Introduction

Pneumonia is an acute infection of the lower airways with the potential to cause significant respiratory distress including tachypnea and increased work of breathing (see Table 1). Hospitalization is recommended for all young infants and those children with moderate to severe disease characterized by hypoxemia in the setting of respiratory distress. Community-acquired pneumonia (CAP) is a leading cause for pediatric hospitalization in the USA, with over 100,000 hospital admissions annually. Disease burden is highest among children under 5 years of age; this population accounts for two thirds of all pneumonia hospitalizations in children [1]. Prematurity and young age increase a child’s risk of developing pneumonia. Modifiable risk factors for pediatric CAP include crowded living conditions, secondhand smoke exposure, and poor nutritional status [2–4].

Table 1 Signs of respiratory distress in pediatric CAP
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Etiology of pediatric CAP

Pneumonia etiology varies by age, underlying conditions, geographic location, vaccine exposure, and seasonality. The introduction of pneumococcal conjugate vaccines (PCV) into childhood immunization schedules has changed the epidemiology of CAP in the USA and worldwide. Methods for identifying viral pathogens continue to improve, highlighting the enormous burden of viruses contributing to pneumonia in children. Several large-scale epidemiologic studies using comprehensive, modern diagnostic methods are currently underway, notably the Pneumonia Etiology Research for Child Health project (PERCH) focusing on the developing world and the Centers for Disease Control and Prevention Epidemiology of Pneumonia in the Community (EPIC) study in the USA [5].

Bacterial causes of CAP

Common bacterial pathogens

Streptococcus pneumoniae remains the most common bacterial pathogen causing pneumonia in children. Staphylococcus aureus and Streptococcus pyogenes are much less common but frequently associated with severe disease. Mycoplasma pneumoniae, and to a lesser extent, Chlamydophila pneumoniae, are common in school-aged children, but also occasionally implicated in cases of pneumonia among younger children [6]. Staphylococcus aureus should be considered when pneumonia is complicated by pleural effusion, empyema, or necrotizing/cavitary lesions, and in children requiring intensive care unit (ICU) admission for respiratory failure or septic shock [7].

The role of pneumococcal conjugate vaccines

Streptococcus pneumoniae causes invasive disease in children ranging from lower respiratory tract infections to meningitis. A seven-valent pneumococcal polysaccharide conjugate vaccine (PCV-7) was licensed in 2000, providing protection from the most common virulent pneumococcal serotypes. PCV-7 has nearly eliminated invasive pneumococcal disease (IPD) due to vaccine serotypes, with disease rates in US children under 5 years old falling from 78.9 cases per 100,000 in the pre-vaccine years 1998–1999 to 2.7 cases per 100,000 in 2004 [8]. This translates into an estimated 47,000 fewer hospitalizations for pneumonia annually in children under 2 years old in 2007–2009 as compared to the pre-vaccine years 1997–1999 [9]. Analysis of data from the State Inpatient Databases in 10 states over a 10-year period following introduction of PCV-7 showed significant reductions in IPD and pneumonia in all age groups, suggesting the development of herd immunity from childhood PCV immunization programs [10]. The 13-valent pneumococcal conjugate vaccine (PCV-13) replaced PCV-7 in 2010, expanding coverage to include six additional virulent pneumococcal serotypes. Culture-proven IPD rates decreased 53 % among eight hospitals in children under 2 years old from 2000 to 2009 to 2011, with a 57 % decline in PCV-13 isolates during this time period [11]. Pneumonia hospitalization rates in Tennessee decreased an additional 27 % in children under 2 years old from PCV-7 years 2001–2010 compared to the post-PCV years 2010–2012 [12]. PCV-13 is predicted to prevent nearly 1 million pneumonia hospitalizations in US children over the next decade [13].

Viral causes of CAP

Viruses have been implicated in 45–77 % of cases of pediatric CAP in epidemiologic studies. Although viruses may be responsible for CAP as a single agent, multi-viral infections, or mixed viral-bacterial infections account for 10–20 % of cases [14]. Respiratory syncytial virus (RSV) is the most common virus detected in children with pneumonia (especially in young infants), followed closely by rhinovirus, which is common in children of all ages. Other viruses responsible for pediatric CAP include influenza, adenovirus, parainfluenza, and human metapneumovirus [6, 14–16].

Since viruses are usually isolated from the upper respiratory tract, it is often difficult to distinguish whether a particular virus is the primary or a contributing cause of lower respiratory tract disease. Other considerations include asymptomatic viral infection or viral shedding following a recent infection. RSV is the only viral pathogen consistently associated with lower respiratory tract disease, whereas rhinovirus and bocavirus are common causes of upper respiratory infection and associated with prolonged viral shedding [14]. In the EPIC study, rhinovirus was detected in 31 % of children hospitalized with pneumonia and 22 % of asymptomatic children presenting for elective outpatient surgery [17]. A metareview reported that rhinovirus may be identified by PCR in up to 15 % of asymptomatic children [18].

Co-infection with viruses and bacteria

Viruses facilitate bacterial infection through direct damage to the respiratory tract and indirect modulation of inflammatory pathways [19]. Analysis of bacteriologic and histopathologic data from the 1918–1919 influenza pandemic indicates that the majority of influenza-related deaths from that period resulted from secondary bacterial pneumonia [20•]. Although mortality was much lower, the 2009 H1N1 influenza pandemic also demonstrated a high number of children with confirmed or suspected secondary bacterial pneumonia. Retrospective studies reported radiologic pneumonia in 34–57 % of children hospitalized with influenza and laboratory confirmed bacterial pneumonia in up to 15 % of hospitalized infants [21, 22].

Diagnosis of CAP

A retrospective cohort study of children evaluated for pneumonia at 36 emergency departments across the USA between 2007 and 2010 reported a wide range in the use of diagnostic testing including chest x-rays (CXRs) (39–76 %),complete blood counts (CBC) (11–29 %) and blood cultures (11–28 %). Children seen at high test-utilizing hospitals had increased odds of hospitalization for CAP (OR 1.86), but no difference in the rate of return visits to the ED [23••]. These results highlighted the need for evidence-based guidelines to standardize diagnostic testing in CAP. In 2011, the Pediatric Infectious Disease Society (PIDS) and the Infectious Disease Society of America (IDSA) released joint guidelines for the management of CAP in children. The PIDS/IDSA guidelines describe the quality of evidence and strength for each recommendation (see Table 2).

Table 2 Summary of PIDS/IDSA guidelines for diagnosis in children hospitalized with CAP [24]
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Imaging modalities

CXR

The PIDS/IDSA guideline recommends the performance of a chest x-ray (CXR) for all children hospitalized with CAP. CXRs help clinicians to assess the extent of disease in children requiring hospitalization, and may reveal complications such as pleural effusion and empyema. While the guideline definition does not require a radiographic diagnosis of pneumonia, studies from developed nations tend to use radiographic pneumonia as the criterion gold standard for diagnosis. CXR may not be reliable early in the course of pneumonia, as radiographic infiltrates may lag behind clinical findings of pneumonia, and CXR findings should not supplant clinical judgment for the diagnosis of childhood CAP. CXR also does not reliably differentiate between viral or bacterial etiologies [14, 25, 26]. While the dose exposure from CXR is much less than for chest CT, cumulative films may contribute to measurable radiation exposure in young children. Thus, follow-up CXRs should be limited to children who fail to improve or worsen after 48–72 h of antibiotic therapy.

Lung ultrasound—an emerging technology

Current use of point-of-care lung ultrasound for the diagnosis of pneumonia is largely limited to the identification of pleural effusion and other local complications. Recent data from Italy suggest that lung ultrasound performed by expert technicians is as accurate as CXR for the diagnosis of pediatric CAP, and outperforms CXR in the diagnosis of complicated pneumonia [27, 28]. A 2013 USA study evaluating point-of-care lung ultrasound performed by emergency medicine clinicians who completed a brief training found that this modality had a sensitivity of 86 % and a specificity of 89 % for the detection of CAP [29]. Lung ultrasound can also be used for follow-up imaging without a risk of cumulative radiation exposure [30]. Lung ultrasound is a promising non-invasive technique for the diagnosis of pneumonia, but both point-of-care testing and expert performance require further evaluation before lung ultrasound can replace CXR for the diagnosis or serial imaging of pneumonia.

Bacterial testing

Blood cultures

There is weak evidence supporting the PIDS/IDSA recommendation for routine use of blood cultures in children hospitalized for CAP. Culture results may guide appropriate treatment and provide important data about the changing etiology of CAP in a post-vaccine era. However, there are drawbacks to the routine use of blood cultures, including a high rate of contamination resulting in false positive culture results. Furthermore, less than 10 % of children hospitalized for uncomplicated CAP have documented bacteremia [33, 34••]. When a pathogen is isolated, culture results may not change antibiotic selection [35, 32]. Others have suggested a strategy that limits blood cultures to children at risk for severe or complicated bacterial disease [31••, 32]. However, until diagnostics are available to consistently distinguish viral from bacterial disease, accurately identifying this population may prove problematic.

Alternatives to blood culture for bacterial pathogen identification include sputum cultures, rapid antigen testing, and polymerase chain reaction (PCR). The pneumococcal urinary antigen test has excellent reported sensitivity, but suffers from a 15 % false positive rate, likely due to upper respiratory tract colonization with Streptococcus pneumoniae [36, 37]. Thus, the urinary antigen test is not recommended for use in children [38]. Whole-blood PCR is more sensitive than culture and targets are available for several bacteria, including Streptococcus pneumoniae, although commercially available tests are lacking. PCR testing of upper respiratory tract samples is not recommended for bacterial pathogens owing to frequent colonization. Testing for M. pneumoniae is the one exception as it is not thought to colonize the upper respiratory epithelium. Sputum cultures are a non-invasive method available for older children who can produce sputum. High quality samples are difficult to obtain from young children and infants who cannot reliably expectorate; however, inducing sputum with inhaled hypertonic saline has been used in research studies with variable results [39].

Viral testing

Rapid testing for influenza is important when influenza is prevalent in the local community. Testing for other viruses may be warranted, particularly if pathogen identification leads to a reduction in unnecessary antibiotic use. Older methods such as viral culture and direct fluorescent antibody (DFA) testing have largely been supplanted by viral PCR testing of upper respiratory tract samples. .

Serology and acute phase reactants

Serologic testing is not recommended in children with uncomplicated CAP as its clinical utility is very low. A complete blood count (CBC) should be performed in children with severe and complicated disease. Although leukocytosis is often associated with bacterial infection, white blood cell count does not easily distinguish between viral and bacterial disease. Anemia and/or thrombocytopenia may signal marrow suppression or platelet dysfunction seen in systemic complications such as sepsis. Acute phase reactants (e.g., C-reactive protein [CRP]) are often elevated in CAP. CRP levels >100 had a positive predictive value of 88 % in predicting radiographic pneumonia in one study, but one thirds of children with pneumonia had normal CRP levels <20 [40]. Furthermore, CRP does not reliably distinguish between viral and bacterial pathogens in CAP. A meta-analysis of eight studies and 1320 children concluded that a CRP level >40 only weakly predicts a bacterial etiology [41]. Serial measurements of CRP may have a role in assessing response to therapy, but further research is needed in this area.

Procalcitonin (PCT) may have more value than CRP as a marker for serious bacterial infections (SBI) in children. Using multiple diagnostic modalities to detect Streptococcus pneumoniae, one study reported that a procalcitonin level <0.5 ruled out pneumococcal pneumonia in over 90 % of cases [42]. Proposed PCT cutoff values indicative of bacterial disease range from 0.25 to 2.5 ng/mL in recently published studies [43–45, 40]. PCT levels may also be used to guide antibiotic therapy. A randomized control trial found no increase in rates of treatment failure when antibiotics were restricted to hospitalized children with PCT levels >0.25. This strategy translated into a 15 % reduction in antibiotic use for those with CAP in the PCT arm and shortened antibiotic duration by 50 % [46••]. Additional research into the clinical utility of PCT and other possible markers of bacterial infection are very much needed.

Diagnosis of complicated CAP

Epidemiology and etiology of complicated CAP

CAP may have local, systemic, or metastatic complications. Parapneumonic effusions have been reported in up to 25 % of children with CAP [24, 47]. Empyema occurs in up to 5 % of children hospitalized with CAP and may be further complicated by the development of necrosis, cavitation, or bronchopleural fistulas. Metastatic complications of CAP (osteomyelitis, meningitis, endocarditis, pericarditis, septic arthritis) are rare.

Although rates of pneumonia declined with PCV introduction, rates of local complications increased by 78 % between 1997 and 2006 [48]. National hospitalization rates for empyema in US children increased from 3 to 6 per 100,000 following the release of PCV-7 [49]. Experts posit that increased rates of complicated pneumonia result from more accurate diagnostic techniques and changes to the spectrum of pathogens responsible for pediatric CAP, as non-vaccine pneumococcal serotypes replace the conjugate vaccine serotypes and virulent strains of Staphylococcus aureus become more prevalent [50, 51].

As with uncomplicated CAP, Streptococcus pneumoniae remains the most common pathogen isolated by pleural fluid cultures, with identification of this pathogen in up to 71 % of empyemas [52•]. Other Streptococcus species and Staphylococcus aureus are less frequently identified. Pleural fluid culture is more likely to identify a pathogen when compared to blood culture [53–55]. Bacterial PCR increases pathogen identification when compared to culture-based methods, improving etiologic yield from 25–35 to 85–88 % in children with empyema [52•, 56].

Diagnosis of parapneumonic effusion and empyema

Parapneumonic complications progress along a continuum from small effusions containing free-flowing fluid to large and often complex infections within the pleural space. A clear transudate often develops in the pleural space in response to local inflammation and pleuritis. When bacteria are present, this fluid is often quickly replaced by purulent material and progressive infection [57, 58]. An initial CXR may show blunting of the costophrenic angle or a peripheral rim of pleural fluid indicative of effusion. A decubitus or lateral CXR may help to determine whether an effusion is free flowing or loculated, but large effusions are nearly impossible to differentiate from other causes of opacification seen on CXR [59]. Lung ultrasound is a superior tool for detecting loculations, septations, and fronds associated with empyema, and can differentiate pleural fluid from consolidated lung tissue [60, 61]. Neither CXR nor ultrasound can definitively diagnose empyema, but children with high grade findings on ultrasound such as organization, septation, and fronds within the pleural fluid have improved outcomes when treated with operative drainage procedures [60].

Diagnosis and treatment of the child with a parapneumonic effusion depends on the size of the fluid collection and the degree of respiratory compromise [24]. Small effusions (<10 mm on lateral CXR or <1/4 of the hemi-thorax on CXR) usually resolve with empiric antibiotic therapy and may be monitored clinically if the child appears well. Repeat imaging should be performed if the child fails to improve. Large (>1/2 hemithorax) and/or more complicated parapneumonic effusions and empyemas are less likely to resolve without a pleural drainage procedure. Pleural fluid specimens should be sent for cell count, gram stain, culture and bacterial PCR (if available) to guide treatment. An elevated pleural leukocyte count may indicate bacterial etiology in cases where a pathogen is not identified by culture or PCR.

Diagnosis of necrotizing pneumonia

Necrotizing pneumonia with abscess and cavity formation is a rare but increasing complication of pediatric CAP [50]. This complication should be suspected in an ill-appearing child with high fever, tachypnea, and tachycardia, or in a child who fails to respond to empiric therapy. CT scans may help to distinguish necrotic cavities and air–fluid levels from abscess formation, but these images may not necessarily change the management of necrotizing disease.

Streptococcus species, Staphylococcus aureus, and Klebsiella pneumoniae are common causes of necrotizing pneumonia in children [62]. Lung abscesses are often polymicrobial in nature, and may involve Staphylococcus aureus, Streptococcus species, gram-negative organisms, and anaerobes. Neurocognitively impaired children may be at increased risk for aspiration of these pathogens from the upper respiratory or GI tracts. Staphylococcus aureus is well described as a cause of severe necrotizing pneumonia in the literature, and is associated with leukopenia, erythroderma, purulent cough, and pulmonary hemorrhage [51, 63].

Treatment of CAP

Empiric antibiotic therapy

Therapy with intravenous (IV) ampicillin or penicillin G should be administered to previously healthy and fully immunized children who are hospitalized for pneumonia. Use of these agents is endorsed by the PIDS/IDSA guidelines as well as other national and international health organizations, and is supported by a strong body of evidence [26, 24, 64, 65]. In the post-PIDS/IDSA guidelines era, first-line use of aminopenicillins has increased significantly, but early studies indicate that physicians continue to treat up to 90 % of hospitalized children with broad spectrum cephalosporins [66]. There is good evidence that treatment with appropriately dosed aminopenicillin therapy overcomes most B-lactam resistance, without impairing readmission rates, length of stay (LOS), or costs of hospitalization [48, 67, 68].

A third-generation cephalosporin (e.g., ceftriaxone) should be administered if the child is not fully immunized, has a life-threatening infection, complications such as empyema, or resides in a region with high rates of pneumococcal resistance to penicillin. When Staphylococcus aureus is suspected, such as in complicated pneumonia and severe disease with systemic manifestations, anti-staphylococcal therapy (including vancomycin or clindamycin in MRSA-prevalent areas) should be added.

Macrolide antibiotics

Macrolides alone do not provide adequate empiric coverage for CAP due to high rates of macrolide resistance among serotypes of Streptococcus pneumoniae [69]. However, macrolides are the preferred therapy for pneumonia due to atypical pathogens. Although the PIDS/IDSA guidelines recommend consideration of macrolide therapy when atypical pathogens are a significant concern, it is impossible to reliably discern atypical CAP from that caused by viruses or other bacteria on clinical grounds alone (Table 3). PCR testing may help to better inform treatment decisions at the point of care. However, even when an atypical pathogen is diagnosed, the utility of treating these infections in children remains unclear [70, 71•]. The answer may depend on the age of the child. In a multicenter retrospective cohort study of over 20,000 children hospitalized with pneumonia, Beta-lactam–macrolide combination therapy decreased LOS by 31 % in children 12–18 years old compared to Beta-lactam monotherapy, but had no effect on children less than 6 years old [72]. Macrolides prove more effective in school-aged children presumably because atypical pathogens are more common in this age group. Macrolides may also be important for those with very severe pneumonia through both immune-modulating and antimicrobial effects [73] [74]. Macrolide therapy is associated with improved outcomes among critically ill adults hospitalized for pneumonia, even when they are infected by macrolide-resistant organisms [55].

Table 3 Empiric antibiotic regimens for pediatric inpatients with CAP adapted from IDSA guidelines
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Treatment of complicated disease

Children with pneumonia complicated by pleural effusion should receive empiric coverage for Streptococcus pneumoniae and other common pathogens. Small parapneumonic effusions may resolve with empiric aminopenicillin antibiotics alone. A third-generation cephalosporin plus anti-staphylococcal coverage is recommended for children with complicated effusions and empyema. For anti-staphylococcal coverage, vancomycin is preferred for life-threatening infections and/or documented MRSA bacteremia. Depending on local resistance profiles, clindamycin may be sufficient for less severe disease or as step-down therapy.

Antibiotic management of lung abscess and necrotizing pneumonia should always include staphylococcal and streptococcal coverage; anaerobic coverage should be strongly considered, especially in cases where aspiration pneumonia is suspected. Children with necrotizing pneumonia require prolonged antibiotic therapy [50].

A 2005 meta-analysis comparing primary medical versus operative management of empyema reported superiority of operative interventions over conservative medical management. This study demonstrated decreased re-intervention rates and time with chest tube in place, shorter duration of antibiotic therapy, shorter length of stay, and decreased in-hospital mortality rates with initial operative management [75]. One multicenter study of US children’s hospitals compared outcomes for patients treated with a variety of drainage procedures including thoracotomy, chest tube placement with and without fibrinolytics, and video-assisted thoracoscopic surgery (VATS). They reported similar outcomes for chest tube placement regardless of whether fibrinolytics were used. There were no significant differences in LOS, but children who received initial VATS were less likely to require additional drainage procedures [76••].

Adjuncts to antimicrobial therapy

Supportive care

Children who are hospitalized for pneumonia should be monitored for hypoxemia and dehydration. Supportive care may include intravenous or oral rehydration, nutritional support, supplemental oxygen, and frequent respiratory monitoring. Patients with acute wheezing and a history of asthma may benefit from bronchodilators and corticosteroids. Cough suppressant therapies are not recommended. In particular, clinicians should be aware of the theoretical risk of respiratory depression from codeine-containing cough syrup [77]. There is similarly insufficient evidence for the use of chest physical therapy or zinc supplementation [78, 79].

Corticosteroid therapy

Recent evidence suggests that corticosteroids only benefit the subpopulation of children with pneumonia who present with wheezing. A study evaluating the use of corticosteroids in children treated for CAP in the emergency department found that children with wheezing benefited from corticosteroids in conjunction with bronchodilator therapy, whereas those without wheezing had a prolonged length of stay and increased risk of readmission when treated with corticosteroids [80]. Corticosteroid therapy was also associated with antibiotic treatment failure when given to outpatients who did not have asthma [81].

Treatment failure and escalation of care

A child that fails to improve after 48–72 h of IV antibiotic therapy should be re-evaluated for inadequate antibiotic coverage and/or complicated pneumonia. Children with worsening clinical status should have a repeat blood culture performed to assess for bacteremia, repeat imaging to assess for the development of local complications, and broadening of their antimicrobial coverage. Transfer to an ICU should be considered for a child with impending respiratory failure or signs of shock (see Table 4).

Table 4 Selected indications for ICU admission in CAP
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Response to therapy and discharge criteria

Children should be considered eligible for discharge on oral antibiotics when they defervesce, their work of breathing improves, and when they no longer require supplemental oxygen or intravenous fluids. Most children hospitalized with uncomplicated pneumonia are discharged within 2–3 days. National and international guidelines recommend a short course of IV antibiotics before transitioning to oral therapy, but the evidence for this recommendation is scant. Emerging research from the developing world suggests a role for initial empiric oral therapy in severe disease, but more studies are needed [82]. In practice, most children receive IV therapy while hospitalized, with transition to oral therapy shortly before discharge.

Oral amoxicillin is preferred over both second- and third-generation oral cephalosporins and macrolides for pneumococcal coverage. Oral cephalosporins cover only 60–70 % of prevalent pneumococcal strains [69]. Oral alternatives useful in cases of penicillin or cephalosporin allergy include amoxicillin-clavulanate, clindamycin, fluoroquinolones, clindamycin, and linezolid (see Table 3). Intramuscular ceftriaxone administered once daily by the pediatrician or home nursing agency is a reasonable alternative to oral amoxicillin that covers >95 % of virulent pneumococcal serotypes. Intramuscular ceftriaxone should be considered for the outpatient treatment of children who no longer require skilled nursing but still need parenteral antibiotics, children who cannot tolerate oral antibiotics, and in cases where outpatient adherence is a concern [69].

The optimal treatment duration is not well defined in the literature. Most guidelines recommend antibiotic treatment for 7–10 days, with the addition of a macrolide for 5 days duration if there is concern for atypical infection. A longer duration of treatment is recommended if Staphylococcus aureus is suspected and in cases of complicated pneumonia.

Conclusions

The worldwide burden of CAP has decreased over the past decade, largely due to widespread pneumococcal immunization. However, CAP remains a leading cause of pediatric hospitalizations, with increasing rates of complicated disease in the post-conjugate vaccine era. Viruses are most common in younger children, while M. pneumoniae is commonly found in school-aged children. Streptococcus pneumoniae and other bacteria remain as important causes of CAP in all age groups and are increasingly associated with local complications. Although recent guidelines suggest limiting diagnostic testing for children with CAP, when managing patients with severe or complicated disease, a CXR and blood culture should be considered to help guide treatment. The role of other testing is less clear. Narrow-spectrum antibiotics, including ampicillin for hospitalized children and amoxicillin for outpatients are first-line therapy for the treatment of most children hospitalized with uncomplicated CAP. Combination therapy with a macrolide may be considered for school-aged children. Critical areas for future research include enhanced diagnostics (rapid, sensitive, cost-effective) for discerning viral from bacterial CAP; a better understanding of determinants of disease severity; and effective prevention and treatment strategies, particularly for viral pathogens.