PAEDIATRIC RESPIRATORY REVIEWS (2007) 8, 195203

MINI-SYMPOSIUM: MICROBIOLOGICAL DIAGNOSTIC PROCEDURES IN RESPIRATORY INFECTIONS

Congenital and neonatal pneumonia

Michael D. Nissen*
Department of Infectious Diseases, Royal Childrens Hospital, Herston Road, Herston, Queensland 4029, Australia
Summary The greatest risk of death from pneumonia in childhood is in the neonatal period. It is estimated that pneumonia contributes to between 750 0001.2 million neonatal deaths annually, accounting for 10% of global child mortality. Congenital and neonatal pneumonias are often a difcult disease to identify and treat, with clinical manifestations often being non-specic. Many of the normal lung defences are compromised in the fetus and neonate, leading to an increased susceptibility to infection. The aetiology and epidemiology of congenital and neonatal pneumonias will depend on the clinical setting and population that the baby belongs to, the stage in the perinatal period, the gestational age of the baby and the denition of pneumonia. Diagnosis, treatment and prevention strategies are therefore also dependent on these factors, and will differ depending on the clinical setting. This review summarizes the current knowledge concerning congenital and neonatal pneumonia worldwide and discusses future directions in the prevention of the disease . 2007 Published by Elsevier Ltd.

INTRODUCTION
The greatest risk of death from pneumonia in childhood is in the neonatal period.1 At least one third of the annual 10.8 million deaths in children worldwide occur in the rst 28 days of life,2 with a substantial proportion of these being due to pneumonia. It is estimated that pneumonia contributes to between 750 000 and 1.2 million neonatal deaths annually, accounting for 10% of global child mortality.3 Of all neonatal deaths, 96% occur in the developing world.2 Congenital and neonatal pneumonias are often difcult to identify and treat. Clinical manifestations are often nonspecic, sharing respiratory and a range of non-inammatory processes. Laboratory ndings also have limited value, with attempts to identify specic microbes often unsuccessful due to the difculty in sample recovery from intrapulmonary sites without contamination. Many organisms are primarily uncultivable or uncultivable due to antimicrobial therapy. Radiological evidence of lung inammation may result from non* Tel.: +61 7 33655021; Fax: +61 7 33655455. E-mail address: theniss@uq.edu.au. 1526-0542/$ see front matter 2007 Published by Elsevier Ltd. doi:10.1016/j.prrv.2007.07.001

infectious causes such as meconium aspiration. Many of the normal lung defences are compromised in the fetus and neonate. These include non-specic barriers such as the glottis and vocal cords, cilary escalator, airway phagocytes, secretory antibodies, mucosal lymphoid tissue, antimicrobial proteins and opsonins. The aetiology and epidemiology of congenital and neonatal pneumonias will depend on: (1) the clinical setting and population that the baby belongs to (e.g. developed/developing world, tertiary/district hospital or community setting); (2) the stage in the perinatal period; (3) the gestational age of the baby, and (4) the denition of pneumonia.1 Diagnosis, treatment and prevention strategies are therefore also dependent on these factors, and will differ depending on the clinical setting.

EPIDEMIOLOGY
Lower respiratory tract infections (LRTI) in neonates can be classied as congenital or neonatal in origin, and are dened by when the infection or pathogen has been acquired.

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Congenital pneumonias are usually part of a transplacental infection, while neonatal pneumonias can evolve from intrauterine or postnatal acquisition. Neonatal pneumonia can be classied as early and late onset.1 Early-onset neonatal pneumonia, in general, is dened as a clinical presentation in the rst 48 h up to 1 week of life, while late-onset neonatal pneumonia occurs in the next 3 weeks. Intrauterine pneumonia is a subgroup of early-onset neonatal pneumonia. It presents as a stillbirth, low Apgar scores or severe respiratory distress and is usually associated with maternal chorioamnionitis. Infected (maternal) amniotic uid is then aspirated in utero, after prolonged rupture of the chorioamniotic membranes, or during delivery of the affected neonate. Congenital pneumonia occurs in the setting of a maternal systemic infection, which may or may not be symptomatic in the mother. Neonatal autopsy studies have determined that intrauterine and early-onset pneumonia occurs in 1038% of stillborns and 2063% of liveborn babies who subsequently died.4 Early investigations of the cause of neonatal deaths in the rst 48 h of life found a pneumonia in 2038% of cases, with the highest incidence in lower socioeconomic groups.5 In an Indian study, >50% of all childhood pneumonia deaths occurred in neonates.6 Birth weight and age of onset strongly determined the mortality risk from pneumonia.1 Case fatality rates are higher for low birth weight infants,7 and for intrauterine and early-onset pneumonia when compared with lateonset disease.8,9 The epidemiology of postpartum and late-onset neonatal pneumonias in general tend to be associated with nosocomial infections, with introduction of pathogens occurring transplacentally via maternal chorioamniotitis or medical intervention. The true incidence of late-onset pneumonia in neonates is difcult to determine since many series do not report the age of onset. The multi-country World Health Organization (WHO) Young Infants Study provides useful data on communityacquired neonatal sepsis, including pneumonia. These data however are skewed towards infants seen in hospital outpatient departments and therefore presentations of intrauterine pneumonia or early-onset pneumonia, which occur mainly in the rst 48 h of life, may not be well represented.10

Table 1 Pathogens associated with congenital and neonatal pneumonias Bacteria Escherichia coli Enterobacter aerogenes Group B streptococcus (S. agalactiae) Group A streptococcus (S. pyogenes) Klebsiella spp Pseudomonas aeruginosa Streptococcus viridans group Staphylococcus aureus Proteus spp Streptococcus pneumoniae Group D and G streptococci Enterococcus spp Haemophilus inuenzae (non-typeable) Staphylococcus epidermidis Salmonella spp Acinetobacter spp Neisseria meningitidis Morganella spp Serratia spp Viruses Herpes simplex virus Respiratory syncytial virus Human metapneumovirus Parainuenzae viruses 1, 2 and 3 Human cytomegalovirus Inuenza A and B viruses Human adenovirus Human immunodeciency virus Fungi Candida albicans Atypical bacteria Chlamydia trachomatis Ureaplasma urealyticum and U. parvum Listeria monocytogenes Treponema pallidum Mycobacterium tuberculosis Pneumocystis jirovecii Bordetella pertussis

AETIOLOGY AND PATHOGENESIS

The epidemiological features of neonatal pneumonia, in general, with their resultant implications for treatment and prevention are sufciently similar to those of neonatal bacteraemia and meningitis, and therefore can be used to understand the aetiology of the disease.1 The aetiology of maternal chorioamnionitis has also been used to understand the aetiology of intrauterine and early-onset pneumonia.1 The pathogens associated

with neonatal pneumonia include numerous bacteria, fungi and viruses (Table 1). Bacterial pneumonia from infected amniotic uid or colonization of the birth canal is linked with maternal chorioamnionitis and fetal asphyxia. It is assumed that asphyxia leads to fetal gasping and aspiration of infected amniotic uid. This hypothesis is based on the histological nding of amniotic uid and/or maternal white blood cells in the affected neonatal lungs.1 The bacterial aetiology of neonatal pneumonia is also inuenced by nosocomial infection in neonatal intensive care units. In some areas of the world high rates of Streptococcus pneumoniae have been detected in late-onset neonatal pneumonia. Also, since lung-derived samples are rarely obtained from neonates,5,8 studies pertaining to neonatal pneumonia contain blood culture data which will underestimate the proportion of cases that are bacterial.1 A diagnosis of pneumonia in a study of Ethiopian infants was not associated with bacteraemia when compared with a clinical diagnosis of sepsis, severe disease or death.11 Atypical bacterial pathogens, e.g. Chlamydia trachomatis, are well recognized as agents of late-onset pneumonia. Bordetella pertussis may present as early-onset or late-onset pneumonia, and is most commonly associated with close contact with an infected parent, sibling, relative or healthcare worker. Viral neonatal pneumonias can either be associated with intrauterine, early-onset or late-onset pneumonias,

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and can be acquired from the birth canal [e.g. herpes simplex virus (HSV)]), infected siblings, parents and/or healthcare workers [e.g. respiratory viruses such as respiratory syncytial virus (RSV)] with or without nosocomial involvement. Congenital pneumonia is caused by a mixture of bacteria, viruses and fungi.

CLINICAL MANIFESTATIONS
The denition of neonatal pneumonia will depend on clinical setting and geographical location, access to medical care and investigations, and public health preventative measures in place in the population. Neonatal pneumonia is suspected in any newborn infant with respiratory distress, the features of which include any of the following: rapid, noisy or difcult breathing, respiratory rate >60 beats/min, chest retractions, cough and/or grunting. The clinical risk factors and features of neonatal pneumonia are listed in Table 2. WHO does not distinguish between neonatal pneumonia and other forms of severe sepsis, such as bacteraemia, since there is much overlap in the clinical signs on presentation, and organ involvement and empiric treatment regimens are similar.1 The sensitivity of clinical ndings for radiologically diagnosed pneumonia in neonates has been evaluated in developing countries.8,13,14 Tachypnoea appears to be the most consistent sign present in 6089% of cases. Other signs appear to be less reliable and include chest recession (3691% of cases), fever (3056%), inability to feed (43 49%), cyanosis (1240%) and cough (3084%).

Table 2 Clinical risk factors and features of neonatal pneumonia (modied from Mathur et al.12) 1. Predisposing factors a. Maternal fever (>38 8C) b. Foul smelling liquor c. Prolonged rupture of membranes (>24 hours) 2. Clinical picture of sepsis a. Poor feeding b. Lethargy c. Poor reexes d. Hypothermia or hyperthermia e. Abdominal distension 3. Chest X-ray suggestive of pneumonia (nodular or coarse patchy inltrate, diffuse haziness or granularity, air bronchogram, lobar or segmental consolidation); radiological changes not resolved within 48 hours 4. Positive sepsis screen (any of the following): a. Bands >20% of leucocytes b. Leucocyte count out of reference range c. Raised C reactive protein d. Raised erythrocyte sedimentation rate

The differentiation of neonatal pneumonia from noninfectious respiratory conditions such as hyaline membrane disease (HMD), transient tachypnoea of newborn and meconium aspiration is problematical since the clinical radiological appearance can be identical, and pathology and radiology services in some facilities may be rudimentary or unavailable. Gestational age of the neonate and time to onset of clinical signs together assist in the clinical diagnosis of pneumonia. However, HMD can occur close to term and intrauterine infection may result in the premature onset of labour. In addition, gestational age assessment may be inaccurate and dependent on the clinical expertise available, so treatment decisions for respiratory distress of the newborn based on the estimated gestational age are not always practical, may be unsafe and may interfere with the true contribution of pneumonia to mortality in the rst week of life.1 The incidence of factors predicting neonatal pneumonia varies between clinical studies and with the methodology used to study the disease.9,12 Babies prospectively admitted to a UK neonatal unit with early-onset pneumonia (before 48 h of age) had risk factors in 17% of cases, but in 41% of these babies early onset of labour was the only predictor of pneumonia. An Indian study, in comparison, found over 50% of neonatal pneumonia cases had no known predisposition or risk factor. Other non-infectious respiratory conditions in the neonatal period must be considered in the assessment of babies with respiratory distress. Pulmonary oedema secondary to congenital heart disease can be confused with late-onset pneumonia. Other rare presentations of neonatal respiratory distress that create diagnostic dilemmas include pulmonary haemorrhage and pulmonary infarct. The presence of an endotracheal tube for mechanical ventilation or medical tubing causing breaches of the respiratory tract mucosal barrier and its local immune system makes bacterial invasion of the lower respiratory tract inevitable, clouding the true incidence of late-onset pneumonia, particularly in developed countries with ready access to neonatal intensive care nurseries. In the UK neonatal study cited above, endotracheal tube bacterial colonization occurred in 94% of articially ventilated babies, most commonly by Gram negative organisms and Staphylococcus epidermitis.9 In only one of seven cases with simultaneous bacteraemia was the same organism grown from blood cultures. Signicantly there was no difference in the incidence or the timing of endotracheal tube colonization between babies who did or did not have late-onset pneumonia, regardless of gestational age or the duration of mechanical ventilation. The suspicion of staphyloccal infection as an aetiological agent for neonatal pneumonia is warranted when skin pustules, cellulitis, oomphalitis (umbilical cord infection), pneumatocoeles or empyema is present.

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ATYPICAL NEONATAL PNEUMONIAS

Chlamydia trachomatis
Chlamydia trachomatis pneumonia can occur at 13 months of age, manifesting as a protracted onset of staccato cough, usually without wheezing or fever. Findings on chest X-ray include hyperination and diffuse bilateral inltrates, with peripheral blood eosinophilia possibly present. Diagnostic testing is usually performed on a nasopharyngeal specimen. Treatment is with a macrolide antibiotic (erythromycin, clarithromycin or azithromycin). The estimated risk of C. trachomatis pneumonia developing in a neonate with maternal colonization is 7%.15 The incidence of C.trachomatis pneumonia in neonates exposed to C. trachomatis in large cohort studies varies from 3 to 16%.16,17 The interpretation of C. trachomatis-associated neonatal pneumonia is hampered because the gold standard of diagnosis by percutaneous lung aspirate is rarely, if ever, performed. The ability now to perform C. trachomatis polymerase chain reaction (PCR) testing on nasopharyngeal or endotracheal aspirates from infants with neonatal pneumonia has increased the sensitivity of detection of this pathogen. It is assumed that C. trachomatis contributes signicantly to neonatal pneumonia in countries where untreated sexually transmitted diseases in women are common. Studies from Ethiopa, Papua New Guinea and Kenya have detected C. trachomatis by direct immunouorescent staining of the nasopharyngeal aspirates of neonates with radiologically conrmed pneumonia in 16%, 22% and 46% of cases, respectively.11,18,19 In Papua New Guinea there was also a borderline association of C. trachomatis pneumonia with S. pneumoniae bacteraemia.18 Whether the inammation of C. trachomatis pneumonia predisposes to secondary bacterial pneumonia by mucosal injury is unknown.

ciency virus (HIV) infection has been described in two southern African studies.23,24 Co-infections with Mycobacteriumtuberculosis, syphilis and cytomegalovirus were common and contributed to the clinical presentation. Congenital HIV infection also increases the mortality rate from neonatal respiratory distress syndrome and sepsis associated with S. pneumoniae and Staphylococcus aureus.

Mycobacterium tuberculosis25
Infants may acquire tuberculosis (TB) by transplacental spread, aspiration or ingestion of infected amniotic uid, or airborne inoculation from close contacts (family members or nursery personnel). Approximately 50% of children born to mothers with active TB develop the disease during the rst year of life if chemoprophylaxis or BCG vaccine is not given. The clinical presentation of neonatal TB is non-specic, but is usually marked by multiple organ involvement. The exposed neonate may present acutely or chronically ill with fever, lethargy, respiratory distress, hepatosplenomegaly or failure to thrive. All cases of suspected congenital TB should have a chest X-ray and cultures of tracheal aspirates, gastric washings, urine and cerebrospinal uid (CSF) for acid-fast bacilli. Skin testing is not sensitive in neonates but should be attempted, with biopsy of liver, lymph nodes, lung or pleura sometimes needed to conrm the diagnosis. Pregnant women with a positive Mantoux skin test but normal chest X-ray should either start chemoprophylaxis during pregnancy or after delivery, depending on the likelihood of their being recently infected and their risk of progression to disease, as well as their clinical evidence of disease. Pregnant women with a positive Mantoux skin test and chest X-ray or symptoms indicative of active disease should be treated with non-teratogenic agents during pregnancy; all household contacts should also be screened. When TB is suspected around delivery, the mother should be assessed by chest X-ray and sputum smear; separation of the mother and her offspring is indicated only if the mother is non-adherent to medical treatment or needs to be hospitalized, or when drugresistant TB is involved. Treatment is with a combination of routine anti-TB drugs such as isonazid, rifampicin, pyrazinamide and streptomycin for up to 12 months depending on the extent of the disease. According to the American Academy of Pediatrics, treatment of latent infection with isoniazid for 9 months is highly effective. This regimen may be extended to 12 months for immunocompromised patients. When drug resistance is suspected, combination therapies, which usually consist of isoniazid with rifampin (rifampicin), are administered until the results of susceptibility tests become available. Organisms resistant to isoniazid only may be treated with rifampin alone for a total of 69 months. All infants with tuberculous disease should be started on four agents (isoniazid, rifampin, pyrazinamide and etham-

Ureaplasma urealyticum and U. parvum

U. urealyticum and U. parvum are part of the normal genital bacterial ora of both men and women. They are found in about 70% of sexually active humans. They are associated with non-specic urethritis (NSU) and infertility, but can also cause maternal and neonatal disease, including chorioamnioitis, stillbirth, premature birth and, in the perinatal period, pneumonia or meningitis.

Treponema pallidum
Fatal cases of congenital syphilis are usually associated with severe pneumonitis (pneumonia alba) and hypoxaemia, especially in developing countries.2022

Human immunodeciency virus

A persistent neonatal pneumonia associated with a rapidly progressive presentation of congenital human immunode-

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butol or streptomycin) until drug susceptibility is assessed. For susceptible intrathoracic TB, isoniazid, rifampin and pyrazinamide are administered for a total of 2 months, at which point pyrazinamide is withdrawn and the other two agents are continued for another 410 months depending on the severity of the disease. The same regimen may be applied in extrapulmonary TB with the exception of skeletal, miliary and central nervous system disease, which require daily administration of isoniazid, rifampin, pyrazinamide and streptomycin for 12 months, followed by isoniazid and rifampin daily or twice weekly for another 10 months. When drug-resistant TB is suspected, a regimen of isoniazid, rifampin and pyrazinamide plus either streptomycin or ethambutol should be prescribed initially, until the results of susceptibility tests become available. HIV-seropositive infants with pulmonary TB should receive isoniazid, rifampin, pyrazinamide and ethambutol or an aminoglycoside for 2 months, followed by isoniazid and rifampin for a total of at least 12 months. Apart from conventional antimycobacterial agents, novel therapeutic modalities, which stimulate the host immune system, such as interleukin-2 (IL-2), IL-12 and g-interferon, have been tested with promising results.

of cases. Mothers of neonates with HSV infection tend to have no history or symptoms of genital infection at the time of delivery. Neonates may present with either local or disseminated disease. Babies with disseminated disease and visceral organ involvement have pneumonitis, hepatitis and/or disseminated intravascular coagulation with or without encephalitis or skin disease. Signs which can occur singly or in combination include temperature instability, lethargy, hypotonia, respiratory distress, apnoeas and seizures. Rapid diagnosis by HSV PCR, immunouorescence of vesicle scrapings or viral culture is essential, with the most common site of retrieval being skin vesicles followed by CSF, eyes and mouth. If no diagnostic virology facilities are available, a Papanicolaou test of a smear from the vesicle base may show characteristic multinucleated giant cells and intranuclear inclusions the Tzanck test. The mortality of untreated disseminated disease is 85%. Treatment halves the mortality rate, and consists of high dose aciclovir (20 mg/kg/q8h for 1421 days), with vigorous supportive therapy.

Respiratory viruses Listeria monocytogenes

Transplacental infection with Listeria monocytogenes can result in fetal dissemination with granuloma formation (skin, liver, adrenals, lymphatics, lungs and brain) called granulomatosis infantisepticum. Aspiration of infected amniotic uid or vaginal secretions can lead to perinatal L. monocytogenes pneumonia manifesting in the rst week of life with respiratory distress, shock and a fulminant course. Nosocomial acquisition has also been reported. Neonates with early-onset L. monocytogenes infection frequently are of low birth weight, have associated obstetric complications and show evidence of sepsis with circulatory and/or respiratory insufciency. Babies with delayed onset are usually full-term, previously well neonates presenting with meningitis or sepsis. A sick neonate whose mother has listeriosis should be evaluated for sepsis, including cultures of the umbilical cord, peripheral blood, CSF, gastric aspirate, meconium, mothers lochia and exudates from cervix and vagina, and grossly diseased parts of the placenta. Treatment should be initiated with ampicillin and an aminoglycoside such as gentamicin. Once a clinical response is seen the aminoglycoside can be discontinued. A minimum 14-day course of ampicillin is usually necessary. The role of respiratory viruses (RSV, inuenza, parainuenza viruses, adenovirus and metapneumovirus) in neonatal pneumonia is well described by retrospective reports. These viruses have been associated with seasonal lateonset pneumonia where viral diagnostic techniques are accessible. Nosocomial outbreaks of respiratory viruses in neonatal nurseries and co-infections with RSV and human metapneumovirus (hMPV) have been described.26 Apnoea may be the sole presenting feature in neonatal viral pneumonias. The risk of death from neonatal pneumonia is higher in early-onset disease, hypoxaemia, low birth weight and absence of tachypnoea.

DIAGNOSIS AND INVESTIGATIONS

Chest X-rays should be performed in any patient with respiratory abnormalities. Blood should be collected for a complete blood count (CBC), C-reactive protein and culture in all cases of neonatal pneumonia. While the yield from blood cultures is low, blood, if possible, should be collected prior to antibiotic therapy to guide secondline treatment in the event of rst-line antibiotic failure. Blood cultures collected simultaneously with endotracheal tube aspirates in mechanically ventilated neonates may also assist in determining the signicance of endotracheal tube colonization. Pus from empyema or skin pustules should be submitted for Gram staining and bacterial culture. The most useful diagnostic tests for congenital pneumonia facilitate identication of the infecting microorganism.27

Herpes simplex virus

HSV is usually transmitted during delivery through an infected maternal genital tract. Transplacental transmission of virus and hospital-acquired spread from one neonate to another by hospital personnel or family may account for 15%

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Bacterial culture
Conventional bacteriological culture is used most widely and is currently the most helpful test. Aerobic incubation of cultures is sufcient for recovery of most responsible pathogens. Although the foul smell of amniotic uid in the setting of maternal chorioamnionitis is often attributable to anaerobes, these organisms are seldom shown to be causative. The culture of fungi, viruses, U. urealyticum and other unusual organisms often requires different microbiological processing but may be warranted in suggestive clinical settings.

been in place, the greater the likelihood that recovered organisms represent colonizers 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.

Culture from extrapulmonary sites

Detection of microorganisms at inamed extrapulmonary sites may be helpful, since concurrent involvement of the lungs is not rare. Studies of abscesses, conjunctivitis, skin lesions and vesicles may be fruitful. Care should be taken to ensure that the specimen submitted is as free of contamination as possible or that the test performed, such as organism-specic DNA probe or PCR-based assay, is less likely to be affected by such factors.

Blood culture
Blood culture with at least 1 ml of blood from an appropriately cleaned and prepared peripheral venous or arterial site is essential, since many neonatal pneumonias are haematogenous 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. Multiple cultures of blood from different sites and/or drawn at different times may increase culture yield, but limited circulating blood volume precludes this as the standard of care in neonates.

Culture from other respiratory sites

In the presence of radiographically visible pleural uid, careful positioning of the infant and cautious thoracentesis after sterile preparation of the sampling site may yield diagnostic ndings on Gram stain, direct microscopy and/ or culture. Sonography may reveal smaller uid pockets and facilitate safer sampling under direct visualization. Although data from neonates are insufcient to draw conclusions, studies in older populations suggest a very high correlation with culture of lung tissue and/or blood. Quantitative culture techniques of bronchoscopic alveolar lavage (BAL) uid have been reported to offer a specicity of >80% depending on the threshold selected (values from >100 to 100 000 CFU/ml have been used). Non-directed non-bronchoscopic protected specimen brush specimens have been obtained through endotracheal tubes 3.0 mm in internal diameter and intuitively appear to offer decreased probability of contamination. Data from neonates are sparse. Unlike bronchoscopically obtained specimens, ensuring that sampling from a particularly involved site has been accomplished is more difcult. Although used much less frequently than in previous decades, the lung puncture technique may still be useful in circumstances where pleural and subpleural lung surfaces are visibly involved and can be well localized. The risk benet ratio merits careful consideration given the risk of such complications as pneumothorax, bronchopleural stula, haemothorax and sampling a non-diagnostic site.

Culture of specimens from lumbar puncture

Routine culture and analysis of spinal uid in infants in whom neonatal pneumonia is suspected is controversial, since the yield is low and many infants with respiratory support requirements do not tolerate lumbar puncture well. Spinal uid may yield a pathogen when blood does not (especially following maternal antibiotic pre-treatment). Presence of a pathogen in the spinal uid 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.

Urine culture
During the rst 3 days of life, urine culture is unlikely to be helpful because most urinary tract infections seen at this age are haematogenous in origin.

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 h to migrate down the trachea. At least one study demonstrated that culture of endotracheal aspirates obtained within 8 h of birth correlates very well with blood culture results and probably reects aspirated infected uid. The longer the tube has

Limitations of bacterial cultures

A number of factors may interfere with the ability to cultivate a likely pathogen from the sites noted, including (but not limited to) the following: (1) pretreatment with antibiotics that limit in vitro but not in vivo growth; (2) contaminants that overgrow the pathogen; (3) pathogens that do not replicate in currently available culture systems;

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(4) sampling of an inappropriate site; and (5) patients in whom the process is inammatory but not infectious, such as with meconium aspiration. Techniques that may help overcome some of these limitations include antigen detection, nucleic acid probes, PCR-based assays or serological tests. Although once widely used, tests such as latex agglutination for detection of Group B streptococcal antigen in urine, serum or other uids have fallen into disfavour because of poor predictive value; however, new generations of nonculture-based technologies continue to undergo development and may be more accurate and widely available in the future.

Serological tests
Serological tests have limited use but may offer some insights. Serological tests for syphilis may suggest or conrm the presence of pneumonia alba, particularly in high risk populations. The value of assessing antibody responses in acute and convalescent sera from infants using ora recovered from endotracheal aspirates has been suggested as being useful. This usually permits diagnosis only retrospectively, but may be useful in infants who fail to respond adequately to empirical therapy or for epidemiological purposes. Concerns persist regarding the specicity of such tests in distinguishing invasion from colonization.

Markers of inammation
The use of markers of inammation 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 non-infectious causes of such abnormal results are numerous, and many reports have been published regarding infants with proven infection who initially had neutrophil indices within reference ranges. Quantitative measurements of C-reactive protein, cytokines (e.g. IL-6), and batteries of acute-phase reactants have been touted as more specic but are plagued by concerns regarding limited positive predictive value because of: (1) lag from infection to abnormalities; and (2) utility of serial measurements, especially with a high negative predictive value. These tests may be useful in assessing the resolution of an inammatory process, including infection, but they are not sufciently precise to establish a diagnosis without additional supporting information. Decisions about antimicrobial therapy should not be based on inammatory markers alone.

WHO recommends using ampicillin (50 mg/kg) every 12 h in the rst week of life, then every 8 h from 24 weeks of age, plus a single daily dose of gentamicin.28 First-line alternatives to ampicillin include benzylpenicillin or amoxicillin, and alternatives to gentamicin are tobramycin or amikacin. If S. aureus is suspected, a penicillinase-resistant penicillin such as ucloxacillin or cloxacillin should be substituted for ampicillin. A randomized trial of once daily gentamicin dosing in Kenyan infants has conrmed a loading dose of 8 mg/kg followed by 2 mg/kg (if weight <2 kg) or 4 mg/kg (if weight >2 kg) in the rst week of life, followed by 4 mg/kg (weight <2 kg) or 6 mg/kg (weight >2 kg) in week 2 of life and above.29 If a neonate fails to respond to rst-line antibiotics, WHO suggests changing to a third-generation cephalosporin or chloramphenicol (only if the neonate is not premature and drug levels can be monitored).28 Bacterial pathogens associated with neonatal pneumonia are demonstrating increased antimicrobial resistance worldwide. Patterns of antimicrobial resistance vary locally and are dependent on whether cases are community or nosocomially acquired.1 Enteric Gram negative bacteria such as Escherichia coli show increasing resistance and all Klebsiella spp are intrinsically resistant to ampicillin, especially if this antibiotic is used for the treatment of maternal fevers and urinary tract infections during pregnancy. Multiresistant Pseudomonas spp and Serratia spp tend to be associated with nosocomial environments and can cause neonatal pneumonia. Antimicrobial resistance in Gram negative bacteria associated with neonatal sepsis ranges from 20 to 84%, depending on the geographical locale.13,3033

Supportive care
The supportive care of neonates with pneumonia is linked with improved outcomes and lower case fatality rates.1 This includes the use of oxygen, detection and treatment of hypoxaemia and apnoea, thermoregulation, detection and treatment of hypoglycaemia, and improved use of intravenous uids and nutritional supplementation via nasogastric feeding. The continuation of breast feeding is recommended unless there is a true contraindication, such as frequent vomiting, gastrointestinal intolerance or a high risk of aspiration. An intravenous preparation containing isotonic saline with 510% dextrose infused at less than regular maintenance rates is recommended, since free water excretion is decreased in infants with acute pneumonic infections. Antimicrobial therapy for atypical respiratory pathogens is based on the organism.

TREATMENT
Antibiotics
There are few randomized treatment trials for neonatal pneumonia.1 Treatment decisions are therefore based on local antimicrobial resistance patterns and clinical cost benet ratios.1

PREVENTION
Strategies to prevent and treat neonatal pneumonia require interventions at all levels of healthcare provision, i.e. community, primary care, district and tertiary hospitals.1

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M. D. NISSEN 4. Vitamin A supplementationatbirth. The precise mechanism for this strategy is unknown, but is thought to reduce S. pneumoniae colonization in early infancy.49,50 5. Proper management of apnoea and respiratory failure in neonates the utilization of alternatives to mechanical ventilation such as continuous positive airway pressure (CPAP), and respiratory stimulants such as theophylline and caffeine.51,52

Measures already shown to be effective in the prevention of neonatal pneumonia include: (1) the active management of premature rupture of maternal chorioamniotic membranes;34 (2) the early and exclusive use of breast feeding;35,36 and (3) avoiding nosocomial pneumonia in neonatal intensive care units where infections due to enteric Gram negative bacilli (E. coli, Klebsiella, Enterobacter and Pseudomonas spp), coagulase negative staphylococci and multiresistant S. aureus are common.3739 Bacterial colonization of endotracheal tubes, humidifers, ventilator tubing, intravenous lines, temperature probes, staff equipment (e.g. stethoscopes) and hands, all predate the onset of neonatal infection. Handwashing is the simplest and most effective intervention for preventing nosocomial neonatal sepsis.40,41 The identication and cleaning of contaminated equipment also prevents nosocomial infection.1 Restricted antibiotic policies have also been shown to prevent neonatal nosocomial infection. The use of benzylpenicillin and tobramycin or gentamicin for early-onset sepsis, and ucloxacillin and tobramycin or gentamicin for late-onset sepsis, instead of cefotaxime and ampicillin resulted in lower neonatal colonization rates with resistant bacteria.42

CONCLUSION
The global impact of neonatal pneumonia is signicant and the epidemiology and aetiology are complex when compared to the pneumonias in older children. Management and prevention strategies for neonatal pneumonias cross multiple levels of the population and healthcare provision, and have broader based effects that are sometimes difcult to measure. The growing prevalence of antibiotic resistance to common and affordable antibiotics will eventually impact morbidity and mortality rates for neonates, especially in the developing world, and emphasize the importance of continuing to develop universal maternal and preventative health programmes.

Future directions
Other preventative measures for neonatal pneumonia that require ongoing and further investigation include: 1. Maternal immunization. Maternal immunization with pneumococcal polysaccharide vaccine and the subsequent induction of vaccine protective antibodies for S. pneumoniae in neonates has been studied in the Gambia, Bangladesh, Philippines and Papua New Guinea.43 46 Subsequent response to vaccine by children whose mothers were immunized during pregnancy, does not appear to be suppressed.46 Regular antenatal monitoring of maternal immunity for rubella antibodies and boosting of rubella immunity following pregnancy by vaccination is already established and has lead to a considerable drop in the incidence of congenital rubella in many developed countries. A further expansion of this strategy to prevent neonatal pneumonia by maternal immunization will occur when maternal vaccines are developed for HSV, cytomegalovirus and HIV.47 2. Prevention and treatmentofmaternalsexually transmitted diseases. Programmes to prevent, detect and treat syphilis, C. trachomatis and HIV would reduce neonatal respiratory disease and improve neonatal outcomes in areas where maternal rates of these sexually transmitted diseases are high. 3. Cleansing the birth canal with antiseptic solution (chlorhexidene 0.25%) at every vaginal examination before delivery.48

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