Pneumonia

  • Thomas A. Hooven
    Affiliations
    Columbia University, Department of Pediatrics, Division of Neonatal–Perinatal Medicine, NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA
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  • Richard A. Polin
    Correspondence
    Corresponding author. Babies Hospital Central, 115, New York, NY, USA.
    Affiliations
    Columbia University, Department of Pediatrics, Division of Neonatal–Perinatal Medicine, NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA
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Published:March 23, 2017DOI:https://doi.org/10.1016/j.siny.2017.03.002

      Abstract

      Neonatal pneumonia may occur in isolation or as one component of a larger infectious process. Bacteria, viruses, fungi, and parasites are all potential causes of neonatal pneumonia, and may be transmitted vertically from the mother or acquired from the postnatal environment. The patient's age at the time of disease onset may help narrow the differential diagnosis, as different pathogens are associated with congenital, early-onset, and late-onset pneumonia. Supportive care and rationally selected antimicrobial therapy are the mainstays of treatment for neonatal pneumonia. The challenges involved in microbiological testing of the lower airways may prevent definitive identification of a causative organism. In this case, secondary data must guide selection of empiric therapy, and the response to treatment must be closely monitored.

      Keywords

      1. Introduction

      The newborn lung is susceptible to bacterial and viral infections, and neonatal pneumonia is a major cause of morbidity and mortality worldwide. Between 152,000 and 490,000 infants aged <1 year die of pneumonia annually [
      • GBD
      2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ]. Although these numbers represent a decline from earlier estimates [
      • GBD
      2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013.
      ,
      Reducing Perinatal and Neonatal Mortality, Report of a Meeting.
      ], neonatal pneumonia remains a considerable global health burden that falls disproportionately on developing countries [
      • GBD
      2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015.
      ,
      • Lee K.
      • Park S.
      • Khoshnood B.
      • Hsieh H.L.
      Human development index as a predictor of infant and maternal mortality rates.
      ,
      • Duke T.
      Neonatal pneumonia in developing countries.
      ].
      Diagnosing pneumonia in the newborn period can be challenging. Compared to older children, neonates show fewer localizing signs of pulmonary infection; pneumonia frequently manifests as a systemic deterioration involving multiple organ systems. Common, non-infectious respiratory complications of prematurity often coexist with and exacerbate pneumonia, and may cloud the clinical impression [
      • Apisarnthanarak A.
      • Holzmann-Pazgal G.
      • Hamvas A.
      • Olsen M.A.
      • Fraser V.J.
      Ventilator-associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: characteristics, risk factors, and outcomes.
      ]. Even when pneumonia is suspected, the technical barriers to lower airway sampling in small infants may render conclusive identification of an etiologic organism impossible [
      • Grgurich P.E.
      • Hudcova J.
      • Lei Y.
      • Sarwar A.
      • Craven D.E.
      Diagnosis of ventilator-associated pneumonia.
      ], necessitating careful reasoning about empiric therapy [
      • Cantey J.B.
      • Patel S.J.
      Antimicrobial stewardship in the NICU.
      ].
      This review covers the risk factors, pathophysiology, diagnosis, and treatment of neonatal pneumonia. The discussion is organized around three disease subtypes, which are distinguished by age at presentation, route of acquisition, and major causative micro-organisms. These subtypes are:
      • Congenital pneumonia: infection established during fetal life may result from an ascending infection across the chorioamniotic membranes or a hematogenous transplacental route.
      • Early-onset pneumonia: develops within the first week of life and results from perinatal pathogen exposure, either intrauterine or during passage through the birth canal.
      • Late-onset pneumonia (including ventilator-associated pneumonia; VAP): develops after the first week of life from environmental, often nosocomial, pathogen exposure.

      2. Neonatal pneumonia risk factors

      2.1 Immature innate and adaptive immunity increases neonatal susceptibility to pneumonia

      Compared to children and adults, newborns have a limited capacity to defend against pulmonary infection. Immature innate immunity – both systemic [
      • La Pine T.R.
      • Joyner J.L.
      • Augustine N.H.
      • Kwak S.D.
      • Hill H.R.
      Defective production of IL-18 and IL-12 by cord blood mononuclear cells influences the T helper-1 interferon gamma response to group B Streptococci.
      ,
      • Kwak D.J.
      • Augustine N.H.
      • Borges W.G.
      • Joyner J.L.
      • Green W.F.
      • Hill H.R.
      Intracellular and extracellular cytokine production by human mixed mononuclear cells in response to group B streptococci.
      ] and localized to the respiratory mucosae and lung parenchyma [
      • Jonsdottir I.
      Maturation of mucosal immune responses and influence of maternal antibodies.
      ,
      • Saini Y.
      • Wilkinson K.J.
      • Terrell K.A.
      • Burns K.A.
      • Livraghi-Butrico A.
      • Doerschuk C.M.
      • et al.
      Neonatal pulmonary macrophage depletion coupled to defective mucus clearance increases susceptibility to pneumonia and alters pulmonary immune responses.
      ] – is a fundamental risk factor for neonatal pneumonia [
      • Dowling D.J.
      • Levy O.
      Ontogeny of early life immunity.
      ], and is more significant in premature and growth-restricted patients [
      • Britt R.D.
      • Faksh A.
      • Vogel E.
      • Martin R.J.
      • Pabelick C.M.
      • Prakash Y.S.
      Perinatal factors in neonatal and pediatric lung diseases.
      ]. Adaptive immunity – mostly in the form of maternally derived IgG – is rudimentary in the immediate newborn period [
      • Sasidharan P.
      Postnatal IgG levels in very-low-birth-weight infants. Preliminary observations.
      ]. Adaptive immunity requires antigenic exposure and molecular refinement during infancy and childhood in order to establish strong protection [
      • Jonsdottir I.
      Maturation of mucosal immune responses and influence of maternal antibodies.
      ].
      Structurally, the newborn lung has key deficiencies in important barrier functions that provide a first line of defense against infection. A relative paucity of resident alveolar macrophages, coupled with impaired mucociliary clearance of debris, permits establishment of early colonization by potential pathogens [
      • Saini Y.
      • Wilkinson K.J.
      • Terrell K.A.
      • Burns K.A.
      • Livraghi-Butrico A.
      • Doerschuk C.M.
      • et al.
      Neonatal pulmonary macrophage depletion coupled to defective mucus clearance increases susceptibility to pneumonia and alters pulmonary immune responses.
      ]. Surfactant deficiency due to prematurity has been linked to enhanced growth of group B streptococcus (GBS) and deterioration in an animal model of Escherichia coli pneumonia. There is also evidence that pulmonary infection inactivates existing surfactant and damages type II pneumocytes, preventing replenishment [
      • Bissinger R.
      • Carlson C.
      • Hulsey T.
      • Eicher D.
      Secondary surfactant deficiency in neonates.
      ]. Surfactant replacement therapy has been shown to improve oxygenation in patients with GBS pneumonia [
      • Herting E.
      • Gefeller O.
      • Land M.
      • van Sonderen L.
      • Harms K.
      • Robertson B.
      Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Members of the Collaborative European Multicenter Study Group.
      ].
      Phagocytosis by neutrophils recruited to the lungs is an essential first step in clearing pulmonary bacterial infection, but neonates show multiple forms of neutrophil dysfunction. Based on a dataset of >30,000 measurements from healthy subjects, ∼2% of term and 5% of preterm newborns have neutropenia (absolute neutrophil count: <1000/μL) at baseline [
      • Schmutz N.
      • Henry E.
      • Jopling J.
      • Christensen R.D.
      Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho charts revisited.
      ]. Newborns also exhibit blunted neutrophil recruitment from the bone marrow in response to infection [
      • Christensen R.D.
      • Rothstein G.
      Exhaustion of mature marrow neutrophils in neonates with sepsis.
      ] and defects in neutrophil chemotaxis to sites of inflammation [
      • Birle A.
      • Nebe C.T.
      • Hill S.
      • Hartmann K.
      • Poeschl J.
      • Koch L.
      Neutrophil chemotaxis in cord blood of term and preterm neonates is reduced in preterm neonates and influenced by the mode of delivery and anaesthesia.
      ]. Neutrophils derived from preterm infants are especially affected.
      The efficiency of pathogen clearance by recruited neutrophils and resident phagocytes – such as macrophages and monocytes – is dependent on opsonization with complement, antibodies, and other non-specific binding proteins, including fibronectin, C-reactive protein (CRP), and mannose-binding lectin [
      • Bajic G.
      • Degn S.E.
      • Thiel S.
      • Andersen G.R.
      Complement activation, regulation, and molecular basis for complement-related diseases.
      ]. In addition to facilitating effective phagocytosis, complement also has important direct microbicidal activities through formation of the membrane attack complex [
      • Bajic G.
      • Degn S.E.
      • Thiel S.
      • Andersen G.R.
      Complement activation, regulation, and molecular basis for complement-related diseases.
      ] and promotes recognition of host cells harboring intracellular pathogens (bacterial or viral) [
      • Tam J.C.H.
      • Bidgood S.R.
      • McEwan W.A.
      • James L.C.
      Intracellular sensing of complement C3 activates cell autonomous immunity.
      ]. Unfortunately, the neonate has lower levels of many complement components, and lacks specific antibodies and accessory opsonins, limiting the capability of the innate immune system to mount an effective response to pneumonia [
      • Drossou V.
      • Kanakoudi F.
      • Diamanti E.
      • Tzimouli V.
      • Konstantinidis T.
      • Germenis A.
      • et al.
      Concentrations of main serum opsonins in early infancy.
      ].

      2.2 Maternal risk factors for congenital pneumonia

      Congenital pneumonia results from maternal infection during pregnancy, and typically presents as one component of a systemic illness.
      Congenital toxoplasmosis is due to primary maternal infection by the intracellular protozoa Toxoplasma gondii. The main maternal risk factors are eating undercooked meat or exposure to cat feces during pregnancy. The risk of transmission to the fetus increases with gestational age, but severity of congenital illness – including pneumonia – decreases as pregnancy progresses [
      • Montoya J.G.
      • Liesenfeld O.
      Toxoplasmosis.
      ].
      Neonatal pneumonia may be one manifestation of congenital cytomegalovirus (CMV) infection, which affects up to 2% of pregnancies [
      • Gaytant M.A.
      • Steegers E.
      • Semmekrot B.A.
      • Merkus H.
      • Galama J.
      Congenital cytomegalovirus infection: review of the epidemiology and outcome.
      ]. Seronegative mothers who develop primary CMV infection during pregnancy are at the highest risk of delivering an affected newborn, with transplacental transmission rates up to 40%; the risk of vertical transmission is highest if maternal infection occurs during the first half of pregnancy. Whereas 10–30% of seropositive mothers experience CMV reactivation during pregnancy, the risk of vertical transmission among this group is only 1–3% [
      • Malm G.
      • Engman M.-L.
      Congenital cytomegalovirus infections.
      ].
      A severe, often hemorrhagic, viral pneumonitis may be one manifestation of disseminated herpes simplex virus (HSV) infection. Pulmonary symptoms are uncommon in skin–eye–mouth or central nervous system disease, the two other forms of neonatal HSV disease [
      • Curfman A.L.
      • Glissmeyer E.W.
      • Ahmad F.A.
      • Korgenski E.K.
      • Blaschke A.J.
      • Byington C.L.
      • et al.
      Initial presentation of neonatal herpes simplex virus infection.
      ]. Respiratory distress is a presenting feature in approximately half of disseminated HSV cases, and typically begins during the first two weeks of life [
      • Curfman A.L.
      • Glissmeyer E.W.
      • Ahmad F.A.
      • Korgenski E.K.
      • Blaschke A.J.
      • Byington C.L.
      • et al.
      Initial presentation of neonatal herpes simplex virus infection.
      ]. Neonatal disseminated HSV infection usually results from ascending intrauterine infection or intrapartum exposure to the infected genital tract. The major risk factors for neonatal HSV are vaginal delivery in the setting of a primary maternal infection with either HSV-1 or HSV-2 [
      • James S.H.
      • Kimberlin D.W.
      Neonatal herpes simplex virus infection.
      ]. Cesarean section or prior maternal exposure to either HSV subtype reduces the risk of transmission considerably [
      • Brown Z.A.
      • Wald A.
      • Morrow R.A.
      • Selke S.
      • Zeh J.
      • Corey L.
      Effect of serologic status and cesarean delivery on transmission rates of herpes simplex virus from mother to infant.
      ]. Demographic risk factors for maternal HSV infection include African- or Mexican-American ethnicity, past history of other sexually transmitted infections, and poverty. Risk correlates directly with age and number of lifetime sexual partners, and inversely with degree of education [
      • Fleming D.T.
      • McQuillan G.M.
      • Johnson R.E.
      • Nahmias A.J.
      • Aral S.O.
      • Lee F.K.
      • et al.
      Herpes simplex virus type 2 in the United States, 1976 to 1994.
      ].

      2.3 Perinatal risk factors for early-onset bacterial pneumonia

      The risk factors for early-onset bacterial pneumonia overlap with those for early-onset bacteremia and meningitis (Box 1), reflecting shared pathogenic mechanisms (discussed in Section 3.1). Chorioamnionitis is a key risk factor for early-onset infection, including pneumonia. Inflammation of the decidua and chorioamniotic membranes often signals microbial invasion of the fetoplacental unit, and can be accompanied by a powerful fetal inflammatory response syndrome (FIRS) that induces structural remodeling of the lungs—leading to simplification of the cellular architecture and increasing the odds of later pneumonia or chronic lung disease [
      • Kramer B.W.
      Antenatal inflammation and lung injury: prenatal origin of neonatal disease.
      ,
      • Aziz N.
      • Cheng Y.W.
      • Caughey A.B.
      Neonatal outcomes in the setting of preterm premature rupture of membranes complicated by chorioamnionitis.
      ]. Chorioamnionitis and FIRS may also trigger preterm rupture of the membranes and preterm labor and delivery, further compounding the infectious risk [
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Chaiyasit N.
      • Yoon B.H.
      • Kim Y.M.
      Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance.
      ].
      Risk factors for early-onset pneumonia.
      Tabled 1
      Prematurity and low birth weight
      Low socio-economic status
      Male gender
      Colonization with a known pathogen (e.g. group B streptococcus)
      Prolonged rupture of membranes >18 h
      Galactosemia (increased susceptibility to infections with Gram-negative organisms)
      Premature rupture of membranes
      Chorioamnionitis

      2.4 Risk factors for late-onset neonatal pneumonia

      The major risk factors for late-onset pneumonia – including VAP – are prematurity, low birth weight, and duration of mechanical ventilation [
      • Kawanishi F.
      • Yoshinaga M.
      • Morita M.
      • Shibata Y.
      • Yamada T.
      • Ooi Y.
      • et al.
      Risk factors for ventilator-associated pneumonia in neonatal intensive care unit patients.
      ,
      • Foglia E.
      • Meier M.D.
      • Elward A.
      Ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients.
      ]. Since these risks are often correlated, it is difficult to conclusively establish the independent contributions from each, and different studies have reached varying conclusions. A 41-month longitudinal study of neonatal nosocomial infections identified a significantly increased risk of pneumonia among patients with birth weight <1500 g [
      • Hemming V.G.
      • Overall J.C.
      • Britt M.R.
      Nosocomial infections in a newborn intensive-care unit.
      ]. However, a prospective study of VAP in almost 200 neonates intubated for at least 48 h identified duration of mechanical ventilation as the sole independent risk factor for pneumonia [
      • Cernada M.
      • Aguar M.
      • Brugada M.
      • Gutiérrez A.
      • López J.L.
      • Castell M.
      • et al.
      Ventilator-associated pneumonia in newborn infants diagnosed with an invasive bronchoalveolar lavage technique.
      ]. Other risk factors for VAP include prior bloodstream infection, low nurse:patient ratios, inadequate environmental air filtration, frequent suctioning (more than eight times per day), and sedation while intubated [
      • Apisarnthanarak A.
      • Holzmann-Pazgal G.
      • Hamvas A.
      • Olsen M.A.
      • Fraser V.J.
      Ventilator-associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: characteristics, risk factors, and outcomes.
      ,
      • Goldmann D.A.
      • Freeman J.
      • William A.
      • Durbin J.
      Nosocomial infection and death in a neonatal intensive care unit.
      ,
      • Singh-Naz N.
      • Yuan T.-M.
      • Chen L.-H.
      • Sprague B.M.
      • Patel K.M.
      • Yu H.-M.
      Risk factors and outcomes for ventilator-associated pneumonia in neonatal intensive care unit patients.
      ].

      3. Pathophysiology

      3.1 Pathogenesis of congenital and early-onset pneumonia

      Amniotic fluid is moderately but incompletely microbicidal and has modest levels of antiviral cytokines [
      • Lepej S.Ž.
      • Vujisić S.
      • Stipoljev F.
      • Mažuran R.
      Interferon-α-like biological activity in human seminal plasma, follicular fluid, embryo culture medium, amniotic fluid and fetal blood.
      ]. During acute intrauterine infection bacterial or viral growth occurs in amniotic fluid, allowing direct contact between the pathogen and the fetal respiratory mucosae [
      • Evans H.E.
      • Levy E.
      • Glass L.
      Effect of amniotic fluid on bacterial growth.
      ,
      • Sitkiewicz I.
      • Green N.M.
      • Guo N.
      • Bongiovanni A.M.
      • Witkin S.S.
      • Musser J.M.
      Transcriptome adaptation of group B streptococcus to growth in human amniotic fluid.
      ]. In addition to demonstrating the causative micro-organism, pathological examination of lungs from stillborns or newborns who died of early-onset pneumonia routinely identifies leukocytes of maternal origin and aspirated amniotic debris, supporting the concept that congenital or early-onset pneumonia may arise from direct mucosal seeding from infected amniotic fluid [
      • Davies P.A.
      Pathogen or commensal?.
      ]. Meconium aspiration increases the risk of pneumonia by decreasing the antimicrobial properties of amniotic fluid and by serving as a vector for bacterial entry and postnatal persistence in the lungs [
      • Florman A.L.
      • Teubner D.
      Enhancement of bacterial growth in amniotic fluid by meconium.
      ,
      • Hutton E.K.
      • Thorpe J.
      Consequences of meconium stained amniotic fluid: what does the evidence tell us?.
      ,
      • Escobar G.J.
      • Li D.K.
      • Armstrong M.A.
      • Gardner M.N.
      • Folck B.F.
      • Verdi J.E.
      • et al.
      Neonatal sepsis workups in infants ≥2000 grams at birth: a population-based study.
      ].
      Another opportunity for pathogens to enter the neonatal respiratory tract occurs during passage through the birth canal. Maternal vaginal colonization with GBS is a key risk factor for developing early-onset GBS sepsis, which often includes pneumonia. In the absence of prophylactic antibiotics, ∼50% of infants born to GBS-colonized mothers will become colonized intrapartum [
      • Pass M.A.
      • Gray B.M.
      • Khare S.
      • Dillon H.C.
      Prospective studies of group B streptococcal infections in infants.
      ]. Aspiration of respiratory secretions containing GBS will—in a small subset—progress to pulmonary infection that quickly leads to hematogenous spread and evolution to full-blown sepsis [
      • Pass M.A.
      • Gray B.M.
      • Khare S.
      • Dillon H.C.
      Prospective studies of group B streptococcal infections in infants.
      ,
      • Lamagni T.L.
      • Keshishian C.
      • Efstratiou A.
      • Guy R.
      • Henderson K.L.
      • Broughton K.
      • et al.
      Emerging trends in the epidemiology of invasive group B streptococcal disease in England and Wales, 1991–2010.
      ]. The same progression from intrapartum mucosal colonization to early-onset pneumonia has been identified for Escherichia coli, Chlamydia trachomatis, Pneumococcus pneumoniae, and Haemophilus influenza [
      • Tamelienė R.
      • Barčaitė E.
      • Stonienė D.
      • Buinauskienė J.
      • Markūnienė E.
      • Kudrevičienė A.
      • et al.
      Escherichia coli colonization in neonates: prevalence, perinatal transmission, antimicrobial susceptibility, and risk factors.
      ,
      • Alexander E.R.
      • Harrison H.R.
      Role of Chlamydia trachomatis in perinatal infection.
      ,
      • Bortolussi R.
      • Thompson T.R.
      • Ferrieri P.
      Early-onset pneumococcal sepsis in newborn infants.
      ,
      • Kinney J.S.
      • Johnson K.
      • Papasian C.
      • Hall R.T.
      • Kurth C.G.
      • Jackson M.A.
      Early onset Haemophilus influenzae sepsis in the newborn infant.
      ].
      The major pathogens responsible for congenital and early-onset pneumonia are listed in Box 2.
      Causes of congenital and early-onset pneumonia.
      Tabled 1
      Congenital pneumonia
      Toxoplasma gondii
       Herpes simplex virus
       Cytomegalovirus
      Treponema pallidum
      Early-onset pneumonia (may also present at birth)
      Streptococcus agalactiae
      Escherichia coli
      Listeria monocytogenes
      Staphylococcus aureus
      Enterococcus spp.
      Haemophilus spp.
      Streptococcus viridans
      Klebsiella
      Enterobacter spp.
       Group A streptococcus
       Coagulase-negative staphylococcus

      3.2 Pathogenesis of late-onset pneumonia and VAP

      Late-onset pneumonia results from colonization of the oropharyngeal mucosa by a potential pathogen, which then seeds the lower respiratory tract where inadequate immune defense permits dissemination. Late-onset pneumonia that develops in the hospital may be termed healthcare-associated pneumonia (previously nosocomial pneumonia), which has distinct epidemiology from late-onset pneumonia occurring after discharge. Multiply drug-resistant bacteria are a more frequent cause of healthcare-associated pneumonia, whereas community-acquired viral infections such as respiratory synctitial virus (RSV), parainfluenza, and adenovirus are more frequent causes of late-onset pneumonia in the home setting [
      • Trouillet J.L.
      • Chastre J.
      • Vuagnat A.
      • Joly-Guillou M.L.
      • Combaux D.
      • Dombret M.C.
      • et al.
      Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.
      ]. Box 3 lists frequently occurring late-onset pneumonia pathogens.
      Causes of late-onset pneumonia, including healthcare-associated pneumonia and ventilator-associated pneumonia (listed from most to least prevalent).
      Tabled 1
      Bacterial
      Pseudomonas aeruginosa
      Enterobacter spp.
      Klebsiella species
      Staphylococcus aureus
      Escherichia coli
      Enterococcus spp.
      Acinetobacter spp.
      Proteus species
      Citrobacter spp.
      Stenotrophomonas maltophilia
      Streptococcus agalactiae
      Viral
       Respiratory synctitial virus
       Human rhinovirus
       Human metapneumovirus
       Adenovirus
       Parainfluenza virus
       Influenza A or B
       Coronavirus
      The source of initial oropharyngeal colonization leading to pneumonia can be exogenous or endogenous. Common exogenous sources include caretaker skin (usually the hands of a medical professional), contaminated equipment, or environmental surfaces. There is strong evidence that inadequate hand hygiene is a major contributor to healthcare-associated neonatal pneumonia. Two large observational studies comparing nosocomial infection rates before and after introduction of intensive handwashing improvement initiatives showed significant decreases in neonatal VAP rates [
      • Lam B.C.C.
      • Lee J.
      • Lau Y.L.
      Hand hygiene practices in a neonatal intensive care unit: a multimodal intervention and impact on nosocomial infection.
      ,
      • Won S.P.
      • Chou H.C.
      • Hsieh W.S.
      • Chen C.Y.
      • Huang S.M.
      • Tsou K.I.
      • et al.
      Handwashing program for the prevention of nosocomial infections in a neonatal intensive care unit.
      ].
      The main endogenous sources of micro-organisms responsible for late-onset pneumonia are the nasal and oropharyngeal mucosae. Pooled oral secretions in the posterior oropharynx can foster local overgrowth of pathogenic species, whose subsequent aspiration sets the stage for pneumonia. An intubated – perhaps sedated – newborn with an uncuffed endotracheal tube (ETT) is at high risk for passage of infected secretions into the lower airways [
      • Cardeñosa Cendrero J.A.
      • Solé-Violán J.
      • Bordes Benítez A.
      • Noguera Catalán J.
      • Arroyo Fernández J.
      • Saavedra Santana P.
      • et al.
      Role of different routes of tracheal colonization in the development of pneumonia in patients receiving mechanical ventilation.
      ,
      • Garland J.S.
      Strategies to prevent ventilator-associated pneumonia in neonates.
      ], necessitating careful attention to head-of-bed elevation and adequate tracheal suctioning.
      Reflux and aspiration of contaminated gastric secretions represents another potential route of pulmonary infection, but the exact role of gastric bacteria in pneumonia pathogenesis remains controversial. Tracheal fluid from intubated infants has been shown to contain gastric pepsin, the concentration of which varies inversely with the degree of head elevation [
      • Garland J.S.
      • Alex C.P.
      • Johnston N.
      • Yan J.C.
      • Werlin S.L.
      Association between tracheal pepsin, a reliable marker of gastric aspiration, and head of bed elevation among ventilated neonates.
      ]. A study of intubated adults who underwent technetium labeling of gastric contents followed by scintigraphy of endotracheal suctioning samples also demonstrated migration of gastric fluids to the airway, and again found that supine positioning exacerbated aspiration [
      • Torres A.
      • Serra-Batlles J.
      • Ros E.
      • Piera C.
      • Puig de la Bellacasa J.
      • Cobos A.
      • et al.
      Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position.
      ].
      However, other studies on adults have suggested that gastric bacteria may not contribute significantly to healthcare-associated pneumonia. Two research groups performed serial microbiological sampling from the trachea, pharynx, and stomach on intubated adults. In one of these studies, 19 subjects who developed VAP also underwent bronchoalveolar lavage (BAL). Examination of culture results from the different sites allowed a temporal reconstruction of bacterial population dynamics, and did not support the theory that frequent migration of gastric bacteria to the airway occurs. Furthermore, none of the patients who developed VAP grew bacteria of gastric origin from BAL samples [
      • Cardeñosa Cendrero J.A.
      • Solé-Violán J.
      • Bordes Benítez A.
      • Noguera Catalán J.
      • Arroyo Fernández J.
      • Saavedra Santana P.
      • et al.
      Role of different routes of tracheal colonization in the development of pneumonia in patients receiving mechanical ventilation.
      ,
      • Feldman C.
      • Kassel M.
      • Cantrell J.
      • Kaka S.
      • Morar R.
      • Goolam Mahomed A.
      • et al.
      The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation.
      ].
      Among intubated infants, the ETT itself represents an important reservoir for micro-organisms. Several studies have demonstrated early and progressive growth of bacterial biofilms on the outer and luminal surfaces of neonatal ETTs [
      • Zur K.B.
      • Mandell D.L.
      • Gordon R.E.
      • Holzman I.
      • Rothschild M.A.
      Electron microscopic analysis of biofilm on endotracheal tubes removed from intubated neonates.
      ]. Of particular concern is the reliable finding that ETT biofilms tend to be enriched for potentially pathogenic species, such as Staphylococcus aureus and a variety of Gram-negative bacilli. Patients with VAP show a high correlation between micro-organisms colonizing the ETT and cultured tracheal secretions, suggesting that ETT biofilms are a probable source of infection [
      • Adair C.G.
      • Gorman S.P.
      • Feron B.M.
      • Byers L.M.
      • Jones D.S.
      • Goldsmith C.E.
      • et al.
      Implications of endotracheal tube biofilm for ventilator-associated pneumonia.
      ]. Furthermore, the artificial surface of the ETT and the complex three-dimensional biofilm in which ETT colonizers subsist increase bacterial resistance to antibiotic therapy [
      • Adair C.G.
      • Gorman S.P.
      • Feron B.M.
      • Byers L.M.
      • Jones D.S.
      • Goldsmith C.E.
      • et al.
      Implications of endotracheal tube biofilm for ventilator-associated pneumonia.
      ]. Finally, the ETT serves as a foreign body that impairs mucociliary transport and prevents effective coughing, further limiting debris clearance from the lower airways [
      • Konrad F.
      • Schreiber T.
      Mucociliary transport in ICU patients.
      ].

      3.3 Pneumonia pathophysiology

      Bacterial or viral growth in the distal airways and the resultant inflammatory response lead to cellular injury that impairs gas exchange, alters pulmonary circulation, and interferes with normal respiratory mechanics.
      In the case of bacterial pneumonia, initial cellular injury results from direct exposure to bacteria-secreted and surface-associated toxins [
      • Whidbey C.
      • Vornhagen J.
      • Gendrin C.
      • Samson J.M.
      • Doering K.
      • Ngo L.
      • et al.
      A bacterial lipid toxin induces pore formation, pyroptosis, and infection-associated fetal injury and preterm birth.
      ,
      • Spaan A.N.
      • Henry T.
      • van Rooijen W.J.M.
      • Perret M.
      • Badiou C.
      • Aerts P.C.
      • et al.
      The staphylococcal toxin panton-valentine leukocidin targets human c5a receptors.
      ]. CMV or disseminated HSV triggers lytic or apoptotic loss of pneumocytes, which serve as viral host cells during pulmonary infection [
      • Sinzger C.
      • Grefte A.
      • Plachter B.
      • Gouw A.S.
      • The T.H.
      • Jahn G.
      Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues.
      ,
      • Massler A.
      • Kolodkin-Gal D.
      • Meir K.
      • Khalaileh A.
      • Falk H.
      • Izhar U.
      • et al.
      Infant lungs are preferentially infected by adenovirus and herpes simplex virus type 1 vectors: role of the tissue mesenchymal cells.
      ,
      • Bem R.A.
      • Bos A.P.
      • Matute-Bello G.
      • van Tuyl M.
      • van Woensel J.B.M.
      Lung epithelial cell apoptosis during acute lung injury in infancy.
      ]. Denudation of the alveolar surfaces interferes with surfactant function, allows transudation of pulmonary edema, and culminates with alveolar collapse.
      The inflammatory response triggered by pulmonary infection may also cause significant injury and dysfunction. Neutrophils recruited to the lungs serve primarily as antimicrobial phagocytes, but also secrete reactive oxygen species and other tissue-damaging molecules such as elastase and urokinase [
      • Wynn J.L.
      • Wong H.R.
      Pathophysiology and treatment of septic shock in neonates.
      ]. This is particularly true of senescent neutrophils, and there is evidence that defects in neonatal neutrophil apoptosis may render them more dangerous to host tissues than neutrophils from adults [
      • Bem R.A.
      • Bos A.P.
      • Matute-Bello G.
      • van Tuyl M.
      • van Woensel J.B.M.
      Lung epithelial cell apoptosis during acute lung injury in infancy.
      ,
      • Allgaier B.
      • Shi M.
      • Luo D.
      • Koenig J.M.
      Spontaneous and Fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils.
      ].
      Airway obstruction from bacterial and inflammatory debris – combined with smooth muscle contraction due to inflammatory mediators such as C3a and C5a – impairs effective ventilation and promotes atelectasis, air trapping, and subsequent ventilation–perfusion mismatch [
      • Köhl J.
      Anaphylatoxins and infectious and non-infectious inflammatory diseases.
      ]. Inflammatory pro-coagulants and vasoconstrictors released by activated endothelial cells and platelets increase pulmonary vascular resistance, potentially triggering pulmonary hypertensive crisis [
      • Wynn J.L.
      • Wong H.R.
      Pathophysiology and treatment of septic shock in neonates.
      ,
      • Siauw C.
      • Kobsar A.
      • Dornieden C.
      • Beyrich C.
      • Schinke B.
      • Schubert-Unkmeir A.
      • et al.
      Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades.
      ]. Already limited surfactant pools fail further. The clinical manifestation of these spiraling infectious and immune processes is a severely ill patient with failing respiratory and circulatory systems.

      4. Diagnosis

      The diagnosis of neonatal pneumonia is based on a combination of physical exam findings, radiographic evidence, and supporting laboratory data. The Centers for Disease Control and Prevention (CDC) criteria for diagnosing pneumonia in patients aged <1 year are radiographic evidence of a persistent consolidation, cavitation, or pleural effusion and evidence of worsening gas exchange plus at least three additional clinical and/or laboratory findings (Box 4) [
      • Centers for Disease Control and Prevention (CDC)
      Pneumonia (ventilator-associated [VAP] and non-ventilator-associated pneumonia [PNEU]) event.
      ]. VAP may be diagnosed in patients who have been intubated for at least 48 h and meet the criteria for pneumonia. Recently, an international working group developed case definitions for significant neonatal infections, including pneumonia. Their diagnostic criteria for pneumonia align with the CDC's, but they also provide guidelines for diagnosis in resource-limited environments [
      • Vergnano S.
      • Buttery J.
      • Cailes B.
      • Chandrasekaran R.
      • Chiappini E.
      • Clark E.
      • et al.
      Neonatal infections: case definition and guidelines for data collection, analysis, and presentation of immunisation safety data.
      ].
      CDC/NNIS definition of pneumonia; must meet criteria in all three categories [
      • Centers for Disease Control and Prevention (CDC)
      Pneumonia (ventilator-associated [VAP] and non-ventilator-associated pneumonia [PNEU]) event.
      ].
      Tabled 1
      (1) Radiographic
       If there is underlying pulmonary or cardiac disease, two serial X-rays demonstrating at least one of the following:
      New or progressive infiltrate
      Consolidation
      Cavitation
      Pneumoatocele
       If there is no underlying pulmonary or cardiac disease, one definitive imaging test result is acceptable
      (2) Worsening gas exchange
       Any of the following:

      O2 desaturation

      Increased oxygen requirement

      Increased ventilator demand
      (3) Clinical/laboratory evidence
       Must have at least three of the following:

      Temperature instability

      Leukopenia (≤4000 WBC/mm3) or leukocytosis (≥15,000 WBC/mm3) and left shift (≥10% band forms);

      New onset of purulent sputum or change in character of sputum, or increased respiratory secretions or increased suctioning requirements;

      Apnea, tachypnea, nasal flaring with retractions of the chest wall or nasal flaring with grunting;

      Wheezing, rales, or rhonchi;

      Cough;

      Bradycardia (<100 beats/min) or tachycardia (>170 beats/min).
      CDC, Centers for Disease Control and Prevention; NNIS, National Nosocomial Infections Surveillance system; WBC, white blood cells.
      Ventilator-associated pneumonia is defined as meeting the above criteria and receiving mechanical ventilation through an endotracheal tube for at least 48 h.
      Unlike other frequently occurring neonatal infections, such as bacteremia or meningitis, microbiological identification of a single pathogen causing pneumonia is often not possible. Invasive lower airway culturing methods such as blind BAL or bronchoscopy with protected brush sampling are sometimes used in pediatric and adult ICUs. However, because of the technical challenges and increased risks associated with performing these techniques on neonates, invasive airway sampling is not considered a first-line diagnostic approach in the neonatal intensive care unit [
      • Centers for Disease Control and Prevention (CDC)
      Pneumonia (ventilator-associated [VAP] and non-ventilator-associated pneumonia [PNEU]) event.
      ]. Pneumonia may lead to hematogenous seeding and bacteremia, but a positive blood culture is neither necessary nor sufficient to diagnose pneumonia.
      Clinical and laboratory assessment of suctioned tracheal sputum samples from an intubated patient may be helpful for diagnosing neonatal pneumonia and for selecting an empiric antibiotic treatment regimen. Increased production of purulent sputum is an important diagnostic criterion and a frequent presenting sign of neonatal pneumonia [
      • Cernada M.
      • Aguar M.
      • Brugada M.
      • Gutiérrez A.
      • López J.L.
      • Castell M.
      • et al.
      Ventilator-associated pneumonia in newborn infants diagnosed with an invasive bronchoalveolar lavage technique.
      ]. Cultures of tracheal sputum rarely yield a single organism, indicating that tracheal secretions usually harbor a variety of colonizing species in addition to any pathogens that might be present [
      • Apisarnthanarak A.
      • Holzmann-Pazgal G.
      • Hamvas A.
      • Olsen M.A.
      • Fraser V.J.
      Ventilator-associated pneumonia in extremely preterm neonates in a neonatal intensive care unit: characteristics, risk factors, and outcomes.
      ]. However, a Gram stain of tracheal sputum that shows a leukocytic infiltrate and a predominance of a single bacterial morphotype (e.g. Gram-positive cocci in pairs and chains for GBS) suggests pneumonia caused by the dominant microbe, which may inform initial treatment. Furthermore, serial Gram stains of suctioned sputum during treatment may be used to track disease resolution or persistence of a single – potentially drug-resistant – organism.
      Newborns with systemic disease and pneumonia should prompt consideration of congenital infection with CMV, HSV, or toxoplasma. Evaluation should include liver function tests including coagulation profiling, urine culture for CMV, surface cultures for HSV, lumbar puncture with CSF cell counts, differential, culture, and polymerase chain reaction (PCR) for HSV and toxoplasma. If the concern for toxoplasmosis or CMV is high, evaluation should include cranial imaging. Antibody titers from the infant and mother may confirm recent exposure [
      • Montoya J.G.
      • Liesenfeld O.
      Toxoplasmosis.
      ,
      • Gaytant M.A.
      • Steegers E.
      • Semmekrot B.A.
      • Merkus H.
      • Galama J.
      Congenital cytomegalovirus infection: review of the epidemiology and outcome.
      ,
      • James S.H.
      • Kimberlin D.W.
      Neonatal herpes simplex virus infection.
      ].
      Late-onset pneumonia caused by viral infection may be indistinguishable from bacterial disease. A recent prospective study found that, out of 137 infants with suspected late-onset sepsis, 7% had a viral infection [
      • Kidszun A.
      • Klein L.
      • Winter J.
      • Schmeh I.
      • Gröndahl B.
      • Gehring S.
      • et al.
      Viral infections in neonates with suspected late-onset bacterial sepsis – a prospective cohort study.
      ]. A variety of high-sensitivity, high-specificity PCR- and enzyme-linked immunosorbent assay (ELISA)-based assays exist for specific viral testing, and many hospitals now run comprehensive, rapid multiplex testing from a single sample of suctioned pharyngeal sputum [
      • Puppe W.
      • Weigl J.
      • Gröndahl B.
      • Knuf M.
      • Rockahr S.
      • von Bismarck P.
      • et al.
      Validation of a multiplex reverse transcriptase PCR ELISA for the detection of 19 respiratory tract pathogens.
      ,
      • Templeton K.E.
      • Scheltinga S.A.
      • Beersma M.F.C.
      • Kroes A.C.M.
      • Claas E.C.J.
      Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza a and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4.
      ].

      5. Treatment

      Regardless of age at disease onset, treatment of suspected bacterial pneumonia should begin immediately with an empiric antibiotic regimen that is broad enough to cover the most likely etiologic organisms, including those that may be drug resistant. As more information becomes available, initial coverage should be narrowed, as much as possible, to limit the drawbacks of prolonged exposure to broad-spectrum antibiotics [
      • Cantey J.B.
      • Patel S.J.
      Antimicrobial stewardship in the NICU.
      ].

      5.1 Empiric therapy for congenital or early-onset pneumonia

      In the case of early-onset pneumonia, ampicillin and an aminoglycoside such as gentamicin is the appropriate starting regimen [
      • Brady M.T.
      • Polin R.A.
      Prevention and management of infants with suspected or proven neonatal sepsis.
      ]. Cefotaxime may be substituted for gentamicin when there is a strong suspicion of concurrent bacterial meningitis. If there is significant concern for HSV, acyclovir should be started immediately. Standard treatment for congenital toxoplasmosis is pyrimethamine and sulfadiazine (plus folinic acid) through one year of age [
      • McAuley J.
      • Boyer K.M.
      • Patel D.
      • Mets M.
      • Swisher C.
      • Roizen N.
      • et al.
      Early and longitudinal evaluations of treated infants and children and untreated historical patients with congenital toxoplasmosis: the Chicago Collaborative Treatment Trial.
      ]. Recent recommendations for treatment of infants with congenital CMV suggest at least six months of treatment with valganciclovir, which limits the extent of neurologic sequelae in infants with symptomatic CMV infection [
      • Kimberlin D.W.
      • Jester P.M.
      • Sánchez P.J.
      • Ahmed A.
      • Arav-Boger R.
      • Michaels M.G.
      • et al.
      National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, Valganciclovir for symptomatic congenital cytomegalovirus disease.
      ,
      • Muller W.J.
      Treatment of perinatal viral infections to improve neurologic outcomes.
      ].

      5.2 Empiric therapy for late-onset pneumonia or VAP

      Choosing empiric antibiotics for suspected late-onset bacterial pneumonia requires more nuance. Thought must be given to local patterns of bacterial antibiotic resistance and to the patient's history (if any) of previous infections, known colonizers, and antibiotic exposures that might have selected for drug-resistant organisms.
      At a minimum, initial therapy should include two antibiotics with coverage of most drug-resistant Gram-positive and Gram-negative species. One of the antibiotics must have activity against meticillin-resistant Staphylococcus aureus (MRSA), a frequent cause of VAP that is associated with poor clinical outcomes [
      • Trouillet J.L.
      • Chastre J.
      • Vuagnat A.
      • Joly-Guillou M.L.
      • Combaux D.
      • Dombret M.C.
      • et al.
      Ventilator-associated pneumonia caused by potentially drug-resistant bacteria.
      ]. Vancomycin or linezolid are acceptable anti-MRSA choices. Although the two antibiotics have never been compared in a head-to-head trial in treatment of neonatal VAP, evidence from pediatric and adult literature suggests that linezolid may have higher efficacy than vancomycin. Acceptable choices for the second antibiotic include piperacillin/tazobactam or gentamicin, although other possibilities may be valid depending on the situation [
      • Wunderink R.
      • Rello P.
      • Cammarata S.K.
      • Croos-Dabrera R.V.
      • Kollef M.H.
      Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia.
      ,
      • Jantausch B.A.
      • Deville J.
      • Adler S.
      • Morfin M.R.
      • Lopez P.
      • Edge-Padbury B.
      • et al.
      Linezolid for the treatment of children with bacteremia or nosocomial pneumonia caused by resistant gram-positive bacterial pathogens.
      ]. Severely ill patients with late-onset pneumonia should be started on a three-drug regimen [
      • American Thoracic Society
      Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      ]. Potential combinations are suggested in Table 1.
      Table 1Initial empiric therapy for ventilator-associated pneumonia in patients with significant risk factors for multidrug-resistant pathogens
      • American Thoracic Society
      Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      .
      Potential pathogensCombination antibiotic therapy
      Multidrug-resistant pathogens

      Pseudomonas aeruginosa

      Klebsiella spp.

      Acinetobacter spp.













      Methicillin-resistant Staphylococcus aureus
      Anti-pseudomonal cephalosporin (cefepime, ceftazidime)

      or

      Anti-pseudomonal carbapenem (imipenem or meropenem)

      or

      β-Lactam/β-lactamase inhibitor (piperacillin–tazobactam)

      plus

      Anti-pseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)

      or

      Aminoglycoside (amikacin, gentamicin, or tobramycin)

      plus

      Linezolid or vancomycin

      5.3 Duration of antibiotic therapy

      Antibiotic therapy should continue for a minimum of 7–14 days. Longer treatment may be warranted in cases of severe, persistent illness, or if there is concurrent infection beyond the lungs. Limited studies comparing different treatment durations have not yielded a clear consensus on the optimal course. An adult study comparing 8-day and 15-day treatment of VAP found no significant difference in mortality or relapse rates. However, the subset of patients with VAP caused by Gram-negative, non-fermenting bacilli who received the 8-day course had higher relapse rates [
      • Chastre J.
      • Wolff M.
      • Fagon J.-Y.
      • Chevret S.
      • Thomas F.
      • Wermert D.
      • et al.
      Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial.
      ]. A 10-day course of therapy is a reasonable starting point for uncomplicated pneumonia, which may be modified as circumstances require.

      6. Prevention of VAP

      The American Thoracic Society and the Infectious Diseases Society of America have published guidelines for reducing the incidence of hospital-acquired pneumonia, including VAP. The recommendations focus on limiting opportunities for cross-contamination between caregivers and patients, decreasing tissue damage from prolonged or recurrent intubation, avoiding unnecessary medication that may promote infection and/or antibiotic resistance, and maximizing oral hygiene and pulmonary toilet [
      • American Thoracic Society
      Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia.
      ].
      Many hospitals have adopted VAP “bundles,” consisting of multiple, simultaneous practices – applied universally to intubated patients – intended to minimize the risk of infection. There is currently no standard neonatal VAP bundle. Practices vary among units, as does the level of evidence for each bundle component. However, overall there is evidence to suggest that care bundles do reduce the risk of VAP [
      • Weber C.D.
      Applying adult ventilator-associated pneumonia bundle evidence to the ventilated neonate.
      ,
      • Azab S.F.A.
      • Sherbiny H.S.
      • Saleh S.H.
      • Elsaeed W.F.
      • Elshafiey M.M.
      • Siam A.G.
      • et al.
      Reducing ventilator-associated pneumonia in neonatal intensive care unit using “VAP prevention bundle”: a cohort study.
      ]. Box 5 summarizes VAP bundle elements that have been implemented in neonatal populations.
      Possible components of a neonatal ventilator-associated pneumonia prevention bundle [
      • Weber C.D.
      Applying adult ventilator-associated pneumonia bundle evidence to the ventilated neonate.
      ].
      Tabled 1
      Hand hygiene
       Meticulous hand hygiene before and after patient contact and handling respiratory equipment.
       Wear gloves when handling ventilator condensate and other respiratory/oral secretions.
      Intubation
       Use a new, sterile ETT for each intubation attempt.
       Ensure that the ETT does not contact environmental surfaces before insertion.
       Use a sterilized laryngoscope.
       Have at least two NICU staff members present for ETT re-taping or repositioning.
      Suctioning practices
       Clear secretions from the posterior oropharynx prior to:
      ETT manipulation;
      patient repositioning;
      extubation;
      reintubation.
      Feeding
       Prevent gastric distention.
       Monitor gastric residuals.
       Adjust feeding to prevent large residuals and/or distention.
      Positioning
       Use side-lying position as tolerated.
       Keep the head of bed elevated 15–30° as tolerated.
       Use left lateral positioning after feedings, as tolerated.
      Oral care
       Provide oral care:
      within 24 h after intubation;
      every 3–4 h;
      prior to reintubation as time allows;
      prior to orogastric tube insertion.
       Use sterile water, mother's milk, or approved pharmaceutical oral care solution
      Respiratory equipment
       Use a separate suction catheter, connection tubing, and canister for oral and tracheal suction.
       Drain ventilator condensate away from the patient every 2–4 h and before repositioning.
       Avoid unnecessary disconnection of the ventilator circuit.
       Change ventilator equipment when visibly soiled or mechanically malfunctioning.
       Use heated ventilator circuits.
      ETT, endotracheal tube; NICU, neonatal intensive care unit.

      7. Conclusion

      Pneumonia is a frequent form of infection among hospitalized neonates, and sporadically affects newborns without additional risk factors. Age of onset and surrounding circumstances, including maternal history, may provide important clues as to etiology, and may help guide initial treatment decisions. Early intervention with broad-spectrum antibiotics is crucial for preventing systemic infection and the worst complications of pneumonia.

      Practice points

      • When considering the diagnosis of neonatal pneumonia, age at disease onset and maternal history can provide valuable clues about the potential pathogen.
      • Neonatal pneumonia is diagnosed based on a combination of clinical, radiographic, and laboratory findings.
      • Suctioned samples of tracheal sputum are usually contaminated with commensal organisms, which can prevent definitive microbiological identification of the pathogen(s). Sputum samples with a predominance of a single bacterial morphotype can help guide initial empiric therapy.
      • Congenital pneumonia is frequently a component of certain TORCH infections, which should be considered, especially in the setting of systemic disease.
      • Hand hygiene and VAP “bundles” are evidence-based approaches to limiting occurrence of late-onset pneumonia.

      Research directions

      • Discovery of biomarkers to identify pneumonia, especially in the setting of prematurity or chronic lung disease, which can make pneumonia harder to identify.
      • Establishing the role of the microbiome and dysbiosis in pneumonia pathogenesis.
      • Characterizing the efficacy of different VAP “bundle” elements.
      • Understanding the long-term morbidities of neonatal pneumonia.

      Conflict of interest statement

      None.

      Funding sources

      None.

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