Pediatric Pneumonia

Pneumonia and other lower respiratory tract infections are the leading causes of death worldwide. Because pneumonia is common and is associated with significant morbidity and mortality, promptly diagnosing pneumonia, correctly recognizing any complications or underlying conditions, and appropriately treating patients are all important. Although in developed countries the diagnosis is usually made on the basis of radiographic findings, the World Health Organization (WHO) has defined pneumonia solely on the basis of clinical findings obtained by visual inspection and on the timing of the respiratory rate.

Pneumonia may originate in the lung or may be a focal complication of a contiguous or systemic inflammatory process. Abnormalities of airway patency as well as alveolar ventilation and perfusion occur frequently due to a range of possible  mechanisms. These derangements often significantly alter gas exchange and dependent cellular metabolism in the many tissues and organs that determine survival and contribute to quality of life. Recognition, prevention, and treatment of these problems are major factors in the care of children with pneumonia.

One particular form of pneumonia present in the pediatric population, congenital pneumonia, presents within the first 24 hours after birth. For more information, see Congenital Pneumonia.

Other respiratory tract diseases such as croup (laryngotracheobronchitis), bronchiolitis, and bronchitis are beyond the scope of this article and are not discussed further.

An inhaled infectious organism must bypass the host's normal nonimmune and immune defense mechanisms in order to cause pneumonia. The nonimmune mechanisms include aerodynamic filtering of inhaled particles based on size, shape, and electrostatic charges; the cough reflex; mucociliary clearance; and several secreted substances (eg, lysozymes, complement, defensins). Macrophages, neutrophils, lymphocytes, and eosinophils carry out the immune-mediated host defenses.

Respiratory tract host defenses

To prevent and minimize injury and invasion by microorganisms and foreign substances, various defense mechanisms have evolved, both systemically and within the respiratory tract. Some mechanisms are nonspecific and are directed against any invasive agent, whereas others are targeted against only microbes or substances with specific antigenic determinants. Many of the defenses are compromised in the fetus and newborn infant. These compromises may result in more frequent breaches and a consequent disruption of normal lung structure and function.[4]

Nonspecific defenses include the glottis and vocal cords, ciliary escalator, airway secretions, migratory and fixed phagocytes, nonspecific antimicrobial proteins and opsonins, and normal relatively nonpathogenic airway flora. Anatomic structures of the upper airway and associated reflexes discourage particulate material from entering. On the other hand, coordinated movement of the microscopic cilia on the tracheal and bronchial epithelia tends to sweep particles and mucus up the airway and away from the alveoli and distal respiratory structures.

Mucoid airway secretions provide a physical barrier that minimizes epithelial adhesion and subsequent invasion by microorganisms. These secretions typically contain complement components, fibronectin, and other proteins that bind to microbes and render them more susceptible to ingestion by phagocytes. Alveolar and distal airway secretions also include whole surfactant, which facilitates opsonization and phagocytosis of pathogens, as well as surfactant-associated proteins A (Sp-A) and D (Sp-D). Both of these latter proteins can modulate phagocytosis, phagocyte production of oxyradicals, and cytokine elaboration.

These secretions also contain direct inhibitory and microbicidal agents, such as iron-binding proteins, lysozymes, and defensins. Typical benign airway commensals, such as alpha-hemolytic streptococci and coagulase-negative staphylococci, occupy mucosal sites and elaborate bacteriocins and other substances that prevent more pathogenic organisms from adhesion, replication, and possible opportunistic invasion.

Newborns typically have sterile respiratory mucosa at birth, with subsequent uncontested colonization by microorganisms from the mother or the environment. Accelerated access to distal respiratory structures and bypass of much of the ciliary escalator occur in infants who require endotracheal intubation. In these infants, increased physical disruption of epithelial and mucosal barriers also occurs. In addition, interventional exposure to high oxygen concentrations, generous airway pressures, and large intrapulmonary gas volumes may interfere with ciliary function and mucosal integrity. The use of less invasive means of respiratory support, such as nasal ventilation, nasal continuous positive airway pressure (CPAP), and nasal cannula (conventional or humidified, high flow), may produce lesser degrees of pulmonary mucosal and parenchymal disruption; however, some disruption is almost always present.

Systemic host defenses

Immunologic defense mechanisms targeted against particular pathogens typically emanate from specifically primed lymphocytes following the presentation of processed antigens by macrophages. These mechanisms include cytotoxic, killer, suppressor, and memory functions; systemic and secretory antibodies; and consequent cascades of cytokines, complement, vasomotor regulatory molecules, hemostatic factors, and other agents. Secretory antibodies are typically multimeric and contain secretory component and J chains that render them more opsonic and more resistant to microbial proteases.

Many of the biochemical cascades triggered by specific immune responses serve to localize microbial invasion, amplify and focus recruitment of phagocytes to the affected sites, and directly disrupt the structural and metabolic integrity of the microbes. The role that these cascades may play in triggering apoptosis (programmed cell death) in host and invader cells is still undergoing exploration.

Secretory antibodies and mucosal lymphoid tissue are absent or minimally functional for the first month of postnatal life. Systemic antibodies may enter pulmonary tissues but usually consist primarily of passively transmitted maternal antibodies. Furthermore, there is reduced transplacental transport of maternal antibodies before 32 weeks' gestation. Specific systemic antibodies can be generated, but many components of the necessary immunologic machinery act relatively sluggishly. Circulating complement components are present at approximately 50% of the concentration found in older children. Nevertheless, components of the alternative pathway are present in sufficient quantities to serve as effective opsonins.

The neonatal granulocyte number frequently decreases in response to early infection (as well as noninflammatory processes such as maternal preeclampsia). On the other hand, the phagocytes that are present often move much more sluggishly to the inflammatory focus, whether they are responding to the presence of a microorganism or inanimate debris. Once at the targeted sites, phagocytes often ingest the invader substances  less efficiently, although intracellular microbicidal activities appear normal. Intercellular communication via cytokines and other mediators is blunted.

The net result of these and other developmental aberrations is that the fetal and neonatal inflammatory response is slower, less efficient, and much less focused than in older children. Infection is less likely to be localized and effectively inhibited by host defenses alone. Inflammation from particulate debris and other foreign substances is isolated less effectively, and the injurious effector portions of the inflammatory cascade are much less precisely targeted.

Pathogenesis

Pneumonia is characterized by inflammation of the alveoli and terminal airspaces in response to invasion by an infectious agent introduced into the lungs through hematogenous spread or inhalation. The inflammatory cascade triggers the leakage of plasma and the loss of surfactant, resulting in air loss and consolidation.

The activated inflammatory response often results in targeted migration of phagocytes, with the release of toxic substances from granules and other microbicidal packages and the initiation of poorly regulated cascades (eg, complement, coagulation, cytokines). These cascades may directly injure host tissues and adversely alter endothelial and epithelial integrity, vasomotor tone, intravascular hemostasis, and the activation state of fixed and migratory phagocytes at the inflammatory focus. The role of apoptosis (noninflammatory programmed cell death) in pneumonia is poorly understood.

Pulmonary injuries are caused directly and/or indirectly by invading microorganisms or foreign material and by poorly targeted or inappropriate responses by the host defense system that may damage healthy host tissues as badly as or worse than the invading agent. Direct injury by the invading agent usually results from synthesis and secretion of microbial enzymes, proteins, toxic lipids, and toxins that disrupt host cell membranes, metabolic machinery, and the extracellular matrix that usually inhibits microbial migration.

Indirect injury is mediated by structural or secreted molecules, such as endotoxin, leukocidin, and toxic shock syndrome toxin-1 (TSST-1). Any of these molecules may alter local vasomotor tone and integrity, change the characteristics of the tissue perfusate, and generally interfere with the delivery of oxygen and nutrients and removal of waste products from local tissues.[5, 6]

On a macroscopic level, the invading agents and the host defenses all tend to increase airway smooth muscle tone and resistance, mucus secretion, and the presence of inflammatory cells and debris in these secretions. These materials may further increase airway resistance and obstruct the airways, partially or totally, causing airtrapping, atelectasis, and ventilatory dead space. In addition, disruption of endothelial and alveolar epithelial integrity may allow surfactant to be inactivated by proteinaceous exudate, a process that may be exacerbated further by the direct effects of meconium or pathogenic microorganisms.

In the end, conducting airways offer much more resistance and may become obstructed, alveoli may be atelectatic or hyperexpanded, alveolar perfusion may be markedly altered, and multiple tissues and cell populations in the lung and elsewhere sustain injury that increases the basal requirements for oxygen uptake and excretory gas removal at a time when the lungs are less able to accomplish these tasks.

Alveolar diffusion barriers may increase, intrapulmonary shunts may worsen, and ventilation/perfusion (V/Q) mismatch may further impair gas exchange despite endogenous homeostatic attempts to improve matching by regional airway and vascular constriction or dilatation. Because the myocardium has to work harder to overcome the alterations in pulmonary vascular resistance that accompany the above changes of pneumonia, the lungs may be less able to add oxygen and remove carbon dioxide from mixed venous blood for delivery to end organs. The spread of infection or inflammatory response, either systemically or to other focal sites, further exacerbates the situation.

Viral infections are characterized by the accumulation of mononuclear cells in the submucosa and perivascular space, resulting in partial obstruction of the airway. Patients with these infections present with wheezing and crackles. Disease progresses when the alveolar type II cells lose their structural integrity and surfactant production is diminished, a hyaline membrane forms, and pulmonary edema develops.

In bacterial infections, the alveoli fill with proteinaceous fluid, which triggers a brisk influx of red blood cells (RBCs) and polymorphonuclear (PMN) cells (red hepatization) followed by the deposition of fibrin and the degradation of inflammatory cells (gray hepatization). During resolution, intra-alveolar debris is ingested and removed by the alveolar macrophages. This consolidation leads to decreased air entry and dullness to percussion; inflammation in the small airways leads to crackles.

Four stages of lobar pneumonia have been described. In the first stage, which occurs within 24 hours of infection, the lung is characterized microscopically by vascular congestion and alveolar edema. Many bacteria and few neutrophils are present. The stage of red hepatization (2-3 days), so called because of its similarity to the consistency of liver, is characterized by the presence of many erythrocytes, neutrophils, desquamated epithelial cells, and fibrin within the alveoli. In the stage of gray hepatization (2-3 days), the lung is gray-brown to yellow because of fibrinopurulent exudate, disintegration of RBCs, and hemosiderin. The final stage of resolution is characterized by resorption and restoration of the pulmonary architecture. Fibrinous inflammation may lead to resolution or to organization and pleural adhesions.

Bronchopneumonia, a patchy consolidation involving one or more lobes, usually involves the dependent lung zones, a pattern attributable to aspiration of oropharyngeal contents. The neutrophilic exudate is centered in bronchi and bronchioles, with centrifugal spread to the adjacent alveoli.

In interstitial pneumonia, patchy or diffuse inflammation involving the interstitium is characterized by infiltration of lymphocytes and macrophages. The alveoli do not contain a significant exudate, but protein-rich hyaline membranes similar to those found in adult respiratory distress syndrome (ARDS) may line the alveolar spaces. Bacterial superinfection of viral pneumonia can also produce a mixed pattern of interstitial and alveolar airspace inflammation.

Miliary pneumonia is a term applied to multiple, discrete lesions resulting from the spread of the pathogen to the lungs via the bloodstream. The varying degrees of immunocompromise in miliary tuberculosis (TB), histoplasmosis, and coccidioidomycosis may manifest as granulomas with caseous necrosis to foci of necrosis. Miliary herpesvirus, cytomegalovirus (CMV), or varicella-zoster virus infection in severely immunocompromised patients results in numerous acute necrotizing hemorrhagic lesions.

Pneumonia can be caused by a myriad of microorganisms. Clinical suspicion of a particular offending agent is derived from clues obtained during the history and physical examination. While virtually any microorganism can lead to pneumonia, specific bacterial, viral, fungal, and mycobacterial infections are most common in previously healthy children. The age of infection, exposure history, risk factors for unusual pathogens, and immunization history all provide clues to the infecting agent.

In a prospective multicenter study of 154 hospitalized children with acute community-acquired pneumonia (CAP) in whom a comprehensive search for an etiology was sought, a pathogen was identified in 79% of children. Pyogenic bacteria accounted for 60% of cases, of which 73% were due to Streptococcus pneumoniae, while the atypical bacteria Mycoplasma pneumoniae and Chlamydophila pneumoniae were detected in 14% and 9%, respectively. Viruses were documented in 45% of children. Notably, 23% of the children had concurrent acute viral and bacterial disease. Mycoplasma pneumoniae and adenovirus coinfection can cause severe community-acquired pneumonia in children.[7]

In the study, preschool-aged children had as many episodes of atypical bacterial lower respiratory tract infections as older children. Multivariable analyses revealed that high temperature (38.4°C) within 72 hours after admission and the presence of pleural effusion were significantly associated with bacterial pneumonia.[8]

Specific etiologic agents vary based on age groups (ie, newborns, young infants, infants and toddlers, 5-year-olds, school-aged children and young adolescents, older adolescents).

Newborns

In newborns (aged 0-30 days), organisms responsible for infectious pneumonia typically mirror those responsible for early onset neonatal sepsis. This is not surprising in view of the role that maternal genitourinary and gastrointestinal tract flora play in both processes. Infections with group B Streptococcus, Listeria monocytogenes, or gram-negative rods (eg, Escherichia coli, Klebsiella pneumoniae) are common causes of bacterial pneumonia. These pathogens can be acquired in utero, via aspiration of organisms present in the birth canal, or by postnatal contact with other people or contaminated equipment.

Group B Streptococcus (GBS) was the most common bacterial isolate in most locales from the late 1960s to the late 1990s, when the impact of intrapartum chemoprophylaxis in reducing neonatal and maternal infection by this organism became evident. E coli has become the most common bacterial isolate among very low birth weight (VLBW) infants (1500 g or less) since that time.[9] Other potential bacterial organisms include the following:

• Nontypeable Haemophilus influenzae (NTHi)

• Other gram-negative bacilli

• Enterococci

• Staphylococcus aureus

Some organisms acquired perinatally may not cause illness until later in infancy, including Chlamydia trachomatis, Ureaplasma​ urealyticum, Mycoplasma hominis, CMV, and Pneumocystis carinii. C trachomatis organisms are presumably transmitted at birth during passage through an infected birth canal, although most infants are asymptomatic during the first 24 hours and develop pneumonia only after the first 2 weeks of life.

Group B streptococci infections are most often transmitted to the fetus in utero, usually as a result of colonization of the mother's vagina and cervix by the organism. Agents of chronic congenital infection, such as CMV, Treponema pallidum (the cause of pneumonia alba), Toxoplasma gondii, and others, may cause pneumonia in the first 24 hours of life. The clinical presentation usually involves other organ systems as well.

Community-acquired viral infections occur in newborns, although less commonly than in older infants. The most commonly isolated virus is respiratory syncytial virus (RSV). The transfer of maternal antibodies is important in protecting newborns and young infants from such infections, making premature infants (who may not have benefited from sufficient transfer of transplacental immunoglobulin [Ig] G]) especially vulnerable to lower-tract disease. In addition, premature infants may have chronic lung disease of prematurity, with associated hyperreactive airways, fewer functional alveoli, and baseline increased oxygen requirements.

Newborns may also be affected by the bacteria and viruses that commonly cause infections in older infants and children. Risk factors for infection include older siblings, group daycare, and lack of immunization.

Young infants

In the young infant (aged 1-3 months), continued concern about the perinatally acquired pathogens mentioned above remains. However, most bacterial pneumonia in this age group is community acquired and involves S pneumoniae, S aureus, and nontypeable H influenzae. S pneumoniae is by far the most common bacterial pathogen in this age group. Infection with any of these pyogenic bacteria may be complicated by lung abscess, parapneumonic effusions, and empyema, although S aureus is notorious for such complications.[10]

At this age, infants are incompletely immunized and remain at higher risk for H influenzae type B and pneumococcal disease, although herd immunity gained from widespread immunization of the population has been broadly protective. It is important to note that the current conjugate pneumococcal vaccine provides protection against 13 common pneumococcal types, but nonvaccine types remain problematic.

Most lower respiratory tract disease in young infants occurs during the respiratory virus season and is viral in origin, particularly in the patient with clinical bronchiolitis. The most common viral agents include RSV, parainfluenza viruses, influenza virus, adenovirus, and human metapneumovirus (hMPV).

Atypical organisms may rarely cause infection in infants. Of these, C trachomatis, U urealyticum, CMV, and P carinii are described.

Bordetella pertussis infection leads to pneumonia in as many as 20% of infected infants (as a complication of the whooping cough infection).

Among other potential atypical bacterial pathogens, U urealyticum and U parvum have been recovered from endotracheal aspirates shortly after birth in VLBW infants and have been variably associated with various adverse pulmonary outcomes, including bronchopulmonary dysplasia (BPD).[11, 12, 13, 14] Whether these organisms are causal or simply a marker of increased risk is unclear.

Infants, toddlers, and preschool-aged children

Viruses remain the most common cause of pneumonia in this age group, accounting for approximately 90% of all lower respiratory tract infections. Tsolia et al identified a viral infection among 65% of hospitalized children with community-acquired pneumonia.[15]

RSV is the most common viral pathogen, followed by parainfluenza types 1, 2, and 3 and influenza A or B. RSV infection occurs in the winter and early spring. Parainfluenza type 3 infection occurs in the spring, and types 1 and 2 occur in the fall. Influenza occurs in the winter.

Other viruses that cause pneumonia less frequently in infants and young children include adenovirus, enterovirus, rhinovirus, and coronavirus. A recent addition to this list is hMPV, which causes an illness similar to RSV and may be responsible for one third to one half of non-RSV bronchiolitis. The herpesviruses (HSV, VZV, and CMV) may rarely cause pneumonia, particularly in children with impaired immune systems.

Bacterial infections in this age group are seen on a regular basis. S pneumoniae is by far the most common bacterial cause of pneumonia. Among hospitalized children with bacterial pneumonia, S pneumoniae accounts for 21-44% of disease.[8, 16, 17] Other agents to consider include H influenzae type B (HiB) (very uncommon in immunized children[18] ), S pyogenes, and S aureus.

Children younger than 5 years, children enrolled in daycare, or those with frequent ear infections are at increased risk for invasive pneumococcal disease and infection with resistant pneumococcal strains. Evidence suggests that breastfeeding has a protective effect against invasive pneumococcal infection.

School-aged children and young adolescents

M pneumoniae is the most frequent cause of pneumonia among older children and adolescents. Mycoplasma accounts for 14-35% of pneumonia hospitalizations in this age group.[8, 15, 19] Children in homeless shelters and group homes and those with household contacts are at particular risk. Similarly, the diagnosis must be considered in immunocompromised children.

In this age group, pyogenic bacterial pneumonia remains a concern, usually caused by S pneumoniae. Other pyogenic bacterial pathogens to consider include S aureus and S pyogenes.

Chlamydophila pneumoniae also causes pneumonia. The related organism, C psittaci, is an unusual cause of pneumonia that occurs in people who work with and handle birds.

In immunosuppressed individuals, opportunistic infections with organisms such as Aspergillus species, Pneumocystis jirovecii, and CMV can occur.

Viral pneumonia remains common in this age group. Influenza pneumonia is a particular concern because ongoing infection with this virus predisposes to the development of bacterial superinfection, usually with S pneumoniae or S aureus.

Older adolescents

M pneumoniae is the most common cause of community-acquired pneumonia during the teenage and young adult years. Atypical pneumonia caused by C pneumoniae can present with identical signs and symptoms. Bacterial pneumonia caused by S pneumoniae is also seen.

Pulmonary infections caused by dimorphic fungi are also seen in this age group. Histoplasma capsulatum, which is found in nitrate-rich soil, is usually acquired as a result of inhalation of spores. Chicken coops and other bird roosts and decaying wood are often-cited sources. Cryptococcus neoformans is a common infection among pigeon breeders, but it is unusual in other immunocompetent individuals.

Blastomyces dermatitides, another dimorphic fungus, is found in certain geographic locations, most notably the Ohio and Mississippi River valleys. As with histoplasmosis, blastomycosis is acquired by inhalation of spores. Although 3 distinct forms of infection exist, the most common is acute pneumonia, which, in previously healthy individuals, most often resolves without treatment.

Viral pneumonias are common in this age group and are usually mild and self-limited, but influenza pneumonia can be severe or protracted, particularly when a bacterial infection follows.

TB pneumonia in children warrants special mention. It can occur in any age group, and it is important to remember that children with TB usually do not present with symptoms until 1-6 months after primary infection. Any child with pneumonia who has a history of TB exposure, or who has traveled to a TB-endemic area of the world needs to be fully evaluated for the possibility of tuberculosis.

Legionella pneumophila, the agent of Legionnaires disease, can also cause pneumonia, although it is uncommon in the pediatric age group.

Not all pneumonia is caused by infectious agents. Children who have severe gastroesophageal reflux (GERD) may develop chemical pneumonitis secondary to recurrent aspiration. Inhalation of certain chemicals or smoke may cause pulmonary inflammation. Additionally, aspiration pneumonia is more common among children with neurologic impairment, swallowing abnormalities, gastrointestinal motility, or a gastrostomy tube. Oral anaerobic flora, with or without aerobes, is the most common etiologic agent.

A study by Thomson et al compared hospital management and outcomes of children with neurologic impairment diagnosed with aspiration versus nonaspiration pneumonia. The study found that hospitalized children with neurologic impairment diagnosed with aspiration pneumonia had significantly longer length of stay; more ICU transfers; greater hospitalization costs; and more 30-day readmissions than did children with neurologic impairment diagnosed with nonaspiration pneumonia.[20]

Immunocompromised children

Some children who are immunocompromised, whether secondary to HIV infection/AIDS, an immune disorder, or chemotherapy for a malignancy, are at risk for pneumonias caused by opportunistic agents. Virtually any bacteria, virus, fungus, or even parasite can invade and infect the lungs if the immune system is sufficiently impaired. Carefully obtained samples for appropriate microbiologic testing are paramount in such patients so that therapy can be optimized.

Children with cystic fibrosis are especially prone to develop infections with S aureus, Pseudomonas aeruginosa, Burkholderia cepacia, and other multidrug-resistant organisms.

P jirovecii pneumonia (PCP) is common in the most severely compromised children and can lead to respiratory failure and death in those who are profoundly immunocompromised. Adenovirus infections can be severe in these children as well, leading to bronchiolitis obliterans or hyperlucent lung syndrome. In addition, CMV poses a great risk to immunocompromised patients.

Fungal pneumonia, caused by Aspergillus, Zygomycetes, or other related fungi, occurs in immunocompromised patients who undergo prolonged hospitalization, have prolonged neutropenia, and/or have received broad-spectrum antibiotics. Patients with underlying hematologic malignancies are at the highest risk.

Patients with sickle cell disease have problems with their complement system as well as functional asplenia; this predisposes them to infection with encapsulated organisms such as S pneumoniae and H influenzae type B. M pneumoniae is also a common agent of pneumonia in this group of patients.

United States statistics

Pneumonia can occur at any age, although it is more common in younger children. Pneumonia accounts for 13% of all infectious illnesses in infants younger than 2 years of age. In a large community-based study conducted by Denny and Clyde, the annual incidence rate of pneumonia was 4 cases per 100 children in the preschool-aged group, 2 cases per 100 children aged 5-9 years, and 1 case per 100 children aged 9-15 years.[21]

Thompson et al reported that, after elderly persons, the second highest rates of influenza-associated hospitalizations in the United States were in children younger than 5 years of age.[22] These investigators evaluated annual influenza-associated hospitalizations by hospital discharge category, discharge type, and age group.

In a randomized double-blind trial, the heptavalent pneumococcal vaccine reduced the incidence of clinically diagnosed and radiographically diagnosed pneumonia among children younger than 5 years of age by 4% and 20%, respectively.[23] Although the overall rate of pneumonia has decreased in the United States with the use of the 7-valent vaccine, the rate of empyema and complicated pneumonia has increased.[24] Following the use of the 13-valent conjugated pneumococcal polysaccharide vaccine, the overall rates of pneumonia are anticipated to drop further. The new vaccine includes serotypes that have become associated with complicated or antibiotic-resistant disease (19A and 6A, for example).

Among school-aged children and adolescents, bronchopneumonia occurs in 0.8-2% of all pertussis cases and 16-20% of hospitalized cases. M pneumoniae accounts for 14-35% of pneumonia hospitalizations in this age group,[8, 15, 19] and mycobacterial pneumonia has recently been noted with increasing frequency in some inner-city areas, particularly among children in homeless shelters and group homes and those with household contacts.

International statistics

Pneumonia and other lower respiratory tract infections are the leading cause of death worldwide. The WHO Child Health Epidemiology Reference Group estimated the median global incidence of clinical pneumonia to be 0.28 episodes per child-year.[25] This corresponds to an annual incidence of 150.7 million new cases, of which 11-20 million (7-13%) are severe enough to require hospital admission. Ninety-five percent of all episodes of clinical pneumonia in young children worldwide occur in developing countries.

Approximately 150 million new cases of pneumonia occur annually among children younger than 5 years of age worldwide. This accounts for approximately 10-20 million hospitalizations.[21] A WHO Child Health Epidemiology Reference Group publication cited the incidence of community-acquired pneumonia among children younger than 5 years of age in developed countries as approximately 0.026 episodes per child-year.[25]  In addition, a study conducted in the United Kingdom showed that 59% of deaths from pertussis are associated with pneumonia.

In general, the prognosis is good. Most cases of viral pneumonia resolve without treatment; common bacterial pathogens and atypical organisms respond to antimicrobial therapy. Long-term alteration of pulmonary function is rare, even in children with pneumonia that has been complicated by empyema or lung abscess.

Patients placed on a protocol-driven pneumonia clinical pathway are more likely to have favorable outcomes. The prognosis for varicella pneumonia is somewhat more guarded. Staphylococcal pneumonia, although rare, can be very serious despite treatment.

Morbidity

Although viral pneumonias are common in school-aged children and adolescents and are usually mild and self-limited, these pneumonias are occasionally severe and can rapidly progress to respiratory failure, either as a primary manifestation of viral infection or as a consequence of subsequent bacterial infection.

Morbidity and mortality from RSV and other viral infections is higher among premature infants and infants with underlying lung disease. Significant sequelae occur with adenoviral disease, including bronchiolitis obliterans and necrotizing bronchiolitis. With neonatal pneumonia, even if the infection is eradicated, many hosts develop long-lasting or permanent pulmonary changes that affect lung function, quality of life, and susceptibility to assorted subsequent infections.

Infants and postpubescent adolescents with TB pneumonia are at increased risk of disease progression. If TB is not treated during the early stages of infection, approximately 25% of children younger than 15 years of age develop extrapulmonary disease.

Bronchopneumonia occurs in 0.8-2% of all pertussis cases and 16-20% of hospitalized cases; the survival rate of these patients is much lower than in those with pneumonia that is attributed to other causes.

Immunocompromised children, those with underlying lung disease, and neonates are at high risk for severe sequelae, and they are also susceptible to various comorbidities. Cryptococcosis may occur in as many as 5-10% of patients afflicted with HIV-AIDS, and acute chest syndrome occurs in 15-43% of patients with sickle cell disease. Individuals with sickle cell disease not only have problems with their complement system, but they also have functional asplenia. These conditions predispose them to infection with encapsulated organisms such as S pneumoniae and H influenzae type B.

Mortality

The United Nations Children's Fund (UNICEF) estimates that 3 million children die worldwide from pneumonia each year; these deaths almost exclusively occur in children with underlying conditions, such as chronic lung disease of prematurity, congenital heart disease, and immunosuppression. Although most fatalities occur in developing countries, pneumonia remains a significant cause of morbidity in industrialized nations.

According to the WHO’s Global Burden of Disease 2000 Project, lower respiratory tract infections were the second leading cause of death in children younger than 5 years of age (about 2.1 million [19.6%]).[25] Most children are treated as outpatients and fully recover. However, in young infants and immunocompromised individuals, mortality is much higher. In studies of adults with pneumonia, a higher mortality rate is associated with abnormal vital signs, immunodeficiency, and certain pathogens.

Complications

Severe respiratory compromise may require intubation and transfer of the patient to a suitable intensive care unit (ICU) for more intensive monitoring and therapy. Indications for transfer include refractory hypoxia, decompensated respiratory distress (eg, lessening tachypnea due to fatigue, hypercapnia), and systemic complications such as sepsis.

Transfer may need to be initiated at a lower threshold for infants or young children, because decompensation may be rapid. Transfer of very sick infants or young children to a pediatric ICU is best accomplished with the assistance of a specialist pediatric transfer team. This may be true even if it entails a slightly longer wait, as compared with a conventional medical transport provider, or even one that provides air transport.

Severe coughing, especially in the context of necrotizing pneumonias or bullae formation, may lead to spontaneous pneumothoraces. These may or may not require treatment depending on the size of the pneumothorax. It is true, whether the pneumothorax is under tension and compromising ventilation or cardiac output.

Other complications include the following:

• Pleural effusion

• Empyema

• Pneumatocele

• Lung abscess

• Necrotizing pneumonia

• Systemic infection with metastatic foci

• Persistent newborn pulmonary hypertension

• Air leak syndrome, including pneumothorax, pneumomediastinum, pneumopericardium, and pulmonary interstitial emphysema

• Airway injury

• Obstructive airway secretions

• Hypoperfusion

• Chronic lung disease

• Hypoxic-ischemic and cytokine-mediated end-organ injury

• Sepsis

Counsel parents about the need to prevent exposure of infants to tobacco smoke, and, as part of anticipatory primary care, educate parents regarding possible later infectious exposures in daycare centers, schools, and similar settings. They should also be reminded of  the importance of hand washing. In addition, discuss the benefit infants may receive from pneumococcal immunization and annual influenza immunization and the potential benefits and costs of RSV immune globulin. Emphasize careful longitudinal surveillance regarding long-term problems associated with growth, development, otitis, reactive airway disease, and other complications.

Most children treated with outpatient antibiotics become much improved within 48 hours following the initiation of treatment. Educate parents about and caution them to look for signs of increasing respiratory distress and to seek medical attention immediately should any of these signs appear.

For patient education resources, consult the Lung Disease and Respiratory Health Center. Also, see patient education articles on topics such as  Bronchoscopy, Viral Pneumonia, and Bacterial Pneumonia.

Newborns with pneumonia rarely cough; more commonly they present with poor feeding and irritability, as well as tachypnea, retractions, grunting, and hypoxemia. Grunting in a newborn suggests a lower respiratory tract disease and is due to vocal cord approximation as they try to provide increased positive end-expiratory pressure (PEEP) and to keep their lower airways open.

After the first month of life, cough is the most common presenting symptom of pneumonia. Infants may have a history of antecedent upper respiratory symptoms. Grunting may be less common in older infants; however, tachypnea, retractions, and hypoxemia are common and may be accompanied by a persistent cough, congestion, fever, irritability, and decreased feeding. Any maternal history of Chlamydia trachomatis infection should be determined.

Infants with bacterial pneumonia are often febrile.  But those with viral pneumonia or pneumonia caused by atypical organisms may have a low-grade fever or may be afebrile. The child's caretakers may complain that the child is wheezing or has noisy breathing. Toddlers and preschoolers most often present with fever, cough (productive or nonproductive), tachypnea, and congestion. They may have some vomiting, particularly post-tussive emesis. A history of antecedent upper respiratory tract illness is common.

Older children and adolescents may also present with fever, cough (productive or nonproductive), congestion, chest pain, dehydration, and lethargy. In addition to the symptoms reported in younger children, adolescents may have other constitutional symptoms, such as headache, pleuritic chest pain, and vague abdominal pain. Vomiting, diarrhea, pharyngitis, and otalgia/otitis are other common symptoms.

Travel history is important because it may reveal an exposure risk to a pathogen more common to a specific geographic area (eg, dimorphic fungi). Any exposure to tuberculosis (TB) should always be determined. In addition, possible exposure to birds (psittacosis), bird droppings (histoplasmosis), bats (histoplasmosis), or other animals (zoonoses, including Q fever, tularemia, and plague) should be considered.

In children with evidence for recurrent sinopulmonary infections, a careful history to determine the underlying cause is needed. The recurrent nature of the infections may serve to  unveil an innate or acquired immune deficiency, an anatomic defect, or another genetic disease (eg, cystic fibrosis, ciliary dyskinesia).

Tuberculosis

A history of TB exposure to possible sources should be obtained in every patient who presents with signs and symptoms of pneumonia (eg, immigrants from Africa, certain parts of Asia, and Eastern Europe; contacts with persons in the penal or detention system; close contact with known individuals with TB). Children with TB usually do not present with symptoms until 1-6 months after primary infection. These may include fever, night sweats, chills, cough (which may include hemoptysis), and weight loss.

The signs and symptoms of pneumonia are often nonspecific and vary widely based on the patient’s age and the infectious organisms involved. Tachypnea is the most sensitive finding in patients with diagnosed pneumonia.

Initial evaluation

Early in the physical examination, identifying and treating respiratory distress, hypoxemia, and hypercarbia are important. Visual inspection of the degree of respiratory effort and accessory muscle use should be performed to determine both the presence and severity of respiratory distress. The examiner should simply observe the patient's respiratory effort and count the respirations for a full minute. In infants, observation should include an attempt at feeding, unless the baby has extreme tachypnea.

Pulmonary findings in all age groups may include accessory respiratory muscle recruitment, such as nasal flaring and retractions at subcostal, intercostal, or suprasternal sites. Signs such as grunting, flaring, severe tachypnea, and retractions should prompt the clinician to provide immediate respiratory support. Retractions result from an effort to increase intra-thoracic pressure in order to compensate for decreased compliance.

An emergency department (ED)-based study conducted in the United States found that respiratory rate alone and subjective clinical impression of tachypnea did not discriminate children with and without radiographic pneumonia.[26]

The World Health Organization (WHO) clinical criteria for pneumonia have also been reported to demonstrate poor sensitivity (34.3%) in diagnosing radiographic pneumonia in children presenting to the pediatric ED.[27] However, children with tachypnea as defined by WHO respiratory rate thresholds were more likely to have pneumonia than were children without tachypnea. The WHO thresholds are as follows:

• Children younger than 2 months: Greater than or equal to 60 breaths/min

• Children aged 2-12 months: Greater than or equal to 50 breaths/min

• Children aged 1-5 years: Greater than or equal to 40 breaths/min

Airway secretions may vary substantially in quality and quantity but are most often profuse and progress from serosanguineous to a more purulent appearance. White, yellow, green, or hemorrhagic colors and creamy or chunky textures are not infrequent. If aspiration of meconium, blood, or other proinflammatory fluid is suspected, other colors and textures reflective of the aspirated material may be observed.

Infants may have external staining or discoloration of skin, hair, and nails with meconium, blood, or other materials when they are present in the amniotic fluid. The oral, nasal and, especially, tracheal presence of such substances is particularly suggestive of aspiration.

An assessment of oxygen saturation by pulse oximetry should be performed early in the evaluation of all children with respiratory symptoms. Cyanosis may be present in severe cases. When appropriate and available, capnography may be useful in the evaluation of children with potential respiratory compromise.

Cyanosis of central tissues, such as the trunk, implies a deoxyhemoglobin concentration of approximately 5 g/dL or more. This is consistent with severe derangement of gas exchange from severe pulmonary dysfunction as in pneumonia. However, congenital structural heart disease, hemoglobinopathy, polycythemia, and pulmonary hypertension (with or without other associated parenchymal lung disease) must also be considered.

Chest pain may be observed with inflammation of or near the pleura. Abdominal pain or tenderness is often seen in children with lower lobe pneumonia. The presence and degree of fever depends on the microorganism involved, but high temperature (38.4°C) within 72 hours after admission and the presence of pleural effusion have both been reported to be significantly associated with bacterial pneumonia.[8]

Pneumonia may occur as a part of an alternate generalized etiology. Therefore, signs and symptoms suggestive of other disease processes, such as rashes and pharyngitis, should be sought during the examination.

Auscultation

Auscultation is perhaps the most important portion of the examination of the child with respiratory symptoms. The examination is often very difficult in infants and young children for several reasons. Babies and young children often cry during the physical examination, making auscultation difficult. The best opportunity for success lies in prewarming hands and instruments and the use of a pacifier to calm the infant. The opportunity to listen to a sleeping infant should never be lost.

Older infants and toddlers may cry because they are ill or uncomfortable. But, most often, they may experience stranger anxiety. For these children, it is best to spend a few minutes with the parents in the child's presence. If the child sees that the parent trusts the examining physician, then he or she may be more willing to let the examiner approach. A small toy may help to gain the child's trust.

Any part of the examination using instruments should be deferred as long as possible, because the child may find the medical equipment threatening. Occasionally, if the child is allowed to hold the stethoscope for a few minutes, he or she becomes less frightened. Even under the best of circumstances, examining a toddler is difficult. If the child is asleep when the physician begins the evaluation, auscultation should be performed early.

Children with respiratory symptoms may have a concomitant upper respiratory tract infection with copious upper airway secretions. This creates another potential problem: the transmission of upper airway sounds. In many cases, the sounds created by upper airway secretions can almost obscure true breath sounds and lead to erroneous diagnoses. If the origin of sounds heard through the stethoscope is unclear, the examiner should listen to the lung fields and then hold the stethoscope near the child's nose. If the sound patterns from both locations are approximately the same, the likely source of the abnormal breath sounds is the upper airway.

Even when the infant or young child is quiet and has a clear upper airway, the child's normal physiology may make the examination difficult. The minute ventilation is the product of the respiratory rate an

Occasionally, a patient has pneumonia that continues to manifest clinically (persistent or unresponsive pneumonia), radiographically (eg, 8 weeks after antibiotic treatment), or both despite adequate medical management. Studies have documented that the usual pathogens (eg, pneumococcus, non-typeable H influenza, Moraxella catarrhalis) may be the causative agents.

Other patients may present with a history of recurrent pneumonias, defined as more than 1 episode per year or more than 3 episodes in a lifetime, and again the organisms responsible are the aforementioned common pathogens.

These patients merit special mention because they require a more extensive workup by a specialist. One useful way to categorize these patients is based on radiographic findings with and without symptoms. This method places these children in 1 of 3 categories that help to narrow the differential diagnoses (see Table below).

A careful history and examination are helpful to further narrow the differential diagnosis. However, more testing is often needed to confirm most of such diagnoses and is generally outside the scope of a primary care provider.

Table. Categorizing Patients Based on Symptoms, to Assist in Differential Diagnosis of Patients With Recurrent Pneumonias (Open Table in a new window)

Diagnostic tests for pneumonia may include the following:

• Pulse oximetry

• Complete blood cell (CBC) count

• Sputum and blood cultures

• Serology

• Chest radiography

• Ultrasonography

Data show that point-of-care ultrasonography accurately helps to diagnose most cases of pneumonia in children and young adults. In a study of 200 babies, children, and young adults (≤21 years), ultrasonography had an overall sensitivity of 86% and a specificity of 89% for diagnosing pneumonia. Ultrasonography may eventually come to replace radiographs for diagnosis.[3, 28]

Identifying the causative infectious agent is the most valuable step in managing a complicated case of pneumonia. Unfortunately, an etiologic agent can be difficult to identify as various organisms cause pneumonia. Bacterial (including mycoplasmal, chlamydial, and acid fast), viral, and fungal infections are relatively common and have similar presentations, complicating clinical diagnosis. Furthermore, basic laboratory testing and radiologic testing are often not helpful in determining the etiology of pneumonia, and the treatments vary widely.

In patients with complicated pneumonia who have not had a treatment response or who require hospital admission, several diagnostic studies aimed at identifying the infectious culprit are warranted. These include cultures, serology, a CBC count with the differential, and acute-phase reactant levels (erythrocyte sedimentation rate [ESR], as well as C-reactive protein [CRP] determination).

Numerous factors may interfere with the ability to grow a likely pathogen in the microbiology laboratory, including (but not limited to) the following: pretreatment with antibiotics that limit in vitro but not in vivo growth, sputum contaminants that overgrow the pathogen, and pathogens that do not replicate in currently available culture systems. Techniques that may help overcome some of these limitations include antigen detection, nucleic acid probes, polymerase chain reaction (PCR)-based assays, or serologic tests.

Although once widely used, tests such as latex agglutination for detection of group B streptococcal antigen in urine, serum, or other fluids have fallen into disfavor because of poor predictive value. Nevertheless, new generations of nonculture-based technologies continue to undergo development and may be more accurate and widely available in the future.

Laboratory testing of children with a clinical diagnosis of pneumonia is not typically necessary in the outpatient setting, since criteria for admission would generally depend on clinical appearance or vital signs. For hospitalized patients, laboratory testing can be helpful to document and to track health improvement or worsening over time.

Testing should include a complete blood cell (CBC) count with differential and the evaluation of acute-phase reactants (ESR, CRP, or both) and sedimentation rate. The total white blood cell (WBC) count and differential may aid in determining whether an infection is bacterial or viral, and, together with clinical symptoms, chest radiography, and ESR, can be useful in monitoring the course of pneumonia. In cases of pneumococcal pneumonia, the WBC count is often elevated.

Before widespread pneumococcal immunization, Bachur et al observed that approximately 25% of febrile children had a WBC count of more than 20,000 cells/µL. However, without lower respiratory tract findings on examination, they had radiographic pneumonia (termed occult pneumonia).[29] Although blood testing was obtained less frequently in the post-Prevnar era, studies by the same group demonstrated that leukocytosis was still associated with occult pneumonia.[30, 31]

Sputum is rarely produced in children younger than 10 years of age, and samples are always contaminated by oral flora. In the cooperative older child with a productive cough, a sputum Gram stain may be obtained (see the image below). However, very few children are able to cooperate with such a test. An adequate sputum culture should contain more than 25 polymorphonuclear (PMN) cells per field and fewer than 10 squamous cells per field.

(Left) Gram stain demonstrating gram-positive cocci in pairs and chains and (right) culture positive for Streptococcus pneumoniae.

In situations in which a microbiologic diagnosis is essential, endotracheal cultures and/or bronchoalveolar lavage culture can be submitted for the isolation of other possible offending pathogens. This is most important in patients with enigmatic and/or severe pneumonia. Furthermore, it should be considered a priority in patients with compromised immune systems. Routine cultures for respiratory pathogens should be requested, along with special stains for PCP and special stains and cultures for Legionella, fungi, and acid-fast organisms. Viral cultures are also routinely requested.

Although blood cultures are technically easy to obtain and relatively noninvasive and nontraumatic, the results are rarely positive in the presence of pneumonia and even less so in cases of pretreated pneumonia. In a study of 168 patients with known pneumonia, Wubbel et al found only sterile blood cultures.[32]

In general, blood culture results are positive in less than 5% of patients with pneumococcal pneumonia. The percentage is even less in patients with Staphylococcus infection. However, a blood culture is still recommended in complicated cases of pneumonia. It may be the only way to identify the pathogen and its antimicrobial susceptibility patterns.

In neonates, blood culture with at least 1 mL of blood from an appropriately cleaned and prepared peripheral venous or arterial site is essential. This is because many neonatal pneumonias are hematogenous in origin and others serve as a focus for secondary seeding of the bloodstream. Older patients should have larger-volume blood culture samples drawn based on their age and the ease with which blood can be obtained. Multiple cultures of blood from different sites and/or those drawn at different times may increase the culture yield.

Guidelines published in 2011 and widely adopted across the United States recommended obtaining blood cultures from hospitalized patients with moderate to severe pneumonia,[33] but subsequent research has called into question the utility of a universal approach to obtaining a culture, in favor of a more targeted approach.[34]  There is rarely a significant change to management or length of hospital stay even in the presence of a documented bacteremia, and the false-positive (contaminant) rate of blood cultures may approach that of true bacteremia if low-risk patients are included. As such, half of all blood cultures will be false-positive, and most of the true-positive cultures have no impact on patient care.

Because of the relatively low yield of cultures, more efforts are under way to develop quick and accurate serologic tests for common lung pathogens, such as M pneumoniae, Chlamydophila species, and Legionella.

In a Finnish study, of 278 patients diagnosed with community-acquired pneumonia, a total of 24 (9%) confirmed diagnoses of Mycoplasma infection were made, all of which had positive results with IgM-capture test with convalescent-phase serum.[35] Acute and convalescent serum samples were collected and tested using enzyme immunoassay for M pneumoniae IgM and IgG antibodies. Nasopharyngeal aspirates were tested using PCR and cultured with a Pneumofast Kit.

Positive results were confirmed with Southern hybridization of PCR products and an IgM test with solid-phase antigen. Using an IgM-capture test in acute-phase serum, 79% of results were positive, 79% were positive using IgG serology, 50% positive using PCR, and 47% positive using culture.[35]

The authors of this study concluded that IgM serologic studies for Mycoplasma infection were not only rapid but also sensitive and were the most valuable tools for diagnosis of M pneumoniae infection in any age group.[35] IgM serology is much more sensitive than cold agglutinin assessments, which are more commonly used to aid in the diagnosis of Mycoplasma infection and which demonstrate positive results in only 50% of cases.

Chlamydophila and Legionella species can be grown by experienced microbiologists. However, serologic testing is also routinely performed to support or establish the diagnosis. Similarly, lung infections caused by dimorphic fungi (eg, histoplasmosis) are more commonly diagnosed serologically.

The use of markers of inflammation to support a diagnosis of suspected infection, including pneumonia, remains controversial because results are nonspecific. Various indices derived from differential leukocyte counts have been used most widely for this purpose, although noninfectious causes of such abnormal results are numerous. Many reports have been published regarding infants with proven infection who initially had neutrophil indices within reference ranges.

Quantitative measurements of CRP, procalcitonin, cytokines (eg, interleukin [IL]-6), inter-alpha inhibitor proteins (IaIp),[36] and batteries of acute-phase reactants have been touted to be more specific but are limited by suboptimal positive predictive value.

Lag time from infection to abnormal values is noted for inflammatory markers. Hence, serial measurements are often necessary and do offer a high negative predictive value. However, although these tests may be useful in assessing the resolution of an inflammatory process, including infection, they are not sufficiently precise to establish a diagnosis without additional supporting information. Decisions about antimicrobial therapy should not be based on inflammatory markers alone.

Relatively rapid testing (1-2 days) of viral infections through multiplex PCR is available in many hospitals. PCR is more sensitive than antigen assays, and for some viruses (eg, hMPV), this study may be the only test available. PCR also shows promise of being useful in diagnosing streptococcal pneumonia. In one series of 63 children with empyema, a pathogen could be detected in 53 (84%) by PCR compared to only 24 (35%) by culture of blood and/or pleural fluid. The most frequently detected pathogen was pneumococcus, found in 45 patients.[37]

PCR is noninvasive, an advantage over lung aspirate or bronchoalveolar lavage (BAL) cultures. Similarly, C pneumoniae infection is diagnosed more readily with PCR than by culture; However, positive test results must correlate with acute symptoms to have any validity, because 2-5% of the population may be asymptomatic when infected with C pneumoniae.

PCR testing for TB is also widely available and is helpful in the early identification of TB as distinguished from other mycobacteria in acid-fast cultures.

These tests are used in diagnosing TB. Mantoux skin test (intradermal [ID] inoculation of 5 tuberculin units [TU] of purified protein derivative [PPD]) results should be read 48-72 hours after placement.

Even if the child has received the bacillus Calmette-Guerin (BCG) vaccine, Mantoux test results should be interpreted using the criteria outlined as follows. In children older than 4 years without any risk factors, test results are positive if the induration (not the area of erythema, which may be larger) is 15 mm or larger. Among children younger than 4 years, those who have an increased environmental exposure to TB or other medical risk factors (eg, lymphoma, diabetes mellitus, malnutrition, renal failure), results are positive if the induration is 10 mm or larger. In immunosuppressed children or those in close contact with others who have known or suspected cases of TB, test results are positive if the induration is 5 mm or larger. Chest radiography helps to confirm the diagnosis of a child with positive Mantoux test results.

In a child with suspected pulmonary TB, the cough may be scarce or nonproductive. Therefore, the best test for diagnosis is an early-morning gastric aspirate sent for acid-fast bacilli (AFB) stain, culture and, if available, PCR. Gastric aspirates should be obtained by first placing a nasogastric (NG) tube the night before sample collection; a sample is aspirated the first thing the following morning, before ambulation and feeding. This should be repeated on 3 consecutive mornings.

In the young child or school-aged child with pneumonia, particularly the patient with a gradual onset of symptoms and a prodrome consisting of headache and abdominal symptoms, a bedside cold agglutinins test may help confirm the clinical suspicion of mycoplasmal infection.

This test is easily performed by placing a small amount of blood in a specimen tube containing anticoagulant and inserting this into a cup filled with ice water. After a few minutes in the cold water, the tube is held up to the light, tilted slightly, and slowly rotated. Small clumps of red blood cells (RBCs) coating the tube are indicative of a positive test result. Unfortunately, this test is positive in only half of the cases of mycoplasmal infection, and it is not very specific.

Although antigen detection assays for S pneumoniae lack a high specificity in children, Neuman and Harper observed that 76% of febrile children with a lobar infiltrate following chest radiography had a positive rapid urine antigen assay.[38]

Although antiviral therapies are not often used, performing a nasal wash or nasopharyngeal swab for RSV and influenza enzyme-linked immunoassay (ELISA) and viral culture can help to establish a rapid diagnosis, which may be helpful in excluding other causes. Viral cultures can be obtained in 1-2 days using newer cell culture techniques and may permit discontinuation of unnecessary antibiotics. In addition, correct diagnosis allows for appropriate placement of patients in the hospital. 

Chest radiography

Although chest radiographs are commonly obtained in the evaluation of pneumonia, they have limited value in the absence of respiratory findings, particularly in young children.[39]  The presence of viral findings alone on a radiograph should not increase rates of antibiotic use.[40]

Chest radiography is indicated primarily in children with complications such as pleural effusions and in those for whom antibiotic treatment fails to elicit a response. Computed tomography (CT) scanning of the chest and ultrasonography are indicated for children with complications such as pleural effusions and for those for whom antibiotic treatment fails to elicit a response. For more information, see Imaging in Pediatric Pneumonia.

Ultrasonography

Chest radiography has been the primary imaging modality used for the evaluation of pneumonia. Nevertheless, ultrasonography has been increasingly utilized in recent years because of its low cost, lack of ionizing radiation, portability, and repeatability.[41]

Ultrasonography is operator dependent, which limits its usefulness. Findings from a meta-analysis indicated a significant diagnostic accuracy (sensitivity of 97% and specificity of 94%).[42]

Flexible fiberoptic bronchoscopy is occasionally useful in obtaining lower airway secretions for culture or cytology. This procedure is most useful in immunocompromised patients who are believed to be infected with unusual organisms (Pneumocystis, other fungi) or in patients who are severely ill.

The technique of direct rigid bronchoscopy may be used in larger infants; fiberoptic technique is occasionally possible in smaller infants or infants in whom the site is not easily reached using the rigid optic technique. Both this technique and protected brush tracheal aspirate sampling may not be well tolerated in infants with significant lung disease or  poor gas exchange and who are very dependent on continuous positive pressure ventilation.

Careful consideration of the diagnostic possibilities is necessary in order to send the samples for the appropriate tests. Contamination of the bronchoscopic aspirate with upper airway secretions is common. Quantitative cultures can help distinguish contamination from infection. In vitro culture and Gram staining of an endotracheal aspirate obtained by aseptic technique as soon as possible after intubation may be useful.

Under typical circumstances, airway commensals take as long as 8 hours to migrate down the trachea. At least one study has demonstrated that culture of endotracheal aspirates obtained within 8 hours of birth correlates very well with blood culture results and probably reflects aspirated infected fluid.[43]  

The absence of significant inflammatory cells in an endotracheal aspirate or other respiratory specimen suggests that organisms recovered from that site are unlikely to be truly invasive (unless the infant is markedly leukopenic). Thus, the organism represents colonization of the respiratory tract and not infection.

Quantitative culture techniques, such as bronchoscopic alveolar lavage have been assessed in non-neonatal populations and reportedly offer a specificity of more than 80%, depending on the threshold selected (values from >100-100,000 colony-forming units [CFU]/mL have been used).[44, 45] Data from studies of neonates with suspected congenital pneumonia are lacking.

Sites distant from the larger bronchi often cannot be sampled. Specimens may have an increased risk of contamination with oral or airway commensals compared with bronchoscopic sampling but are thought to be more accurate than a conventional endotracheal aspirate.

Nondirected specimens have been obtained through endotracheal tubes 3 mm or greater in internal diameter and intuitively appear to offer decreased probability of contamination. Data from neonates are sparse.[46] In contrast to specimens obtained by bronchoscopy, ensuring precise sampling from a particular involved site is much more difficult.

Lung aspiration is underutilized and is a significantly more efficient method of obtaining a culture. If a prominent infiltrate can be adequately localized in multiple planes, direct aspiration of the infected lung may be performed for culture or biopsy. Lung CT scanning may facilitate such precise localization.

Lung aspiration is associated with a greater risk of postprocedural air leak. It usually requires a larger-bore needle than is used in obtaining pleural fluid. Because the risk associated with this procedure is high, lung aspiration is usually reserved for patients who are ill enough to require hospitalization, have not improved with previous empiric treatment, or are immunocompromised and more accurate etiology is required. A lung aspirate should not be performed in patients who are on ventilators, who have a bleeding diathesis, or who are suspected of having an infection with Pneumocystis.

A study demonstrated positive blood cultures implicated an organism in 18% of patients compared with 52% with positive lung aspirates.[47] The investigators compared the incidence of positive culture results obtained with blood culture with positive culture results obtained by lung aspiration in 100 children aged 3-58 months presentingwith pneumonia. The organisms obtained in the blood and lung aspirate differed in 4 of 8 children in whom both culture results were positive. These results suggest that a blood culture may not always accurately reveal the lung pathogen responsible.[47]

Other studies have demonstrated lung aspirate results to be positive in 50-60% of patients known to have pneumonia. In these studies, 1.5-9% of patients had a pneumothorax and 0.7-3% had transient small hemoptysis complicating the results of their lung aspiration procedures.

Although used much less frequently than in previous decades, diagnostic lung puncture may still be useful in circumstances wherein pleural and subpleural lung surfaces are visibly involved and can be well localized.[48] Risk-benefit considerations merit careful thought be given to the risks of such complicating factors as pneumothorax, bronchopleural fistula, and hemothorax, as well as the sampling of a nondiagnostic site. This is a high-risk procedure and should not be considered a routine procedure in the diagnosis or treatment of pneumonia in the neonate.

This procedure is performed for diagnostic and therapeutic purposes in children with pleural effusions (eg, when pleural fluid is impinging on lung or cardiac function). See the image below.

A breakdown of test results and recommended treatment for pneumonia with effusion. Gm = Gram; neg = negative; pos = positive; VATS = video-assisted thoracic surgery

In the presence of radiographically visible fluid, careful positioning of the infant and thoracentesis after sterile preparation of the sampling site may yield diagnostic findings by Gram staining, direct microscopy, and/or culture. If the Gram stain or the culture result from the pleural fluid is positive or the WBC count is higher than 1000 cells/mL, by definition, the patient has an empyema, which may require drainage for complete resolution. Ultrasonography may reveal smaller fluid pockets and facilitate safer sampling under direct visualization.

Although data from neonates are insufficient to draw conclusions, studies in older populations suggest a very high correlation with culture of lung tissue and/or blood. Other therapeutic decisions can be made based on the properties of the effusion.

For more information, see Infections of the Lung, Pleura, and Mediastinum.

No specific histologic findings are reported in most patients with pneumonias beyond evidence of inflammation, cellular infiltration, and exudation into alveolar spaces and the interstitium. Sputum, lavage, or biopsy material may yield useful diagnostic findings.

Tissue samples of lung tissue in human infants have typically been obtained from an unrepresentative sample population. Such a sample population usually includes only infants with severe pulmonary disease that results in death or threatens to do so or infants who die of other causes and have coincidental sampling of the lung. Consequently, direct observations regarding histologic changes in mild or moderate pneumonia are sparse and are often supplemented by extrapolation from animal disease models, human adults with similar diseases, or other more severe cases in human infants that resulted in death or biopsy. Despite these limitations, certain observations in congenital pneumonia recur, whether or not a specific pathogen is implicated.[49]

Macroscopically, the lung may have diffuse, multifocal, or very localized involvement with visibly increased density and decreased aeration. Frankly hemorrhagic areas and petechiae on pleural and intraparenchymal surfaces are common. Airway and intraparenchymal secretions may range from thin and watery to serosanguineous to frankly purulent, and they are frequently accompanied by small to moderate pleural effusions that display variable concentrations of inflammatory cells, protein, and glucose.

Conventional microscopy reveals that inflammatory cells are particularly prominent in the alveoli and airways. Mononuclear cells (macrophages, natural killer cells, small lymphocytes) are usually noted early, and granulocytes (eosinophils, neutrophils) typically become more prominent later. Microorganisms of variable viability or particulate debris may be observed within these cells. If systemic neutropenia is present, the number of inflammatory cells may be reduced. Alveoli may appear to be atelectatic from surfactant destruction or dysfunction, partially expanded with proteinaceous debris (often resembling hyaline membranes), or hyperexpanded secondary to partial airway obstruction from inflammatory debris or meconium.

Hemorrhage in the alveoli and in distal airways is frequent. Vascular congestion is common. Vasculitis and perivascular hemorrhage are observed less frequently, whereas inflammatory changes in interstitial tissues are less common in newborns than is the case in older individuals.

Microscopic examination of tissue following immunohistochemical staining or other molecular biologic techniques can identify the herpes virus and an increasing number of other organisms. In patients with TB, acid-fast bacilli are present and can be detected using the Ziehl-Neelsen stain or can be grown on Lowenstein-Jensen medium. Caseating granulomas are highly suspicious, even in the absence of detectable organisms. Findings of foamy alveolar casts are practically diagnostic for P jirovecii pneumonia, and cup-shaped organisms are often found, using Gomori methenamine silver staining or by direct immunofluorescence.

Fungal elements may be seen using Gomori methenamine silver staining or periodic acid-Schiff (PAS) staining. Aspergillus and Zygomycetes species may be seen using simple hematoxylin and eosin (H&E) staining. The specific morphology of the organisms may be diagnostic, but, occasionally, subculturing or immunostaining may be required.

Clinically, it is difficult to distinguish patients with bacterial pneumonia from those with viral illnesses. Therefore, decisions concerning antibiotic prescription for children suspected of having community-acquired pneumonia (CAP) can be challenging. Although pneumonia is commonly caused by viral organisms in children, many children diagnosed with pneumonia are treated empirically with antibiotics.[50] Research has shown that the intention to prescribe antibiotics based on clinical findings is the strongest predictor for antibiotic prescription.[51]

Treatment decisions for children with pneumonia are dictated on the basis of the likely etiology of the infectious organism and the age and clinical status of the patient. Antibiotic administration must be targeted to the likely organism, bearing in mind the age of the patient, the history of exposure, the possibility of resistance (which may vary, depending on local resistance patterns), and other pertinent history.

After initiating therapy, the most important tasks are resolving the symptoms and clearing the infiltrate. Following successful therapy, symptoms resolve much sooner than the infiltrate. In a study of adults with pneumococcal pneumonia, the infiltrate did not completely resolve in all patients until 8 weeks after therapy. However, resolution occurred sooner in most patients. If therapy fails to elicit a satisfactory response, the entire treatment approach must be reconsidered.

The Pediatric Infectious Diseases Society and the Infectious Diseases Society of America created evidence-based guidelines for the management of CAP in infants and children older than 3 months. These guidelines address site-of-care management, diagnosis, antimicrobial therapy, adjunctive surgical therapy, and prevention. While these guidelines do not represent the only approach to diagnosis and therapy, these recommendations may assist in decreasing morbidity and mortality rates in children with CAP.[33]

A retrospective study by Handy et al concluded that antibiotic choice for children with CAP varied widely across practices for reasons other than the microbiologic etiology. The study found that 40.7% of the 10,414 children in the study (4239) received amoxicillin. However, 42.5% (4430) received macrolides, and 16.8% (1745) received broad-spectrum antibiotics.[52, 53]

Another study by Williams et al found that there was an improvement at children’s hospitals in the use of penicillin to treat pneumonia after the publication of the 2011 Pediatric Infectious Diseases Society/Infectious Diseases Society of America pneumonia guideline. Before the guideline was published < 10% of children’s hospitals prescribed penicillin to treat pneumonia versus 27.6% following its publication.[54, 53]  Children with pneumonia usually benefit from guideline-based antibiotic therapy.[55]  Antibiotic stewardship programs are associated with a reduction in the use of broad-spectrum antibiotics.[56]

Pulse oximetry should be performed during the prehospital evaluation of children with suspected pneumonia, and supplemental oxygen should be administered, Pulse oximetry can improve outpatient diagnosis of pediatric pneumonia.[57] However, many school-aged children do not require hospitalization and respond well to oral antibiotics. Usually, these patients are not toxic appearing or hypoxic enough to require supplemental oxygen. Unless they are vomiting, they do not require intravenous fluids or antibiotics. A parapneumonic effusion that requires drainage usually dictates a hospital admission.

Children younger than 5 years are hospitalized more often. But their clinical status, degree of hydration, degree of hypoxia, and need for intravenous therapy dictate this decision. Hospitalization should be considered for infants who are younger than 2 months or premature because of the risk of apnea in this age group.[58]

Children who are toxic appearing may require resuscitation and respiratory support. Treatment of critically ill children (those requiring ventilation) should include timely administration of appropriate antibiotics. Delays of only a few hours in one retrospective study were associated with significantly longer durations of ventilation, intensive care unit (ICU) stay, and total hospitalization.[59] Chest radiography should be performed to identify the presence of an effusion/empyema. Drainage of a restrictive or infected effusion or empyema may enhance clearance of the infection and improves lung mechanics. Antibiotic therapy should include vancomycin (especially in areas where penicillin-resistant streptococci have been identified) and the administration of a second- or third-generation cephalosporin.

Red blood cells (RBCs) should be administered to achieve a hemoglobin concentration of 13-16 g/dL in the acutely ill infant to ensure optimal oxygen delivery to the tissues. Delivery of adequate amounts of glucose and maintenance of thermoregulation, electrolyte balance, and other elements of neonatal supportive care are also essential aspects of clinical care.

Attempts at enteral feeding often are withheld in favor of parenteral nutritional support until respiratory and hemodynamic status is sufficiently stable.

Initial priorities in children with pneumonia include the identification and treatment of respiratory distress, hypoxemia, and hypercarbia. Grunting, flaring, severe tachypnea, and retractions should prompt immediate respiratory support. Children who are in severe respiratory distress should undergo tracheal intubation if they are unable to maintain oxygenation or have decreasing levels of consciousness.

Increased respiratory support requirements, such as increased inhaled oxygen concentration, positive pressure ventilation, or continuous positive airway pressure (CPAP), are commonly required before recovery begins. Bi-level positive airway pressure (BiPAP) may also be used to help support respiratory effort as a stand-alone intervention or as a bridge to intubation. Criteria for institution and weaning of supplemental oxygen and mechanical support are similar to those for other neonatal respiratory diseases. Extra humidification of inspired air (eg, room humidifiers) is also not useful, although supplemental oxygen is frequently humidified for patient comfort.

Adequate gas exchange depends not only on alveolar ventilation, but also on the perfusion and gas transport capacity of the alveolar perfusate (ie, blood). Preservation of pulmonary and systemic perfusion is essential, using volume expanders, inotropes, afterload reduction, blood products, and other interventions (eg, inhaled nitric oxide) as needed. Excellent lung mechanics provide little relief if perfusion is not simultaneously adequate.

The choice of an initial empiric agent is selected according to the susceptibility and resistance patterns of the likely pathogens and experience at the institution.

Antibiotic agents

The vast majority of children diagnosed with pneumonia in the outpatient setting are treated with oral antibiotics.

High-dose amoxicillin is used as a first-line agent for children with uncomplicated community-acquired pneumonia, which provides coverage for Streptococcus pneumoniae. Second- or third-generation cephalosporins and macrolide antibiotics such as azithromycin are acceptable alternatives. However, they should not be used as first-line agents because of lower systemic absorption of the cephalosporins and pneumococcal resistance to macrolides. Treatment guidelines are available from the Cincinnati Children's Hospital Medical Center[60] and, more recently, from the Infectious Diseases Society of America (IDSA).[33]

Macrolide antibiotics are useful in school-aged children, because they cover the most common bacteriologic and atypical agents such as Mycoplasma, Chlamydophila, and Legionella. However, increasing levels of resistance to macrolides among pneumococcal isolates should be considered (depending on local resistance rates). One study suggests that penicillin and macrolide resistance among S pneumoniae isolates has been increasing.[61]  

Hospitalized patients can be safely treated with narrow-spectrum agents such as ampicillin. Indeed, this is the mainstay of current guidelines for pediatric community-acquired pneumonia.[33, 62, 63]  Children who appear toxic should receive antibiotic therapy that includes vancomycin, along with a second- or third-generation cephalosporin. This may pertain particularly in communities where penicillin-resistant pneumococci and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent.

If gram-negative pneumonia is suspected and beta-lactam antibiotics are administered, some data suggest that continuous exposure to an antimicrobial concentration greater than the mean inhibitory concentration (MIC) for the organism may be more important than the amplitude of the peak concentration. Intramuscular treatment or intravenous therapy with the same total daily dose but a more frequent dosing interval may be advantageous. This may be especially true if the infant's condition fails to respond to conventional dosing. Comparative data to confirm the superiority of this approach are lacking.

Whether this approach offers any advantage with use of agents other than beta-lactams is unclear. A study by Williams et al reported no statistically significant difference in length of hospital stay between children hospitalized with pneumonia and those treated with a beta-lactam alone versus children treated with a beta-lactam plus a macrolide combination therapy.[64]

Studies in adults have demonstrated that aminoglycosides reach the bronchial lumen marginally when administered parenterally, although alveolar delivery is satisfactory.[65, 66] Endotracheal treatment with aerosolized aminoglycosides has been reportedly effective for marginally susceptible organisms in bronchi.

On the other hand, cefotaxime appears to attain adequate bronchial concentrations via the parenteral route. Limited in vitro and in vivo animal data suggest that cefotaxime may retain more activity than aminoglycosides in sequestered foci, such as abscesses. However, such foci are rare in congenital pneumonia, and adequate drainage may be more important than the selection of antimicrobial agents.

Recovery of a specific pathogen from a normally sterile site (eg, blood, urine, cerebrospinal fluid [CSF]) permits narrowing the spectrum of antimicrobial therapies. It may thus reduce the selection of resistant organisms and costs of therapy. Repeated culture of the site after 24-48 hours is usually warranted to ensure sterilization and to assess the efficacy of therapy.

Endotracheal aspirates are not believed to represent a normally sterile site, although they may yield a pathogen that is a true invasive culprit. Repeated culturing of an endotracheal aspirate that identified the presumptive pathogen in a particular case may not be helpful because colonization may persist even if tissue invasion has ceased.

Decreasing respiratory support requirements, clinical improvement, and resolution revealed in radiographs also support the efficacy of therapy. When appropriate, assess plasma antibiotic concentrations to ensure adequacy and reduce the potential for toxicity. Failure to recover an organism does not preclude an infectious etiology. The continuation of empiric therapy may be advisable unless the clinical course or other data strongly suggest that a noninfectious cause is responsible for the presenting signs.

Continue to perform careful continued examinations for evidence of complications that may warrant a change in therapy or dosing regimen, surgical drainage, or other intervention.

Anti-inflammatory therapy

Evidence-supported options for targeted treatment of inflammation independent of antimicrobial therapy are severely limited.[67] Considerable speculation suggests that current antimicrobial agents, directed at killing invasive organisms, may transiently worsen inflammatory cascades and associated host injury because dying organisms release proinflammatory structural and metabolic components into the surrounding microenvironment. This is not to imply that eradicating invasive microbes should not be a goal. However, other methods of eradication or methods of directly addressing the pathologic inflammatory cascades await further definition. In pneumonia resulting from noninfectious causes, the quest for targeted, effective, and safe anti-inflammatory therapy may be of even greater importance.

A few small studies in adults suggest that the use of glucocorticoids might be beneficial in the treatment of serious (hospitalized) community-acquired pneumonia. However, the study design and sample size limit the ability to properly interpret these data.[68] Until definitive studies are performed, corticosteroids should not be routinely used for uncomplicated pneumonia.

Antiviral agents

Most infants with respiratory syncytial virus (RSV) pneumonia do not respond to antimicrobials. Serious infections with this organism often occur concurrently in infants with underlying lung disease.

Influenza A viruses, including 2 subtypes (H1N1) and (H3N2), and influenza B viruses currently circulate worldwide. However, the prevalence of each can vary among communities and within a single community over the course of the influenza season. In the United States, 4 prescription antiviral medications (oseltamivir, zanamivir, amantadine, rimantadine) have been approved for the treatment and chemoprophylaxis of influenza.

Influenza A pneumonia that is particularly severe or when it occurs in a high-risk patient may be treated with zanamivir or oseltamivir. The neuraminidase inhibitors have activity against influenza A and B viruses, whereas the adamantanes only have activity against influenza A viruses.

Check for resistance patterns exhibited by other antiviral agents indicated for the treatment or chemoprophylaxis of influenza. Since January 2006, the neuraminidase inhibitors (oseltamivir, zanamivir) have been the only recommended influenza antiviral drugs because of widespread resistance to the adamantanes (amantadine, rimantadine) among influenza A (H3N2) virus strains.

From 2007 to 2008, a significant increase in the prevalence of oseltamivir resistance was reported among influenza A (H1N1) viruses worldwide. During the 2007-2008 influenza season, 10.9% of H1N1 viruses tested in the United States were resistant to oseltamivir.

These reports prompted the US Centers for Disease Control and Prevention (CDC) to issue revised interim recommendations for antiviral treatment and prophylaxis of influenza. Zanamivir is recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure is suspected.

A second-line alternative is the combination of oseltamivir plus rimantadine rather than oseltamivir alone. Local influenza surveillance data and laboratory testing can assist the physician on the subject of antiviral agent choice. Complete recommendations are available from the CDC.

Herpes simplex virus pneumonia is treated with parenteral acyclovir. Cytomegalovirus (CMV) pneumonitis should be treated with intravenous ganciclovir or foscarnet.

Antifungal agents

Invasive fungal infections, such as those caused by Aspergillus or Zygomycetes species, are treated with amphotericin B or voriconazole.

Bronchodilators

Bronchodilators should not be routinely used. Bacterial lower respiratory tract infections rarely trigger asthma attacks, and the wheezing that is sometimes heard in patients with pneumonia is usually caused by airway inflammation, mucus plugging, or both and does not respond to a bronchodilator. However, infants or children with reactive airway disease or asthma may react to a viral infection with bronchospasm, which responds to bronchodilators.

A thin layer of fluid (approximately 10 mL) is usually found between the visceral and parietal pleura and helps prevent friction. This pleural fluid is produced at 100 mL/h. Ninety percent of the fluid is reabsorbed on the visceral surface, and 10% is reabsorbed by the lymphatics. Pleural fluid accumulates when the balance between production and reabsorption is disrupted. A transudate accumulates in the pleural cavity when changes in the hydrostatic or oncotic pressures are not accompanied by changes in the membranes. Increased membrane permeability and hydrostatic pressure often result from inflammation and result in a subsequent loss of protein from the capillaries and an accumulation of exudates in the pleural cavity.

When a child with pneumonia develops a pleural effusion, thoracentesis should be performed for diagnostic and therapeutic purposes. The pleural fluid should be obtained to assess pH and glucose levels. Gram staining and culture, CBC count with differential, and protein assessment should be performed. Amylase and lactase dehydrogenase (LDH) levels can also be measured. But these measurements are less useful in a parapneumonic effusion than in effusions of other etiologies. The results are helpful in determining whether the effusion is a transudate or an exudate and help to determine the best course of management for the effusion.

Drainage of parapneumonic effusions with or without intrapleural instillation of a fibrinolytic agent (eg, tissue plasminogen activator [TPA]) may be indicated. Chest tube placement for drainage of an effusion or empyema may be performed. A video-assisted thoracic surgery (VATS) procedure may be performed for decortication of organized empyema or loculated effusions.

For more information, see Infections of the Lung, Pleura, and Mediastinum.

Aside from avoiding infectious contacts, which is difficult for many families who require the use of daycare facilities, vaccination should be the primary mode of prevention. Since the introduction of the conjugated Haemophilus influenzae type b (Hib) vaccine, the rates of Hib pneumonia have significantly declined. However, the diagnosis should still be considered in unvaccinated persons, including those younger than 2 months, who have not received their first dose of vaccine.

Conjugated and unconjugated polysaccharide vaccines for S pneumoniae have been developed for infants and children, respectively. A 13-valent conjugated vaccine (Prevnar 13) was approved in 2010 and replaces PCV7 for all doses. PCV13 includes serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. In 2021, a 15-valent conjugate vaccine (PCV15; Vaxneuvance) is indicated for active immunization for prevention of invasive disease caused by S pneumoniae in individuals aged 6 weeks and older. Use for primary vaccination and catch-up immunization in children aged 6 weeks and older is interchangeable with PCV13. It contains all serotypes in the PVC13 vaccine plus 22F and 33F.[18]  

 Pneumococcal vaccine polyvalent (Pneumovax) covers 23 different strains. The 23-valent polysaccharide vaccine (PPVSV) is recommended for children aged 24 months and older who are at high risk for contracting a pneumococcal disease.

An influenza vaccine is recommended for children aged 6 months and older. The vaccine exists in 2 forms: inactivated vaccine (various products), administered as an intramuscular injection, and a cold-adapted attenuated vaccine (FluMist), administered as a nasal spray, which is licensed only for persons aged 2-49 years.

Although the influenza vaccine is especially recommended for children at high risk, such as those with bronchopulmonary dysplasia (BPD), cystic fibrosis, or asthma, the use of FluMist is cautioned in persons with known asthma because of reports of transient increases in wheezing episodes in the weeks following its administration. However, in years when vaccine strains have been mismatched with the circulating influenza strains, FluMist has provided good protection (approximately 70%), even when the inactivated vaccine was entirely ineffective.

Clinical trials are ongoing to lower the age of administration of Fluzone, one of the inactivated intramuscular vaccines, to 2 months (currently approved for children 6 months and older) to help protect this high-risk, but unvaccinated, population. The safety and efficacy of this approach remain unknown.

Pneumocystis carinii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole 3 times a week is widely used in immunocompromised children and has all but eradicated this organism in patients receiving prophylactic treatments.

The use of pneumococcal and Hib vaccines and penicillin prophylaxis in patients with sickle cell disease have helped reduce the incidence of bacterial infections in these children.

RSV prophylaxis consists of monthly intramuscular injections of palivizumab at a dose of 15 mg/kg (maximum volume, 1 mL per injection; multiple injections may be required per dose). This strategy is currently recommended for high-risk infants only (ie, premature infants and newborns with congenital heart disease). Monthly injections during the RSV season approximately halve the rate of serious RSV disease that leads to hospitalization. This expensive therapy is generally restricted to infants at high risk, such as children younger than 2 years with chronic lung disease of prematurity, premature infants younger than 6 months (or with other risk factors), and children with significant congenital heart disease.

Malnutrition is a known risk factor for infections, but zinc deficiency in particular has been shown to increase the risk of childhood pneumonia. In areas of the world where zinc deficiency is common, supplementation may significantly reduce the incidence of childhood pneumonia.[69]

Consultations

Consultation is not needed in the care of most children with pneumonia. However, children who have underlying diseases may benefit from consultation with the specialist involved in their long-term care. For example, most children with cystic fibrosis are monitored by a pulmonologist.

Consultation with a pediatric infectious disease specialist may be appropriate in the treatment of a child with persistent or recurrent pneumonia, and children with pleural effusions or empyema should be referred to a tertiary medical center, where thoracentesis can be performed. This procedure may be performed in an emergency department setting and may require subspecialty consultation.

Although some pneumonias are destructive (eg, adenovirus) and can cause permanent changes, most childhood pneumonias have complete radiologic clearing. If a significant abnormality persists, consideration of an anatomic abnormality is appropriate.

Careful longitudinal surveillance for long-term problems with growth, development, otitis, reactive airway disease, and other complications should be performed.

Drug therapy for pneumonia is tailored to the situation. Because the etiologic agents vary, drug choice is affected by the patient's age, exposure history, likelihood of drug resistance (eg, pneumococcus), and clinical presentation.

Beta-lactam antibiotics (eg, amoxicillin, cefuroxime, cefdinir) are preferred for outpatient management. Macrolide antibiotics (eg, azithromycin, clarithromycin) are useful in most school-aged children to cover the atypical organisms and pneumococcus. Local variations in microbial drug resistance require different approaches to therapy, including cases caused by pneumococcus. Any child with a positive purified protein derivative (PPD) test result and infiltrate on chest radiographs requires additional testing for tuberculosis and polymicrobial treatment.

Agents typically used initially in the treatment of newborns and young infants with pneumonia include a combination of ampicillin and either gentamicin or cefotaxime. The selection of cefotaxime or gentamicin must be based on experience and considerations at each specific medical center and in each patient. Combination therapy provides reasonable antimicrobial efficacy against the pathogens that typically cause serious infection in the first days of life. Other agents or combinations may be appropriate for initial empiric therapy if justified by the range of pathogens and susceptibilities encountered in a particular clinical setting.

Isolation of a specific pathogen from a normally sterile site in the infant allows revision of therapy to the drug that is least toxic, has the narrowest antimicrobial spectrum, and is most effective. Dosing intervals for ampicillin, cefotaxime, gentamicin, and other antimicrobial agents typically require readjustment in the presence of renal dysfunction.

In a randomized, placebo-controlled study of 820 pediatric patients with mild pneumonia, researchers found that treatment with oral amoxicillin (50 mg/kg/day) twice daily was as effective as amoxicillin given 3 times a day. Treatment failure occurred in 23% of the twice-daily group and 22.8% of the thrice-daily group in the intention-to-treat analysis, and in 21.3% and 20.1% of these groups, respectively, in the per-protocol analysis. Among the 277 patients with radiologically confirmed pneumonia, treatment failure occurred in 18.8% of patients in both groups.[70]

Class Summary

The penicillins are bactericidal antibiotics that work against sensitive organisms at adequate concentrations and inhibit the biosynthesis of cell wall mucopeptide. Examples of penicillins include amoxicillin (Amoxil, Trimox), penicillin VK, and ampicillin.

Amoxicillin (Amoxil, Trimox)

Amoxicillin interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. This drug is an appropriate first-line agent in children in whom pneumococcal disease is strongly suspected. Amoxicillin offers the advantages of being relatively palatable and having a tid-dosing schedule, but it has limited activity against gram-negative bacteria due to resistance.

Ampicillin (Marcillin, Omnipen, Polycillin)

Ampicillin has bactericidal activity against susceptible organisms and is used as an alternative to amoxicillin when patients are unable to take medication orally.

Penicillin VK (Beepen-VK, Pen Vee K)

Penicillin VK inhibits the biosynthesis of cell wall mucopeptide and is bactericidal against sensitive organisms when adequate concentrations are reached. This drug is most effective during the stage of active multiplication, but inadequate concentrations may produce only bacteriostatic effects. Penicillin VK may be used as an alternative to amoxicillin in the treatment of outpatients with pneumonia in whom pneumococcal disease is strongly suspected, but it has limited activity against gram-negative bacteria.

Class Summary

Cephalosporins are structurally and pharmacologically related to penicillins. They inhibit bacterial cell wall synthesis, resulting in bactericidal activity. Cephalosporins are divided into first, second, and third generation. First-generation cephalosporins have greater activity against gram-positive bacteria, and succeeding generations have increased activity against gram-negative bacteria and decreased activity against gram-positive bacteria.

Cefpodoxime (Vantin)

Cefpodoxime inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins. The tablet should be administered with food.

Cefprozil (Cefzil)

Cefprozil binds to one or more of the penicillin-binding proteins, which, in turn, inhibits cell wall synthesis and results in bactericidal activity.

Cefdinir (Omnicef)

Cefdinir binds to one or more of the penicillin-binding proteins, which, in turn, inhibits cell wall synthesis and results in bactericidal activity.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity that arrests bacterial growth by binding to one or more penicillin-binding proteins. Ceftriaxone has lower efficacy against gram-positive organisms but higher efficacy against resistant organisms.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin with gram-negative spectrum that arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth. This drug has a lower efficacy against gram-positive organisms.

Cefuroxime (Zinacef, Ceftin, Kefurox)

Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity first-generation cephalosporins have. This drug adds activity against P mirabilis, H influenzae, E coli, K pneumoniae, and M catarrhalis. The condition of the patient, severity of infection, and susceptibility of the causative microorganism determines the proper dose and route of administration.

Ceftaroline (Teflaro)

Beta-lactam cephalosporin with activity against aerobic and anaerobic gram-positive and aerobic gram-negative bacteria. It is indicated in children aged ≥2 months for treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli.

Ceftazidime/avibactam (Avycaz)

Indicated for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) now includes pediatric patients aged 3 months and older caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae. 

Avibactam is a diazabicyclooctanone, non-β-lactam, β-lactamase inhibitor. Alone has no antibacterial activity at clinically relevant doses. When combined with ceftazidime, avibactam protects ceftazidime from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of ceftazidime to include many gram-negative bacteria normally not susceptible to ceftazidime. 

Class Summary

Anti-infectives such as vancomycin are effective against some types of bacteria that have become resistant to other antibiotics.

Vancomycin (Vancocin)

Vancomycin is a tricyclic glycopeptide antibiotic with bactericidal action that primarily results from the inhibition of cell-wall biosynthesis. In addition, vancomycin alters bacterial cell membrane permeability and RNA synthesis. Antibiotic therapy should include vancomycin (particularly in areas where penicillin-resistant streptococci have been identified) and a second- or third-generation cephalosporin.

Class Summary

Macrolide antibiotics have bacteriostatic activity and exert their antibacterial action by binding to the 50S ribosomal subunit of susceptible organisms, resulting in inhibition of protein synthesis.

Erythromycin-sulfisoxazole (Pediazole)

Erythromycin is a macrolide antibiotic with a large spectrum of activity that binds to the 50S ribosomal subunit of the bacteria, which inhibits protein synthesis. Sulfisoxazole expands erythromycin's coverage to include gram-negative bacteria and inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). The dose for the combination of the 2 drugs is based on the erythromycin component.

Azithromycin (Zithromax)

Azithromycin is used to treat mild to moderate microbial infections. Bacterial or fungal overgrowth may result with prolonged antibiotic use.

Clarithromycin (Biaxin)

Clarithromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Erythromycin (E.E.S., E-Mycin, Ery-Tab)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest. This drug is used for the treatment of staphylococcal and streptococcal infections. In children, age, weight, and severity of infection determine the proper dosage. When bid dosing is desired, half-total daily dose may be taken q12h. For more severe infections, double the dose.

Class Summary

Aminoglycosides are bactericidal antibiotics used to primarily treat gram-negative infections. They interfere with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits.

Gentamicin

Gentamicin is an aminoglycoside antibiotic for gram-negative coverage that is typically used in combination with agents against gram-positive organisms. When administered parenterally, this agent offers antimicrobial efficacy against many gram-negative pathogens commonly encountered in the first few days of life, including E coli, Klebsiella species, and other enteric organisms, as well as many strains of nontypeable H influenzae.

Gentamicin is also variably effective against some strains of certain gram-positive organisms, including S aureus, enterococci, and L monocytogenes. Gentamicin crosses the blood-brain barrier into the CNS less well and theoretically poses a greater risk of renal toxicity or ototoxicity than cefotaxime and other third-generation cephalosporins, which are the common alternatives.

Gentamicin is associated with much less rapid emergence of resistant organisms in a closed environment (eg, neonatal ICU), and has a broader range of susceptible gram-negative organisms. Gentamicin has been reported to offer additive or synergistic activity against enterococci when used with ampicillin.

Class Summary

These agents are used in the treatment of patients with TB. Antimycobacterial agents are a miscellaneous group of antibiotics whose spectrum of activity includes Mycobacterium species. They are used to treat TB, leprosy, and other mycobacterial infections.

Isoniazid (Laniazid, Nydrazid)

Isoniazid has the best combination of effectiveness, low cost, and minor side effects of this class of drugs. Isoniazid should be the first-line agent unless the patient has known resistance or another contraindication. Therapeutic regimens for less than 6 months demonstrate unacceptably high relapse rate.

Coadministration of pyridoxine is recommended if peripheral neuropathies secondary to isoniazid therapy develop. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended.

Ethambutol (Myambutol)

Ethambutol diffuses into actively growing mycobacterial cells, such as tubercle bacilli and impairs cell metabolism by inhibiting synthesis of one or more metabolites, which, in turn, causes cell death.

No cross-resistance has been demonstrated; however, mycobacterial resistance is common with previous therapy. Use ethambutol in these patients in combination with second-line drugs that have not been previously administered. Administer q24h until permanent bacteriologic conversion and maximal clinical improvement is observed. Absorption of this drug is not significantly altered by food.

Rifampin (Rifadin, Rimactane)

Rifampin is used in combination with at least one other antituberculous drug and inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which in turn blocks RNA transcription. Rifampin treatment duration is for 6-9 months or until 6 months have elapsed from conversion to sputum culture negativity.

Streptomycin

Streptomycin sulfate is used in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin). The total period of treatment for TB is a minimum of 1 year; however, indications for terminating streptomycin therapy may occur at any time. Streptomycin is recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Pyrazinamide

Pyrazinamide is a pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against Mycobacterium tuberculosis, depending on the concentration of the drug attained at the site of infection. Its mechanism of action is unknown.

For patients who are drug susceptible, administer for the initial 2 months of a 6-month or longer treatment regimen. Treat patients who are drug resistant with individualized regimens.

Class Summary

These agents must be initiated early to adequately inhibit the replicating virus. This is difficult because the clinical situation usually deteriorates over several days, such that by the time the child's condition is poor enough to require medical attention, the window of opportunity has passed.

Unfortunately, oseltamivir resistance emerged in the United States during the 2008-2009 influenza season; the CDC issued revised interim recommendations for antiviral treatment and prophylaxis of influenza. Thus, zanamivir (Relenza) is recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure is suspected. Complete recommendations are available from the CDC.

Ribavirin (Virazole)

Ribavirin inhibits viral replication by inhibiting DNA and RNA synthesis and is effective against RSV, influenza virus, and herpes simplex virus. However, there has been little evidence to demonstrate that ribavirin has much clinical benefit in a hospital setting.

Oseltamivir (Tamiflu)

Oseltamivir inhibits neuraminidase, which is a glycoprotein on the surface of influenza virus that destroys an infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, oseltamivir decreases the release of viruses from infected cells and, thus, viral spread. This drug has been effective for treatment of influenza A or B infection and is administered within 40 h of symptom onset.

Unfortunately, oseltamivir resistance emerged in the United States during the 2008-2009 influenza season; the CDC issued revised interim recommendations for antiviral treatment and prophylaxis of influenza. Thus, zanamivir (Relenza) is recommended as the initial choice for antiviral prophylaxis or treatment when influenza A infection or exposure is suspected. Complete recommendations are available from the CDC.

A second-line alternative is a combination of oseltamivir plus rimantadine, rather than oseltamivir alone. Local influenza surveillance data and laboratory testing can assist the physician regarding antiviral agent choice.

Zanamivir (Relenza)

Zanamivir is an inhibitor of neuraminidase, which is a glycoprotein on the surface of the influenza virus that destroys the infected cell's receptor for viral hemagglutinin. By inhibiting viral neuraminidase, release of viruses from infected cells and viral spread are decreased. Zanamivir is effective against both influenza A and B and is administered by inhalation through a Diskhaler oral inhalation device. Circular foil discs that contain 5-mg blisters of drug are inserted into supplied inhalation device.

Acyclovir (Zovirax)

Acyclovir inhibits activity of both HSV-1 and HSV-2 and is the drug of choice for the treatment of pneumonia in children with herpes viruses (eg, herpes simplex, varicella). Patients experience less pain and faster resolution of cutaneous lesions when used within 48 hours from rash onset.

Class Summary

Aside from avoiding infectious contacts, vaccination is the primary mode of prevention. Vaccines provide immunity to a disease by stimulating antibody formation and can be either killed or attenuated live.

Influenza virus vaccine quadrivalent (Afluria Quadrivalent, Fluarix Quadrivalent, FluLaval Quadrivalent)

Quadrivalent vaccines contain two strains of influenza A and two of influenza B. The vaccine induces antibodies specific to virus strains contained in vaccine. Each year, the US Public Health Service determines which viral strains will be included in the seasonal influenza vaccine that will antigenically represent the viral strains most likely to circulate in the next flu season. It is administered as an IM injection. Afluria, Fluzone, FluLaval, and Fluarix Quadrivalent vaccines are approved for children aged 6 months or older.

Influenza virus vaccine quadrivalent, cell-cultured (Flucelvax Quadrivalent)

Cell-derived (ie, egg-free) vaccine indicated for adults and pediatric patients aged 2 years or older.

Influenza virus vaccine quadrivalent, intranasal (FluMist Quadrivalent)

Indicated for immunization in patients aged 2-49 years.The Advisory Committee on Immunization Practices (ACIP) recommended return of intranasal flu vaccine in the U.S. for 2018-2019 season. The recommendation was based on positive results from a U.S. study in children between the ages of 2 to <4 years evaluating the shedding and antibody responses of the H1N1 strain in the live attenuated influenza vaccine (LAIV).

Pneumococcal vaccine 13-valent (Prevnar 13)

Indicated for routine vaccination in infants. Also for high-risk who are immunocompromised (eg, HIV, cancer, renal disease) or have functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants.

Capsular polysaccharide vaccine against 13 strains of S pneumoniae, conjugated to nontoxic diphtheria protein, including serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.

Pneumococcal vaccine 15-valent (Vaxneuvance)

Indicated for active immunization for prevention of invasive disease caused by Streptococcus pneumoniae in individuals aged 6 weeks and older.

Use for primary vaccination and catch-up immunization in children aged 6 weeks and older is interchangeable with PCV13.

Recommended for routine vaccination in adults aged 65 years and older who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown. If PCV15 is used, this should be followed 1 year later by a dose of PPSV23.

Also indicated for adults aged 19-64 years with certain underlying medical conditions or other risk factors who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown (followed by a dose of PPSV23). 

Contains all serotypes in the PVC13 vaccine plus 22F and 33F.