Congenital Pneumonia

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Background

Pneumonia is an inflammatory pulmonary process that may originate in the lung or 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 various 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.

Such pathologic problems, superimposed on the underlying difficulties associated with the transition from intrauterine to extrauterine life, pose critical challenges to the immature human organism. Recognition, prevention, and treatment of these problems are major factors in the care of high-risk newborn infants.

This article focuses on pneumonia that presents within the first 24 hours after birth. Although pneumonia is an important cause of morbidity and mortality among ne wborn infants, it remains a difficult disease to identify promptly and treat.[1, 2, 3, 4] (See Treatment and Management, as well as Medication.)

Clinical manifestations are often nonspecific (see Clinical Presentation).

Neonatal pneumonia shares respiratory and hemodynamic signs with a host of noninflammatory processes.[5] (See Diagnosis.)

Radiographic and laboratory findings have limited predictive value. (See Workup.)

Therapy in infants with neonatal pneumonia is multifaceted and includes both antimicrobial therapy and respiratory support. The goals of therapy are to eradicate infection and provide adequate support of gas exchange to ensure the survival and eventual well being of the infant (see Treatment and Management).

Go to Pneumonia, Pediatric and Afebrile Pneumonia Syndrome for more complete information on these topics.

Pathophysiology

Pneumonia that becomes clinically evident within 24 hours of birth may originate at 3 different times. The 3 categories of congenital pneumonia are as follows:

True congenital pneumonia

True congenital pneumonia is already established at birth. It may become established long before birth or relatively shortly before birth. Transmission of congenital pneumonia usually occurs via 1 of 3 routes:

If the mother has a bloodstream infection, the microorganism can readily cross the few cell layers that separate the maternal from the fetal circulation at the villous pools of the placenta. The mother may be febrile or have other signs of infection, depending on the integrity of her host defenses, the responsible organism, and other considerations.

Transient bacteremia following daily activities, such as brushing teeth, defecating, and other potential disruptions of colonized mucoepithelial surfaces, is a well known phenomenon and may result in hematogenous transmission without significant maternal illness. However, the likelihood of hematogenous transmission is increased if the mother has continuous bloodstream infection with a relatively large quantity of microorganisms. In this case, the mother is more likely to have suggestive signs and symptoms.

Because host defenses are limited in fetuses, dissemination and illness may result. The fetus is likely to have systemic disease.

Ascending infection from the birth canal and aspiration of infected or inflamed amniotic fluid have significant common features. Infection of amniotic fluid often involves ascending pathogens from the birth canal but may result from hematogenous seeding or direct introduction during pelvic examination, amniocentesis, placement of intrauterine catheters, or other invasive procedures. Ascension may occur with or without ruptured amniotic membranes.

Most bacterial infections produce clinical signs of infection in the mother, but infections may not be evident if the membranes rupture shortly after inoculation, similar to drainage of an abscess. Some nonbacterial organisms, such as Ureaplasma species (U urealyticum or Uparvum), may be present in the amniotic cavity for long periods yet cause minimal symptoms in the mother.

If the fetus aspirates infected fluid prior to delivery, organisms that reach the distal airways or alveoli may need to cross only 2 cell layers (alveolar epithelium and capillary endothelium) to enter the bloodstream. Typically, these infants present with more pulmonary than systemic signs, but this is not always the case.

Intrapartum pneumonia

Intrapartum pneumonia is acquired during passage through the birth canal. It may be acquired via hematogenous or ascending transmission, from aspiration of infected or contaminated maternal fluids, or from mechanical or ischemic disruption of a mucosal surface that has been freshly colonized with a maternal organism of appropriate invasive potential and virulence.

Postnatal pneumonia

Postnatal pneumonia in the first 24 hours of life originates after the infant has left the birth canal. It may result from some of the same processes described above, but infection occurs after the birth process. Colonization of a mucoepithelial surface with an appropriate pathogen from a maternal or environmental source and subsequent disruption allows the organism to enter the bloodstream, lymphatics, or deep parenchymal structures.

The frequent use of broad-spectrum antibiotics in many obstetrical services and neonatal intensive care units (NICUs) often results in predisposition of an infant to colonization by resistant organisms of unusual pathogenicity. Invasive therapies typically required in these infants often allow microbes accelerated entry into deep structures that ordinarily are not easily accessible.

Enteral feedings may result in aspiration events of significant inflammatory potential. Indwelling feeding tubes may further predispose infants to gastroesophageal reflux and other aspiration events.

Pathogenesis

In neonatal pneumonia, pulmonary and extrapulmonary injuries are caused directly and 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 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.[6, 7]

Indirect injury is mediated by structural or secreted molecules, such as endotoxin, leukocidin, and toxic shock syndrome toxin-1, which 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.

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.

On a macroscopic level, the invading agents and the host defenses both tend to increase airway smooth muscle tone and resistance, mucous 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 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.

Etiology

Neonatal pneumonia may be infectious or noninfectious. 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.

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. Despite the decreased frequency, GBS remains a common isolate in early-onset (aged < 3 d) infections in term and near-term infants. Since that time, Escherichia coli has become the most common bacterial isolate among very low birth weight infants (≤1500 g).[8] Other prominent bacterial organisms include the following:

Among nonbacterial potential pathogens, U urealyticum and U parvum have been frequently recovered from endotracheal aspirates shortly after birth in very low birth weight infants and have been variably associated with various adverse pulmonary outcomes, including bronchopulmonary dysplasia (BPD).[10, 11, 12, 13, 14] Whether this organism is causal or simply a marker of increased risk is unclear.

Numerous comparative therapeutic trials have suggested that BPD prevention offers no or limited benefit among certain subgroups. These organisms have also been recovered from normally sterile sites (eg, blood, cerebrospinal fluid [CSF], lung tissue) in critically ill infants in whom antimicrobial treatment appeared to be warranted. Whether the improvement was due to or despite such treatment remains controversial.

Agents of chronic congenital infection, such as cytomegalovirus, Treponema pallidum, Toxoplasma gondii, rubella, and others, may cause pneumonia in the first 24 hours of life. Clinical presentation usually involves other organ systems as well.[15, 16]

Chlamydia organisms presumably are 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.

Few case reports have identified vertical transmission of Neisseria gonorrhoeae causing congenital pneumonia. However, in a recent study, the blood and sputum cultures were negative but the cells of N gonorrhea were obtained in gastric aspirate culture. The chest radiograph was consistent with fine reticulogranular infiltration, confirming pneumonia.[17]

Infections with Streptococcus pneumonia (Pneumococcus) are infrequent in the neonatal period but are associated with high morbidity and mortality rates. In the neonatal period, pneumococcal infections can present in the form of pneumonia, sepsis, or meningitis with early or late onset. The transmission of the organism is not clear but is suspected to be either by vertical transmission from vaginal colonization of Pneumococcus or horizontal due to local infections or infections by nonvaccine serogroups.[18]

Respiratory viral pathogens such as respiratory syncytial virus, influenza virus, adenovirus, and others may be transmitted vertically or shortly after birth by contact with infected family members or caregivers. However, infection by immediate postnatal transmission of these organisms rarely becomes apparent during the first 24 hours.

Congenital tuberculosis is rare but fatal cause of congenital pneumonia if left untreated. An untreated pregnant woman with tuberculosis can spread infection to a fetus by hematogenous spread through the umbilical cord or by aspiration or ingestion of amniotic fluid. Signs and symptoms of congenital tuberculosis may be nonspecific, which may preclude early diagnosis and treatment.[19, 20]

Congenital candidiasis can lead to pneumonia and respiratory distress within 24 hours of life. In addition, it is characterized by diffuse erythematous papules.[21]

Epidemiology

Pneumonia occurs frequently in newborn infants, although reported rates vary considerably depending on the diagnostic criteria used and the characteristics of the population under study. Most reports cite frequencies in the range of 5-50 per 1000 live births, with higher rates in the settings of maternal chorioamnionitis, prematurity, and meconium in the amniotic fluid. Many cases are likely unreported or undetected; thus, the cited frequency is almost certainly a low estimate.

Determination of mortality rates among infants with congenital pneumonia is complicated by variations in diagnostic criteria and the thoroughness with which this condition is sought. Among infants with congenital pneumonia associated with proven blood-borne infection, mortality is in the range of 5-10%, with rates as high as 30% in infants with very low birth weight. Pneumonia is a contributing factor in 10-25% of all deaths that occur in neonates younger than 30 days.

Prognosis

Continued growth and development of pulmonary and other tissues offers good prospects for long-term survival and progressive improvement in most infants who survive congenital pneumonia. Nevertheless, although quantitation of risk is difficult and is strongly influenced by gestational age, congenital anomalies, and coexisting cardiovascular disease, there is a consensus that congenital pneumonia increases the following:

Significant predictors of mortality in ventilated patients include the following[22] :

Patient Education

Education of parents whose infant has had congenital pneumonia is principally directed toward subsequent care. Counsel parents regarding the need to prevent exposure of infants to tobacco smoke. Educate parents regarding the benefit infants may receive from pneumococcal immunization and annual influenza immunization. Discuss potential benefits and costs of respiratory syncytial virus immune globulin.

As part of anticipatory primary care, educate parents regarding later infectious exposures in daycare centers, schools, and similar settings and the importance of hand washing. Emphasize careful longitudinal surveillance for long-term problems with growth, development, otitis, reactive airway disease, and other complications.

For patient education information, see the Procedures Center, as well as Bronchoscopy.

History

Prenatal features that suggest an increased risk for congenital pneumonia include the following:

Review antenatal screening tests for infection, such as serologic tests for syphilis and birth canal tests for Neisseria gonorrhoeae, Chlamydia species, or group B Streptococcus, as well as any treatment courses and testing for cure.

Intrapartum antibiotic therapy reduces the risk of postpartum maternal infection and infection of the infant in the presence of some of these risk factors but does not eliminate the risk. The potential for selection of pathogens resistant to antibiotics used for intrapartum therapy remains controversial.

Absence of these risk factors does not exclude pneumonia.

Physical Examination

Physical findings may be pulmonary, systemic, or localized. All pulmonary findings are not necessarily present in all affected infants. Many extrapulmonary findings are nonspecific and may be seen in many other common neonatal conditions. Some signs of respiratory distress cannot be manifested if the infant is affected by other processes that result in apnea, such as poor tolerance of labor, exposure to transplacental respiratory depressants, or CNS anomaly or injury.

Pulmonary findings

Respiratory manifestations may include persistent tachypnea (respiratory rate >60/min), expiratory grunting, and accessory respiratory muscle recruitment (eg, nasal flaring and subcostal, intercostal, or suprasternal retraction).

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. Aspiration of meconium, blood, or other inflammatory fluid may produce other colors and textures reflective of the aspirated material.

Rales, rhonchi, and cough should prompt careful consideration of pneumonia in the differential diagnosis, although all these signs are observed much less frequently in infants with pneumonia than in older individuals. Alternative causes include noninflammatory processes, such as heart failure, condensation from humidified gas administered during mechanical ventilation, or endotracheal tube displacement. .

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

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

Increased respiratory support requirements, such as increased inhaled oxygen concentration, positive pressure ventilation, or continuous positive airway pressure are common.

Infants with pneumonia may manifest asymmetry of breath sounds and chest excursions, which suggest air leak or emphysematous changes secondary to partial airway obstruction.

Systemic findings

In the neonate, the systemic findings seen in pneumonia are similar to the signs and symptoms seen in sepsis or other severe infections. Systemic findings include the following:

Other systemic findings include adenopathy and hepatomegaly. Adenopathy suggests long-standing infection. Hepatomegaly from infection may result from certain chronic causative agents, cardiac impairment, or increased intravascular volume. Apparent hepatomegaly may result if therapeutic airway pressures result in generous lung inflation and downward displacement of a normal liver.

Localized findings

Localized findings may include the following:

True congenital pneumonia

Infants whose pneumonia is already established at birth have clinical signs of pneumonia almost immediately after birth. Further deterioration is frequent as the process progresses and the infant is confronted with the exigencies of adapting to extrauterine existence.

If the infant tolerated labor poorly or has been exposed to agents that depress respiratory effort, the infant may initially be apneic, with no ability to manifest signs of respiratory distress.

Intrapartum pneumonia

Infants who aspirate proinflammatory foreign material (eg, meconium or blood) during passage through the birth canal may manifest pulmonary signs immediately after or very shortly after birth. In contrast, infants with infectious processes often have a honeymoon period of a few hours before sufficient invasion, replication, and inflammatory response have occurred to cause clinical signs.

Postnatal pneumonia

Infants who become infected after leaving the birth canal are often relatively asymptomatic at birth or manifest noninflammatory pulmonary disease consistent with gestational age, but develop signs that progress well after 24 hours.

Complications of Congenital Pneumonia

Congenital pneumonia is associated with a number of potential complications, including the following:

Approach Considerations

Diagnostic criteria for congenital pneumonia remain controversial in the absence of histopathologic specimens. Criteria range from very liberal (to minimize the probability of missing a case) to very stringent (to minimize the possibility of labeling some other condition inappropriately). An example of the former includes only respiratory difficulties and persistent radiographic evidence of infiltrates.

More stringent standards often also mandate the presence of respiratory support requirements, laboratory markers of systemic inflammation, and inflammatory respiratory secretions (using quantitative or semiquantitative threshold criteria). Diagnosis in the clinical setting is usually based on a combination of historical, physical, radiographic, microbiologic, and laboratory findings.

Go to Pneumonia, Pediatric and Afebrile Pneumonia Syndrome for more complete information on these topics.

Radiography

Numerous radiographic patterns are consistent with neonatal pneumonia and a multitude of other pathologic processes.[26] (See the images below.) A synthesis of all available information and careful consideration of the differential diagnosis is essential to establishing the diagnosis, although empiric antimicrobial treatment usually cannot be deferred because of inability to prospectively exclude the diagnosis.



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Anteroposterior chest radiograph in an infant born at 28 weeks' gestation was performed following apnea and profound birth depression. Subtle reticulo....



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Full-term infant (note ossified proximal humeral epiphyses, consistent with full term) with progressive respiratory distress from birth following deli....



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Patchy infiltrates most prominent along left cardiothymic margin in a full-term infant (note proximal humeral ossific nuclei) born to an afebrile woma....

A well-centered, appropriately penetrated, anteroposterior chest radiograph is essential. Other views may also be warranted, to clarify anatomic relationships and air-fluid levels.

Be aware that any image reflects conditions only at the instant when the study was performed. Because neonatal lung diseases, including pneumonia, are dynamic, initially suggestive images may require reassessment based on subsequent clinical course and findings in later studies.

When considering pneumonia, devote particular attention to the following:

Diffuse relatively homogeneous infiltrates that resemble the ground-glass pattern of respiratory distress syndrome are suggestive of a hematogenous process, although aspiration of infected fluid with subsequent seeding of the bloodstream cannot be excluded.

Patchy irregular densities that obscure normal margins are suggestive of antepartum or intrapartum aspiration, especially if such opacities are distant from the hilus. Patchy irregular densities in dependent areas that are more prominent on the right side are more consistent with postnatal aspiration.

Generalized hyperinflation with patchy infiltrates suggests partial airway obstruction from particulate or inflammatory debris. However, the contribution of positive airway pressure from respiratory support must also be considered.

Pneumatoceles (especially with air-fluid interfaces) and prominent pleural fluid collections also support the presence of infectious processes.

Single or multiple prominent air bronchograms 2 or more generations beyond the mainstem bronchi reflect dense pulmonary parenchyma (possibly an infiltrate) highlighting the air-filled conducting airways.

A well-defined dense lobar infiltrate with bulging margins is unusual.

Lateral or oblique projections may help to better define structures whose location and significance are unclear.

Ultrasonography

Ultrasonography may be helpful in selected circumstances. Ultrasonography is particularly useful for identifying and localizing fluid in the pleural and pericardial spaces. However, the presence of air within the lungs limits the use of ultrasonography.

Computed Tomography or Magnetic Resonance Imaging

CT or MRI may be helpful for evaluating the following:

CT or MRI is also helpful for establishing the presence of infiltrate, atelectasis, or other acquired processes. Such studies may be particularly useful for localizing infiltrates, abscesses, or infected fluid before percutaneous sampling attempts

Go to Imaging in Pediatric Pneumonia for more complete information on this topic.

Cultures

The most useful laboratory tests for congenital pneumonia facilitate the identification of an infecting microorganism. Results can be used for therapeutic decisions as well as prognostic and infection control considerations.

Conventional bacteriologic culture is used most widely and is currently most helpful. Aerobic processing is sufficient for recovery of most responsible pathogens. Although the foul smell of amniotic fluid in the setting of maternal chorioamnionitis is often attributable to anaerobes, these organisms are seldom shown to be causative.

Culture of fungi, viruses, U urealyticum,U parvum, and other nonbacterial organisms often requires different microbiologic processing but may be warranted in suggestive clinical settings.

A number of factors may interfere with the ability to grow a likely pathogen, including (but not limited to) the following:

Techniques that may help overcome some of these limitations include antigen detection, nucleic acid probes, 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; however, new generations of non–culture-based technologies continue to undergo development and may be more accurate and widely available in the future.

Blood culture

Blood culture with at least 1 mL of blood from an appropriately cleaned and prepared peripheral venous or arterial site is essential because many neonatal pneumonias are hematogenous in origin and others serve as a focus for secondary seeding of the bloodstream. Blood culture samples drawn through freshly placed indwelling vascular catheters may be helpful, but the possibility of contamination rises the longer the catheter is in place. Contemporary automated microbiologic processing systems facilitate differentiation of true pathogens from contaminants, since the former are usually recovered within 12-24 hours, while the latter frequently take much longer.

Multiple cultures of blood from different sites and/or those drawn at different times may increase culture yield, but limited circulating blood volume precludes this as the standard of care in neonates on the first day of life.

Cerebrospinal fluid culture

Routine culture and analysis of cerebrospinal fluid (CSF) in infants in whom congenital pneumonia is suspected is controversial because the yield is low and many infants with respiratory support requirements do not tolerate lumbar puncture well. However, CSF may yield a pathogen when blood does not, especially following maternal antibiotic pretreatment.[27] In addition, the presence of a pathogen in the CSF may indicate the need for alteration in the selection, dosage, and duration of antibiotic therapy even if cultures from other sites yield the same organism.

Culture of specimens from endotracheal aspiration

Culture and Gram stain 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 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.[28]

The longer the endotracheal tube has been in place, the greater the likelihood that recovered organisms represent colonizing organisms rather than invasive pathogens. Nonetheless, recovery of a single recognized pathogen in large quantities may be helpful in the selection of antibiotic therapy, especially if culture results from normally sterile sites are negative.

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). In such cases, the organism represents colonization of the respiratory tract and not infection.

Culture from other respiratory sites

In certain situations, culture of pleural fluid, bronchoscopic alveolar lavage fluid, nonbronchoscopic protected specimen brush samples, or specimens obtained by lung puncture may be valuable.

Culture from extrapulmonary lesions

Detection of microorganisms at inflamed extrapulmonary sites may be helpful because concurrent involvement of the lungs is not rare. Studies of abscesses, conjunctivitis, skin lesions, and vesicles may be fruitful.

Take care to ensure that the specimen submitted is as free of contamination as possible. Tests such as organism-specific DNA probe or polymerase chain reaction (PCR)–based assay are less likely to be affected by such factors.

Urine culture

During the first 3 days of life, urine culture is unlikely to be helpful because most urinary tract infections at this age are hematogenous.

Serologic Tests

Serologic tests have limited use but may offer some insights in congenital pneumonia secondary to cytomegalovirus or toxoplasmosis. Serologic tests for syphilis may suggest or confirm the presence of pneumonia alba, particularly in high-risk populations.

Giacoia and colleagues espoused the value of assessing antibody responses in acute and convalescent sera from infants using flora recovered from endotracheal aspirates.[29] This usually permits diagnosis only retrospectively, but may be useful in infants who fail to adequately respond to empiric therapy or for epidemiologic purposes. Concerns persist regarding the specificity of such tests in distinguishing invasion from colonization.

Markers of Inflammation

The use of markers of inflammation to support a diagnosis of suspected infection, including pneumonia, remains controversial.

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 C-reactive protein, procalcitonin, cytokines (eg, interleukin-6), interalpha inhibitor proteins,[30] and batteries of acute-phase reactants have been touted to be more specific but are limited by suboptimal positive predictive value. There is a lag time from infection to the development of abnormal values. Serial measurements are often necessary, but do offer a high negative predictive value.

These tests may be useful in assessing the resolution of an inflammatory process, including infection, but 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.

Thoracentesis

In neonates with radiographically visible pleural fluid, careful positioning of the infant and thoracentesis after sterile preparation of the sampling site may provide specimens that yield diagnostic findings on Gram stain, direct microscopy, and/or culture. Ultrasonography may reveal smaller fluid pockets and facilitate safer sampling under direct visualization. Although data from studies in neonates are insufficient to draw conclusions, studies in older populations suggest a very high correlation with culture of lung tissue and blood.

The risk of pneumothorax or laceration of intercostal vessels is real but can be minimized by the use of proper technique, including use of the Z-technique (stretching the skin down over the entry site, so that release after the procedure will permit the return of tissues to their usual location with occlusion of the path of the needle), entry over the superior rib margin (to minimize inadvertent puncture of intercostal vessels) at a dependent site where fluid is most likely to collect, continuous aspiration once the skin is penetrated, and no further advancement once fluid is obtained. Sonographic guidance may facilitate performance.

This procedure may be therapeutic as well as diagnostic if the pleural fluid is impinging on lung or cardiac function.

Bronchoscopy

Transbronchial biopsy and guided aspiration or brush specimens obtained via direct bronchoscopy may be advantageous in some circumstances.[31] 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 technique. Both this technique and protected brush tracheal aspirate sampling may not be well tolerated in infants with significant lung disease and poor gas exchange who are very dependent on continuous positive pressure ventilation.

Quantitative culture of bronchoscopic alveolar lavage fluid has been assessed in non-neonatal populations and reported to offer a specificity of greater than 80%, depending on the threshold selected (values from >100 to 100,000 cfu/mL have been used).[32, 33] Data from studies of neonates with suspected congenital pneumonia are lacking.

Protected Brush Tracheal Aspirate Sampling

Nonbronchoscopic protected specimen brush can be used to obtain culture material through endotracheal tubes 3 mm or greater in internal diameter.[34] 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.

Data from neonates are sparse at present. Unlike bronchoscopically obtained specimens, ensuring sampling from a particular involved site is more difficult. Sites distant from the larger bronchi often cannot be sampled.

Lung Aspiration

If a prominent infiltrate can be adequately localized in multiple planes, direct aspiration of the infected lung may be performed for culture or biopsy.[35] Lung CT may facilitate such localization.

Lung aspiration usually requires a larger-bore needle than is used to obtain pleural fluid and is associated with a greater risk of postprocedural air leak than thoracentesis.

Lung aspiration is used much less frequently than in previous decades. This is a high-risk procedure, with potential complications that include pneumothorax, bronchopleural fistula, hemothorax, and sampling a nondiagnostic site.

Lung aspiration should not be considered a routine aspect of the diagnosis or treatment of pneumonia in the neonate. Rather, this technique is usually reserved for circumstances in which empiric therapy is failing, less invasive cultures and detection tests are unrewarding, and/or the infant continues to deteriorate. With advances in surgical techniques and increased experience, many clinicians prefer to seek open surgical biopsy or thoracoscopic sampling in such circumstances, especially because success and specimen size are greater and the ability to deal directly with any complication is enhanced.

Histologic Findings

Tissue samples of lung tissue in human infants have typically been obtained from an unrepresentative population. The 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 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.[36]

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 frequently are accompanied by small-to-moderate pleural effusions that display variable concentrations of inflammatory cells, protein, and glucose.

Frank empyema and abscesses are unusual in newborn infants. Particulate meconium or vernix may be visible, especially in the more proximal airways, following aspiration episodes. Superimposed changes, such as air leak, emphysema, and sloughed airway mucosa, may be seen as a consequence of volutrauma, pressure-related injury, oxygen toxicity, and other processes that reflect the vigorous respiratory support often provided to these infants in an attempt to manage derangements of gas exchange caused by the underlying illness.

With conventional microscopy, inflammatory cells are particularly prominent in 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 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.

Microscopic examination of tissue following immunohistochemical staining or other molecular biologic techniques can identify the herpes virus and an increasing number of other organisms.

Hemorrhage in the alveoli and in distal airways is frequent. Vascular congestion is common; vasculitis and perivascular hemorrhage are seen less frequently. Inflammatory changes in interstitial tissues are less common in newborns than in older individuals.

Examination of the placenta may be useful. An unusually large placenta with a thick umbilical cord or necrotizing funisitis is suggestive of congenital syphilis, with an increased risk of congenital pneumonia alba. Although results of early maternal serologic screening may have been negative, false-negative results from the prozone phenomenon or infection later in pregnancy may occur. Careful microscopic examination for trophozoites may establish a diagnosis of congenital toxoplasmosis long before other confirmatory tests become available. Other evidence of inflammation or infection derived from gross inspection, microscopy, or specific microbiologic testing may also be useful.

Approach Considerations

Therapy in infants with neonatal pneumonia is multifaceted. The goals of therapy are to eradicate infection and provide adequate support of gas exchange to ensure the survival and eventual well being of the infant.

Evidence-supported options for targeted treatment of inflammation independent of antimicrobial therapy are severely limited.[37] There is considerable speculation 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 constituents into the surrounding microenvironment. This is not to imply that eradication of invasive microbes should not be a goal; however, other methods of eradicating pathogens or methods of directly dealing with the pathologic inflammatory cascades await further definition.

Drainage of a restrictive or infected effusion or empyema may enhance clearance of the infection and will improve lung mechanics.

Even if the infection is eradicated, many hosts develop long-lasting or permanent pulmonary changes that adversely affect lung function, quality of life, and susceptibility to later infections.

In pneumonia resulting from noninfectious causes, the quest for targeted, effective, and safe anti-inflammatory therapy may be of even greater importance.

Go to Pneumonia, Pediatric and Afebrile Pneumonia Syndrome for more complete information on these topics. Additionally, see Surgical Treatment of Infections of the Lung, Pleura, and Mediastinum for more complete information on this topic.

Antimicrobial Therapy

Initial empiric antibiotics are selected according to the susceptibility pattern of the likely pathogens, experience at the institution, and knowledge of delivery of drugs to the suspected infected sites within the lung. Empiric use of azithromycin or other macrolides for presumed Ureaplasma infection is not currently evidence based and should be reserved for infants who have that organism recovered from a normally sterile site or who are critically ill and do not have a more likely cause of infection.[38, 39]

Because bacteremia is common as both a cause and a consequence of congenital pneumonia, attaining an adequate plasma concentration of the antimicrobial agent via a parenteral route is essential. Alveolar delivery of antibiotics typically occurs via diffusion of non–protein-bound drug and is usually satisfactory if plasma concentrations and alveolar perfusion are adequate.

At most institutions, initial empiric therapy consists of ampicillin and either gentamicin or cefotaxime. Dosage regimens vary according to gestational and postnatal age, as well as renal function. Observational studies have suggested increased adverse outcomes, including an increased risk of death, in neonates who receive cefotaxime rather than gentamicin as a routine component of initial empiric neonatal treatment.[40, 41]

Whether the adverse outcomes with cefotaxime are causal, coincidental, or secondary to some other associated factor is unclear. Nevertheless, in some circumstances (eg, renal dysfunction, hearing or ear abnormalities, gram-negative central nervous system infection, maternal myasthenia gravis, high local incidence of gentamicin-resistant but cefotaxime-sensitive organisms), cefotaxime may be preferable to gentamicin.

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 face of renal dysfunction or once the infant is older than 7 days (if the infant still requires antimicrobial therapy).

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 for the organism may be more important than the amplitude of the peak concentration. Intramuscular or intravenous therapy with the same total daily dose but more frequent dosing may be advantageous if the infant 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.

Studies in human adults have demonstrated that aminoglycosides reach the bronchial lumen marginally when administered parenterally, although alveolar delivery is satisfactory.[42, 43] Endotracheal treatment with aerosolized aminoglycosides has been reportedly effective for marginally susceptible organisms in bronchi, whereas cefotaxime appears to attain adequate bronchial concentrations via the parenteral route. Limited in vitro and animal data suggest that cefotaxime may retain more activity than aminoglycosides in sequestered foci, such as abscesses, although such foci are rare in congenital pneumonia, and adequate drainage may be more important than antimicrobial selection.

Recovery of a specific pathogen from a normally sterile site (eg, blood, urine, cerebrospinal fluid) permits narrowing the spectrum of antimicrobial therapy and may thus reduce the selection of resistant organisms and costs of treatment. 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 considered to represent a normally sterile site, although they may yield an organism that is a true invasive pathogen. Reculture 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 been terminated.

Decreasing respiratory support requirements, clinical improvement, and resolution revealed on 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 exclude an infectious etiology; continuation of empiric therapy may be advisable unless the clinical course or other data strongly suggests that a noninfectious cause is responsible for the presenting signs.

Although meconium is usually sterile, most clinicians opt for adjunctive antimicrobial therapy when meconium was present in the amniotic fluid because concurrent aspiration of pathogens or antecedent bacteremia as a cause of intrauterine meconium passage and subsequent aspiration usually cannot be excluded.

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

The duration of antimicrobial therapy for neonatal pneumonia has not been rigorously assessed in comparative trials. Most clinicians treat infants for 7-10 days if clinical signs resolve rapidly. If positive results on culture were found at a normally sterile site, continuing treatment for 7-10 days following sterilization is prudent. Longer periods of therapy may be warranted if a sequestered focus, such as empyema or abscess, is seen or if metastatic infection develops. Herpes simplex infection with central nervous system involvement may require 21 or more days of antiviral treatment.

Respiratory Support

Adequate gas exchange depends not only on alveolar ventilation, but also on 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 do little good if perfusion is not simultaneously adequate.

Criteria for institution of and weaning from supplemental oxygen and mechanical support are similar to those for other neonatal respiratory diseases. Be aware that lung disease in these patients is often structurally heterogeneous, with subpopulations of normally inflated, hyperinflated, atelectatic, obstructed, fluid-filled, and variably perfused alveoli that may require multiple adjustments of ventilatory pressures, flows, rates, times, and modalities.

A number of respiratory management issues require special consideration in newborn infants in whom pneumonia is suspected. These include airway patency, ventilatory support, and pulmonary hypertension.

Airway patency

Assurance of airway patency may be more challenging in neonates with pneumonia because of the often profuse, potentially obstructive secretions and mucopurulent exudates of variable viscosity. Judicious suctioning is warranted. Deep suctioning should be avoided because it can cause airway trauma and swelling, which, in turn, may cause large airway obstruction.

Gentle vibration and percussion is used in some centers to mobilize the secretions, although appropriately designed studies do not support routine use of this technique. At least one report cautions that long-term routine percussion may be associated with brain injury in premature infants with a birth weight less than 1500 g.[44] Potential benefit may exceed potential risks with targeted use in specific infants with secretion problems.

Use of mucolytic agents, such as acetylcysteine or recombinant DNase, may be required to mobilize dense inspissated secretions but also may induce bronchospasm and be poorly tolerated.

Any endotracheal tube requires careful positioning and may require periodic replacement to ensure patency. Endotracheal perfluorocarbon and exogenous surfactant lavage have both been suggested as possible means of safely mobilizing thick potentially obstructive material, including meconium, even from distal airways. Bronchoscopic removal may be plausible if the airway is sufficiently large.

Prevention or reduction of atelectasis may reduce bacterial growth and/or bacterial translocation.[45]

Comparative trials of sufficient size to document the safety and efficacy of these approaches are sparse.

Ventilatory support

Ventilatory support may be rendered unusually challenging by alveoli with variable degrees of inflation from the unpredictable distribution of surfactant inactivation, partial airway obstruction, and fluid exudation.

Take care to ensure that the airway pressures required to attain alveolar stability interfere as little as possible with myocardial function, venous return, and alveolar perfusion. A survey of neonatal intensive care units in the United Kingdom reported volume-targeted ventilation as the most commonly used modality for neonatal pneumonia.[46]

The use of high-frequency or patient-triggered ventilatory techniques may offer better recruitment of alveolar lung volume, but data are sparse.

Neonatal pneumonia is associated with surfactant inactivation and/or increased catabolism.[47] Exogenous surfactant may be beneficial in selected infants.[48] Although randomized controlled trials in human infants for this indication are lacking, animal studies and an increasing number of clinical reports have suggested the adjunctive utility of exogenous surfactant.[49, 50] Many clinicians elect to administer surfactant when mechanical ventilation is required with greater than 60% oxygen concentration. Time to clinical response and requirement for multiple doses are both reported to be greater than in infants with respiratory distress syndrome.

Bolus administration of surfactant may be considered for neonates with meconium aspiration syndrome and progressive respiratory failure; surfactant adminstration should also be considered in neonates with group B streptococcal pneumonia.[48]

A guideline from the American Academy of Pediatrics (AAP) advises that rescue treatment with surfactant may be considered for infants with hypoxic respiratory failure attributable to secondary surfactant deficiency (eg, meconium aspiration syndrome or pneumonia).[51] However, the AAP notes that is important for medical personnel to have the requisite technical and clinical expertise to administer surfactant safely and to deal with multisystem illness.

Pulmonary hypertension

Pulmonary hypertension with significant intrapulmonary and extrapulmonary shunting is not uncommon with pneumonia, especially in postterm, term, and near-term infants with sufficient pulmonary vascular smooth muscle to develop systemic or suprasystemic pulmonary vascular resistance.

The optimal therapeutic strategy for pulmonary hypertension remains unresolved. Increased systemic vascular resistance, paralysis, inhaled nitric oxide[52] and/or infused epoprostenol are vigorously used by many clinicians, whereas others advocate less aggressive approaches.

A randomized collaborative trial in the United Kingdom demonstrated that extracorporeal membrane oxygenation (ECMO) was significantly better than conventional therapy in preventing death; however, infants with pneumonia comprised only a fraction of the total study population.[53] Among all newborn infants who are sick enough to require ECMO, those with an underlying diagnosis of pneumonia have a higher mortality rate than those with all noninfectious diseases, except congenital diaphragmatic hernia.[54]

Other Supportive Measures

Red blood cells 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.

Nutrition

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

Transfer

If appropriate respiratory, hemodynamic, or nutritional support cannot be safely and effectively administered at the hospital of birth, stabilize the neonate and transfer to a tertiary care neonatal intensive care unit.

Deterrence/Prevention

Consider intrapartum antibiotic chemoprophylaxis with penicillin or another appropriate antimicrobial agent in mothers at risk for early-onset group B streptococcal disease. Risk factors are as follows:

Consult the Red Book for the most current recommendations for infants at risk for group B streptococcal sepsis/pneumonia.[55]

Prevention strategies may include antepartum and intrapartum broad-spectrum antibiotic treatment in mothers with preterm rupture of membranes or in whom chorioamnionitis is suspected.

In the presence of particulate amniotic fluid meconium, suction the trachea immediately after birth if the infant is not vigorous.[56]

Currently, there is little evidence demonstrating the potential efficacy of the following interventions in neonates:

Medication Summary

The frequency of bacterial infection as the primary cause or as a superimposed complication of pulmonary inflammation in general, and congenital pneumonia in particular, usually mandates antibiotic administration as the cornerstone of therapy.

Agents typically used initially 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 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.

Consultation of appropriate neonatal references, such as Neofax, is recommended when using antibiotics in these patients. Similarly, an appropriate reference should be used when using adjunctive therapy such as bronchodilators, mucolytics, nitric oxide, or epoprostenol.

Ampicillin

Clinical Context:  This parenteral agent offers antimicrobial efficacy against many pathogens encountered in infections that occur in the first few days of life, including, but not limited to, group B Streptococcus, many types of other streptococci, L monocytogenes, and some strains of E coli, enterococci, and nontypeable H influenzae.

Cefotaxime (Claforan)

Clinical Context:  Cefotaxime is a third-generation cephalosporin with gram-negative spectrum. Cefotaxime arrests bacterial cell wall synthesis, which in turn inhibits bacterial growth. When administered parenterally, this agent offers antimicrobial efficacy against many gram-negative pathogens that are commonly encountered in the first few days of life, including E coli, nontypeable H influenzae, Klebsiella species, and other enteric organisms. Cefotaxime crosses the blood-brain barrier into the CNS reasonably well and theoretically poses less risk of renal toxicity or ototoxicity than gentamicin and other aminoglycosides, which are the common alternatives. It is less likely than gentamicin to interfere with function of neuromuscular junction in infants born to mothers with myasthenia gravis.

However, compared with gentamicin, cefotaxime is more costly, is associated with much more rapid emergence of resistant organisms in a closed environment (eg, NICU), covers a slightly narrower range of gram-negative organisms, and has not been demonstrated to yield superior outcomes in a randomized controlled trial of neonatal patients.

Gentamicin

Clinical Context:  Gentamicin is an aminoglycoside antibiotic used for gram-negative coverage. Gentamicin 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. It 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 greater risk of renal toxicity or ototoxicity than cefotaxime and other third-generation cephalosporins, which are the common alternatives. Compared with cefotaxime, gentamicin is less costly, is associated with much less rapid emergence of resistant organisms in a closed environment (eg, NICU), and covers a broader range of gram-negative organisms.

Gentamicin has been reported to offer additive or synergistic activity against enterococci when used with ampicillin.

Azithromycin

Clinical Context:  Empiric use of azithromycin or other macrolides for presumed Ureaplasma infection is not currently evidence based and should be reserved for infants who have that organism recovered from a normally sterile site or who are critically ill and do not have a more likely cause of infection. Azithromycin acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected. It concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Erythromycin (Ery-Tab, Erythrocin, EryPed, E.E.S.)

Clinical Context:  Erythromycin is a macrolide antibiotic with a large spectrum of activity. Erythromycin binds to the 50S ribosomal subunit of the bacteria, which inhibits protein synthesis.

Like azithromycin, the use of erythromycin for presumed Ureaplasma infection is not currently evidence based and should be reserved for infants who have that organism recovered from a normally sterile site or who are critically ill and do not have a more likely cause of infection.

Orally administered erythromycin has been associated with the development of infantile hypertrophic pyloric stenosis in infants younger than 1 month.

Class Summary

The frequency of bacterial infection as the cause or a major complication of congenital pneumonia usually mandates antibiotics as a cornerstone of therapy.

Acyclovir (Zovirax)

Clinical Context:  Acyclovir treatment should be considered when a diagnosis of herpes simplex virus is suspected and when the infant is not responding to antibiotic therapy.

Class Summary

Antiviral agents interfere with viral replication and weaken or abolish viral activity. An example of an antiviral agent is acyclovir (Zovirax).

Author

Muhammad Aslam, MD, Professor of Pediatrics, University of California, Irvine, School of Medicine; Neonatologist, Division of Newborn Medicine, Department of Pediatrics, UC Irvine Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Brian S Carter, MD, FAAP, Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Attending Physician, Division of Neonatology, Children's Mercy Hospital and Clinics; Faculty, Children's Mercy Bioethics Center

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Mariam L Abdul-Latif, MD, Neonatal-Perinatal Medicine Fellow, Department of Pediatrics, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Roger G Faix, MD Professor, Department of Pediatrics (Neonatology), University of Utah School of Medicine

Roger G Faix, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, American Society for Microbiology, National Perinatal Association, Society for Pediatric Research, and Utah Medical Association

Disclosure: Nothing to disclose.

References

  1. Barton L, Hodgman JE, Pavlova Z. Causes of death in the extremely low birth weight infant. Pediatrics. 1999 Feb. 103(2):446-51. [View Abstract]
  2. Duke T. Neonatal pneumonia in developing countries. Arch Dis Child Fetal Neonatal Ed. 2005 May. 90(3):F211-9. [View Abstract]
  3. Heron MP, Smith BL. Deaths: leading causes for 2003. Natl Vital Stat Rep. 2007 Mar 15. 55(10):1-92. [View Abstract]
  4. Nissen MD. Congenital and neonatal pneumonia. Paediatr Respir Rev. 2007 Sep. 8(3):195-203. [View Abstract]
  5. Feria-Kaiser C, Furuya ME, Vargas MH, Rodriguez A, Cantu MA,. Main diagnosis and cause of death in a neonatal intensive care unit: do clinicians and pathologists agree?. Acta Paediatr. 2002. 91(4):453-8. [View Abstract]
  6. Barnett ED, Klein JO. Bacterial infections of the respiratory tract. Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. 6th ed. Philadelphia, Pa: Elsevier Saunders Co; 2006. 297-317.
  7. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997 Jul. 112(1):235-43. [View Abstract]
  8. Stoll BJ, Hansen NI, Higgins RD, et al. Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003. Pediatr Infect Dis J. 2005 Jul. 24(7):635-9. [View Abstract]
  9. Srinivasjois RM, Kohan R, Keil AD, Smith NM. Congenital Mycoplasma pneumoniae pneumonia in a neonate. Pediatr Infect Dis J. 2008 May. 27(5):474-5. [View Abstract]
  10. Kotecha S, Hodge R, Schaber JA, et al. Pulmonary Ureaplasma urealyticum is associated with the development of acute lung inflammation and chronic lung disease in preterm infants. Pediatr Res. 2004 Jan. 55(1):61-8. [View Abstract]
  11. Katz B, Patel P, Duffy L, Schelonka RL, Dimmitt RA, Waites KB. Characterization of ureaplasmas isolated from preterm infants with and without bronchopulmonary dysplasia. J Clin Microbiol. 2005 Sep. 43(9):4852-4. [View Abstract]
  12. Heggie AD, Bar-Shain D, Boxerbaum B, Fanaroff AA, O'Riordan MA, Robertson JA. Identification and quantification of ureaplasmas colonizing the respiratory tract and assessment of their role in the development of chronic lung disease in preterm infants. Pediatr Infect Dis J. 2001 Sep. 20(9):854-9. [View Abstract]
  13. Ballard HO, Bernard P, Whitehead V, et al. Determining the incidence of Ureaplasma spp. and its role in development of bronchopulmonary dysplasia. [Abstract 3858.111]. Pediatric Academic Societies Meeting 2009. Baltimore, MD. May 3, 2009. aps-spr.org. Available at http://www.abstracts2view.com/pas/view.php?nu=PAS09L1_3037. Accessed: June 11, 2009.
  14. Morioka I, Fujibayashi H, Enoki E, Yokoyama N, Yokozaki H, Matsuo M. Congenital pneumonia with sepsis caused by intrauterine infection of Ureaplasma parvum in a term newborn: a first case report. J Perinatol. 2010 May. 30(5):359-62. [View Abstract]
  15. Fischer C, Meylan P, Bickle Graz M, et al. Severe postnatally acquired cytomegalovirus infection presenting with colitis, pneumonitis and sepsis-like syndrome in an extremely low birthweight infant. Neonatology. 2010 Jun. 97(4):339-45. [View Abstract]
  16. Sanchez MO, Chang AB. Congenital rubella pneumonitis complicated by Pneumocystis jiroveci infection with positive long term respiratory outcome: a case report and literature review. Pediatr Pulmonol. 2009 Dec. 44(12):1235-9. [View Abstract]
  17. Chang JH, Huang YL, Chen CC, Li SY. Vertical transmission of Neisseria gonorrhoeae to a female premature neonate with congenital pneumonia. J Formos Med Assoc. 2013 Oct. 112(10):648-9. [View Abstract]
  18. Hermoso Torregrosa C, Carrasco Zalvide M, Ferrer Castillo MT. Streptococcus pneumoniae: an unusual pathogen in neonatal sepsis of vertical transmission. Arch Bronconeumol. 2012 Nov. 48(11):425-6. [View Abstract]
  19. Patel S, DeSantis ER. Treatment of congenital tuberculosis. Am J Health Syst Pharm. 2008 Nov 1. 65(21):2027-31. [View Abstract]
  20. Varik RS, Shubha AM, Lewin M, Alexander B, Kini U, Das K. Infantile pulmonary tuberculosis: the great mimic. Pediatr Surg Int. 2012 Jun. 28(6):627-33. [View Abstract]
  21. Wang SM, Hsu CH, Chang JH. Congenital candidiasis. Pediatr Neonatol. 2008 Jun. 49(3):94-6. [View Abstract]
  22. Iqbal Q, Younus MM, Ahmed A, et al. Neonatal mechanical ventilation: Indications and outcome. Indian J Crit Care Med. 2015 Sep. 19 (9):523-7. [View Abstract]
  23. Chen CH, Wen HJ, Chen PC, Lin SJ, Chiang TL, Hsieh IC. Prenatal and postnatal risk factors for infantile pneumonia in a representative birth cohort. Epidemiol Infect. 2012 Jul. 140(7):1277-85. [View Abstract]
  24. Boo NY, Cheah IG. Risk factors associated with necrotising enterocolitis in very low birth weight infants in Malaysian neonatal intensive care units. Singapore Med J. 2012 Dec. 53(12):826-31. [View Abstract]
  25. Puri A, Yadav PS, Saha U, Singh R, Chadha R, Choudhary SR. A case series study of therapeutic implications of Type IIIb4: A rare variant of esophageal atresia and distal tracheoesophageal fistula. J Pediatr Surg. 2013 Jul. 48(7):1463-9. [View Abstract]
  26. Haney PJ, Bohlman M, Sun CC. Radiographic findings in neonatal pneumonia. AJR Am J Roentgenol. 1984 Jul. 143(1):23-6. [View Abstract]
  27. Wiswell TE, Baumgart S, Gannon CM, Spitzer AR. No lumbar puncture in the evaluation for early neonatal sepsis: will meningitis be missed?. Pediatrics. 1995 Jun. 95(6):803-6. [View Abstract]
  28. Sherman MP, Goetzman BW, Ahlfors CE, Wennberg RP. Tracheal aspiration and its clinical correlates in the diagnosis of congenital pneumonia. Pediatrics. 1980 Feb. 65(2):258-63. [View Abstract]
  29. Giacoia GP, Neter E, Ogra P. Respiratory infections in infants on mechanical ventilation: the immune response as a diagnostic aid. J Pediatr. 1981 May. 98(5):691-5. [View Abstract]
  30. Chaaban H, Singh K, Huang J, Siryaporn E, Lim YP, Padbury JF. The role of inter-alpha inhibitor proteins in the diagnosis of neonatal sepsis. J Pediatr. 2009 Apr. 154(4):620-622.e1. [View Abstract]
  31. Gokdemir Y, Cakir E, Kut A, Erdem E, Karadag B, Ersu R, et al. Bronchoscopic evaluation of unexplained recurrent and persistent pneumonia in children. J Paediatr Child Health. 2013 Mar. 49(3):E204-7. [View Abstract]
  32. Gauvin F, Dassa C, Chaibou M, et al. Ventilator-associated pneumonia in intubated children: comparison of different diagnostic methods. Pediatr Crit Care Med. 2003 Oct. 4(4):437-43. [View Abstract]
  33. Gauvin F, Lacroix J, Guertin MC, et al. Reproducibility of blind protected bronchoalveolar lavage in mechanically ventilated children. Am J Respir Crit Care Med. 2002 Jun 15. 165(12):1618-23. [View Abstract]
  34. Labenne M, Poyart C, Rambaud C, et al. Blind protected specimen brush and bronchoalveolar lavage in ventilated children. Crit Care Med. 1999 Nov. 27(11):2537-43. [View Abstract]
  35. Klein JO. Diagnostic lung puncture in the pneumonias of infants and children. Pediatrics. 1969 Oct. 44(4):486-92. [View Abstract]
  36. Wigglesworth JS. Perinatal Pathology. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1996. 131-57, 184-7.
  37. Wynn JL, Neu J, Moldawer LL, Levy O. Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis. J Perinatol. 2009 Feb. 29(2):79-88. [View Abstract]
  38. Ballard HO, Bernard P, Hayes D, et al. Use of azithromycin for the prevention of bronchopulmonary dysplasia: a randomized, double-blind, placebo controlled trial. [Abstract 4515.2]. Pediatric Academic Societies Meeting 2009. Baltimore, MD. May 4, 2009. aps-spr.org. Available at http://www.abstracts2view.com/pas/view.php?nu=PAS09L1_3053. Accessed: June 11, 2009.
  39. Ballard HO, Bernard P, Whitehead V, et al. Use of azithromycin for the early treatment of Ureaplasma spp. in preterm infants: a randomized, double-blind, placebo controlled trial. [Abstract 4515.3]. Pediatric Academic Societies Meeting 2009. Baltimore, MD. May 4, 2009. aps-spr.org. Available at http://www.abstracts2view.com/pas/view.php?nu=PAS09L1_3037. Accessed: June 11, 2009.
  40. Clark RH, Bloom BT, Spitzer AR, Gerstmann DR. Empiric use of ampicillin and cefotaxime, compared with ampicillin and gentamicin, for neonates at risk for sepsis is associated with an increased risk of neonatal death. Pediatrics. 2006 Jan. 117(1):67-74. [View Abstract]
  41. de Man P, Verhoeven BA, Verbrugh HA, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli. Lancet. 2000 Mar 18. 355(9208):973-8. [View Abstract]
  42. Braude AC, Hornstein A, Klein M, Vas S, Rebuck AS. Pulmonary disposition of tobramycin. Am Rev Respir Dis. 1983 May. 127(5):563-5. [View Abstract]
  43. Pennington JE. Penetration of antibiotics into respiratory secretions. Rev Infect Dis. 1981 Jan-Feb. 3(1):67-73. [View Abstract]
  44. Harding JE, Miles FK, Becroft DM, et al. Chest physiotherapy may be associated with brain damage in extremely premature infants. J Pediatr. 1998 Mar. 132(3 Pt 1):440-4. [View Abstract]
  45. van Kaam AH, Lachmann RA, Herting E, et al. Reducing atelectasis attenuates bacterial growth and translocation in experimental pneumonia. Am J Respir Crit Care Med. 2004 May 1. 169(9):1046-53. [View Abstract]
  46. Chowdhury O, Wedderburn CJ, Lee S, Hannam S, Greenough A. Respiratory support practices in infants born at term in the United Kingdom. Eur J Pediatr. 2012 Nov. 171(11):1633-8. [View Abstract]
  47. Carnielli VP, Zimmermann LJ, Hamvas A, Cogo PE. Pulmonary surfactant kinetics of the newborn infant: novel insights from studies with stable isotopes. J Perinatol. 2009 May. 29 Suppl 2:S29-37. [View Abstract]
  48. Keiser A, Bhandari V. The role of surfactant therapy in nonrespiratory distress syndrome conditions in neonates. Am J Perinatol. 2016 Jan. 33 (1):1-8. [View Abstract]
  49. Herting E, Gefeller O, Land M, et al. Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Members of the Collaborative European Multicenter Study Group. Pediatrics. 2000 Nov. 106(5):957-64; discussion 1135. [View Abstract]
  50. Herting E, Sun B, Jarstrand C, et al. Surfactant improves lung function and mitigates bacterial growth in immature ventilated rabbits with experimentally induced neonatal group B streptococcal pneumonia. Arch Dis Child Fetal Neonatal Ed. 1997 Jan. 76(1):F3-8. [View Abstract]
  51. [Guideline] Engle WA. Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics. 2008 Feb. 121(2):419-32. [View Abstract]
  52. NINOSG. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. The Neonatal Inhaled Nitric Oxide Study Group. N Engl J Med. 1997 Feb 27. 336(9):597-604. [View Abstract]
  53. ECMO. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet. 1996 Jul 13. 348(9020):75-82. [View Abstract]
  54. IELSO. 1999 Summary Report of the Registry for International Extracorporeal Life Support Organization. 1999. 1-10.
  55. AAP. Red Book. Available at http://aapredbook.aappublications.org/. Accessed: November 18, 2010.
  56. Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szyld E, Weiss K, et al. Delivery room management of the apparently vigorous meconium-stained neonate: results of the multicenter, international collaborative trial. Pediatrics. 2000 Jan. 105(1 Pt 1):1-7. [View Abstract]
  57. Guzoglu N, Demirkol FN, Aliefendioglu D. Haemorrhagic pneumonia caused by Stenotrophomonas maltophilia in two newborns. J Infect Dev Ctries. 2015 May 18. 9(5):533-5. [View Abstract]
  58. Hermansen CL, Mahajan A. Newborn respiratory distress. Am Fam Physician. 2015 Dec 1. 92 (11):994-1002. [View Abstract]

Anteroposterior chest radiograph in an infant born at 28 weeks' gestation was performed following apnea and profound birth depression. Subtle reticulogranularity and prominent distal air bronchograms were consistent with respiratory distress syndrome, prompting exogenous surfactant and antimicrobial therapy. Initial smear of endotracheal aspirate revealed few neutrophils but numerous, small, gram-negative coccobacilli. Culture of blood and tracheal aspirate yielded florid growth of nontypeable Haemophilus influenzae.

Full-term infant (note ossified proximal humeral epiphyses, consistent with full term) with progressive respiratory distress from birth following delivery to a febrile mother through thick, particulate, meconium-containing fluid and recovery of copious meconium from the trachea. Right clavicle is fractured without displacement. Note the coarse dense infiltrates obscuring the cardiothymic silhouette bilaterally with superimposed prominent air bronchograms. Listeria monocytogeneswas recovered from the initial blood culture.

Patchy infiltrates most prominent along left cardiothymic margin in a full-term infant (note proximal humeral ossific nuclei) born to an afebrile woman 18 hours after membranes ruptured. The infant was initially vigorous but developed gradual onset of progressive respiratory distress beginning at 2 hours and prompting endotracheal intubation and transfer to a tertiary center at age 10 hours. Note blunting of the right costophrenic angle, a thin radiodense rim along the lateral right hemithorax, and a fluid line in the right major fissure, all consistent with pleural effusion. Gram staining of pleural fluid recovered at thoracentesis indicated occasional gram-negative bacilli. Tracheal aspirate, pleural fluid, and blood all yielded Escherichia coliupon culture. The dense right upper lobe may appear to suggest lobar infiltrate, but upward bowing of the fissure is more suggestive of volume loss, as in atelectasis, than the bulging picture expected with dense pneumonic change. This lobe appeared normal and appropriately inflated on a subsequent film 2 hours later, also suggestive of atelectasis. Umbilical venous catheter and endotracheal tube were positioned properly on the follow-up film.

Anteroposterior chest radiograph in an infant born at 28 weeks' gestation was performed following apnea and profound birth depression. Subtle reticulogranularity and prominent distal air bronchograms were consistent with respiratory distress syndrome, prompting exogenous surfactant and antimicrobial therapy. Initial smear of endotracheal aspirate revealed few neutrophils but numerous, small, gram-negative coccobacilli. Culture of blood and tracheal aspirate yielded florid growth of nontypeable Haemophilus influenzae.

Full-term infant (note ossified proximal humeral epiphyses, consistent with full term) with progressive respiratory distress from birth following delivery to a febrile mother through thick, particulate, meconium-containing fluid and recovery of copious meconium from the trachea. Right clavicle is fractured without displacement. Note the coarse dense infiltrates obscuring the cardiothymic silhouette bilaterally with superimposed prominent air bronchograms. Listeria monocytogeneswas recovered from the initial blood culture.

Patchy infiltrates most prominent along left cardiothymic margin in a full-term infant (note proximal humeral ossific nuclei) born to an afebrile woman 18 hours after membranes ruptured. The infant was initially vigorous but developed gradual onset of progressive respiratory distress beginning at 2 hours and prompting endotracheal intubation and transfer to a tertiary center at age 10 hours. Note blunting of the right costophrenic angle, a thin radiodense rim along the lateral right hemithorax, and a fluid line in the right major fissure, all consistent with pleural effusion. Gram staining of pleural fluid recovered at thoracentesis indicated occasional gram-negative bacilli. Tracheal aspirate, pleural fluid, and blood all yielded Escherichia coliupon culture. The dense right upper lobe may appear to suggest lobar infiltrate, but upward bowing of the fissure is more suggestive of volume loss, as in atelectasis, than the bulging picture expected with dense pneumonic change. This lobe appeared normal and appropriately inflated on a subsequent film 2 hours later, also suggestive of atelectasis. Umbilical venous catheter and endotracheal tube were positioned properly on the follow-up film.