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Neonatal Pneumonia in Developing Countries: Arch. Dis. Child. Fetal Neonatal Ed
Neonatal Pneumonia in Developing Countries: Arch. Dis. Child. Fetal Neonatal Ed
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Notes
REVIEW
Pneumonia contributes to between 750 000 and 1.2 was proven on culture in 31 (9.7%), and ano-
ther 62 (19.5%) had radiographic signs of
million neonatal deaths and an unknown number of pneumonia.10
stillbirths each year world wide. The aetiology depends on
time of onset. Gram negative bacilli predominate in the first CLASSIFICATION AND PROBLEMS IN
week of life, and Gram positive bacteria after that. UNDERSTANDING THE EPIDEMIOLOGY
OF NEONATAL PNEUMONIA
Streptococcus pneumoniae probably causes about 25% of Neonatal pneumonia can be arbitrarily classified
neonatal pneumonia. Interventions that would reduce as early and late onset. There are various
mortality from this condition would have a large range of definitions of early onset pneumonia; some
authors have used 48 hours as a cut off, others
beneficial effects: improved maternal health, better have suggested 7 days. Because of the way some
management of other common neonatal conditions, and aetiology studies have been reported, and the
reduced long term childhood and adult morbidity. differences in aetiology, it may be operationally
useful to separate the disease classification
...........................................................................
between the first week of life and the subsequent
three weeks. In most series, Gram negative
I
t is estimated that 3.9 million of the 10.8 bacteria predominate in the first week and Gram
million deaths in children annually world wide positive bacteria predominate subsequently.
occur in the first 28 days of life.1 More than Intrauterine pneumonia can be considered a
96% of all neonatal deaths occur in developing subgroup of early onset disease; this presents as
countries, and pneumonia accounts for a sub- stillbirth, low Apgar scores, or severe respiratory
stantial proportion of these. Intrauterine and distress at the time of birth and is commonly
early onset pneumonia was found at autopsy in associated with chorioamnionitis. Intrauterine
10–38% of stillborn and 20–63% of liveborn and early onset pneumonia is acquired by
babies who subsequently died (with all but one transplacental spread or from aspiration of
of six studies in the range of 20–32%).2 In a infected amniotic fluid after prolonged rupture
separate series of 1044 autopsies on neonatal of membranes or during delivery. Intrauterine
deaths in the first 48 hours of life, 20–38% had pneumonia also occurs in the setting of a
pneumonia, with the highest incidence in poorer systemic infection in the mother, such as rubella,
socioeconomic groups.3 There are therefore likely cytomegalovirus, Treponema pallidum, Listeria
to be between 750 000 and 1.2 million neonatal monocytogenes, tuberculosis, and HIV. These infec-
deaths annually where pneumonia is involved,4 tions may be asymptomatic in the mother.
and neonatal pneumonia accounts for 10% of Associated features include hepatosplenomegaly,
global child mortality. thrombocytopenia, and jaundice.
Throughout childhood, the greatest risk of Pneumonia acquired from bacterial infection
death from pneumonia is in the neonatal period. of amniotic fluid or colonisation of the birth
In a field trial of community based management canal is often associated with chorioamnionitis
of childhood pneumonia in India, more than half and evidence of fetal asphyxia. How asphyxia
of all child deaths from pneumonia occurred relates to pneumonia is not certain, but it can
among neonates.5 Pneumonia mortality risk is cause fetal gasping and aspiration of contami-
strongly dependent on birth weight and age of nated amniotic fluid. That pneumonia occurs
onset. Case fatality rates are much higher for from aspiration is supported by the common
intrauterine or early onset pneumonia than for finding of amniotic fluid debris or maternal
late onset neonatal pneumonia,6 7 and higher leucocytes in the histological examination of the
among low birthweight newborns.8 lungs.
The proportion of neonatal respiratory distress It can be difficult to distinguish early onset
that is caused by pneumonia will depend on pneumonia from hyaline membrane disease; the
.......................
where the source population is from (tertiary clinical picture and radiographic appearance can
Correspondence to: hospital, district hospital, or community), the be identical, and in many settings radiology and
Dr T Duke, Centre for stage in the perinatal period, the gestational age bacteriology are unavailable. Gestational age and
International Child Health, of the babies and the availability of intensive onset of symptoms provide clues in many cases.
University Department of
Paediatrics, Royal care, and the definition of pneumonia. Of 150 However, hyaline membrane disease also occurs
Children’s Hospital, neonates with respiratory distress presenting to a close to term (in infants of diabetic mothers, and
Parkville, Vic 3052, referral hospital in India, 103 (68.7%) were rarely surfactant protein deficiency), intrauterine
Australia; trevor.duke@ diagnosed to have pneumonia.9 Using a different acquisition of infection often results in prema-
rch.org.au
case definition in a teaching hospital in Brazil, of ture onset of labour, and gestational age assess-
Accepted 9 August 2004 318 infants presenting with respiratory distress ments are often not possible in settings where
....................... within the first 4 days of life, bacterial infection antenatal care is minimal and health workers are
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F212 Duke
not trained in this type of clinical scoring. Therefore basing CLINICAL FEATURES
treatment decisions for respiratory distress in the newborn on A definition of neonatal pneumonia was proposed in one
estimated gestational age is impractical and unsafe. The Indian study (shown in the box),9 but none have been
difficulty in distinguishing pneumonia from hyaline mem- prospectively validated. This complex algorithm has limited
brane disease and other non-infective respiratory conditions application: at best in tertiary settings and as a standardised
of the newborn—for example, transient tachypnoea of the research tool. In most health facilities, laboratory testing, and
newborn—presents a problem in understanding the con- often radiology, are unavailable.
tribution of pneumonia to mortality in the first week of life. In primary and many secondary healthcare facilities, it is
The literature on the bacterial aetiology of neonatal sensible to consider neonatal pneumonia within the spec-
pneumonia is influenced by studies that include nosocomial trum of neonatal sepsis. For practical purposes, WHO does
infection in neonatal intensive care units.11 12 Many studies not distinguish between neonatal pneumonia and other
do not report the age of onset. A further difficulty is that forms of severe sepsis, such as bacteraemia or urinary tract
blood cultures will underestimate the proportion of pneu- infection. There is much overlap in clinical signs and organ
monia that is bacterial, and lung puncture studies have rarely involvement, and empirical treatment regimens are similar.
been performed on neonates.3 6 In Ethiopia, a diagnosis of Studies that have evaluated the clinical signs of radio-
pneumonia in young infants was negatively associated with graphically proven neonatal pneumonia have reported some
bacteraemia, compared with the diagnoses of clinical sepsis, consistent and some apparently contradictory findings
‘‘severe disease’’, or ‘‘eventually fatal sepsis’’.13 In studies (table 1). Tachypnoea is present in 60–89% of cases. Chest
where a high proportion of infants have previously received recession is present in over 80% of cases in most studies,
antibiotics, the highest yield has come from the combination although one6 found that subcostal and intercostal retrac-
of blood culture, lung puncture culture, and serum and lung tions were only present in 36% of cases. Cough was absent in
aspirate latex agglutination antigens.14
The multi-country World Health Organisation young infant
study has provided the most useful data yet on the aetiology Definition of neonatal pneumonia used in one
of community acquired neonatal sepsis, including pneumo- Indian study 9
nia from a range of developing countries. However, this study
predominantly recruited young infants from outpatient A neonate with respiratory distress (any of: rapid, noisy, or
departments in hospitals. This limited the number of difficult breathing; respiratory rate .60/min; chest retrac-
neonates recruited from, or soon after, birth; thus intrauter- tions; cough; grunting) who has: (a) a positive blood culture
ine pneumonia and early onset pneumonia, which present in or (b) any two or more of the following:
the first 48 hours of life, was not as well represented.
The following assumptions may be valid. The epidemiology (1) Predisposing factors
of neonatal pneumonia and implications for treatment and
prevention are sufficiently similar to those of neonatal – Maternal fever (.38˚C)
bacteraemia, meningitis, and other forms of sepsis that blood – Foul smelling liquor
culture and cerebrospinal fluid isolates can be used to – Prolonged rupture of membranes (.24 hours)
understand the aetiology, notwithstanding the underestima-
tion of pneumonia disease incidence without lung aspirates. (2) Clinical picture of sepsis
Data on the aetiology of chorioamnionitis can be used to
understand the aetiology of intrauterine and early onset – Poor feeding
pneumonia. – Lethargy
– Poor reflexes
– Hypothermia or hyperthermia
Table 2 Yield from cultures of lung puncture on 755 – Abdominal distension
neonates who were stillborn or died in the first 72 hours
(3) Radiograph suggestive of pneumonia (nodular or coarse
of life3
patchy infiltrate, diffuse haziness or granularity, air
Bacteria Number bronchogram, lobar or segmental consolidation);
radiological changes not resolved within 48 hours
Escherichia coli 71
Aerobacter aerogenes 45 (4) Positive sepsis screen (any of the following):
Streptococcus beta haemolytic 29
Pseudomonas aeruginosa 27 – Bands .20% of leucocytes
Streptococcus viridans 21
Staphylococcus aureus 17
– Leucocyte count out of reference range
Proteus vulgaris 11 – Raised C reactive protein
Streptococcus non haemolytic (Group D) 8
– Raised erythrocyte sedimentation rate
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Neonatal pneumonia in developing countries F213
about two thirds of cases in two studies,6 14 but in less than Table 4 Bacterial pathogens isolated from blood culture
20% of cases from one study.6 For the purposes of designing or cerebrospinal fluid in 1313 neonates aged 7–29 days
primary care treatment strategies, Singhi and Singhi15 in the multi-centre WHO young infant study,17 and in 260
suggested that the standard definition for neonatal pneumo- neonates 8–30 days in Kenya
nia could be ‘‘cough and chest wall recession’’ or ‘‘a history of
rapid breathing and chest wall retraction’’. Use of cough and WHO young English
respiratory rate .50 breaths/min as the definition would Bacterial pathogens infant study et al18 Total
have missed radiographically proven pneumonia in 25% of Total 1313 260 1573
the cases in their series. Total positive cultures 64 (4.9%) 22 (8.5%) 86 (5.5%)
S pyogenes 14 5 19
Staph aureus 15 3 18
FACTORS PREDICTING EARLY ONSET PNEUMONIA S pneumoniae 8 4 12
Predictive factors may be absent from many neonates with Escherichia coli 10 1 11
early onset pneumonia. A study of neonates in the United Salmonella spp 8 0 8
Kingdom with early onset pneumonia found that risk factors Group B Streptococcus 2 6 8
Klebsiella pneumoniae 2 0 2
were present in 78%, but in almost half (17 of 35) the only
Enterobacter 2 0 2
predictor was early onset of labour.16 In India, only 40% (42 of H influenzae 1 1 2
103) of mothers of neonates with pneumonia had identifiable Group G Streptococcus 1 0 1
risk factors: fever, prolonged rupture of membranes Acinetobacter 1 0 1
(.24 hours), leaking amniotic fluid, or foul smelling liquor.9 Pseudomonas 0 1 1
Enterococcus spp 0 1 1
A problem with the methodology of the latter study is that
known risk factors are used as one criterion to define
pneumonia (box), therefore investigation of the proportion of
neonatal pneumonias with these factors is a circular
argument. Nevertheless, in this study from India, .50% of not of a magnitude sufficient to cause death or severe
neonates with an eventual diagnosis of pneumonia had no respiratory distress at birth). Table 3 lists the bacterial causes
known predisposing factors. This suggests that other criteria found in studies from developing countries that clearly
used to diagnose pneumonia in this study were non-specific, distinguished early from late onset neonatal sepsis and
and the proportion of neonatal respiratory distress that was pneumonia. Escherichia coli, group B Streptococcus, Klebsiella
ascribed to pneumonia (68%) is an overestimate, or that spp, Staphylococcus aureus and Streptococcus pneumoniae were the
some predisposing factors for neonatal pneumonia are most commonly isolated bacteria. In a further study that did
difficult to recognise. not make a clear distinction between early and late causes,
among 150 Indian neonates presenting at a median of
AETIOLOGY AND PATHOPHYSIOLOGY 164 hours of life with respiratory distress, of whom 103 were
Intrauterine pneumonia diagnosed with pneumonia, blood cultures were positive in
In an investigation of the aetiology of chorioamnionitis and 49 cases (48%): Klebsiella in 28, Staph aureus in seven,
perinatal infection, cultures of lung puncture and aspirate coagulase negative Staphylococci in seven.9
were carried out on 755 neonates who were stillborn or died
in the first 72 hours of life.3 Table 2 lists the bacteria isolated. Late onset neonatal pneumonia
Late onset neonatal pneumonia needs to be distinguished
Early onset neonatal pneumonia from pulmonary oedema secondary to a congenital heart
Early onset neonatal pneumonia results from infection lesion, and rarely from other pathology such as pulmonary
acquired by aspiration after early rupture of membranes or haemorrhage or infarct. To understand the aetiology of late
during labour, or an initially lower grade intrauterine onset, community acquired neonatal pneumonia there is a
infection associated with maternal chorioamnionitis (but need to exclude series from neonatal units in Western
Bacterial pathogens isolated from blood culture or cerebrospinal fluid in the first week of life in 360 neonates from
17 18
the multicentre WHO young infant study, 432 neonates in the first week of life in Kenya, and in 261 neonates
with respiratory distress in the first 4 days of life in Brazil.
GBS, Group B Streptococcus.
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F214 Duke
countries, where colonisation of endotracheal tubes and outpatient’s department. Positive C trachomatis nasopharyn-
breaches in local immunity lead to bacteria entering the geal aspirates were found in 33% (100 of 303) of infants with
lower respiratory tract. Until the WHO young infant severe pneumonia, 18% (38 of 217) of those with non-severe
study,8 13 17 19 the aetiology of community acquired, late onset pneumonia, and 9% (26 of 295) of young infants with no
neonatal infection in developing countries had not been pneumonia, sepsis, meningitis, or conjunctivitis. The pre-
widely studied. Table 4 lists the major pathogens isolated sence of Chlamydia was associated with radiographic evidence
from blood cultures or cerebrospinal fluid in neonates aged of pneumonia as well as hypoxaemia, and there was a
7–29 days in this study and in a study from Kenya. Bacterial borderline association of positive C trachomatis nasopharyn-
isolation in the WHO study was from blood cultures, geal aspirates and pneumococcal bacteraemia.25 Recovery
cerebrospinal fluid, pus swabs, and conjunctival swabs. rates were high (.85%) despite antibiotics against Chlamydia
Given that more than half of all childhood bacterial being rarely used, suggesting either that Chlamydia predis-
pneumonias are not associated with bacteraemia, this series poses, perhaps by mucosal injury, to secondary bacterial
of studies is likely to have underestimated the proportion of infection, which is more serious in the setting of co-infection,
neonatal pneumonias that are bacterial in origin. but still responds adequately to conventional antibiotics or
Two lung aspirate studies from India (table 5) have Chlamydia responds sufficiently to commonly used antibiotics
highlighted the importance of Gram positive bacteria in for young infant sepsis.
neonatal pneumonia: one study found S pneumoniae (14 out Among Kenyan neonates aged 7–30 days with pneumonia,
of 50) and Staph aureus (14 out of 50) to be the most common 24 of 52 (46%) had the combination of both interstitial
causes of neonatal pneumonia.6 A second study found pneumonia and colonisation of the upper airways with
S pneumoniae antigen positive in serum or lung aspirate of C trachomatis.26 In Ethiopia, of 202 infants ,3 months of age
10 of 44 (22%) neonates with pneumonia (but no cultures of presenting to an outpatient’s department, 32 (15.8%) had a
S pneumoniae were positive), and Gram negative bacilli were nasopharyngeal aspirate positive for C trachomatis.13
cultured in 11 of 44 (25%).14 The age of onset of infection in On the basis of pooled results from 10 studies, the
these two studies was not reported, but in a study of neonates estimated risk of Chlamydia pneumonia developing in an
with pneumococcal sepsis in the United States, the median infant whose mother is colonised with C trachomatis is 7%
age of onset was 18.9 days (SD 4.6). For those in whom (95% confidence interval 5.1% to 9.4%).27 The two largest
pneumonia was the major site of infection, the age of onset cohort studies of infants exposed to C trachomatis reported
was 12.3 days (SD 12.4).20 The yield from these two lung pneumonia incidences of 3%28 and 16%.29 No studies have
aspirate studies, one of which also used non-culture used the optimum method for determining the cause of
techniques, was 62% compared with less than 10% in other pneumonia: isolation of C trachomatis from a percutaneous
studies that relied on blood and cerebrospinal fluid bacterial lung aspirate.
cultures alone. Apart from intrauterine infections, the viral aetiology of
neonatal pneumonia has not been systematically studied.
Atypical pathogens Respiratory syncitial virus has been shown to be a common
Congenital syphilis is still a major cause of neonatal infection pathogen in infants under 6 months of age,30 31 and it is
in many developing countries, and fatal cases are invariably likely that this virus is an important cause of seasonal late
associated with severe pneumonitis and hypoxaemia (pneu- onset neonatal pneumonia in some settings in developing
monia alba). In a study from Papua New Guinea,21 congenital countries.
syphilis was the cause of death in 13.5% (17 of 126) neonates,
and the case fatality rate for congenital syphilis was 33%.22 HIV and neonatal pneumonia
Severe hypoxaemia was common.23 In Malawi, independent There are several reasons why HIV infection is a risk factor for
risk factors for neonatal death included maternal syphilis the development of neonatal pneumonia and increases the
(hazard ratio 2.4; 95% confidence intervals 1.3 to 4.4), low risk of mortality from the latter. Although HIV infection
birth weight, and first pregnancy.24 usually becomes manifest clinically in later infancy, a rapidly
Chlamydia trachomatis may contribute substantially to late progressive congenital form of HIV associated with persistent
onset neonatal pneumonia in countries where untreated pneumonia in the neonatal period has been described from
sexually transmitted infections are common. The evidence for South Africa and Zimbabwe.32 33 This is associated with
this is circumstantial, but suggestive of a major effect. In hepatosplenomegaly, lymphadenopathy, prematurity, and
Papua New Guinea, evidence of C trachomatis was found growth retardation. Co-infection with tuberculosis, syphilis,
by direct immunofluorescence in 22% (138 of 638) of naso- and cytomegalovirus are common and may be responsible for
pharyngeal aspirates from young infants presenting to an the early manifestations of this disease.32 34 Maternal HIV
infection increases the probability of death from neonatal
respiratory distress syndrome and predisposes to sepsis from
Table 5 Lung aspirate studies in neonatal pneumonia streptococci and staphylococci.33 Among mothers and infants
Shakunthala Misra in Pune, India using cow, goat, or buffalo milk as a substitute
Bacteria et al 6 et al14 Total for human milk to reduce the risk of mother to child HIV
transmission, the rate of hospital admission in the neonatal
Total 50 44 94
Positive isolate 31 (62%) 27 (61%) 58 (62%) period from pneumonia (and other infections) was much
S pneumoniae 14 10* 24 higher than for the neonates of HIV positive mothers who
Staph aureus 14 0 14 breast fed.35
Klebsiella 0 5 5
S epidermidis 0 4 4
Streptococcus 2 2 4 ROLE OF HYPOXAEMIA IN NEONATAL PNEUMONIA
Pseudomonas 1 2 3 Hypoxaemia is a common complication of neonatal illness,
E coli 0 1 1
Salmonella 0 1 1 because of primary respiratory disease (pneumonia, hyaline
Morganella 0 1 1 membrane disease, transient tachypnoea of the newborn)
Enterobacter 0 1 1 and because apnoea is a common non-specific response to
sepsis, hypothermia, and hypoglycaemia. There have been
*S pneumoniae isolated from lung puncture using counter-
immunoelectrophoresis antigen testing.
few investigations of the incidence of hypoxaemia in
neonatal illness in developing countries. The incidence varies
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Neonatal pneumonia in developing countries F215
Misra et al 14 India; university hospital 44 14 (32%) NR Slow respiratory rate; low birth weight
6
Shakunthala et al India; university hospital 50 24 (48%) 23/17 First week presentation; low birth weight
neonatal unit
Mathur et al 9 India; university hospital 103 32 (31%) NR A-aDO2 .250 mm Hg
neonatal unit
Bang et al 45 India; community based 65 10 (15%) NR Referral indications: stridor, unconsciousness,
intervention study convulsions or inability to suck
15
Singhi & Singhi India; university hospital 89 7 (8%) NR Slow respiratory rate
emergency department
presentations
7
Webber et al UK; university hospital 76 11 (14%) 35/10 First week presentation
neonatal unit
Total 427 98 (23%)
with the level of health facility. Hypoxaemia was present in hypoxaemia, low birth weight,6 8 14 and absence of tachy-
38.5% of infants under 2 months of age presenting to a pnoea (table 7).
tertiary hospital emergency department in India (SpO2 ,90)36
and in 43% of neonates admitted to a provincial hospital in
TREATMENT
Papua New Guinea (SpO2 ,86%, more than 2SD below the
There are no published randomised treatment trials of
population mean at 1600 m).23 In Papua New Guinea,
neonatal pneumonia, and few for neonatal sepsis in devel-
hypoxaemia was present in 77% of neonates with pneumo-
oping countries.37 38 Empirical treatment decisions must
nia, but also in 36% of neonates without clinically definable
therefore be based on local resistance patterns and the costs,
acute lower respiratory tract infection.23 Because of referral of
more seriously ill infants, a higher proportion of neonates benefits, and availability of various antibiotic regimens. There
seen at tertiary hospitals than at primary care facilities will are also some informative trials using retrospective or
have hypoxaemia. However, hypoxaemia is a common contemporaneous non-randomised control groups in com-
feature of neonatal illness even in primary care facilities. munities and hospitals in developing countries.
Among infants less than 2 months of age presenting to eight
remote rural primary health centres in Papua New Guinea, Antibiotics
one or more signs of severe respiratory compromise were For the management of neonatal sepsis, WHO recommends
present in 25% (128 of 511): fast respiratory rate (102); giving ampicillin (50 mg/kg) every 12 hours in the first week
severe chest indrawing (74); cyanosis (35); or apnoea (32). of life and every eight hours from 2–4 weeks, plus a single
Each of these signs was associated with an increased risk of daily dose of gentamicin.39 First line alternatives to ampicillin
death. Pulse oximetry was not performed in this study; are benzylpenicillin or amoxicillin, and alternatives to
however, 49 infants (9.6%) had cyanosis or apnoea, two of gentamicin are kanamycin or streptomycin. Where there is
the most specific clinical signs for neonatal hypoxaemia.23 strong evidence of staphylococcal infection (skin pustules,
Detection of hypoxaemia in neonates using clinical signs is cellulitis, umbilical cord infection, pneumatocoeles, or
difficult. In a study in Papua New Guinea, cyanosis was the empyema), cloxacillin or flucloxacillin, where these are
most sensitive sign, but will still miss up to one quarter of available, should be substituted for ampicillin.
neonates with hypoxaemia. A respiratory rate within the A daily dose regimen for gentamicin was piloted in a
normal range of 30–60 breaths/min was found in just over randomised trial in Kenyan infants less than 3 months of
half of all neonates with hypoxaemia. Incidences of age. A regimen that consisted of a loading dose of 8 mg/kg
hypoxaemia of 10% in primary care facilities and more than followed by 2 mg/kg (if weight ,2 kg) or 4 mg/kg (if weight
30% at hospitals of first referral represent huge numbers .2 kg) in the first week of life, or 4 mg/kg (weight ,2 kg) or
globally, and need for oxygen is rarely matched by available 6 mg/kg (weight .2 kg) resulted in a higher proportion of
resources. initial gentamicin concentrations within the therapeutic
range and a lower rate of potentially toxic gentamicin
OUTCOME concentrations, than a three times a day dose schedule.37
Table 6 summarises published case fatality rates in commu- Pus, from empyema or skin pustules, should be examined
nity based and hospital based studies, most of which come after Gram staining, where laboratory facilities are available.
from India. Mortality in early neonatal pneumonia is much The yield from blood cultures is low, and culture facilities will
higher (74% and 29% in the two series that reported case not be available in most health centres and secondary referral
fatality rate by age) than for late onset disease. Risk factors hospitals where neonates present with pneumonia, but
for death from neonatal pneumonia are early onset disease, where possible blood for culture should be taken before
Table 7 Data showing that absence of tachypnoea is a risk factor for mortality
Number in RR range who died/total number in RR range (CFR)
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F216 Duke
antibiotics are given, to guide second line antibiotic back up in case of power failure may be optimal in rural
treatment in the event of treatment failure. hospitals in developing countries.
For neonates who are failing to respond to first line Appropriate attachments for delivering oxygen have
antibiotics, WHO suggests changing to chloramphenicol or a recently been reviewed;49 in resource limited settings, use of
third generation cephalosporin.39 Chloramphenicol should nasal oxygen prongs is optimal but often limited by cost and
not be used in premature infants, and should be avoided in availability. They do not require humidification, and low flow
the first week of life. rates (0.5–2 litres/min) are effective in correcting hypoxae-
Antibiotic resistance among neonatal pathogens is increas- mia in most infants. A nasopharyngeal catheter is the most
ing world wide. Reported rates of resistance depend partly on efficient method for delivering oxygen, providing the highest
the proportion of cases that are acquired in hospitals, where partial pressure of alveolar oxygen for a given flow rate;
multiresistant Pseudomonas, Klebsiella, Serratia, and other however, these are associated with higher complication rates
enteric Gram negative bacilli are more common than in than nasal prongs and do require humidification. A nasal
community acquired sepsis.11 40 Gentamicin resistance among catheter, inserted half way into the nasal passage, may be the
Gram negative bacteria causing neonatal sepsis range from; most widely used method in developing countries: low flow
20% in Kenya;41 24% in India;14 43% in one study from rates are adequate, complications are rare, cost is a fraction of
Pakistan42 and 78–84% in another;43 66% in Papua New that of nasal prongs, and, where oxygen catheters are
Guinea;40 and 77% in Guatemala.11 Despite high rates of unavailable, nasogastric tubes are often used. Giving oxygen
reported resistance, the combination of ampicillin and through a tube directed into a head box is inefficient in
gentamicin is still probably optimal first line treatment for health facilities where oxygen supplies are limited. High flow
severe community acquired neonatal pneumonia in most rates (.4 litres/min) are required to achieve a high fraction
settings. of inspired oxygen and to avoid carbon dioxide accumulation
Community based recognition and treatment within a standard neonatal head box.
Training village health workers to recognise the clinical signs Many neonates with severe pneumonia will be unable to
of neonatal pneumonia has been shown to reduce total and feed well in the acute stage of the illness and require
pneumonia mortality in several projects in remote areas. A nasogastric or intravenous fluids. Although there are no
meta-analysis of five studies of community based trials from randomised trials to inform fluid management, in infants
India, Pakistan, Bangladesh, Tanzania, and Nepal showed a with bronchiolitis, free water excretion is noticeably reduced
pooled reduction in total mortality of 27% (95% confidence in the acute stage compared with during convalescence,
interval 18% to 35%) and a reduction in pneumonia mortality suggesting activation of water conservation mechanisms. In
of 42% (95% confidence interval 57% to 22%).44 animal models of pneumococcal sepsis, free water excretion
Antibiotics used in these studies included oral cotrimox- is reduced to 25% of baseline values within hours of
azole (for five days),5 45 procaine penicillin, and oral ampi- infection. Hyponatraemia is found in about 30% of cases of
cillin. Investigators in India who originally used pneumonia in some series, is associated with high anti-
cotrimoxazole with substantial reductions in neonatal mor- diuretic hormone secretion, and is more common in children
tality,5 45 later used cotrimoxazole with a daily dose of with cyanosis,50 suggesting that the more severe the
gentamicin with apparently additional benefit.46 pneumonia, the better the physiological water conservation,
In these non-randomised community trials, supervision and the less exogenous fluid required to maintain homo-
and community motivation was very high. There is a need to eostasis. Giving fluid by a nasogastric tube allows the
know if this approach can be translated to other developing continuation of breast milk feeding and maintenance of
countries. some energy intake, avoidance of hypoglycaemia and the
complications of intravenous fluid administration, and is
Oxygen and supportive care cheaper than intravenous fluids. This is preferred unless
Major improvements to neonatal outcomes can occur by there is a true contraindication to feeding, such as frequent
standardising provision of neonatal care in rural and district vomiting, intolerance of enteral feeds, or high risk of
hospitals. In the Eastern Highlands of Papua New Guinea, aspiration. In these circumstances, isotonic saline plus up
where general improvements were made to neonatal care to 10% dextrose run at lower than traditional maintenance
(better provision of oxygen, detection and treatment of rates may be most appropriate, and feeds introduced as soon
apnoea, thermoregulation, detection and treatment of hypo- as the contraindication to enteral feeding has resolved.51
glycaemia, protocols for the safe use of intravenous fluids,
and improved nutrition), case fatality from pneumonia was
more than 50% lower during a 30 month period after the PREVENTION
interventions compared with the 30 months before.47 There are several reasons why interventions that can only be
Mortality also fell from other causes, particularly low birth delivered in hospitals will make little impact on deaths from
weight, emphasising the values of a syndromic approach and neonatal pneumonia. In many societies, neonates are not
general supportive measures rather than a diagnosis specific taken outside the home, even if they are sick, so referral to a
approach to neonatal care. These improvements occurred hospital is impossible. Often there is a preference for
while WHO standard antibiotic treatment regimens were traditional village remedies. In addition, because the signs
used throughout the two periods of study, and apart from of severe illness can be very subtle in neonates, parents may
oxygen and pulse oximetry did not require any intensive not recognise that their infant is sick until it is too late, and
technologies. geographical and financial constraints make referral to
Using oxygen, on the basis of objective evidence of hospital very difficult for much of the world’s population.
hypoxaemia, has the potential for large reductions in On the other hand, interventions solely at community level
neonatal and child mortality.48 Various methods are available will not fully address the often fatal complications of
for delivering oxygen, particularly cylinders of compressed hypoxaemia and apnoea. Improving supportive care and the
gas and oxygen concentrators. Oxygen cylinders are costly safety and accessibility of hospitals for seriously ill newborn
and heavy to transport, but can be used anywhere. Oxygen babies is a high priority globally. A comprehensive approach
concentrators are more cost effective in places remote from to prevention and treatment of neonatal pneumonia would
oxygen supply systems, but require a continuous power therefore involve interventions at community level, in
supply. A system of using concentrators with a cylinder as a primary health facilities, and in district and tertiary hospitals.
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Neonatal pneumonia in developing countries F217
Some preventive interventions have been shown to lead to fully explored.66 The possibilities increase for maternal
improved outcomes. Other interventions have shown efficacy immunisation, as more potential vaccine candidates become
in research or atypical circumstances, and there is a need to available, including herpes simplex, cytomegalovirus, and
evaluate the feasibility in other settings. For some preventive HIV vaccines.67
interventions and treatment, there are sound reasons for
further investigation of their potential role. Prevention and treatment of sexually transmitted
infections
PREVENTIVE MEASURES SHOWN TO BE EFFECTIVE Programmes to prevent and treat syphilis, Chlamydia, and HIV
Active management of preterm rupture of membranes would substantially improve neonatal outcomes and reduce
Antibiotic administration after preterm rupture of mem- much of the neonatal respiratory disease caused by these
branes is associated with a delay in delivery and a reduction infections. In a Kenyan maternity hospital, an antenatal
in major markers of neonatal morbidity (neonatal infection, treatment programme for syphilis based on rapid plasma
use of oxygen therapy, and abnormal cerebral ultrasound reagin testing significantly improved pregnancy outcomes.68
scans).52 Encouraging treatment and referral of mothers with However, tackling this issue is logistically difficult in
preterm rupture of membranes would reduce the number of countries where antenatal care is not accessed by most
babies born with intrauterine and early onset pneumonia.53 women, and where laboratory facilities in remote health
clinics are absent or limited. Accurate rapid testing would
Promotion of basic newborn care in communities have more utility than laboratory based serological tests, but
Early and exclusive breast feeding has been shown to rapid test kits are often expensive, of variable sensitivity, and
decrease the risk of pneumonia in infants outside the field trials in developing countries are few. In South Africa
neonatal period, and there is every reason to expect a similar and rural Gambia, the rapid plasma reagin test had positive
or greater protective effect against late onset neonatal predictive value (for subsequent confirmation of syphilis by
pneumonia.54 55 laboratory based serological testing) of around 50%, and
sensitivity around 75%.69 70 Other rapid tests may have greater
Prevention of nosocomial pneumonia predictive power, but are more costly. Retesting in pregnancy
Nosocomial pneumonia accounts for a large proportion of may be required in some settings.71 There is an urgent need
deaths from late onset pneumonia in industrialised countries for further evaluation of rapid screening tests for use in
and in developing countries with neonatal intensive care health clinics.
units. In these environments, infections due to enteric Gram
Cleansing the birth canal with antiseptic solution
negative bacilli (particularly Klebsiella, Enterobacter, and
In a non-randomised controlled trial in Malawi, cleansing the
Pseudomonas), coagulase negative staphylococci, and, in some
birth canal with 0.25% chlorhexidine at every vaginal
units methicillin resistant Staph aureus are common.56–58
examination before delivery was associated with a lower rate
Infections occur because of colonisation of endotracheal
of admissions for neonatal sepsis, lower mortality from
tubes, humidifier apparatus, ventilator tubing, and intrave-
infectious causes and lower overall neonatal mortality, and
nous lines, and is transmitted by hands of clinical staff and
lower maternal postpartum infection rate, than when no
on other equipment (stethoscopes, etc). The single most
cleansing was done.72
important intervention for infection control for protecting
newborns from nosocomial sepsis is hand washing.59 60 In
Vitamin A supplementation at birth
addition, randomised trial evidence suggests that restricted
Two large randomised trials have shown that vitamin A
antibiotic policies prevent nosocomial infections in neonates.
supplementation at birth reduces young infant mortality.73 74
In a multicentre randomised control trial, penicillin and
Giving 24 000 IU vitamin A on day 1 and day 2 of life in India
tobramycin for early onset sepsis, and flucloxacillin and
resulted in a 22% reduction in total mortality at 6 months of
tobramycin for late onset sepsis resulted in much lower
age; the greatest impact was in the period 2 weeks to
incidence of colonisation with resistant bacteria than the
3 months of age, and in those of birth weight ,2000 g. A
combination of ceftriaxone and amoxycillin.61 A regimen
possible reason for this is reduced S pneumoniae colonisation
avoiding the use of amoxycillin and third generation
in early infancy. Within this large randomised control trial,
cephalosporins restricts the resistance problem. Prevention
nasopharyngeal colonisation with Pneumococcus was less
of infection also requires the identification and cleaning of
common at 4 months of age.75 In another trial in
contaminated equipment.
Indonesian newborn, the risk of death was 64% lower (95%
confidence interval 13% to 84%), and the incidence of cough
APPROACHES WARRANTING FURTHER and fever were significantly lower in the first 4 months in
INVESTIGATION those who were given 50 000 IU vitamin A on the first day of
Maternal immunisation life. This may shift the age of first infection to later in infancy
Giving pneumococcal polysaccharide vaccine to mothers when mortality will be less, therefore there are major
provided protective antibodies in newborns against implications for the timing of the first dose of vitamin A in
S pneumoniae in the Philippines, Papua New Guinea, supplemental programmes.
Bangladesh, and the Gambia.62–65 Antibodies are acquired
through both the maternal-fetal circulation and breast milk.64 Management of apnoea and respiratory failure
In the Gambia, pneumococcal antibodies were found to Apnoea is a common complication of neonatal pneumonia,
disappear rapidly during the first months of life; so, to occurring in 28–43% of cases,6 76 and respiratory failure
achieve sustained protection, maternal vaccination would unresponsive to oxygen invariably precedes a fatal outcome.
need to be supplemented by infant vaccination, and breast In some hospitals, provision of mechanical ventilation may
feeding promoted. In Papua New Guinea, there was evidence do more harm than good because staff are not experienced
that vaccine response was not suppressed in older infants with its use, or because the combination of poor infection
whose mothers had been vaccinated during pregnancy. Given control practices and colonised endotracheal tubes means
the finding from limited lung aspirate studies that 25% of that nosocomial pneumonia will cause the deaths of more
neonatal pneumonia is due to Pneumococcus, even protection babies than mechanical ventilation would save. Underwater
in the first few months of life may be extremely beneficial, bubble continuous positive airway pressure (CPAP)77 may
and the full potential of maternal immunisation should be have a role in the management of apnoea or severe
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F218 Duke
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