurulent phase where an increase in leukocytes and a positive Gram stain indicative of infected fluid are observed (Chap. 19). With the development of pus in the pleural space, fibrin deposition between the visceral and parietal pleura ensues. The infected fluid accordingly becomes loculated, fibrin and cellular debris accumulate and more fluid becomes apparent as lymphatic channels become obstructed. The organizing stage (stage 3) is characterized by infiltration of fibroblasts, thickening of the pleural membranes and "trapped" lobes (Chap. 26).

In the initial stages of a pleural effusion, fluid removal is amenable to simple needle thoracentesis or via chest tube placement. This approach may be both diagnostic and therapeutic (Chap. 19). In the later stages, these approaches may not be successful as the loculated, purulent fluid may be difficult to drain. Video-assisted thoracoscopic surgery (VATS) to evacuate pleural fluid and perform decortications with debridement of thickened pleural membranes is a surgical option. On the other hand, some clinicians favor an approach of chest tube placement in conjunction with a fibrinolytic agent such as tissue plasminogen activator instilled into the chest tube (Chap. 27). Less frequently, continuing medical therapy with IV antibiotics alone to manage pneumonias with large effusions is an option. Though S. pneumoniae is the most common cause of pneumonias with effusions, other organisms such as Group A Streptococcus, S. aureus, H. influenzae, Pseudomonas aeruginosa, and Mycoplasma spp. can also cause complicated parapneumonic effusions.

The development of a pulmonary abscess is another complication of bacterial pneumonias, including those caused by S. pneumoniae. A lung abscess is a thick-walled cavity containing pus, leukocytes, and cellular debris. In some circumstances, it is the result of an aspiration event, especially in children with neurodevelopmental deficits. The clinical presentation of a pulmonary abscess mirrors that of children with typical bacterial pneumonias, with fever and cough being the prominent features. The course of illness may be subacute with a slower evolution of signs and symptoms. The chest radiograph shows a typical appearance of a fluid-filled cavity with an air-fluid level (Fig. 40.4). Chest ultrasound or CT scan may be an adjunct to diagnosis and guide possible drainage procedures. Most clinicians recommend IV antibiotics for up to 2 weeks with an additional 2-4 weeks of oral therapy. Newer information suggests that draining abscess fluid or placing a pigtail catheter in the cavity in conjunction with IV antibiotic therapy may shorten the hospital stay.

Other Bacterial Pathogens

H. influenzae type B was a frequent cause of significant bacterial disease among children in the past. Invasive diseases caused by H. influenzae type B include sepsis, meningitis, epiglottitis, cellulitis, and pneumonia. An effective vaccine to prevent disease caused by this organism became available in the late 1980s and resulted in a dramatic decrease in the incidence of these illnesses. Although H. influenzae type B is no longer a significant cause of bacterial pneumonia in affluent countries, the worldwide morbidity and mortality from this organism remains an important problem. Nearly 90% of children who develop infections with this pathogen are <5 years of age, and the majority of these are <2 years old. Pneumonias due to H. influenzae cannot be differentiated by clinical criteria from pneumonias caused by other bacteria. Radiographic findings vary, with pleural effusion a common finding. Because of the risk of systemic complications (bacteremia, meningitis) in children <12 months of age in whom H. influenzae is considered a likely pathogen, IV antibiotics should be administered. Older children who are at lower risk of developing these complications may be treated with oral therapy.

While not very common, the community-acquired pneumonia caused by Group A Streptococcus (S. pyogenes) is often associated with a particularly protracted and difficult course in some children. Group A Streptococcus causes a variety of infections involving the upper respiratory tract and skin, but when it involves the lower respiratory tract, a diffuse infection with interstitial pneumonia may occur. In its severe form, necrosis of the airway mucosa and lung parenchyma takes place accompanied by hemorrhage, exudates, edema, and pleural involvement (Chap. 34). Previous infection with influenza virus, measles, or Varicella may place the patient at particular risk of developing severe complications of Group A Streptococcal disease.

In most cases of community-acquired pneumonia caused by Staphylococcus aureus, infection is either by direct inoculation of the organism into the respiratory tree or, less commonly, following bacteremic illness. Exceptions are those patients with indwelling catheters or a recent history of intravenous drug use, where the bacteremic route more commonly causes pneumonia (Chap. 28). Since most clinical protocols for treatment of community-acquired pneumonias do not include therapy directed against S. aureus, the clinical picture may be one of ongoing fever, cough, chills, and supplemental oxygen requirement. A subacute or acute deterioration in clinical status may be observed if this organism is not suspected. Radiographically, unilateral lung involvement is typical with confluent bronchopneumonia and alveolar infiltrates (Chap. 15). As the illness evolves, these areas may coalesce and cavitate, leading to the formation of pneumatoceles. In a large proportion of patients whose pneumonia is caused by S. aureus, complicated parapneumonic effusions and empyema develop. More severely in some patients, a pyopneumothorax may occur characterized by both pus and air in the pleural space. With the increasing prevalence of methicillin-resistant S. aureus (MRSA) in the United States and elsewhere, antibiotic therapy may need to be adjusted to account for this organism, depending on local microbiologic surveillance data.

Since viral pathogens are one of the primary causes of pneumonia, it is not unreasonable to forego antibiotics when the clinical picture appears due to a virus. As noted above however, this may be difficult since the clinical course, radiographic findings, and laboratory tests may not be sufficiently discriminatory. For routine instances of community-acquired pneumonias where a bacterial pathogen is suspected, oral antibiotics are generally sufficient. Macrolides such as clarithromycin or azithromycin are attractive choices for activity against most causes of pneumonia, including Mycoplasma and Chlamydia spp. Hospitalization and IV antibiotics should be considered in the following: infants <6 months; those who are more acutely ill with systemic symptoms; patients with S_aO₂ <92% in room air; children with gastric upset; or patients who have not responded to oral therapy. Other complications that occur in the course of a community-acquired pneumonia, including empyema or lung abscess, also would warrant an inpatient stay for IV therapy. The choice of IV antibiotic therapy when a specific etiology is known is shown in Table 40.3. Of course, drug allergies may dictate a change in therapeutic decisions. Antibiotic choices also must take into account the age of the patient and the specific pathogens most likely at that age. For example, in a newborn hospitalized with pneumonia, a combination of ampicillin and gentamicin is preferred for organisms such as Group B Streptococcus, E. coli, and other gram-negative bacilli.

For children between 3 and 12 weeks of age, where organisms such as C. trachomatis, Bordetella pertussis, or Urea-plasma urealyticum are a consideration, macrolides are the drug of choice. As sensitivity patterns of the organisms causing community-acquired pneumonia have changed over the years, recommendations for oral antimicrobial therapy in the older child have evolved. When standard doses of amoxicillin fail to improve the clinical picture, high-dose amoxicillin is combined with clavulanate. In the school-aged child or adolescent, an oral macrolide may be added or used as monotherapy. As noted before, complications from bacterial pneumonias require longer courses of both parenteral and oral therapy. A patient's response to antibiotic therapy should take into account clinical signs and symptoms, rather than radiographic findings as the latter may take several weeks to resolve. Reduction in cough or chest pain, the absence of fever, normalization of oxygenation, and the ability to tolerate oral feedings are key indicators that the patient has improved.