20/10/2017 Neonatal pneumonia - UpToDate

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Neonatal pneumonia

Author: Michael E Speer, MD

Section Editors: Joseph A Garcia-Prats, MD, Morven S Edwards, MD
Deputy Editor: Carrie Armsby, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Jul 27, 2017.

INTRODUCTION — Pneumonia is an important cause of neonatal infection and accounts for significant
morbidity and mortality, especially in developing countries [1,2].

The epidemiology, microbiology, clinical manifestations, diagnosis, and treatment of neonatal pneumonia are
reviewed here. Neonatal sepsis and specific pathogens are discussed separately. (See "Clinical features,
evaluation, and diagnosis of sepsis in term and late preterm infants" and "Management and outcome of sepsis in
term and late preterm infants".)

PATHOGENESIS — Neonatal pneumonia can have early or late onset. Bacteria are the principal pathogens for
both types. (See 'Microbiology' below.)

Routes of acquisition — The route of acquisition varies in part with the time of onset of the pneumonia.

Early-onset pneumonia — Early-onset pneumonia, generally within three days of birth, is acquired from the
mother by one of three routes:

● Intrauterine aspiration of infected amniotic fluid.

● Transplacental transmission of organisms from the mother to the fetus through the placental circulation.

● Aspiration during or after birth of infected amniotic fluid. The neonate can aspirate vaginal organisms,
leading to respiratory colonization and, in some cases, pneumonia. Vaginal colonization with such
organisms as group B streptococcus (GBS) does not necessarily result in overt maternal infection.

Late-onset pneumonia — Late-onset pneumonia, which occurs during hospitalization or after discharge,
generally arises from organisms colonizing the hospitalized newborn or is nosocomially acquired from infected
individuals or contaminated equipment. Microorganisms can invade through injured tracheal or bronchial mucosa
or through the bloodstream.

Mechanism of injury in GBS pneumonia — In GBS pneumonia, the level of beta-hemolysin expression
appears to correlate directly with the ability of the organism to injure lung epithelial cells [3,4]. Studies suggest
the hemolysin acts as a pore-forming cytolysin. The injury results in increased permeability that contributes to the
development of alveolar edema and hemorrhage. This mechanism also may be partially responsible for
bloodstream extension. Because surfactant phospholipid inhibits beta-hemolysin-associated lung epithelial cell
injury, preterm infants who are deficient in surfactant may be more severely affected [3,4].

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PATHOLOGY — The pathologic changes vary with the type of organism: bacterial or viral. Bacterial pneumonia
is characterized by inflammation of the pleura, infiltration or destruction of bronchopulmonary tissue, and
leukocyte and fibrinous exudate within alveoli and the bronchi/bronchioles [5,6]. Bacteria often are seen within
the interstitial spaces, alveoli, and bronchi/bronchioles [5].

Viruses typically cause an interstitial pneumonia. The pneumonia induced by rubella, for example, is
characterized by infiltration of mononuclear cells and lymphocytes. Extensive inflammation occasionally occurs
with hyaline membrane formation, followed by varying degrees of interstitial fibrosis and scarring [7-9].

EPIDEMIOLOGY — In resource-rich settings, the estimated incidence of pneumonia is <1 percent among full-
term infants and approximately 10 percent in preterm infants [10,11]. By contrast, the incidence of neonatal
pneumonia at autopsy ranges from 20 to 32 percent of liveborn and from 15 to 38 percent of stillborn infants [11].

Congenital pneumonia is a common cause of mortality among extremely low birth weight (ELBW) infants (ie, BW
<1000 g), accounting for nearly 30 percent of deaths in one series [12]. Pneumonia caused by maternal enteric
organisms frequently accompanies chorioamnionitis and/or funisitis in these congenital infections.

In resource-limited settings, pneumonia is major contributor to infant mortality. The World Health Organization
estimated that in 2015 pneumonia caused >900,000 deaths worldwide in children under five years old, with the
majority of deaths occurring in infants <1 year old [13]. In one study conducted in a rural area in central India,
mortality secondary to pneumonia in the first month was 29 per 1000 live births; more than one-half of all
pneumonia deaths in children occurred in newborns [14]. These figures may underestimate the burden of
neonatal pneumonia in resource-limited settings because many newborns do not receive medical care.

RISK FACTORS — Risk factors associated with early-onset pneumonia include prolonged rupture of the fetal
membranes (>18 hours), maternal amnionitis, preterm delivery, fetal tachycardia, and maternal intrapartum fever
[15,16].

Infants who require assisted ventilation are at highest risk for late-onset pneumonia. Data from adults, which are
thought to be applicable to neonates, suggest that the risk of nosocomial pneumonia is approximately four times
higher in intubated than in nonintubated patients [17]. Other risk factors include:

● Anomalies of the airway (eg, choanal atresia, tracheoesophageal fistula, and cystic adenomatoid
malformations)
● Severe underlying disease
● Prolonged hospitalization
● Neurologic impairment resulting in aspiration of gastrointestinal contents

Nosocomial infections occasionally are traced to poor handwashing or overcrowding [18].

MICROBIOLOGY — Bacterial, viral, spirochetal, protozoan, and fungal pathogens can cause pneumonia.

Early-onset pneumonia — Bacterial pathogens are the most common cause of early- and late-onset
pneumonia, although the specific organisms may differ (table 1).

Bacterial infections — Most early-onset pneumonia is caused by aerobic bacteria, although anaerobes such
as Bacteroides spp. occasionally are recovered. Group B streptococcus (GBS) is the most common cause of
early-onset pneumonia in the United States and other resource-rich countries, although gram negative
organisms are emerging cause [19]. (See "Group B streptococcus: Virulence factors and pathogenic
mechanisms" and "Group B streptococcal infection in neonates and young infants", section on 'Pneumonia'.)

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In one study from the United Kingdom of 35 infants with early-onset pneumonia, GBS was responsible for 57
percent of the cases [20]. Different organisms may predominate in other locations, especially developing
countries [2,21-23]. In a review of neonatal pneumonia in developing countries, pathogens responsible for early-
onset neonatal sepsis and pneumonia included Escherichia coli, GBS, Klebsiella spp, Staphylococcus aureus,
and Streptococcus pneumoniae [2].

Other less common bacterial pathogens include Listeria monocytogenes and Mycobacterium tuberculosis, both
of which can be transmitted transplacentally. Although transplacental infection by M. tuberculosis often results in
primary liver involvement, pneumonia may be the sole manifestation or may accompany hepatic disease [24].
Tuberculosis (TB) occurs with greater frequency in human immunodeficiency virus (HIV)-infected patients, and
congenital TB also has become more common [25].

Possible link of Ureaplasma urealyticum to chronic lung disease — One bacterial pathogen, Ureaplasma
urealyticum, has been linked potentially to the development of acute and chronic lung disease [26-30]. This
connection has been shown in both small series and a meta-analysis [27].

● In one study of 47 infants weighing <1500 g, radiographic features of pneumonia were more frequent within
seven days in those colonized with U. urealyticum than in noncolonized infants (53 versus 21 percent) [26].
Evidence of "precocious" chronic lung disease by radiography also was more common in patients with a
positive culture for the organism (23 versus 2 percent). Infants with a positive U. urealyticum culture had a
relative risk of 11.0 (95% CI 1.6-75.5) for oxygen dependence at 36 postmenstrual weeks [26].

● In another report, tracheal aspirates were obtained prior to administration of surfactant or antibiotics from
105 very low birth weight (VLBW) infants who required mechanical ventilation before 12 hours of age [28].
Infants positive for U. urealyticum were more likely to have chronic lung disease at 28 days, but not at 36
postmenstrual weeks [28].

The efficacy of antimicrobial therapy is uncertain. Two small trials of erythromycin therapy in colonized infants
failed to show an effect on the development of chronic lung disease [29,30]. In addition, there are data to suggest
that some isolates of Ureaplasma are not susceptible to erythromycin [31-33].

Viral infections — Herpes simplex virus (HSV) is the most common viral agent to cause early-onset
pneumonia, usually following acquisition from the mother at the time of birth [34]. HSV pneumonia occurs in 33 to
54 percent of disseminated HSV infections and usually is fatal in spite of treatment [16,34]. (See "Neonatal
herpes simplex virus infection: Clinical features and diagnosis", section on 'Disseminated disease'.)

Other viruses can cause pneumonia, usually via transplacental transmission from a mother who acquires the
infection late in pregnancy. Examples include adenovirus, enteroviruses, and mumps [16,35,36]. Interstitial
pneumonitis can also occur in congenital rubella infection and congenital cytomegalovirus (CMV) infection [37].
(See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Symptomatic neonate'
and "Congenital rubella syndrome: Clinical features and diagnosis", section on 'In neonates'.)

Fungal infections — Candida spp. and other fungal pathogens also are responsible for neonatal pneumonia
[38,39]. In one prospective study, approximately 25 percent of VLBW infants were colonized by Candida in the
gastrointestinal and respiratory tracts, presumably during labor and delivery [40]. Pneumonia occurs in
approximately 70 percent of infants with systemic candidiasis [41].

Other pathogens — Occasionally, early-onset pneumonia is seen in patients with congenital toxoplasmosis
and syphilis [42].

Late-onset pneumonia — Hospitalized infants often are colonized with organisms that are different from normal
flora and these can cause late-onset pneumonia.

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Bacterial infections — There is limited information on the bacterial etiology for community-acquired, late-
onset pneumonia [2]. There appears to be a predominance of gram-positive bacteria including S. pyogenes, S.
aureus, and S. pneumoniae. Other bacterial pathogens have been implicated in late-onset pneumonia, some of
which have characteristic features:

● S. aureus and Klebsiella pneumoniae are notable for inducing extensive tissue damage, abscess formation,
and empyema [43].

● These and other pathogens (eg, Escherichia coli, Serratia marcescens, Enterobacter cloacae, S.
pneumoniae, and Pseudomonas aeruginosa) may cause pneumatoceles [44-46].

● Citrobacter diversus, frequently associated with brain abscesses in neonates, can also cause lung abscess
[44].

● Bacillus cereus has been associated with necrotizing pneumonia in preterm infants [47] and with pneumonia
secondary to contaminated ventilator circuits [48].

● Chlamydia trachomatis has a long incubation period and typically is associated with pneumonia occurring
between two and four weeks of age [49]. A possible association between early lung disease and a positive
tracheal culture for C. trachomatis has been reported [50]. In developing countries where untreated sexually
transmitted disease is common, C. trachomatis nasal carriage rate is between 15 and 20 percent and is a
risk factor for pneumonia [2,22,51].

Viral infections — Numerous viruses, including adenovirus, parainfluenza, rhinovirus, enteroviruses,

influenza, and respiratory syncytial virus (RSV), cause pneumonia in the neonatal period [16,52,53]. Most infants
initially are healthy, but have ill family members. In a series of 40 newborns with viral pneumonia, nine were born
at less than 37 weeks gestation, and RSV accounted for 55 percent of the cases [52]. RSV is most prevalent
during the winter months and results in significant morbidity and mortality. Viral pathogens are also a common
cause of hospital-acquired respiratory infections in the neonatal intensive care unit. (See "Nosocomial viral
infections in the neonatal intensive care unit", section on 'Respiratory viruses'.)

Fungal infections — Candida spp. occasionally cause late-onset pneumonia, particularly in extremely low
birth weight (ELBW) infants who have received prolonged antibiotic therapy and have respiratory tract
colonization [21,54-56]. Corticosteroid administration may increase the risk of systemic infection from Candida
spp. in preterm infants [57,58], potentially increasing the risk of pneumonia.

A rare cause of pneumonia is aspergillosis, which frequently is fatal [59]. Aspergillus infection can occur in
clusters, particularly during hospital renovations [60].

CLINICAL MANIFESTATIONS — Early-onset pneumonia commonly presents with respiratory distress beginning
at or soon after birth. Infants may have associated lethargy, apnea, tachycardia, and poor perfusion, sometimes
progressing to septic shock. Some infants develop pulmonary hypertension. Other signs include temperature
instability, metabolic acidosis, and abdominal distension. None of these signs is specific for pneumonia, and
respiratory distress also can be caused by noninfectious causes (table 2).

Late-onset pneumonia is marked by changes in the overall condition of the newborn and can include nonspecific
signs of apnea, tachypnea, poor feeding, abdominal distention, jaundice, emesis, respiratory distress, and
circulatory collapse. Ventilator-dependent infants may have increased oxygen and ventilator requirements or
purulent tracheal secretions.

DIAGNOSIS — The diagnosis of neonatal pneumonia is based on a combination of clinical, radiographic, and
microbiologic findings. Because signs of pneumonia are nonspecific, neonates with sudden onset of respiratory

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distress or other signs of illness should be evaluated for pneumonia, including a complete sepsis evaluations.
The evaluation for neonatal sepsis is discussed in greater detail separately. (See "Clinical features, evaluation,
and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial management'.)

Cultures — Cultures of blood and cerebrospinal fluid should be obtained. In infants who are intubated, Gram
stain and culture of tracheal aspirates may help identify the pathogen [61-64]. In patients with pleural effusions, if
pleural fluid is sampled for therapeutic reasons, it can be sent for Gram stain and culture. If viral or other
nonbacterial infection is suspected, specific studies should be obtained including polymerase chain reaction
(PCR) and viral cultures.

Chest radiography — The chest radiograph can confirm the clinical diagnosis of pneumonia. Bilateral alveolar
densities with air bronchograms are characteristic [65], but irregular patchy infiltrates or occasionally a normal
pattern also occur [66]. Pneumonia caused by group B streptococcus (GBS) or other pathogens is difficult to
distinguish from respiratory distress syndrome (RDS) in preterm infants [67-69]. The presence of pleural
effusions may be helpful because they occur in up to 67 percent of patients with pneumonia, but are rarely found
in RDS. However, pleural effusions also can be seen in patients with transient tachypnea of the newborn,
congenital heart disease, hydrops fetalis, and congenital lymphangiectasia [66].

TREATMENT — Successful treatment depends upon the pathogen, early recognition of the infection, and early
therapy prior to the development of irreversible injury.

Depending on the severity of respiratory distress, initial management may include oxygen supplementation and
mechanical ventilation, in addition to empirical antibiotic therapy. (See "Overview of neonatal respiratory distress:
Disorders of transition", section on 'Initial management'.)

Bacterial infection — The choice of empiric regimens is based upon whether the infection is early or late onset.

Early-onset pneumonia — For early-onset pneumonia (ie, age ≤3 days), empiric parenteral antibiotic
treatment is started until culture results are available. Once a specific organism is identified, therapy is modified
according to the susceptibility pattern.

For most neonates, we suggest initial empiric coverage with ampicillin and gentamicin (dosing is based upon
weight, renal function, postnatal age, and postmenstrual age) [70]. Ampicillin is effective against group B
streptococcus (GBS), most other strains of streptococci, L. monocytogenes, and some gram-negative bacteria.
Ampicillin plus gentamicin also has synergistic activity against many of these organisms [71]. In communities in
which a substantial proportion of gram-negative bacilli are resistant to gentamicin, another aminoglycoside (eg,
amikacin) should be substituted.

Third-generation cephalosporins, although active against many gram-negative organisms, should not generally
be used for suspected early-onset sepsis or pneumonia. Gram-negative bacilli can rapidly develop resistance to
cephalosporins by either inducible or chromosomally mediated beta-lactamase activity [71,72]. In addition, a
large observational study found that the risk of death from early-onset sepsis was increased in neonates who
received cefotaxime as initial empiric treatment compared with those who received gentamicin [73].

Late-onset pneumonia — The choice of empiric therapy for late-onset pneumonia depends upon the
prevalence and sensitivity of bacteria in both the community and the hospital. For most term infants >3 days old,
we suggest vancomycin plus an aminoglycoside for initial therapy because of the high prevalence of
staphylococcal species resistant to penicillins (eg, Staphylococcus epidermidis and methicillin-resistant S. aureus
[MRSA]). Dosing of these medications is based upon the infant's weight, renal function, postnatal age, and
postmenstrual age. Because of the emergence of vancomycin-resistant enterococci (VRE) and S. aureus with
reduced susceptibility to vancomycin, vancomycin should be continued only if there is no alternative [74].

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Isolation of extended spectrum beta-lactamase (ESBL)-producing organisms is increasing. Meropenem is the

drug of choice for treatment of infections caused by these organisms [70,71,75]. Meropenem is active against
gram-negative aerobic organisms with chromosomally mediated ampC beta-lactamases or ESBL-producing
strains, except carbapenemase-producing strains. Amikacin has the most activity against ESBL-producing
strains among the aminoglycosides.

The duration of therapy is guided by the infecting pathogen and the response of the patient. The usual treatment
course for uncomplicated pneumonia is 10 to 14 days.

Viral infections — Specific agents for the treatment of viral pneumonia are limited. For most viral infections
acquired in the perinatal or postnatal period, therapy remains supportive.

Herpes simplex virus — If herpes simplex virus (HSV) pneumonia is suspected, intravenous acyclovir (60
mg/kg per day in 3 divided doses for 21 days) is recommended [76]. HSV pneumonia usually is fatal despite
treatment [16,34]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on
'Disseminated disease' and "Neonatal herpes simplex virus infection: Management and prevention", section on
'Acyclovir therapy'.)

Respiratory syncytial virus — Ribavirin is the only available specific treatment for respiratory syncytial virus
(RSV) pneumonia; however, it is generally not recommended in infants and young children because efficacy in
this population has not clearly been proven. RSV prophylaxis is suggested for high-risk infants (eg, those with
chronic lung disease and/or born at <29 weeks gestation). (See "Respiratory syncytial virus infection:
Treatment", section on 'Ribavirin' and "Respiratory syncytial virus infection: Prevention", section on 'Indications
for palivizumab'.)

OUTCOME — The prognosis of neonatal pneumonia depends upon the severity of the disease, the gestational
age of the patient, underlying medical conditions, and the infecting organism. Increased mortality is associated
with preterm birth, preexisting chronic lung disease, or immune deficiencies. Most term neonates managed in
resource-rich settings recover well without long-term sequelae.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Sepsis in neonates" and
"Society guideline links: Pediatric pneumonia".)

SUMMARY AND RECOMMENDATIONS

● Pneumonia is an important cause of neonatal infection and is a major contributor to infant mortality
worldwide. In resource-rich countries, the estimated incidence of pneumonia in full-term infants is <1 percent
and increases to 10 percent in preterm infants. (See 'Introduction' above and 'Epidemiology' above.)

● Neonatal pneumonia can be classified by the infant's age as follows:

• Early-onset pneumonia (≤3 days), which is generally acquired from the mother during labor or delivery.
(See 'Early-onset pneumonia' above.)

• Late-onset pneumonia (>3 days of age) is typically due to nosocomial organisms from previous
colonization of the infant or transmission from care providers or contaminated equipment. (See 'Late-
onset pneumonia' above.)

● There are a large number of viral, bacterial, and fungal pathogens that cause neonatal pneumonia (table 1).
Early-onset bacterial pneumonia is most commonly caused by group B streptococcus. (See 'Microbiology'
above.)

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● Risk factors associated with early-onset pneumonia include prolonged rupture of the fetal membranes (>18
hours), maternal amnionitis, preterm delivery, fetal tachycardia, and maternal intrapartum fever. Late-onset
disease is associated with mechanical ventilation, airway anomalies, prolonged hospitalization, and
aspiration of gastrointestinal contents due to neurologic impairment. (See 'Risk factors' above.)

● Early-onset pneumonia commonly presents with respiratory distress beginning at or soon after birth. Other
clinical manifestations, also seen in late-onset disease, are nonspecific and include temperature instability,
apnea, lethargy, tachycardia, poor perfusion, tachypnea, and poor feeding. (See 'Clinical manifestations'
above.)

● The diagnosis of neonatal pneumonia is based on a combination of clinical, radiographic, and microbiologic
findings. (See 'Diagnosis' above.)

● Infants with pneumonia should be treated with empirical antibiotic therapy that provides broad coverage for
the most likely pathogens. The choice of antibiotic regimen depends on timing of disease onset (early-
versus late-onset) and local antibiotic resistance patterns. For most full-term neonates with early-onset
pneumonia, we suggest initial empiric coverage with ampicillin and gentamicin (Grade 2C). For most full-
term neonates with late-onset pneumonia, we suggest initial empiric coverage with vancomycin plus an
aminoglycoside (eg, gentamicin) (Grade 2C). When results of microbiologic tests are available, antibiotic
therapy is directed toward the specific pathogen. (See 'Treatment' above.)

● The prognosis of neonatal pneumonia depends upon the severity of the disease, the gestational age of the
patient, underlying medical conditions, and the infecting organism. (See 'Outcome' above.)

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75. American Academy of Pediatrics. Escherichia coli and other Gram-negative bacilli (septicemia and meningit
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GRAPHICS

Common organisms associated with neonatal pneumonia according to route of

acquisition

Transplacental Amniotic fluid

Rubella Cytomegalovirus

Cytomegalovirus Herpes simplex virus

Herpes simplex virus Enteroviruses

Adenovirus Genital mycoplasma

Mumps virus Listeria monocytogenes

Toxoplasma gondii Chlamydia trachomatis

Mycobacterium tuberculosis Mycobacterium tuberculosis

Treponema pallidum Group B streptococci

Listeria monocytogenes Escherichia coli

At delivery Haemophilus influenzae (nontypable)

Group B streptococci Ureaplasma urealyticum

Escherichia coli Nosocomial

Staphylococcus aureus Staphylococcus aureus

Klebsiella sp Staphylococcus epidermidis

Other streptococci Group B streptococci

Haemophilus influenzae (nontypable) Klebsiella sp

Candida sp Enterobacter

Chlamydia tachomatis Pseudomonas

Ureaplasma urealyticum Bacillus cereus

Citrobacter diversus

Influenza virus

Respiratory synctial virus

Enteroviruses

Herpes virus

Candida sp

Aspergillus sp

Graphic 81323 Version 1.0

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Noninfectious causes of neonatal respiratory distress

Anatomic/development defects Physiologic/pathologic

Primary pulmonary hypoplasia disorders

Cystic adenomatoid malformation Transient tachypnea of the newborn

Tracheoesophageal fistula Respiratory distress syndrome

Diaphragmatic hernia Meconium aspiration pneumonia

Congenital heart disease Pulmonary hemorrhage

Choanal atresia Pulmonary edema

Tracheal web Pneumothorax

Laryngotracheomalacia Hydrothorax/chylothorax

External compression of the trachea (eg, goiter) Aspiration pneumonia

Central nervous system malformation Hypoglycemia

Hydrocephalus Metabolic acidosis

Genetic (eg, immotile cilia syndrome, surfactant protein B deficiency, urea Respiratory alkalosis
cycle defect) Central nervous system injury

Graphic 56457 Version 2.0

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Contributor Disclosures
Michael E Speer, MD Nothing to disclose Joseph A Garcia-Prats, MD Nothing to disclose Morven S
Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Carrie Armsby, MD,
MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

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