Lower Respiratory Tract Infections

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CHAPTER 67

Lower Respiratory Tract Infections Michael Weinstein and Lucinda P. Leung

PNEUMONIA Approximately 80% of all episodes of pneumonia occur in children younger than 8 years, with the highest incidence in children between 2 and 4 years of age.1 Pneumonia accounts for up to 20% of all pediatric hospital admissions.2 Although most deaths due to pneumonia occur in the developing world, where it is the leading cause of mortality among children, pneumonia was responsible for 800 childhood deaths in the United States in 1996.3 Despite the frequency with which pneumonia is encountered in hospitalized children, its management remains a source of controversy. The reasons for this controversy include a lack of practical, sensitive, and specific diagnostic tests for determining the causative agents of pneumonia (the cause is identified in less than half of cases) and a shortage of clinical studies comparing antibiotic regimens and adjunctive therapies in a methodologically rigorous manner.

Differential Diagnosis Because standard diagnostic testing is often unrevealing, management is guided by epidemiologic studies. The most helpful predictor of the responsible pathogen is the child’s age (Table 67-1). In young infants, Chlamydia trachomatis and respiratory viruses, including respiratory syncytial virus, influenza, parainfluenza, adenovirus, and metapneumovirus, predominate. C. trachomatis typically causes an afebrile pneumonitis syndrome characterized by diffuse pulmonary infiltrates and air trapping, with radiographic findings more severe than the clinical presentation. Severely ill infants who present with high fever, toxicity, or large effusions or lung abscess are much more likely to have a bacterial infection caused by Streptococcus pneumoniae (most common), Streptococcus pyogenes (group A streptococcus), Staphylococcus aureus, or Haemophilus influenzae. In preschool children, the incidence of viral pneumonia declines, and bacterial pathogens, particularly S. pneumoniae, predominate. Although these generalities hold true across most epidemiologic studies, exceptions must be considered. For example, Mycoplasma pneumoniae is an important pathogen in older preschool-age children. In school-age children and adolescents, M. pneumoniae, Chlamydophila pneumoniae, and S. pneumoniae are the most common causes, and disease due to respiratory viruses is much less frequent.4 Clinical Presentation Fever, cough, tachypnea, respiratory distress, and the finding of decreased breath sounds and crackles on auscultation are the hallmarks of pneumonia. Auscultatory findings may be normal and unreliable in young infants. Fever and abdominal pain suggestive of an acute abdomen are not 382

uncommon, particularly in the presence of lobar consolidation adjacent to the diaphragm or a parapneumonic effusion. For practical purposes, pneumonia can be defined as the presence of fever or acute respiratory symptoms accompanied by a new parenchymal infiltrate on a chest radiograph. A clinical diagnosis of pneumonia can be made reliably with careful observation and a physical examination, and the clinical assessment guides the decision whether to perform chest radiography. Since tachypnea is nearly always present, lack of this sign can help eliminate the diagnosis of pneumonia. When counted over two 30-second intervals in a quiet child, tachypnea is defined as greater than 60 breaths per minute in infants younger than 2 months, greater than 50 breaths per minute in children 2 to 12 months old, and greater than 40 breaths per minute in children older than 12 months.5 Because tachypnea is also observed in other conditions (e.g., metabolic acidosis), chest retractions, other signs of increased work of breathing, and auscultatory findings are more specific physical signs. The absence of tachypnea, increased work of breathing, abnormal auscultatory findings, and hypoxemia estimated by pulse oximetry reliably excludes the presence of pneumonia and the need for radiologic evaluation.5

Diagnosis A pathogen is identified in 40% to 60% of cases, depending on the diagnostic tests used and the population studied.6 The lack of practical, noninvasive, specific diagnostic tests means that treatment is usually empirical, guided by epidemiologic studies. The inclusion of discordant patient populations (e.g., hospitalized versus ambulatory) hampers the interpretation of these studies. Further, isolation of a pathogen from nasopharyngeal secretions (e.g., respiratory syncytial virus by antigen detection) does not exclude bacterial coinfection. Although serologic tests have been widely used in population-based epidemiologic studies, the need for convalescent titers makes this an impractical tool in individual cases. Distinguishing between viral and bacterial pathogens based on clinical, radiographic, and indirect laboratory signs is unreliable. The presence of features such as coryza, conjunctivitis, myalgia, and ill contacts, typically thought to be an indicator of viral pathogens, is actually not helpful in distinguishing between bacterial and viral causes.7 Similarly, laboratory tests such as complete blood count, erythrocyte sedimentation rate, and C-reactive protein, though abnormal in children with pneumonia, lack specificity. Few radiographic features are useful in distinguishing between viral and bacterial pathogens. Pneumonia secondary to viral causes typically has an interstitial pattern on chest radiographs, but lobar consolidation, typical of bacterial pathogens, may also be seen, particularly with respiratory syncytial virus infection. M. pneumoniae infection

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Chapter 67 Table 67-1 Common Causes of Pneumonia by Age Age

Pathogen

1-3 mo

Chlamydia trachomatis Respiratory syncytial virus Parainfluenza virus Metapneumovirus Streptococcus pneumoniae Bordetella pertussis Staphylococcus aureus

3 mo-5 yr

Respiratory syncytial virus Parainfluenza virus Metapneumovirus Influenza Adenovirus Streptococcus pneumoniae Haemophilus influenzae, nontypable* Mycoplasma pneumoniae Streptococcus pyogenes Mycobacterium tuberculosis

5-15 yr

Mycoplasma pneumoniae Chlamydophila pneumoniae Streptococcus pneumoniae Mycobacterium tuberculosis

*Rarely seen in immunocompetent children in developed nations.

characteristically produces diffuse interstitial infiltrates out of proportion to the clinical findings, but it occasionally causes lobar consolidation, pleural effusion (usually small and bilateral, if present), and atelectasis. The most helpful radiographic finding is a significant parapneumonic effusion, which is almost always due to bacterial pathogens. Similarly, the finding of a round infiltrate (“round pneumonia”) is suggestive of pneumococcal pneumonia. Blood cultures are seldom positive in cases of pneumonia. In one study, the rate of bacteremia in children with pneumonia who required hospitalization was approximately 7%.8 In contrast, bacteremia was detected in only 9 of 580 children (1.6%; 95% confidence interval, 0.7 to 2.9) aged 2 to 24 months with pneumonia who were treated as outpatients.9 Both these studies were conducted before introduction of the pneumococcal conjugate vaccine. The epidemiology of childhood pneumonia continues to change as new diagnostic tests identify previously unknown pathogens (e.g., human metapneumovirus)10 and vaccination alters the incidence of other infections. H. influenzae type B, previously a common cause of childhood pneumonia, has been virtually eradicated, and there is evidence that the pneumococcal conjugate vaccine may reduce the incidence of pneumonia by up to 20% in the first 2 years of life.11

Treatment In infants and children diagnosed with pneumonia, indications for hospitalization include young age (younger than 3 months), immunocompromised status, significant pleural effusion or respiratory distress, signs of toxicity, dehydration, inability to tolerate oral antibiotics, lack of response to prior oral antibiotic therapy, and caregivers’ inability to provide adequate care. Children with hypoxia

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necessitating supplemental oxygen at presentation require initial hospitalization. In practice, the most useful diagnostic tests in identifying a pathogen are blood culture, despite its low yield, and viral antigen detection by immunofluorescence on a nasal or nasopharyngeal swab. Bacterial cultures of nasopharyngeal or throat swabs are not indicated because they do not accurately reflect lower respiratory tract flora. Serology for S. pneumoniae and M. pneumoniae may play a role but does not provide results rapidly enough to be practically useful. S. pneumoniae urinary antigen detection tests demonstrate high sensitivity and specificity for diagnosing pneumococcal pneumonia in adults; however, this test is not useful in children because a positive result is strongly associated with nasopharyngeal S. pneumoniae colonization.12,13 Detection of the M. pneumoniae genome in nasopharyngeal secretions by polymerase chain reaction is highly sensitive but not widely available. Thoracentesis performed for a significant parapneumonic effusion can be helpful for diagnostic purposes if the child has not already received prolonged antibiotic therapy (see the later discussion of complicated pneumonia). Tuberculin skin testing and testing of gastric aspirates or induced sputum for mycobacterial culture, acid-fast staining, and nucleic acid amplification should be done if tuberculosis is suspected. Antibiotic therapy is usually empirical (Table 67-2), reflecting the most likely pathogen based on the child’s age (see Table 67-1), clinical presentation, and local resistance patterns. S. pneumoniae is the most frequent cause of bacterial pneumonia in children requiring hospitalization, but it has become increasingly resistant to β-lactam antibiotics. With pneumococci, penicillin resistance is mediated by an alteration in penicillin-binding proteins; therefore, the minimum inhibitory concentrations of all β-lactams increase with those of penicillin. Despite the increase in pneumococcal resistance, β-lactam agents, including penicillin G and ampicillin, are still effective for the treatment of penicillin-nonsusceptible pneumococcal pneumonia, and good outcomes can be achieved with high doses of these agents. Along with penicillin and ampicilln, ceftriaxone and cefotaxime are considered the parenteral drugs of choice for pneumococcal pneumonia. Penicillin resistance in pneumococci does not involve β-lactamse production; therefore, use of a β-lactam–β-lactamase inhibitor combination (e.g., ampicillin-sulbactam) does not provide a therapeutic advantage against penicillin-resistant S. pneumoniae. Vancomycin is the only effective agent in vitro against highly penicillinresistant strains, but there is little role for this drug in the treatment of community-acquired pneumonia. When broader-spectrum coverage is desired (e.g., against S. aureus), combination coverage with a β-lactam that provides antistaphylococcal activity (e.g., oxacillin, ampicillin-sulbactam) or clindamycin should be used. The addition of a macrolide (erythromycin, azithromycin, clarithromycin) can be considered in children older than 5 years and in cases of suspected atypical pneumonia. Telithromycin, a ketolide class antibiotic, was approved in 2004 by the U.S. Food and Drug Administration (FDA) for patients 18 years of age or older. This agent has high activity against respiratory tract pathogens, including penicillin-resistant pneumococci, and in trials it proved to be at least as effective and safe as clarithromycin and azithromycin.14,15 However, recent concerns

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Table 67-2 Empirical Antibiotics for Pneumonia by Age Age

Parenteral Therapy

Oral Therapy

1-3 mo

Penicillin G, ampicillin, or ceftriaxone or cefotaxime, ± erythromycin 40 mg/kg/day

Not recommended

3 mo-5 yr

Penicillin G, ampicillin, or ceftriaxone or cefotaxime, ± macrolide (erythromycin, azithromycin)

Amoxicillin (high dose)* Alternative: cefuroxime

5-15 yr

Penicillin G, ampicillin, or ceftriaxone or cefotaxime, ± macrolide (erythromycin, azithromycin)

Clarithromycin, azithromycin or erythromycin Alternative: amoxicillin (high dose) or cefuroxime or levofloxacin

*High-dose amoxicillin (80-100 mg/kg/d) is used to treat strains of pneumococcus that have some degree of penicillin resistance.

about telithromycin-related hepatotoxicity should prompt pediatricians to consider this medication only if other options are not available. Amoxicillin has the lowest minimum inhibitory concentration against penicillinresistant strains of S. pneumoniae compared with other oral β-lactams and is the oral drug of choice for the treatment of suspected pneumococcal pneumonia. High-dose ampicillin (200 mg/kg per day) is effective in children with pneumonia caused by even resistant pneumococcal strains.16 Although cefuroxime has been used effectively for the treatment of pneumococcal disease, bacteriologic failure and subsequent increased mortality have been reported in adults.17 Stepdown to oral therapy is appropriate once a clinical response has been observed and the child can tolerate oral antibiotics. Chest physiotherapy generally does not have a role in the treatment of uncomplicated community-acquired pneumonia. It may be effective in a child with neurologic or swallowing dysfunction and aspiration pneumonia, helping to mobilize and clear secretions. Follow-up chest radiographs to document resolution are unnecessary in a child with uncomplicated pneumonia who does not have persistent symptoms or signs.18 Repeat radiographs should be reserved for children with complicated pneumonia (e.g., empyema, loculated effusions, pneumatoceles, air leak). SPECIAL CONSIDERATIONS

Aspiration Pneumonia Aspiration pneumonia is a frequent reason for hospital admission and an important cause of morbidity and mortality in neurologically impaired children. Although feeding tubes are now widely used in children with neurologic dysfunction and have led to improved nutritional status and prolonged survival, aspiration pneumonia remains a significant problem and challenge. Aspiration pneumonia and pneumonitis are discussed in Chapter 76. Tuberculosis One third of the world’s population is infected with Mycobacterium tuberculosis, and between 2 million and 3 million people die from the disease each year.19 The 1990s saw a resurgence of tuberculosis (TB) and increasing drug resistance in North America. In children, the TB risk is greatest in those from endemic areas or those having contact with caregivers or visitors from endemic areas, including Asia, Africa, the Caribbean, Latin America, and the Middle East. Aboriginal and disadvantaged populations are also at greater risk.

Pulmonary TB is the most common clinical presentation of the disease in children. Nearly 50% of children with active pulmonary TB are asymptomatic and come to attention when a chest radiograph is performed for other indications. Symptomatic children may present with cough, fever, weight loss, or failure to thrive. Night sweats are uncommon in young children. Extrapulmonary disease, most commonly lymphadenitis, bone and joint infections, and meningitis, can present concurrently. The most common radiographic finding is mediastinal lymphadenopathy; other findings include signs of airway obstruction such as consolidation or atelectasis, miliary disease, and pleural effusions. Cavitary disease, usually seen with reactivation of latent TB, is generally not encountered in young children. Diagnosis is made by isolation of M. tuberculosis by acidfast bacilli staining, culture, or nucleic acid amplification from early-morning gastric aspirates or induced sputum, usually done on 3 consecutive days. However, cultures generally take 2 to 3 weeks to grow, and gastric aspirates are diagnostic in less than 50% of children with pulmonary TB. Therefore, the combination of a positive tuberculin skin test, signs and symptoms consistent with TB disease, and consistent findings on chest radiographs is adequate to identify a case of TB. The tuberculin skin test is interpreted as positive with induration of 5 mm or more in children suspected of having contact with an individual with contagious TB disease, suspected of having TB disease, or with immunosuppression, including human immunodeficiency virus (HIV). Induration of 10 mm or more is considered positive in children younger than 4 years, those with chronic medical conditions (e.g., diabetes), or children with increased exposure to TB (e.g., child or caregiver from a high-prevalence region). Induration of 15 mm or more is considered positive in all individuals.20 Treatment of pan-susceptible pulmonary TB usually consists of isoniazid, rifampin, and pyrazinamide for 2 months, followed by isoniazid and rifampin alone for an additional 4 months. If resistant TB is suspected or proved, four-drug therapy with isoniazid, rifampin, pyrazinamide, and ethambutol is usually recommended for at least 6 months. COMPLICATED PNEUMONIA Parapneumonic effusions are frequently present in children with community-acquired pneumonia. Most of these effusions are small and resolve with successful treatment of the underlying pneumonia. However, some effusions are

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Chapter 67 large or composed of fibrinous loculations, leading to a complex, persistent collection that can cause significant morbidity and requires intervention. Complicated pneumonia can thus be defined as a pneumonic process accompanied by such an effusion, lung abscess, or pneumatocele; complicated parapneumonic effusions are the focus here. There is evidence that the incidence of complicated parapneumonic effusions has been increasing in recent years in both Europe and North America. This is a puzzling development, especially in light of the introduction of the conjugate pneumococcal vaccine, which in some studies has been associated with a reduction in the incidence of pneumococcal lower respiratory tract infection—probably the most common cause of complicated pneumonia in children.21

Pathophysiology Parapneumonic effusions develop in three characteristic stages defined by the length of time and the type of constituent cells and inflammatory response evident in the pleural fluid. The first stage consists of an acute exudative phase characterized by free-flowing fluid composed of acute inflammatory cells in the pleural fluid as a consequence of the adjacent pneumonic process. This stage is relatively brief (<24 to 48 hours), and there may be no further progression if the effusion is small and the underlying pneumonia is treated expeditiously. The second stage is termed the fibrinopurulent phase (lasting 2 to 14 days); it develops after 24 to 48 hours and is characterized by the presence of fibrin, which leads to the formation of strands and pockets of inflammatory fluid that can organize and develop into a chronic collection that does not easily resolve. If parapneumonic effusions are not dealt with in the first and second stages, a third organizing stage can ensue, characterized by the formation of collagen in the pleural space and an inelastic pleural peel that develops around the lung, preventing proper expansion. Stage 3 parapneumonic effusions may require decortication to allow proper lung expansion. It is important to note, however, that this traditional three-stage concept is based primarily on findings in adults with parapneumonic effusions and that in children, this clinical entity has a distinctly different natural history. Further, much of the early literature dealing with parapneumonic effusions dealt specifically with tuberculous infections; this scenario is not easily generalizable to previously healthy children with parapneumonic effusions secondary to community-acquired pneumonia. Thus, it is more practical to think of parapneumonic effusions as existing on a continuum, with free-flowing exudative fluid on one end and multiple loculations or frank pus (empyema) on the other. Significant parapneumonic effusions are generally a consequence of bacterial pneumonia. Although S. aureus was thought to play a significant role in the past, the primary culprit is now S. pneumoniae, with an increasing incidence of group A β-hemolytic streptococcal infections appearing as well. As is the case with community-acquired pneumonia in general, studies of parapneumonic effusions in children are limited by the infrequent identification of a causative organism. This is partly attributable to the fact that diag-

LOWER RESPIRATORY TRACT INFECTIONS

nostic thoracentesis is seldom performed in children and to the fact that children are often treated with antibiotics before a significant parapneumonic effusion develops or is recognized.

Clinical Presentation The presence of a significant parapneumonic effusion is heralded by a combination of signs and symptoms, including persistent fever despite empirical antibiotic therapy for community-acquired pneumonia; respiratory distress; pleuritic chest, shoulder, or abdominal pain; tracheal deviation; scoliosis; and auscultatory findings such as reduced air entry, bronchial breath sounds and egophony above the area of effusion, dullness to percussion, and reduced tactile fremitus in the area of dullness. These auscultatory findings are less reliable in young children. Diagnosis Features to be assessed on plain radiographs include opacification of the pleural space with an underlying parenchymal consolidation, blunting of the costophrenic angle, mediastinal shift, and other features of complicated pneumonia, including air leak, pneumatocele, and lung abscess. A lateral decubitus film can provide further evidence of pleural effusion if doubt exists and can help determine whether the fluid is free-flowing. A width of 10 mm on a decubitus film is considered significant; although this is based on adult literature, it is a practical benchmark for determining whether an effusion needs further investigation and treatment. Ultrasonography can also provide helpful diagnostic information, including a more accurate estimation of the size of the pleural fluid collection and the composition of the effusion. In addition, the presence of stranding and loculations can be determined. In adults, the presence of multiple fluid loculations is predictive of effusions that will not resolve with antibiotic therapy alone and will likely require further intervention.22 Similar prognostic value has been shown in children, but it is not as widely established or accepted. Ultrasonography can be performed without sedation, is not associated with radiation risks, and provides a helpful adjunctive diagnostic modality in children who might require intervention for a parapneumonic effusion. Computed tomography can further delineate the lung parenchyma; this might be useful if a large pneumatocele or abscess develops. In the case of pleural effusion, however, computed tomography does not provide additional relevant information, and it often requires sedation and involves significant radiation exposure. The size of the parapneumonic effusion can help guide management (Fig. 67-1). Small effusions (<10 mm on decubitus films) are likely to resolve without intervention with resolution of the underlying pneumonia. Moderate effusions (>10 mm but less than half the hemithorax) may also resolve with conservative management, but diagnostic thoracentesis should be strongly considered before beginning antibiotic therapy. Large effusions (more than half the hemithorax) are much more likely to require therapeutic as well as diagnostic intervention.22 Thoracentesis can provide helpful diagnostic information in addition to identifying an organism by

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SYSTEMS APPROACH culture. Pleural pH less than 7.20 and a glucose level less than 2.4 mmol/L have been associated with complicated effusions that are likely to require intervention (Table 67-3).22 Once again, these criteria have been established in adults; it is unclear whether they have similar diagnostic utility in children.

EFFUSION SUSPECTED CLINICALLY

⬎10 mm on decubitus CXR

No

Yes

Continue with conservative Rx

Consider thoracentesis and ultrasound of chest for effusion size and characteristics

No

Large/loculated

Yes

Consider thoracostomy tube ⫹Ⲑ⫺ fibrinolytics or VATS if • Persistent fever • Poor response to antibiotics • Respiratory distress • Poor prognostic factors on UⲐS (multiple loculations) or pleural fluid analysis (pH ⬍7.2, glucose ⬍2.4 mmol/mL)

Figure 67-1 Algorithm for the management of parapneumonic effusion. CXR, chest x-ray; Rx, treatment; U/S, ultrasonography; VATS, video-assisted thoracoscopic surgery.

Treatment Antibiotic Therapy Various studies of the epidemiology of parapneumonic effusions have identified the importance of S. pneumoniae, group A streptococci, and, to a lesser extent, S. aureus as the most important causative agents. Cefuroxime provides good empirical coverage against these pathogens; others advocate more extended combination therapy consisting of cefotaxime and either an antistaphylococcal penicillin (e.g., cloxacillin, oxacillin, nafcillin) or clindamycin. Treatment can be narrowed if an organism is identified through blood or pleural fluid culture. In areas with a high prevalence of methicillin-resistant S. aureus, empirical therapy should include either clindamycin or vancomycin. Data on the optimal duration of treatment are lacking. Once the fever resolves, children with a relatively straightforward course can receive oral antibiotic therapy for an additional 7 to 10 days. In children with more complicated courses, an additional 7 to 14 days of intravenous antibiotic therapy should be considered after the resolution of fever. The typical duration of therapy is 21 days. Adjunctive Therapy A major clinical decision is whether further therapy should be undertaken for a significant parapneumonic effu-

Table 67-3 Pleural Fluid Studies in Complicated Pneumonia Study Routine Cell count and differential

Glucose pH LDH Gram stain Acid fast stain Cultures* Additional studies to consider Mycoplasma PCR Viral antigen immunofluorescence Viral culture Total protein Amylase Cholesterol Cytology Chylomicrons, triglycerides

Comments Usually >10,000 U/mL in parapneumonic effusion PMN predominance in bacterial PPE Lymphocytes and mononuclear cells predominate in TB, lymphoma, chylothorax Low glucose (<40 mg/dL) more likely to require intervention Low pH (<7.20) more likely to require intervention If high (>1000 U/mL) or pleural fluid-plasma ratio >0.6, more likely to be exudative effusion and require intervention If positive, more likely to require intervention May be positive with Myocbacterium tuberculosis or Nocardia Insensitive in setting of prior antibiotic therapy Also obtain PCR of nasal aspirate Also obtain immunofluorescence of nasal aspirate; consider PCR testing for adenovirus May be positive with negative immunofluorescence Indicative of exudates if >3 g/dL and pleural-serum ratio >0.5 If concern for pancreatic disease or esophageal rupture If >60 mg/dL and pleural fluid-cholesterol ratio >0.3, indicative of exudate To exclude malignancy Along with cholesterol if chylothorax suspected

*Aerobic and anaerobic; consider mycobacterial and fungal. LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PMN, polymorphonuclear neutrophils; PPE, parapneumonic effusion; TB, tuberculosis.

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Chapter 67 sion, and what that therapy should be. Severe respiratory distress with or without a mediastinal shift in the setting of a large effusion is a clear indication for drainage, but this scenario is uncommon. The most common factors taken into consideration include persistent fever after initial parenteral antibiotic therapy has begun, significant chest pain, largesized effusions, and inadequate improvement with conservative therapy alone. The results of ultrasound studies and pleural fluid analysis may be predictive of effusions that are destined to fail antibiotic therapy and warrant early intervention. The available options include prolonged antibiotic therapy alone, serial therapeutic thoracentesis, thoracostomy tube drainage, thoracostomy tube insertion with intrapleural fibrinolytic therapy, video-assisted thoracoscopic surgery (VATS), and open surgical intervention. In adults, a clinical practice guideline has advocated fibrinolytic therapy, VATS, or open surgery in the management of high-risk parapneumonic effusions, as defined by radiographic and pleural fluid criteria.22 However, adult studies and guidelines are not easily applicable to children. Parapneumonic effusions are associated with significant mortality in adults—an outcome that is very uncommon in children—and adults frequently have comorbid conditions. Disease in adults is thus more severe and justifies a more aggressive treatment approach. In children, outcomes such as length of hospital stay, need for second procedures, time to recovery, school absenteeism, effect on pulmonary function and radiographic tests, and cost are more important measures of efficacy. Few studies have been performed in children comparing the various treatment options. One randomized study compared intrapleural fibrinolytic therapy with saline placebo in children who had undergone thoracostomy tube insertion for drainage of a parapneumonic effusion.23 The rationale for using intrapleural fibrinolytics is that they break down the fibrin loculations in the effusion, leading to increased drainage and subsequent resolution of the effusion. The study found a significant reduction in hospital stay in the group treated with intrapleural urokinase. It also found that the use of small-caliber, flexible catheters, which can be inserted by interventional radiologists, was associated with less discomfort. Urokinase has been unavailable in recent years, however, owing to its derivation from human urine. Similarly, streptokinase has been used as an intrapleural fibrinolytic, but because of the relatively high incidence of adverse reactions, such as fever and chest wall pain, physicians are reluctant to use it. A recent nonrandomized study found intrapleural recombinant tissue plasminogen activator to be an effective and safe fibrinolytic therapy in children who did not respond well to thoracostomy tube drainage alone.24 Studies in both adults and children have shown intrapleural fibrinolysis to be a safe therapy, with infrequent local or systemic bleeding owing to its minimal systemic absorption. Most studies describe using either one dose or multiple (up to six) doses of fibrinolytics instilled into the pleural cavity through a thoracostomy tube and left in place for 1 to 12 hours before resuming drainage. The dose of tissue plasminogen activator used in published studies has ranged from 2 mg (the standard dose for treatment of blocked venous catheters) to 4 mg diluted in 20 to 50 mL of saline. Recent authors have advocated early surgical management, including VATS, as the preferred treatment for para-

LOWER RESPIRATORY TRACT INFECTIONS

pneumonic effusions. They cite nonrandomized studies describing reduced hospital stays in children treated with primary surgical intervention compared with those treated initially with fibrinolytics or thoracostomy drainage alone.25 VATS involves the insertion of instruments and cameras through small keyhole incisions, disrupting the fibrinous loculations and effecting drainage and lung reexpansion. Thoracostomy tubes are left in place after the procedure. Disadvantages of VATS include the requirement for general anesthesia (thoracostomy tube insertion can be achieved with sedation or local anesthesia), the need for multiple incisions, and the learning curve for surgeons to achieve proficiency in the procedure. A meta-analysis was performed of studies comparing primary nonoperative therapy (e.g., thoracentesis, thoracostomy tube drainage) with primary operative therapy (e.g., thoracotomy, VATS).26 The primary outcome assessed was therapeutic failure—defined as failure of a primary intervention, necessitating subsequent operative intervention. Among the eight studies included in this analysis, patients undergoing primary operative intervention had a lower risk of therapeutic failure (relative risk, 0.09; 95% confidence interval, 0.04 to 0.23) compared with those receiving nonoperative therapy. However, the meta-analysis was limited by the fact that all the included studies were retrospective and nonrandomized and that none had been adjusted for potentially important confounding variables such as age, organism, or use of fibrinolytic therapy. Further, contrasting the available treatment options by comparing outcomes is difficult. Studies included different patient populations, and management strategies varied dramatically by center. For example, some studies addressing parapneumonic effusions included only children who had failed prolonged conservative therapy with thoracostomy tube drainage and antibiotics alone. Others studied children treated with various therapies early in the course of the disease, when a benefit was more likely to be observed. These confounding variables are highlighted by the fact that some series reported a need for open surgical procedures in nearly 20% of patients, while others reported no need for surgical intervention. These limitations underscore the need for large prospective, controlled trials to determine which children with complicated parapneumonic effusions benefit from further treatment and which option is the preferred therapy. To obtain adequately powered studies, it is likely that multicenter trials will be necessary.

Course of Illness Once the child has improved clinically, a step-down to oral antibiotics is appropriate. Children who respond rapidly to treatment are often treated for 10 to 14 days, or for a week after defervescence. Those with a more protracted illness and slow radiographic resolution may be treated empirically for several more weeks. Follow-up chest radiographs are indicated for children with complicated pneumonia to ensure resolution. Radiographic resolution generally takes weeks to months, and pleural thickening months after the illness is not uncommon. Few studies have addressed long-term outcomes; however, in the small number of children who have undergone pulmonary function testing, few abnormalities were found.27

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Admission Criteria In infants and children with a diagnosis of pneumonia, factors to consider when decision regarding hospitalization is made include Young age (<3 months) Immunocompromised status Significant pleural effusion Indications for admission would include Respiratory distress Hypoxemia Signs of toxicity Lack of response to prior oral antibiotic therapy Inability to maintain hydration status and tolerate oral antibiotics Inability of caregivers to manage patients at home

• • • • • • • • •

Consultation Consultation with general surgery or cardiothoracic surgery can assist with diagnostic evaluation and management, including diagnostic/therapeutic thoracentesis, chest tube, or definitive surgery (decortication or VATS). Consultation with infectious diseases can provide guidance regarding empiric antibiotic therapy, especially since the organisms are not commonly isolated.

•

history, diagnosis, and treatment of this condition. Future studies will need to address these issues so that more rational and informed management decisions can be made. Collaboration among centers will be required for adequately powered studies to be achieved.

In a Nutshell

• Fever, cough, tachpnea, and focal findings on auscul•

•

•

Discharge Criteria Resolution of toxicity, respiratory distress, and hypoxemia Removal of chest tubes and confirmation that follow-up chest radiographs show no recurrence of significant effusion or pneumothorax Ability to maintain hydration and to tolerate oral medications, including antibiotics and pain medication if needed Adequate follow-up with primary care physician or, if needed, subspecialist

• • • •

On the Horizon

• Pneumonia will clearly be an important condition

•

encountered in the hospitalized child. Many of the upcoming developments are likely to relate to the increasing array of practical diagnostic tests that are available to the clinician to better identify causal pathogens and to allow anti-infective therapy to be appropriately tailored. Nucleic acid amplification techniques are likely to become more widely used and standardized. The effect of the conjugate pneumococcal vaccine on the incidence of pneumococcal pneumonia and lower respiratory tract infections in general in children will be further elucidated, and the epidemiology may be further altered by future vaccinations. Concerns regarding increased antibiotic resistance as well the potential increase in tuberculosis and emerging infections are just several potential sources of concern. The incidence of complicated pneumonias has been increasing. Despite this recognition, there is a lack of adequate studies relating to the epidemiology, natural

•

tation or chest radiography are characteristic of pneumonia. Pathogens that cause pneumonia are not commonly isolated; therefore, antibiotic coverage is usually empirically based on the most likely pathogen. Factors such as the patient’s age, clinical presentation, and local antibiotic resistance patterns are guiding factors. Parapneuomonic effusions generally progress from a free-flowing to fibropurulent fluid in the first few days. A third organizing stage with development of an inelastic pleural peel can ensue over the following days to weeks. The size and nature of pleural effusions as well as the patient’s condition can help guide medical and interventional management of complicated pneumonia.

SUGGESTED READING Colice GL, Curtis A, Deslauriers J, et al: Medical and surgical treatment of parapneumonic effusions: An evidence-based guideline. Chest 2000;18:1158-1171. Hilliard TN, Henderson AJ, Langton Hewer SC: Management of parapneumonic effusion and empyema. Arch Dis Child 2003;88:915-917. Lichenstein R, Suggs AH, Campbell J: Pediatric pneumonia. Emerg Med Clin North Am 2003;21(2):451-473.

PERTUSSIS Pertussis is an acute infectious disease caused by the bacterium Bordetella pertussis. Outbreaks of pertussis were described as early as the 15th century, but the causative bacterium was not isolated until 1906. Pertussis is also called whooping cough, which is descriptive of the high-pitched inspiratory noise (“whoop”) made by infected children. Pertussis was one of the most common childhood diseases in the 20th century and a major cause of childhood mortality in the United States. There were more than 200,000 cases of pertussis reported annually before pertussis vaccine became available in the 1940s. With the advent of widespread vaccination in the United States, the incidence has decreased more than 80% compared with the prevaccine era. Pertussis remains a major health problem among children in developing countries, however, with an estimated 285,000 deaths resulting from the disease worldwide in 2001. In the United States, adolescents and adults have accounted for more than half of reported pertussis cases in recent years. There are periods of increased disease that occur in 3- to 5-year cycles.

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Pathophysiology Pertussis is primarily a toxin-mediated disease, and B. pertussis is only infectious in humans. B. pertussis is a gramnegative nonmotile coccobacillus that is acquired by contact with aerosolized droplets from infected patients, and infection is limited to the ciliated epithelium of the respiratory tract. The bacteria attach to the respiratory cilia and produce toxins that paralyze the cilia, cause inflammation of the respiratory tract, and impair clearance of pulmonary secretions. A variety of pertussis components and their contribution to disease have been studied. The antigenic and biologically active components currently thought to be responsible for the clinical features of pertussis disease include pertussis toxin, filamentous hemagglutinin, agglutinogens, adenylate cyclase, pertactin, and tracheal cytotoxin. The pertussis toxin is the major virulence protein and is expressed only by B. pertussis. It aids attachment of the bacteria to respiratory epithelium and has multiple systemic effects, including enhancement of insulin secretion, inhibition of leukocyte phagocytic function, and induction of lymphocytosis by inhibition of migration from the bloodstream. Filamentous hemagglutinin, pertactin, and agglutinogens play a role in the attachment to respiratory epithelium. Adenylate cyclase contributes to impairing the phagocytic function of lymphocytes, and tracheal toxin has a role in ciliary stasis. An immune response to one or more of these components produces immunity to subsequent clinical illness, although that immunity is not permanent. Clinical Presentation B. pertussis disease presents with a wide clinical spectrum, and several clinical case definitions for pertussis exist. Pertussis is defined by the World Health Organization as a case diagnosed as pertussis by a physician in a person with a cough lasting at least 2 weeks with at least one of the following symptoms: paroxysms of coughing, inspiratory whooping, and post-tussive vomiting without other apparent cause. The incubation period is commonly 7 to 10 days, with a range of 4 to 21 days. The clinical course of the illness is typically divided into three stages: catarrhal, paroxysmal, and convalescent. The first stage, the catarrhal stage, is characterized by nonspecific symptoms such as rhinorrhea, sneezing, low-grade fever, and a mild cough. Caregivers often do not seek medical attention for these common symptoms, especially in infants and young children. These nondistinctive symptoms rarely prompt investigation even if such patients are brought to medical attention. Over the subsequent 1 to 2 weeks the cough gradually becomes more severe and the second stage, the paroxysmal stage, begins. Fever is usually minimal through the course of illness. During the paroxysmal stage of classic pertussis disease the patient has bursts of numerous, rapid coughs, and at the end of the paroxysm, a long inspiratory effort is usually accompanied by a characteristic high-pitched crowing or whoop as air is inspired across an inflamed partially closed glottis. Patients younger than 6 months of age may not have the strength to have a whoop, but they will have paroxysms of coughing and may also have choking, gasping, or apnea. Thick, clear mucus may be discharged with the coughing

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spells. Children and young infants often appear ill and distressed during the attack. A range of color changes may be seen, including cyanosis or pallor, and some children may develop a plethoric appearance to the face during coughing spells. Post-tussive emesis and exhaustion commonly follow the event. The patient’s appearance is usually normal after recovery from the coughing paroxysm. During the first 1 or 2 weeks of the paroxysmal stage, the coughing spells typically increase in frequency, then remain at the same level for 2 to 3 weeks, and then will gradually decrease. Paroxysms may occur more frequently at night. The paroxysmal stage usually lasts 1 to 6 weeks but may persist for up to 10 weeks before entering the third stage. In the third stage, the convalescent stage, the cough becomes less paroxysmal and gradually disappears over several weeks. Paroxysms often recur, especially with subsequent respiratory infections, for many months after the onset of pertussis. This is not due to reactivation or reinfection with B. pertussis. Adolescents, adults, and those partially protected by vaccination may still become infected with B. pertussis but will often have milder disease and usually do not demonstrate three distinct stages of disease. They may be asymptomatic or may present with illness ranging from a mild cough to classic pertussis, with persistent cough lasting more than 7 days. Inspiratory whoop is uncommon in this population.

Differential Diagnosis Prolonged cough may be seen with adenovirus, parainfluenza, influenza, respiratory syncytial virus (RSV), or Mycoplasma pneumoniae infection and may be difficult to distinguish from pertussis. Co-infection with more than one respiratory pathogen is not uncommon. Adenovirus may present with sore throat and conjunctivitis not typical of pertussis. Mycoplasma may also present with fever, headache, and lung examination findings, such as rales, with patchy infiltrates on chest radiograph that are not common with pertussis. Pneumonia due to Chlamydia trachomatis or pneumoniae classically presents with a staccato cough, which implies a breath with each cough. Tachypnea, rales, and wheezes are often present. Patients with RSV infection often have prominent rhinorrhea with bronchiolitis symptoms that accompany or closely follow the nasal symptoms. Bordetella parapertussis causes a similar although milder disease and is seen predominantly in Europe. Infection with Bordetella bronchiseptica is more commonly an animal infection although there are case reports of human infection. Foreign body aspiration, gastroesophageal reflux, aspiration pneumonia, and asthma/reactive airways disease are noninfectious processes that may also present with intractable or prolonged cough (see Chapter 45). Diagnosis The gold standard for diagnosis of pertussis is isolation of B. pertussis by culture. The fastidious nature of this organism results in the need for careful collection and culture methods. Isolation of B. pertussis using direct plating is most successful during the catarrhal stage. Specimens should be obtained from the posterior nasopharynx, not from the throat. Cotton swabs should not be used because they will inhibit the growth

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of B. pertussis. Samples should be obtained using Dacron or calcium alginate swabs or by aspiration and should be plated directly onto the selective media. A holding broth or transport medium should be used if plating is not performed immediately. The cultures are grown for 10 to 14 days. Success in isolating the organism declines if the patient has had prior antibiotic therapy effective against B. pertussis, if specimen collection is delayed beyond the first 2 weeks of illness, or if the patient has been vaccinated. Polymerase chain reaction (PCR) testing of nasopharyngeal swabs or aspirates is an increasingly available rapid, sensitive, and specific method of diagnosing pertussis. However, there are currently no FDA-licensed PCR tests available. Many recommend the use of PCR in addition to culture, not as a replacement for culture, because bacterial isolates may be required for evaluation of antimicrobial resistance or for molecular typing. Dacron swab or nasal wash is the recommended method of collection; calcium alginate swabs inhibit PCR and therefore should not be used for PCR testing.28 Direct fluorescent antibody (DFA) testing of nasopharyngeal specimens may be useful as a screening test for pertussis. However, DFA testing of nasopharyngeal secretions has been shown in some studies to have low sensitivity and variable specificity. An elevated IgG titer to pertussis toxin is suggestive of recent infection in an individual who has not received immunization within 2 years. However, there are currently no commercially available serologic tests that are approved by the FDA and diagnostic levels have not been established.28 Leukocytosis due to lymphocytosis occurs in the late catarrhal and paroxysmal stages in unimmunized patients who may present with classic disease. Lymphocyte counts above the mean are seen in more than 75% of unimmunized patients with pertussis but only one third of pertussis patients demonstrate a significant lymphocytosis (values above the upper limit of the 95% confidence interval of the age-specific mean).29 The lymphocytes seen in pertussis are not atypical cells. Patients with mild or modified cases of pertussis and adolescents may not present with lymphocytosis.

Complications Complications of pertussis may include pneumonia, middle ear infection, anorexia, dehydration, failure to thrive, seizures, rectal prolapse, encephalopathy, pulmonary hypertension, apneic episodes, and death. Eighty percent of deaths from pertussis occur in children under age 1 year.30-32 The case fatality rate in 1990-1999 was 1% in infants 0 to 2 months of age and 0.5% in infants 2 to 11 months of age.33 The most common complication, as well as the cause of most pertussis-related deaths, is secondary bacterial pneumonia. Neurologic complications such as seizures and encephalopathy may occur as a result of hypoxia from coughing, or possibly from toxin. Neurologic complications of pertussis are more common among infants. Complications resulting from pressure effects of severe paroxysms include pneumothorax, epistaxis, hernias, and rectal prolapse. Adolescents and adults may also develop complications of pertussis such as difficulty sleeping, urinary incontinence, and pneumonia.

Treatment/Management The single most effective control measure is maintaining the highest possible level of immunization in the community. Anyone who comes into close contact with a person who has pertussis should receive antibiotics to prevent spread of the disease. People who have or may have pertussis should stay away from young children and infants until properly treated. Treatment during the catarrhal stage may lead to resolution of the infection or may alleviate symptoms. Treatment during the paroxysmal or convalescent phases will have limited effect on established paroxysms, emesis, or apnea but is recommended in order to limit the spread of disease to others. Prophylaxis is recommended for household contacts. Macrolide agents are the first-line treatment choices. According to Centers for Disease Control and Prevention (CDC) guidelines published in 2005, for patients greater than 1 month of age, azithromycin, clarithromycin, or erythromycin is preferred for treatment. For infants less than 1 month of age, azithromycin is the drug of choice, and clarithromycin and erythromycin are not recommended. In these neonates, trimethoprim-sulfamethoxazole (TMPSMZ) is the recommended alternative agent.28,34 These recommendations from the CDC are provided despite the fact that the FDA has not licensed any macrolide for use in infants less than 6 months of age. Specific dosing recommendations are provided in Table 67-4. Postexposure prophylaxis is recommended for household contacts and those in close contact with an infectious patient. Dosing is the same as for treatment (see Table 67-4). Admission Criteria Indications for admission include severe paroxysms of cough, cyanosis or apnea with or without cough, extreme fatigue or apnea after cough, obstruction after cough (from mucous plugs), inability to feed, and seizures. Children may also need to be hospitalized for pneumonia, the most common complication of pertussis. Infants younger than 6 months commonly require hospitalization for management of apnea, hypoxia, and feeding difficulties. Intensive care may be required for infants with severe respiratory failure, pulmonary hypertension, or severe apnea and hypoxia requiring ventilator support. Supportive care is the mainstay of management. Environmental stimulation should be limited, a detailed cough record should be maintained, and oral intake with daily weights should be recorded. Electronic monitoring for heart rate, respiratory rate, and oxygen saturation is also indicated. Patients should be placed on standard and droplet precautions for the first 5 days on effective treatment or for 21 days after the onset of symptoms if untreated. Discharge Criteria Infant can tolerate adequate oral or enteral fluids and nutrition to maintain hydration and gain weight. Infant does not become hypoxic or bradycradic with coughing episodes. Caretakers are reliable and comfortable with infant’s condition. Reliable outpatient follow-up has been established.

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Table 67-4 Recommended Antimicrobial Treatment and Postexposure Prophylaxis for Pertussis, by Age Group PRIMARY AGENTS

ALTERNATE AGENT*

Age Group

Azithromycin

Erythromycin

Clarithromycin

TMP-SMZ

<1 month

Recommended agent; 10 mg/kg per day in a single dose for 5 days (only limited safety data available)

Not preferred; erythromycin is associated with infantile hypertrophic pyloric stenosis; use if azithromycin is unavailable; 40-50 mg/kg per day in 4 divided doses for 14 days

Not recommended (safety data unavailable)

Contraindicated for infants aged <2 months (risk for kernicterus)

1-5 months

10 mg/kg per day in a single dose for 5 days

40-50 mg/kg per day in 4 divided doses for 14 days

15 mg/kg per day in 2 divided doses for 7 days

Contraindicated at age <2 months; for infants aged ≥2 months, TMP 8 mg/kg per day, SMZ 40 mg/kg per day in 2 divided doses for 14 days

Infants (aged ≥6 months) and children

10 mg/kg in a single dose on day 1 then 5 mg/kg per day (maximum: 500 mg) on days 2-5

40-50 mg/kg per day (maximum: 2 g per day) in 4 divided doses for 14 days

15 mg/kg per day in 2 divided doses (maximum: 1 g per day) for 7 days

TMP 8 mg/kg per day, SMZ 40 mg/kg per day in 2 divided doses for 14 days

Adults

500 mg in a single dose on day 1 then 250 mg per day on days 2-5

2 g per day in 4 divided doses for 14 days

1 g per day in 2 divided doses for 7 days

TMP 320 mg per day, SMZ 1600 mg per day in 2 divided doses for 14 days

*Trimethoprim sulfamethoxazole (TMP-SMZ) can be used as an alternative agent to macrolides in patients aged ≥2 months who are allergic to macrolides, who cannot tolerate macrolides, or who are infected with a rare macrolide-resistant strain of Bordetella pertussis. From Centers for Disease Control and Prevention: Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR 2005;54(No. RR-14):1-16.

Consultation The need for cardiorespiratory support warrants involvement with intensivists. Subspecialty consultation is usually prompted by the development of specific complications (e.g., if seizures or encephalopathy develop, input from pediatric neurologists may be appropriate). Prevention The incidence of pertussis has markedly decreased worldwide with the advent of effective vaccinations. Major epidemics have been mostly eliminated. Current vaccination strategies fail to control the circulation of B. pertussis in part because they do not capture the adolescent and adult reservoirs and in part because there is inadequate adherence to immunization guidelines worldwide. The vaccination effort has shifted pertussis epidemiology and now we see a reported increase in the incidence of pertussis among adolescents and adults, who function as a reservoir of pertussis for neonates and infants. Studies suggest that vaccine-induced cellular and humoral immunity lasts 3 to 5 years. Booster vaccination induces another 7 to 8 years of immunity. Natural infection with B. pertussis seems to confer a similar length of immunity as vaccination with whole cell pertussis (5 to 8 years).

Children who have recovered from documented pertussis do not need additional doses of pertussis vaccine. Satisfactory documentation includes recovery of B. pertussis on culture or typical symptoms and clinical course when these are epidemiologically linked to a culture-confirmed case. If confirmation of pertussis infection is lacking, vaccination should be completed. In 2005, the FDA licensed two new Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis) vaccines for adolescents and adults. On the Horizon

• Pertussis has persisted in the adult and adolescent reservoir. The emergence of new pertussis variants from the strains that form the basis for the pertussis vaccines (whole cell and acellular) raises concerns for future vaccine effectiveness. There is no current laboratory or epidemiologic evidence to indicate a relationship between the genetic variations among the isolates and the effectiveness of current immunization practices, vaccine types, or the increasing incidence of pertussis. Recently licensed (2005) vaccines targeting adolescents (10 to 18 years of age) and people 11 to 64

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years of age should offer immune boosting to our reservoir and should also reduce the incidence of disease in infants and young children. Vaccines that target the reservoir of pertussis infection can help achieve herd immunity and possible eradication. Resistance of B. pertussis to macrolide agents has been reported rarely. Monitoring of the resistance pattern is ongoing.

In a Nutshell

• Pertussis should be suspected in infants and children

•

• • • •

with paroxysmal cough or severe cough for more than 5 to 7 days. Infants who develop apnea, cyanosis, or gagging with cough should be evaluated for pertussis. Culture is the gold standard when pertussis is suspected, but polymerase chain reaction testing is becoming a more widely available test that provides more rapid results. Confirmed cases of pertussis should be reported. Macrolide antibiotics are the first choice for treatment and postexposure prophylaxis of pertussis. All close contacts should receive prophylaxis. Management is primarily supportive care. Immunization is essential for control and goals of future eradication of this disease. Adolescents and adults are currently the reservoir for this disease and should also be evaluated for delayed or inadequate immunization to pertussis.

Suggested Reading American Academy of Pediatrics: Pertussis. In Pickering LK (ed): Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006, pp 498-520. Centers for Disease Control and Prevention: Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis. 2005 CDC Guidelines. MMWR 2005;54(No. RR-14):1-16. Tan T: Summary: Epidemiology of pertussis. Pediatr Infect Dis J 2005;24(5 Suppl):S35-38.

References 1. Low DE, Kellner JD, Allen U, et al: Community-acquired pneumonia in children: A multidisciplinary consensus review. Can J Infect Dis 2003; 14(Suppl B):3B-11B. 2. Lichenstein R, Suggs AH, Campbell J: Pediatric pneumonia. Emerg Med Clin North Am 2003;21:451-473. 3. Dowell SF, Kupronis BA, Zell ER: Mortality from pneumonia in children in the United States, 1939 through 1996. N Engl J Med 2000;342:13991407. 4. Wubbel L, Muniz L, Ahmed A, et al: Etiology and treatment of community-acquired pneumonia in ambulatory children. Pediatr Infect Dis J 1999;18:98-104. 5. Margolis P, Gadomski A: Does this infant have pneumonia. JAMA 1998;279:308-313. 6. Jadavji T, Law B, Lebel MH, et al: A practical guide for the diagnosis and treatment of pediatric pneumonia. Can Med Assoc J 1997;156:S703S711. 7. Turner RB, Lande AE, Chase P, et al: Pneumonia in pediatric outpatients: Cause and clinical manifestations. J Pediatr 1987;111:194-200.

8. Byington CL, Spencer LY, Johnson TA, et al: An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema R risk factors and microbiological associations. Clin Infect Dis 2002;34:434-440. 9. Shah SS, Alpern ER, Zwerling L, et al: Risk of bacteremia in young children with pneumonia treated as outpatients. Arch Pediatr Adolesc Med 2003;157:389-392. 10. Williams JV, Harris PA, Tollefson SJ, et al: Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med 2004;350:443-450. 11. Black SB, Shinefield HR, Ling S, et al: Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:810-815. 12. Dowell SF, Garman RL, Liu G, et al: Evaluation of Binax Now, an assay for detection of pneumococcal antigen in urine samples, performed among pediatric patients. Clin Infect Dis 2001;32:824-825. 13. Dominguez J, Blanco S, Rodrigo C, et al: Usefulness of urinary antigen detection by an immunochromatographic test for diagnosis of pneumococcal pneumonia in children. J Clin Microbiol 2003;41:2161-2163. 14. Stratton CW, Brown SD: Comparative in vitro activity of telithromycin and beta-lactam antimicrobials against community-acquired bacterial respiratory tract pathogens in the United States: Findings from the PROTEKT US study, 2000-2001. Clin Ther 2004;26:522-530. 15. Tellier G, Niederman MS, Nusrat R, et al: Clinical and bacteriological efficacy and safety of 5 and 7 day regimen of clarithromycin twice daily in patients with mild to moderate community-acquired pneumonia. J Antimicrob Ther 2004;54:515-523. 16. Pallares R, Linares J, Vadillo M, et al: Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia from Barcelona, Spain. N Engl J Med 1995;333:474-480. 17. Yu VL, Chiou CC, Feldman C, et al: An international prospective study of pneumococcal bacteremia: Correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003;37:230237. 18. Gibson NA, Hollman AS, Paton JY: Value of radiological follow up of childhood pneumonia. BMJ 1993;307:1117. 19. Smith KC: Tuberculosis in children. Curr Probl Pediatr 2001;1:5-30. 20. American Academy of Pediatrics: Tuberculosis. In Pickering LK (ed): Red Book: 2003 Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, Ill, American Academy of Pediatrics, 2003, p 643. 21. Byington CL, Spencer LY, Johnson TA, et al: An epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: Risk factors and microbiological associations. Clin Infect Dis 2002;34:434-440. 22. Colice GL, Curtis A, Deslauriers J, et al: Medical and surgical treatment of parapneumonic effusions: An evidence-based guideline. Chest 2000;18:1158-1171. 23. Thomson AH, Hull J, Kumar MR, et al: Randomized trial of intrapleural urokinase in the treatment of childhood empyema. Thorax 2002;57:343347. 24. Weinstein M, Restrepo R, Chait PG, et al: Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Pediatrics 2004;113:e182-e185. 25. Hilliard TN, Henderson AJ, Langton Hewer SC: Management of parapneumonic effusion and empyema. Arch Dis Child 2003;88:915-917. 26. Avansino JR, Goldman B, Sawin RS, Flum DR: Primary operative versus nonoperative therapy for pediatric empyema: A meta-analysis. Pediatrics 2005;115:1652-1659. 27. Redding GJ, Walund L, Walund D, et al: Lung function in children following empyema. Am J Dis Child 1990;144:1337-1342. 28. American Academy of Pediatrics: Pertussis. In Pickering LK, Baker CJ, Long SS, McMillan JA (eds): Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006, pp 498-520. 29. Heininger U, Klich K, Stehr K, Cherry JD: Clinical findings in Bordetella pertussis infections: Results of a prospective multicenter surveillance study. Pediatrics 1997;100:10.

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Chapter 67 30. Crowcroft NS, Andrews N, Rooney C, et al: Deaths from pertussis are underestimated in England. Arch Dis Child 2002;86:336-338. 31. Van Buynder PG, Owen D, Vurdien JE, et al: Bordetella pertussis surveillance in England and Wales: 1995-1997. Epidemiol Infect 1999;123:403. 32. Crowcroft NS, Pebody RG: Recent developments in pertussis. Lancet 2006;367;1926-1936.

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33. Vitek CR, Pascual FB, Baughman A-I, Murphy TV: Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J 2003;22:628-634. 34. Centers for Disease Control and Prevention: Recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: 2005 CDC guidelines. MMWR 2005;54(No. RR-14): 1-16.

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