j.1365-3156.2009.02364.x

Systematic Review

Pneumonia in severely malnourished children in developing

countries – mortality risk, aetiology and validity

of WHO clinical signs: a systematic review

Mohammod Jobayer Chisti1,2,*, Marc Tebruegge3,4,5,*, Sophie La Vincente2,5, Stephen M. Graham2,5

and Trevor Duke2,5,6

1 Clinical Science Division, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh2 Centre for International Child Health, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital,

Melbourne, Australia3 Infectious Diseases Unit, Department of General Medicine, Royal Children’s Hospital, Melbourne, Australia4 Department of Paediatrics, University of Melbourne, Australia5 Murdoch Children’s Research Institute (MCRI), Melbourne, Australia6 Discipline of Child Health, School of Medicine, University of Papua New Guinea, Port Moresby, Papua New Guinea

Summary objectives To quantify the degree by which moderate and severe degrees of malnutrition increase the

mortality risk in pneumonia, to identify potential differences in the aetiology of pneumonia between

children with and without severe malnutrition, and to evaluate the validity of WHO-recommended

clinical signs (age-specific fast breathing and chest wall indrawing) for the diagnosis of pneumonia in

severely malnourished children.

methods Systematic search of the existing literature using a variety of databases (Medline, EMBASE,

the Web of Science, Scopus and CINAHL).

results Mortality risk: Sixteen relevant studies were identified, which universally showed that

children with pneumonia and moderate or severe malnutrition are at higher risk of death. For severe

malnutrition, reported relative risks ranged from 2.9 to 121.2; odds ratios ranged from 2.5 to 15.1.

For moderate malnutrition, relative risks ranged from 1.2 to 36.5. Aetiology: Eleven studies evaluated

the aetiology of pneumonia in severely malnourished children. Commonly isolated bacterial pathogens

were Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, and

Haemophilus influenzae. The spectrum and frequency of organisms differed from those reported in

children without severe malnutrition. There are very few data on the role of respiratory viruses and

tuberculosis. Clinical signs: Four studies investigating the validity of clinical signs showed that

WHO-recommended clinical signs were less sensitive as predictors of radiographic pneumonia in

severely malnourished children.

conclusions Pneumonia and malnutrition are two of the biggest killers in childhood. Guidelines for

the care of children with pneumonia and malnutrition need to take into account this strong and often

lethal association if they are to contribute to the UN Millennium Development Goal 4, aiming for

substantial reductions in childhood mortality. Additional data regarding the optimal diagnostic

approach to and management of pneumonia and malnutrition are required from regions where death

from these two diseases is common.

keywords aetiology, chest indrawing, fast breathing, malnutrition, mortality, pneumonia, sensitivity,

specificity

*Both authors considered joint first authors.

Tropical Medicine and International Health doi:10.1111/j.1365-3156.2009.02364.x

volume 14 no 10 pp 1173–1189 october 2009

ª 2009 Blackwell Publishing Ltd 1173

Introduction

Pneumonia is the biggest single cause of childhood deaths

under the age of five years in developing countries

(UNICEF ⁄ WHO 2006; Graham et al. 2008). Globally

there are more than nine million deaths among the under-

five population each year, of which about three million are

due to pneumonia (Black et al. 2003; Bryce et al. 2005).

Of these deaths, 90–95% occur in developing countries

(Williams et al. 2002; Mulholland 2003). The success of

the fourth United Nations Millennium Development Goal

4 (MDG 4), which aims to reduce child mortality by

two-thirds by 2015, will therefore depend in no small part

on a reduction of this enormous burden of child deaths

from acute respiratory infection.

Several interventions that aim to reduce the global

burden of deaths from pneumonia have been identified as

priorities. These include improving nutrition and rates of

breast-feeding, reducing indoor air-pollution, reducing

housing overcrowding, improving access to antibiotics,

care-seeking behaviour and referral practices, and

improving the quality of case management (Sazawal &

Black 1992; Mulholland 2007; Dherani et al. 2008; Roth

et al. 2008). If pneumonia case management is to have a

significant impact on global child mortality it is pertinent

that it is appropriate for those groups of children at highest

risk of death – neonates, HIV-infected and malnourished

children (Graham et al. 2008). Among these, malnourished

children represent the largest group. More than half of all

child deaths are associated with malnutrition. Pneumonia

is common in malnourished children and frequently

associated with fatal outcome (Rice et al. 2000; Bryce et al.

2005; Loeb & High 2005; Nannan et al. 2007). Of

children with malnutrition requiring hospital admission,

up to two-thirds are diagnosed with pneumonia (Shimeles

& Lulseged 1994; Ahmed et al. 1999).

With this review, we sought to explore the interaction

between pneumonia and malnutrition. Specifically, we

aimed to quantify the degree by which moderate and severe

malnutrition increases the mortality risk in pneumonia, to

identify differences in pneumonia aetiology between

severely and not severely malnourished children, and to

evaluate the validity of clinical signs recommended for the

diagnosis of pneumonia by the World Health Organization

(WHO) in severely malnourished children.

Methods

We conducted a search of the existing literature to identify

reports focusing on severe malnutrition and pneumonia.

Severe malnutrition was defined as follows: <-3 z score of

weight for age (W ⁄ A) or weight for height (W ⁄ H) of the

median of the National Centre for Health Statistics

(NCHS) or <60% W ⁄ A of the median of the NCHS or

according to Wellcome classification (Jelliffe 1966; Well-

come Trust International Working Party 1970). Moderate

malnutrition was defined as <-2 to ‡-3 Z score of W ⁄ A or

W ⁄ H of the median of the NCHS or 60–74% W ⁄ A of the

median of the NCHS. The following databases were

searched: PubMed (1955–2008), EMBASE (1980–2008),

ISI Web of Science (1955–2008), Scopus (1950–2008)

and CINAHL (1981–2008). No limits were set, except

for the search of EMBASE, which was limited by age

(details below). The search strategies and outcomes are

summarised in Table 1. The searches were conducted in

January 2009. All abstracts retrieved by the individual

searches were reviewed. Full-text articles were retrieved

and evaluated if the abstract suggested potential relevance.

In addition to the publications identified by the electronic

database search (Table 1) a further two relevant publica-

tions were identified from the bibliographies (Tupasi 1985;

Post et al. 1992). In some instances where the original

publication contained insufficient information the authors

were contacted and asked to provide further details.

Inclusion criteria were (a) mortality risk: studies inves-

tigating fatal outcomes in children with pneumonia and

moderate and ⁄ or severe malnutrition, (b) aetiology: studies

reporting on bacteriological or virological investigations in

children with pneumonia and severe malnutrition, and

(c) clinical signs: studies in severely malnourished children

which compared, as a minimum, the sensitivity and

specificity of age-specific fast breathing and ⁄ or lower chest

wall indrawing with chest radiograph as the gold standard

for the diagnosis of pneumonia. Excluded were (i) reports

that included fewer than 10 malnourished children,

(ii) reports which did not use standard definitions for

malnutrition or provided no definition and (iii) reports in

which the respective data could not be clearly separated on

the basis of nutritional status.

Results

Pneumonia-related mortality risk in moderate and severe

malnutrition

Fifteen published studies evaluating mortality risk were

identified (Tupasi 1985; Tupasi et al. 1988, 1990c;

Deivanayagam et al. 1992; Post et al. 1992; Nathoo et al.

1993; Agrawal et al. 1995; Banajeh et al. 1997; Sehgal

et al. 1997; Yoon et al. 1997; Man et al. 1998; Bahwere

et al. 2004; Johnson et al. 2008; Nantanda et al. 2008;

Naheed et al. 2009); additionally, the results of a currently

unpublished study from Bangladesh (M.J. Chisti, unpub-

lished data) were included (Table 2). Nine publications

Tropical Medicine and International Health volume 14 no 10 pp 1173–1189 october 2009

M. J. Chisti et al. Pneumonia in severely malnourished children

1174 ª 2009 Blackwell Publishing Ltd

include data from Asia, six present data from Africa, while

one paper originates from South-America. All but one

report (Deivanayagam et al. 1992) exclusively included

children younger than 6 years of age.

In all studies identified in our literature search there was

a significant association between severe malnutrition and

mortality among children with pneumonia (Figure 1).

Among the seven studies reporting the relative risk (RR) of

mortality in children with severe malnutrition in compar-

ison to those without, the RR ranged from 2.9 to 121.2.

Notably, in the study reporting the latter RR (Yoon et al.

1997) confidence intervals were not provided and this

value appears high compared to the findings of other

studies. In the remaining studies 95% confidence intervals

(CIs) ranged between 2.0 and 13.1 (lower limit) and

4.1–55.7 (upper limit) (Tupasi 1985, 1988; Nathoo et al.

1993; Yoon et al. 1997; Man et al. 1998; Bahwere et al.

2004; Johnson et al. 2008). Among the nine studies

reporting the odds ratio (OR), OR ranged from 2.5 to 15.1,

with 95% CIs ranging between 1.01 and 5.4 (lower limit)

and 4.8–42.4 (upper limit) (Tupasi et al. 1990c;

Deivanayagam et al. 1992; Post et al. 1992; Agrawal et al.

1995; Banajeh et al. 1997; Sehgal et al. 1997; Nantanda

et al. 2008; Naheed et al. 2009).

Mortality in children with moderate malnutrition could

be determined in seven of the 16 studies above (Table 3). In

this group the RR of death ranged from 1.2 to 36.5. The

latter figure was reported without corresponding CI (Yoon

et al. 1997). In the remaining studies 95% CIs ranged

between 0.6 and 5.7 (lower limit) and 2.0–22.4 (upper

Table 1 Search strategy used to identify relevant publications and outcome

Database Strategy and keywords used

Initial search

results (matches)

Relevant publications

Mortality risk Aetiology Clinical signs

Medline

(keyword)

Pneumonia AND (malnutrition OR

malnourished OR undernutrition ORmarasmus OR kwashiorkor) AND

(infant OR child* OR pediatric OR

paediatric)

557 Thirteen papers Ten papers Four papers

Medline

(MeSH)

((‘Malnutrition’[Mesh] OR ‘Protein-

Energy Malnutrition’[Mesh]) AND

‘Pneumonia’[Mesh] AND (‘Child, Pre

school’[Mesh] OR ‘Infant’[Mesh]))

142 Eight papers* Two papers* One paper*

EMBASE (exp pneumonia.mp) AND

(malnutrition ⁄ OR malnourished ⁄ OR

undernutrition ⁄ OR marasmus ⁄ OR

kwashiorkor.mp)Limited to (infant <to one year> OR child

<unspecified age> OR preschool child

<1–6 years> OR school child

<7–12 years>)

207 Seven papers* Three papers* Two papers*

Web of Science Pneumonia AND (malnutrition OR

malnourished OR undernutrition OR

marasmus OR kwashiorkor) AND(infant OR child* OR pediatric OR

paediatric)

241 Seven papers* Five papers* Three papers*

Scopus Pneumonia AND (malnutrition OR

malnourished OR undernutrition ORmarasmus OR kwashiorkor) AND

(infant OR child* OR pediatric OR

paediatric)

655 Eleven papers* Six papers* Four papers*

CINAHL Pneumonia AND (malnutrition ORmalnourished OR undernutrition OR

marasmus OR kwashiorkor) AND

(infant OR child* OR pediatric ORpaediatric)

23 One paper* No papers No papers

*No new publications identified.




Tab

le2

Impact

of

sever

em

aln

utr

itio

non

mort

alit

yri

skass

oci

ate

dw

ith

pneu

monia

Ref

eren

ceC

ountr

y

Age

gro

up

(month

s)

Tota

lno.

of

pati

ents

⁄no.

of

dea

ths

Tota

lno.

of

seve

rely

maln

ouri

shed

pati

ents

⁄no.

of

dea

ths

RR

*or

OR

(CI)

Adju

sted

�⁄n

on-a

dju

sted

Sev

erit

yof

maln

utr

itio

n

Nahee

det

al.

(2009)

Bangla

des

h2–59

4155

⁄150

208

⁄27

4.6

(2.9

–7.4

)N

on-a

dju

sted

<-3

zsc

ore

of

W⁄A

Nanta

nda

etal

.(2

008)

Uganda

2–59

157

⁄24

40

⁄18

15.1

(5.4

–42.4

)A

dju

sted

for

cyanosi

s,

gru

nti

ng,

hypoxaem

ia,

pneu

monia

sever

ity,

HIV

infe

ctio

n

<-3

zsc

ore

of

W⁄A

Johnso

net

al.

(2008)

Nig

eria

0.5

–60

321

⁄34

36

⁄12

4.3

(2.3

–8.0

)N

on-a

dju

sted

Wel

lcom

ecl

ass

ifica

tion

Bahw

ere

etal

.(2

004)

Congo

0–60

793

⁄95

174

⁄42

2.8

*(2

.0–4.1

)N

on-a

dju

sted

<-3

zsc

ore

of

W⁄H

Man

etal

.(1

998)

Gam

bia

0–60

2193

⁄153

405

⁄62

3.0

*(2

.2–4.1

)�N

on-a

dju

sted

<-3

zsc

ore

of

W⁄A

Yoon

etal

.(1

998)

Phil

ippin

es0–5

9942

⁄39

–6.6

*A

dju

sted

for

co-v

aria

tes

<-3

zsc

ore

of

W⁄A

6–11

–5.1

*A

dju

sted

for

co-v

aria

tes

12–22

–121.2

Adju

sted

for

co-v

aria

tes

Banaje

het

al.

(1997)

Yem

en0–59

529

⁄52

121

⁄26

4.0

2(2

.1–7.6

)N

on-a

dju

sted

<60%

W⁄A

Seh

gal

etal

.(1

997)

India

0.5

–60

201

⁄21

–3.9

(1.0

1–9.7

)A

dju

sted

for

age,

inabilit

y

tofe

ed,

bandem

ia,

dia

rrhoea

<-3

zsc

ore

of

W⁄A

Agra

wal

etal

.(1

995)

India

2–60

127

⁄15

10

⁄35

7.0

(2.1

–22.8

)N

on-a

dju

sted

<60%

W⁄A

Nath

oo

etal

.(1

993)

Zim

babw

e1–60

704

⁄104

82

⁄–3.8

*(2

.7–5.4

)A

dju

sted

for

pneu

monia

sever

ity,

age,

dura

tion

of

cough,

pre

vio

us

hosp

ital

adm

issi

on

<60%

W⁄A

Dei

vanaya

gam

etal

.(1

992)

India

1–132

210

⁄70

–5.8

(2.2

–15.6

)A

dju

sted

for

pneu

monia

sever

ity,

gast

roen

teri

tis

and

men

ingit

is<60%

W⁄A

Post

etal

.(1

992)

Bra

zil

0–11

253

⁄127

60

⁄47

11.7

(4.2

–32.6

)A

dju

sted

for

bre

ast

feed

ing,

soci

o-e

conom

icst

atu

s

<-3

zsc

ore

of

W⁄A

Tupasi

etal

.(1

990)

Phil

ippin

es0–59

528

⁄88

246

⁄45

2.5

(1.3

–4.8

)A

dju

sted

for

concu

rren

tm

easl

es,

clin

ical

com

pli

cati

on,

sever

eil

lnes

s,gen

der

<-3

zsc

ore

of

W⁄A

Tupasi

etal

.(1

988)§

Phil

ippin

es0–59

729

⁄34

83

⁄12

27.0

*(1

3.1

–55.7

)A

dju

sted

for

AL

RI

sever

ity,

bact

erea

mia

<60%

W⁄A

Tupasi

etal

.(1

985)

Phil

ippin

es0–59

810

⁄34

321

⁄25

12.8

*A

dju

sted

for

co-v

aria

tes

<60%

W⁄A

M.J

.C

his

ti,

unpubli

shed

data

)

Bangla

des

h0–59

198

⁄24

80

⁄18

5.2

(1.2

–22.0

)A

dju

sted

for

sever

ese

psi

s,

hypoxae

mia

,lo

bar

conso

lidati

on,

met

abolic

aci

dosi

s

<-3

zsc

ore

of

W⁄A

*R

elati

veri

sk.

�Acc

ord

ing

toanaly

sis

per

form

edby

the

ori

gin

al

auth

ors

.D

iffe

rent

studie

suse

ddif

fere

nt

class

ifica

tions

for

the

sever

ity

of

pneu

monia

⁄AL

RI.

�Calc

ula

ted

from

data

pro

vid

edin

the

ori

gin

alm

anusc

ript.

§Stu

dy

use

dnati

onal

refe

rence

valu

esfo

rth

edefi

nit

ion

of

maln

utr

itio

n.

Abbre

via

tions

use

d:

AL

RI,

acu

telo

wer

resp

irato

rytr

act

infe

ctio

n;

CI,

confiden

cein

terv

al;

no.,

num

ber

;O

R,

odds

rati

o.




limit) (Tupasi et al. 1988; Post et al. 1992; Yoon et al.

1997; Man et al. 1998; Bahwere et al. 2004; Johnson et al.

2008; M.J. Chisti, unpublished data).

In addition to these original studies we identified one

review by Caulfield et al. (2004) on the causes of mortality

in malnourished children. In this paper the authors

summarised the observations from 10 studies conducted in

sub-Saharan Africa and Asia. They also present estimates

of the mortality risks based on additional information

provided by the authors of these studies and further

statistical analysis. The original reports contained

insufficient data for us to specifically calculate the

Bahwere 2004

Banajeh 1997

Sehgal 1997

Agrawal 1995

Deivanayagam 1992

Post 1992

Tupasi 1990

Chisti (unpublished)

0 10 20 3040 50 60

Odd

s ra

tioR

elat

ive

risk

Man 1998

Nathoo 1993

Tupasi 1988

Naheed 2009

Nantanda 2008

Figure 1 Summary of studies reporting

the mortality risk associated with severe

malnutrition among children with

pneumonia. Graphical representation ofstudies identified in the literature search.

Studies not providing confidence intervals

were not included in the figure. The dotted

line indicates a mortality risk [relative risk(RR) or odds ratio (OR)] equalling one.

The boxes represent RRs and ORs reported

by individual studies; the horizontal linesindicate the corresponding confidence

intervals.

Table 3 Impact of moderate malnutrition on mortality risk associated with pneumonia

Reference Country

Age group

(months)

Total no. of

patients ⁄no. of deaths

Total no. of

moderatelymalnourished

patients ⁄no. of deaths RR (CI)

Adjusted* ⁄ non-

adjusted

Severity of

moderate

malnutrition

Johnson et al. (2008) Nigeria 0.5–60 321 ⁄ 34 144 ⁄ 17 3.6 (1.2–11.7)� Non-adjusted 60–74% W ⁄ ABahwere et al. (2004) Congo 0–60 793 ⁄ 95 99 ⁄ 10 1.2 (0.6–2.4)� Non-adjusted <-2 to ‡-3 z

score of W ⁄ HMan et al. (1998) Gambia 0–60 2193 ⁄ 153 507 ⁄ 35 1.6 (1.1–2.6)� Non-adjusted <-2 to ‡-3 z

score of W ⁄ AYoon et al. (1998) Philippines 0–5 9942 ⁄ 39 – 4.1 Adjusted for co-variates <-2 to ‡-3 z

score of W ⁄ A6–11 – 3.4 Adjusted for co-variates

12–22 – 36.5 Adjusted for co-variates

Post et al. (1992) Brazil 0–11 253 ⁄ 127 48 ⁄ 26 1.5 (1.04–2.0)� Non-adjusted <-2 to ‡-3 zscore of W ⁄ A

Tupasi et al. (1988)� Philippines 0–59 729 ⁄ 34 220 ⁄ – 11.3 (5.7–22.4) Adjusted for ALRI

severity, bacteraemia

60–74% W ⁄ A

Chisti et al. (2009,

unpublished data)

Bangladesh 0–59 198 ⁄ 24 44 ⁄ 4 3.2 (0.6–16.9)� Non-adjusted <-2 to ‡-3 zscore of W ⁄ A

*According to analysis performed by the original authors. Different studies used different classifications for the severity ofpneumonia ⁄ ALRI.

�Calculated from data provided in the original manuscript comparing children with moderate malnutrition with those without moderate or

severe malnutrition.�Study used national reference values for the definition of malnutrition.

ALRI, acute lower respiratory tract infection; CI, confidence interval; no., number; OR, odds ratio; RR, relative risk.




Tab

le4

Bact

eria

lis

ola

tes

inse

ver

ely

maln

ouri

shed

childre

nw

ith

pneu

monia

Ref

eren

ceC

ountr

yA

ge

gro

up

Num

ber

of

pati

ents

wit

h

pneu

monia

Nutr

itio

nal

statu

s

Aet

iolo

gic

alagen

t,

num

ber

of

isola

tes

(per

centa

ge�

)

Sourc

eof

sam

ple

(s)

Shim

eles

&L

uls

eged

(1994)

Eth

iopia

4–60

month

s57

Kw

ashio

rkor,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

Kle

bsi

ella

pneu

monia

e10

(18%

)

Salm

onel

la(n

on-t

yphi)

3(4

%)

Stap

hyl

oco

ccus

aure

us

2(3

%)

Esc

her

ichia

coli

1(2

%)

Pse

udom

onas

spp.

1(2

%)

Blo

od

cult

ure

s

Adeg

bola

etal

.(1

994)

The

Gam

bia

3–60

month

s159*

Under

nutr

itio

n,

Kw

ashio

rkor,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

Stre

pto

cocc

us

pneu

monia

e11

(7%

)Sa

lmonel

lasp

p.

4(3

%)

Myc

obac

teri

um

tuber

culo

sis

4(3

%)

Hae

mophil

us

influen

zae

(type

b)

3(2

%)

H.

influen

zae

(non-t

ypable

)3

(2%

)S.

aure

us

1(1

%)

E.

coli

1(1

%)

K.

pneu

monia

e1

(1%

)M

ora

xel

lasp

p.

1(1

%)

Lung

asp

irat

es,

blo

od

cult

ure

s

Johnso

net

al.

(1993)

Nig

eria

0–23

month

s11

Kw

ashio

rkor,

Mara

smic

-

kw

ash

iork

or

S.pneu

monia

e2

(18%

)

S.au

reus

2(1

8%

)

K.

pneu

monia

e1

(9%

)Sa

lmonel

lasp

p.

1(9

%)

Blo

od

cult

ure

s

Fagbule

etal

.(1

993)

Nig

eria

9m

onth

s–

5yea

rs

99

Kw

ashio

rkor,

Mara

smus,

Mara

smic

-kw

ash

iork

or

Kle

bsi

ella

spp.

39

(39%

)

S.au

reus

30

(30%

)

E.

coli

9(9

%)

Lung

asp

irat

es

Fri

edla

nd

(1992)

South

Afr

ica

2–84

month

s–

§K

was

hio

rkor,

Mara

smus,

Mara

smic

-kw

ash

iork

or

S.pneu

monia

e12

H.

influen

zae

4

E.

coli

2

Blo

od

cult

ure

s

Johnso

net

al.

(1992)

Nig

eria

0.5

–59

month

s50

Kw

ashio

rkor,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

S.au

reus

10

(20%

)

K.

pneu

monia

e2

(4%

)Sa

lmonel

lasp

p.

1(2

%)

Blo

od

cult

ure

s

Ber

kow

itz

(1983)

South

Afr

ica

4–53

month

s18

Kw

ashio

rkor,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

E.

coli

2(1

1%

)

K.

pneu

monia

e2

(11%

)Sa

lmonel

lasp

p.

1(6

%)

S.pneu

monia

e1

(6%

)

Blo

od

cult

ure

s




Tab

le4

(Conti

nued

)

Ref

eren

ceC

ountr

yA

ge

gro

up

Num

ber

of

pati

ents

wit

h

pneu

monia

Nutr

itio

nal

statu

s

Aet

iolo

gic

alagen

t,

num

ber

of

isola

tes

(per

centa

ge

�)Sourc

eof

sam

ple

(s)

Dia

llo

etal

.(1

979)

Nig

eria

0–8

month

s56

Kw

ash

iork

or,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

S.pneu

monia

e10

(18%

)

S.au

reus

8(1

4%

)A

lpha-

haem

oly

tic

Stre

pto

cocc

us

6(1

1%

)

E.

coli

2(4

%)

Gro

up

ASt

repto

cocc

us

1(2

%)

Gro

up

FSt

repto

cocc

us

1(2

%)

Salm

onel

lasp

p.

1(2

%)

Lung

asp

irate

s

More

hea

det

al.

(1974)

Thail

and

10–50

month

s12

Kw

ash

iork

or,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

S.pneu

monia

e1

(8%

)H

.in

fluen

zae

1(8

%)

M.

tuber

culo

sis

1(8

%)

Lung

asp

irate

s

Hughes

etal

.(1

969)

India

0.8

–33

month

s16

Bel

ow

3rd

per

centi

lefo

r

wei

ght

and

length

H.

influen

zae

6(3

8%

)S.

pneu

monia

e2

(13%

)L

ung

asp

irate

s

Chis

tiet

al.

(2009)

Bangla

des

h0–59

month

s31

Kw

ash

iork

or,

Mara

smus,

Mara

smic

-

kw

ash

iork

or

Pse

udom

onas

spp.

2(6

%)

Aci

net

obac

ter

spp.

2(6

%)

K.

pneu

monia

e1

(3%

)

E.

coli

1(3

%)

Ente

robac

ter

spp.

1(3

%)

Stre

pto

cocc

us

spp.

1(3

%)

Blo

od

cult

ure

s

Tota

l509

Tota

lis

ola

tes:

215

Num

ber

of

isola

tes

(per

centa

ge�

):

Kle

bsi

ella

spp.

56

(26.0

%)

S.au

reus

53

(24.6

%)

S.pneu

monia

e39

(18.1

%)

E.

coli

18

(8.4

%)

H.

influen

zae

17

(7.9

%)

Salm

onel

lasp

p.

11

(5.1

%)

Str

epto

cocc

i(o

ther

)9

(4.2

%)

M.

tuber

culo

sis

5(2

.3%

)

Pse

udom

onas

spp.

3(1

.4%

)A

cinet

obac

ter

spp.

2(0

.9%

)

Mora

xel

lasp

p.

1(0

.5%

)

Ente

robac

ter

spp.

1(0

.5%

)

*Stu

dy

popula

tion

com

pri

sed

of

51%

of

chil

dre

nw

ith

oed

emato

us

maln

utr

itio

n⁄m

ara

smus

and

40%

wit

hse

ver

eunder

nutr

itio

n.

�Per

centa

ge

refe

rsto

the

pro

port

ion

of

childre

nin

whom

the

resp

ecti

ve

org

anis

mw

as

isola

ted

(out

of

the

tota

lst

udy

popula

tion).

§T

ota

lnum

ber

of

pati

ents

not

men

tioned

;per

centa

ges

wer

eth

eref

ore

not

calc

ula

ted.

�Per

centa

ge

refe

rsto

the

pro

port

ion

each

bact

eria

lorg

anis

mhas

contr

ibute

dto

the

tota

lnum

ber

of

isola

tes

(n=

215).




mortality risk associated with pneumonia. However, in all

studies combined, the RR of fatal outcome associated with

moderate and severe malnutrition and pneumonia was

estimated to be 4.03 (95% CI: 2.67–6.08) and 8.09 (95%

CI: 4.36–15.01), respectively, compared to well nourished

children.

Aetiology of pneumonia in children with severe

malnutrition

Eleven studies that evaluated the aetiology of pneumonia in

severely malnourished children and fulfilled the inclusion

criteria were identified, comprising a total of 509 children

(Table 4). A further 18 publications (Mimica et al. 1971;

Escobar et al. 1976; Silverman et al. 1977; Shann et al.

1984a; Christie et al. 1988; Gonzaga et al. 1990; Rahman

et al. 1990; Tupasi et al. 1990a,b; Johnson et al. 1993;

Aderele et al. 1995; Garcia 1996; Falade et al. 1997; Scott

& Hall 1999; Vuori-Holopainen & Peltola 2001; Bahwere

et al. 2004; Johnson et al. 2008; Nantanda et al. 2008)

reporting on mixed study populations comprised of

malnourished and well-nourished children were excluded,

as these reports did not specify which organisms were

isolated in each of the two groups. We excluded one

further study that exclusively focused on Staphylococcus

aureus infections in malnourished children (Aderele et al.

1994).

All reports included originated from Africa or Asia, and

all but one focused on children younger than 5 years of

age. The majority of studies included a relatively small

number of severely malnourished children with only five of

the studies including more than 50 patients. Six studies

used blood cultures alone to identify the causative organ-

ism (Berkowitz 1983; Friedland 1992; Johnson et al. 1992,

1993; Shimeles & Lulseged 1994; M.J. Chisti, unpublished

data), four used lung aspirates alone (Hughes et al. 1969;

Morehead et al. 1974; Diallo et al. 1979; Fagbule 1993),

and one study used a combination of blood cultures and

lung aspirates (Adegbola et al. 1994).

The findings varied considerably between individual

studies (Table 4). In all four studies originating from

Nigeria (Diallo et al. 1979; Johnson et al. 1992, 1993;

Fagbule 1993) S. aureus was a relatively common isolate,

accounting for 14–30% of the cases. In one of these studies

(Fagbule 1993) Klebsiella species were isolated in 39% of

the cases, while these organisms were significantly less

frequent in the other three studies from the same country

(Diallo et al. 1979; Johnson et al. 1992, 1993). However,

similar findings were reported by studies from Ethiopia

(Shimeles & Lulseged 1994) and South Africa (Berkowitz

1983), in which Klebsiella species were identified as the

causative agent in 18% and 11% of the cases, respectively.

Escherichia coli was another relatively common isolate in

some studies. In one South African study (Berkowitz 1983)

this organism accounted for 11% of the isolates. However,

the total number of isolates in this study was small, and

solid conclusions can therefore not be made. Strikingly,

Streptococcus pneumoniae was not isolated from any case

in three studies including a total of 206 patients (Johnson

et al. 1992; Fagbule 1993; Shimeles & Lulseged 1994) and

only accounted for a small proportion of cases in a further

four studies (Hughes et al. 1969; Morehead et al. 1974;

Berkowitz 1983; Johnson et al. 1993). Streptococcus

pneumoniae was a common isolate in only three reports,

being responsible for 7–18% of the cases (Diallo et al.

1979; Friedland 1992; Adegbola et al. 1994). Similarly,

only four of the eleven studies reported cases in whom

Haemophilus influenzae was identified as the causative

agent (Hughes et al. 1969; Morehead et al. 1974; Friedland

1992; Adegbola et al. 1994). Haemophilus influenzae

isolates were not typed in most studies.

The total number of isolates in all reports combined was

215. Overall, the most commonly isolated organisms in

severely malnourished children with pneumonia were,

in descending order: Klebsiella species, S. aureus,

S. pneumoniae, E. coli, H. influenzae and Salmonella

species (Figure 2). Other organisms, including

Acinetobacter species, Pseudomonas species, Moraxella

species and Enterobacter species were rare.

Three of the studies also investigated viral aetiology

(Hughes et al. 1969; Berkowitz 1983; Johnson et al. 1993).

However, only one detailed study of viral agents in

malnourished children with pneumonia was identified

(Adegbola et al. 1994). The authors reported that in 55 of

158 (35%) children a viral agent was identified, comprising

adenovirus (17%), respiratory syncytial virus (6%),

parainfluenza virus (6%), herpes simplex virus (6%),

Other

Salmonella spp.5% Klebsiella spp.

26%

S. pneumoniae18%

S. aureus25%

H. influenzae8%

E. coli8%

Figure 2 Bacterial isolated (n = 215) from all published reports.




Tab

le5

Sen

siti

vit

yand

spec

ifici

tyof

clin

ical

featu

res

of

pneu

monia

inch

ildre

nw

ithout

sever

em

aln

utr

itio

n

Auth

or,

yea

r,co

untr

yIn

clusi

on

crit

eria

Age

range

Num

ber

of

pati

ents

Cli

nic

al

para

met

erSen

siti

vit

y(%

)Spec

ifici

ty(%

)N

utr

itio

nal

statu

s

Fas

tbre

athin

gSham

o‘o

net

al.,

2004,

Jord

an

Cough

or

bre

athin

gdif

ficu

ltie

s0–6

yea

rs147

WH

O-d

efined

fast

bre

ath

ing*

99

98

Wel

lnouri

shed

Cher

ian

etal

.,1997,

India

Cough

0–6

yea

rs42

WH

O-d

efined

fast

bre

ath

ing*

76

–W

ell

nouri

shed

Fala

de

etal

.,1995,

The

Gam

bia

Cough

or

bre

athin

gdif

ficu

ltie

s3

month

s–5

yea

rs255

WH

O-d

efined

fast

bre

ath

ing*

79

65

Wel

lnouri

shed

Cam

pbel

let

al.,

1988,

The

Gam

bia

Cough

or

bre

athin

g

dif

ficu

ltie

s

0–5

yea

rs154

‡50

⁄min

71

98

Wel

lnouri

shed

Sin

ghi

etal

.,1994,

India

Cough

or

bre

athin

g

dif

ficu

ltie

s

2–6

month

s138

‡50

⁄min

87

95

Wel

lnouri

shed

7–11

month

s66

‡50

⁄min

83

96

12–35

month

s142

‡40

⁄min

94

99

36–60

month

s76

‡40

⁄min

72

97

Mulh

oll

and

etal

.,1992,

Phil

ippin

es&

Sw

azi

land

Cough

or

bre

athin

g

dif

ficu

ltie

s

0–5

yea

rs730

‡40

⁄min

83

(in

Manil

a)

77

(in

Sw

azi

land)

68

(in

Manil

a)

69

(in

Sw

azi

land)

Wel

lnouri

shed

‡50

⁄min

62

(in

Manil

a)

77

(in

Sw

azi

land)

92

(in

Manil

a)

69

(in

Sw

azi

land)

Pala

fox

etal

.,2000,

Mex

ico

Cough

or

rhin

orr

hoea

0–5

yea

rs110

*W

HO

-defi

ned

fast

bre

ath

ing

74

67

Wel

lnouri

shed

Gupta

etal

.,1996,

India

Cough

or

bre

athin

g

dif

ficu

ltie

s

0–5

yea

rs222

�Fast

bre

athin

g83

98

*W

ell

nouri

shed

Ches

tin

dra

win

g⁄r

etra

ctio

ns

Sham

o‘o

net

al.,

2004,

Jord

an

Cough

or

bre

athin

g

dif

ficu

ltie

s

0–6

yea

rs147

Ches

tin

dra

win

g88

77

Wel

lnouri

shed

Cher

ian

etal

.,1997,

India

Cough

0–6

yea

rs42

Subco

stal

retr

act

ion

76

–W

ell

nouri

shed

Sin

ghi

etal

.,1994,

India

Cough

or

bre

athin

g

dif

ficu

ltie

s

2–6

month

s138

Ches

tin

dra

win

g95

91

Wel

lnouri

shed

7–11

month

s66

Ches

tin

dra

win

g89

92

12–35

month

s142

Ches

tin

dra

win

g94

96

36–60

month

s76

Ches

tin

dra

win

g76

95

Pala

fox

etal

.,2000,

Mex

ico

Cough

or

rhin

orr

hoea

0–5

yea

rs110

Ches

tin

dra

win

g71

59

Wel

lnouri

shed

Gupta

etal

.,1996,

India

Cough

or

bre

athin

gdif

ficu

ltie

s0–5

yea

rs222

Ches

tin

dra

win

g62

98

�Wel

lnouri

shed

Fas

tbre

athin

gan

din

dra

win

gco

mbin

edC

her

ian

etal

.,1997,

India

Cough

0–6

yea

rs42

*W

HO

-defi

ned

fast

bre

ath

ing

plu

ssu

bco

stal

retr

act

ion

87

–W

ell

nouri

shed

Mulh

oll

and

etal

.1992,

Phil

ipin

es&

Sw

azi

land

Cough

or

bre

athin

gdif

ficu

ltie

s0–5

yea

rs730

‡50

⁄min

plu

sin

dra

win

g65

(in

Manil

a)

69

(in

Sw

azi

land)

91

(in

Manil

a)

89

(in

Sw

azi

land)

Wel

lnouri

shed




influenza A virus (5%), measles virus (3%) and influenza B

virus (1%).

Clinical features in the diagnosis of pneumonia in

malnourished children

In the early 1990s the WHO introduced guidelines for the

diagnosis of pneumonia based primarily on clinical fea-

tures. Age-specific fast breathing and chest wall indrawing

are the two main features used to diagnose pneumonia and

categorise severity in resource-limited settings.

Studies of the validity of these clinical features have been

published before (Shann et al. 1984b; Campbell et al.

1988; Cherian et al. 1988; Harari et al. 1991) and since

(Mulholland et al. 1992; Redd et al. 1994; Singhi et al.

1994; Dai et al. 1995; Taylor et al. 1995; Gupta et al.

1996; Palafox et al. 2000; Shamo’on et al. 2004; March

Mde & Sant’Anna 2005) the formulation of the WHO

case-management strategy. Some studies were conducted

specifically on children without malnutrition (Campbell

et al. 1988; Mulholland et al. 1992; Singhi et al. 1994;

Falade et al. 1995; Gupta et al. 1996; Cherian et al. 1997;

Palafox et al. 2000; Shamo’on et al. 2004); others did not

specify nutritional status of the study population (Shann

et al. 1984b; Cherian et al. 1988; Harari et al. 1991; Redd

et al. 1994; Dai et al. 1995; March Mde & Sant’Anna

2005). Only four published studies have specifically eval-

uated the validity of the WHO-recommended clinical signs

for the diagnosis of pneumonia in severely malnourished

children (Aref et al. 1992; Falade et al. 1995; Cherian et al.

1997; Wafula et al. 1998). The results are summarized in

Tables 5 and 6.

In the majority of studies in children without severe

malnutrition, both fast breathing and chest indrawing were

reported to perform well as clinical predictors of pneu-

monia. The sensitivity of both parameters was generally

close to or above 80%; the specificity was above 90% in

the majority of studies.

In children with severe malnutrition, the sensitivity of

fast breathing as a predictor of radiographically proven

pneumonia ranged from 14% to 76%, and specificity from

66% to 100%. Wafula et al. (1998) reported that the

sensitivity of fast breathing was only 37% in severely

malnourished children below the age of five years, even

with a cut-off set as low as 40 breaths per min. Falade et al.

(1995) found that lowering the WHO-recommended cut-

offs by five breaths per minute increased sensitivity slightly

from 61% to 76%, while simultaneously decreasing

specificity from 79% to 66%. For chest indrawing alone,

sensitivity was overall poor and widely variable (range:

17–71%), while specificity was high (range: 95–98%).

Only two studies reported on the specificity and sensitivityTab

le5

(Conti

nued

)

Auth

or,

yea

r,co

untr

yIn

clusi

on

crit

eria

Age

range

Num

ber

of

pati

ents

Clinic

al

para

met

erSen

siti

vit

y(%

)Spec

ifici

ty(%

)N

utr

itio

nal

statu

s

Cam

pbel

let

al.,

1988,

The

Gam

bia

Cough

or

bre

athin

gdif

ficu

ltie

s0–5

yea

rs154

‡50

⁄min

plu

sin

dra

win

g93

97

Wel

lnouri

shed

*L

ess

than

2m

onth

sof

age:

‡60

⁄min

,2–12

month

sof

age:

‡50

⁄min

,12–60

month

sof

age:

‡40

⁄min

.�I

nfa

nts

:‡5

0bre

ath

s⁄m

in,

12

to35

month

s:‡4

0bre

ath

s⁄m

in,

36–60

month

s:‡3

0bre

ath

s⁄m

in.

�Stu

dy

incl

uded

3%

sever

ely

maln

ouri

shed

chil

dre

n.

WH

O:

Worl

dH

ealt

hO

rganiz

ati

on.




Tab

le6

Sen

siti

vit

yand

spec

ifici

tyof

clin

ical

featu

res

of

pneu

monia

inse

ver

ely

maln

ouri

shed

chil

dre

n

Auth

or,

yea

r,co

untr

yIn

clusi

on

crit

eria

Tota

lst

udy

popula

tion

(no.)

Maln

ouri

shed

childre

n(n

o.)

Age

range

Cli

nic

al

para

met

er

Sen

siti

vit

y

(%)

Spec

ifici

ty

(%)

Nutr

itio

nal

statu

s

Fas

tbre

athin

gW

afu

laet

al.,

1998,

Ken

ya

Hosp

italise

dse

ver

ely

maln

ouri

shed

childre

n

107

103

0–5

yea

rs‡4

0⁄m

in37

85

Kw

ashio

rkor,

mara

smus,

and

mara

smic

-kw

ash

iork

or

‡50

⁄min

25

96

‡60

⁄min

14

100

Cher

ian

etal

.,1997,

India

Runny

nose

or

cough

of

rece

nt

onse

t,w

ith

or

wit

hout

feve

r

312

16

0–6

yea

rsW

HO

-defi

ned

fast

bre

athin

g

75

–M

ara

smus

Fala

de

etal

.,1995,

The

Gam

bia

Cough,

bre

athin

g

dif

ficu

ltie

sor

ches

tpain

742

487

3m

onth

s–

5yea

rs

WH

O-d

efined

fast

bre

athin

g

61

79

W⁄A

<70%

and

⁄or

kw

ash

iork

or,

and

mara

smic

-kw

ash

iork

or

<5

bre

aths

⁄min

bel

ow

WH

Odefi

nit

ions

76

66

Are

fet

al.,

1992,

Egypt

Hosp

italise

dse

ver

ely

maln

ouri

shed

childre

n

100

100

4m

onth

s–

3yea

rs

‡40

⁄min

73

89

Kw

ashio

rkor,

mara

smus,

and

mara

smic

-kw

ash

iork

or

‡50

⁄min

42

95

Ches

tin

dra

win

gW

afu

laet

al.,

1998,

Ken

ya

Hosp

italise

dse

ver

ely

maln

ouri

shed

childre

n

107

103

0–5

yea

rsC

hes

tin

dra

win

g35

96

Kw

ashio

rkor,

mara

smus,

and

mara

smic

-kw

ash

iork

or

Cher

ian

etal

.,1997,

India

Runny

nose

or

cough

of

rece

nt

onse

t,w

ith

or

wit

hout

feve

r

312

16

0–6

yea

rsSubco

stal

retr

act

ion

87

–M

ara

smus

Fala

de

etal

.,1995,

The

Gam

bia

Cough,

bre

athin

gdif

ficu

ltie

sor

ches

tpain

742

487

3m

onth

s–5

yea

rsC

hes

tin

dra

win

g17

98

W⁄A

<70%

and

⁄or

Kw

ashio

rkor,

and

mara

smic

-kw

ash

iork

or

Are

fet

al.,

1992,

Egypt

Hosp

italise

dse

ver

ely

maln

ouri

shed

childre

n

100

100

4m

onth

s–

3yea

rs

Ches

tin

dra

win

g71

95

Kw

ashio

rkor,

mara

smus,

and

mara

smic

-kw

ash

iork

or

Fas

tbre

athin

gan

din

dra

win

gco

mbin

edC

her

ian

etal

.,1997,

India

Runny

nose

or

cough

of

rece

nt

onse

t,w

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of both indicators combined. The study by Cherian et al.

(1997) reported a sensitivity of 87% for the combination of

WHO-defined fast breathing and subcostal retractions

(specificity not reported). Aref et al. (1992) assessed the

performance of a combination of fast breathing and chest

wall indrawing, reporting a sensitivity of 60% and 39%

when fast breathing was defined as ‡40, or alternatively

‡50 breaths ⁄ min, respectively. The specificity was reported

to be 97% and 100%, respectively.

Discussion

This review has shown that both severe and moderate

degrees of malnutrition substantially increase the risk of

death among children with pneumonia. This is important

information for clinicians. In many health facilities in

developing countries, a moderate degree of malnutrition is

so commonplace it is often not recorded as an admission

diagnosis, the increased risk of death is not appreciated,

and no additional intervention is provided. The studies

evaluating the impact of moderate malnutrition are

relatively few, and in two of seven studies the confidence

intervals included one. However, the number and

proportion of moderately malnourished children included

in the studies that provided the relevant information (six of

seven studies) was substantial (n = 1062; 23.7% of a

total of 4487 patients). Similarly, in those studies in which

the relevant patient numbers were available (13 of 16

studies), severely malnourished children represented a

considerable group (n = 1866; 16.2% of a total of 11 497

patients).

Importantly, there is evidence that there is a gradation of

mortality risk, with a significantly increased risk associated

with severe malnutrition in all studies (Figure 1). However,

the magnitude of this increase varied between studies. This

might be due to the heterogeneity between study popula-

tions and methodologies, including differences in the

proportion of children with severe malnutrition, geo-

graphical variations, and the prevalence of other important

co-morbidities such as human immunodeficiency virus

(HIV) infection. Factors contributing to the increased

mortality risk include immunodeficiency associated with

malnutrition, high rates of co-morbidities, delayed health-

seeking behaviour among families of children with mal-

nutrition, and potentially delays in diagnosis due to the

insensitivity of clinical signs. Few of the studies listed in

Tables 2 and 3 were conducted in settings with high HIV

prevalence. Notably, the study by Nathoo et al. (1993)

from Zimbabwe found that HIV-infected children pre-

senting with pneumonia were more severely malnourished

than HIV-uninfected children, and had an increased risk of

death.

A bacterial cause of pneumonia was identified in 42% of

the 509 children with severe malnutrition included in this

review. Diagnostic procedures for bacterial pneumonia

such as those used in these studies have recognised

limitations for detecting all cases of bacterial pneumonia

and therefore the actual proportion of children with

bacterial pneumonia is likely to be considerably higher

(Scott & Hall 1999). Five studies in this review used lung

aspirates and reported isolation rates ranging from 25% to

79% (Morehead et al. 1974; Fagbule 1993). Blood cultures

– used in eight of the studies – are a safer alternative.

However, in most of the reports included in this review the

yield of blood cultures was below 40% (Berkowitz 1983;

Johnson et al. 1992, 1993; Shimeles & Lulseged 1994).

The data summarised in this review suggest that the

spectrum and frequency of causative organisms may be

different in severely malnourished children. Klebsiella

species and S. aureus were the most common causative

organisms in severely malnourished children in all reports

combined. In contrast, studies of community-acquired

pneumonia in children in industrialised countries have

shown S. pneumoniae to be the most common causative

bacterial organism (McCracken 2000; Sinaniotis &

Sinaniotis 2005; Hale & Isaacs 2006). Studies of

bacterial pneumonia in developing countries predomi-

nately including children without severe malnutrition also

reported S. pneumoniae and H. influenzae as the most

common pathogens (Shann et al. 1984a; Berman 1991).

However, with the increased uptake of pneumococcal and

H. influenzae type b vaccines in developing countries, it

appears likely that these pathogens will become relatively

less important as causative agents of pneumonia (Martin

et al. 2004; Adegbola et al. 2005; CDC 2008; Morris et al.

2008; Scott & English 2008). Escherichia coli and

Salmonella species were other Gram-negative organisms

that were relatively common in severely malnourished

children with pneumonia, while infrequent in children

without severe malnutrition.

Other authors have previously expressed their concern

regarding the microbiological techniques used in some

studies of pneumonia aetiology, potentially leading to an

underestimation of more fastidious organisms such as

H. influenzae (Shann et al. 1984a). In addition, the use of

antibiotics prior to culture will also introduce a potential

bias against isolation of sensitive organisms. Antibiotics are

commonly prescribed for acute respiratory infection at

peripheral health facilities prior to referral and presenta-

tion to central hospitals and nutritional rehabilitation

units. None of the studies in this review reported testing for

antibacterial activity in the urine, the only modality to

objectively ascertain whether antibiotics had been given

previously. Further, severely malnourished children who




develop pneumonia after admission will usually be receiv-

ing a broad-spectrum antibiotic such as cotrimoxazole as

routine prophylaxis. Such practices are likely to substan-

tially reduce the likelihood of isolating pathogens sensitive

to these commonly used antibiotics, especially S. pneu-

moniae and H. influenzae (Shann et al. 1984a; Berman

1991). Furthermore, most studies included in this review

did not describe the timing of investigations and interven-

tions in detail. Often it was unclear what proportion of

cases were potentially hospital-rather than community-

acquired. It is therefore possible that in combination these

factors have considerably distorted the microbiological

data reported.

The currently recommended first-line treatment of

pneumonia in severely malnourished children is chloram-

phenicol [World Health Organization (WHO) 1991;

Ahmed et al. 1999; WHO 1999]. However, a recent, large

comparative multicentre study on very severe pneumonia,

which also included a considerable number of children

with severe malnutrition, suggests that the combination of

parenteral ampicillin and gentamicin may be superior to

chloramphenicol (Asghar et al. 2008). One potential

reason for the superiority of ampicillin and gentamicin is

that these antibiotics may be more effective against enteric

Gram-negative bacilli than chloramphenicol. Nevertheless,

it is likely that there are considerable differences between

regions regarding the extent and spectrum of antibiotic

resistance of bacterial organisms. Therefore, guidelines for

the empiric therapy of pneumonia should ideally be based

on the knowledge of local resistance patterns.

Three areas related to the aetiology of pneumonia in

severely malnourished children remain largely unexplored.

Firstly, the role of viral infections in this setting is unclear.

Few data exist on which viral agents predominate in these

children and whether the spectrum of viruses differs from

that observed in well-nourished children. Secondly, the role

of Mycobacterium tuberculosis presenting as acute lower

respiratory infection in severely malnourished children has

not been well studied, despite the likely importance in TB

endemic settings. Thirdly, the causes of pneumonia in HIV-

infected children with co-existing malnutrition have also not

been sufficiently studied (Robertson & Molyneux 2001;

Bachou et al. 2006), despite the great potential relevance to

public health in countries with high HIV prevalence.

The optimal diagnosis of pneumonia relies on a combi-

nation of history, clinical signs and chest X-ray. While

chest X-rays are generally considered to be a reliable

diagnostic tool in all forms of pneumonia, interobserver

variability in their interpretation can be substantial (Sarria

et al. 2003; Bada et al. 2007; Pauls et al. 2007).

Radiographic changes may be vague or inconclusive or

even absent despite the presence of clinical signs of

pneumonia (Doherty 1991; Hamid et al. 1996; Wafula

et al. 1998). Conversely, clinical signs of pneumonia can be

absent in the presence of radiological signs of pneumonia

(Bachur et al. 1999; Murphy et al. 2007).

Adequate laboratory and radiological services are

frequently not available in primary health care facilities

where malnourished children present with pneumonia.

Auscultation performed by primary healthcare workers in

resource-poor settings has not been sufficiently validated as

a diagnostic tool in pneumonia. Given these limitations,

the WHO recommends that the diagnosis of pneumonia

should primarily be based on visible clinical parameters,

including respiratory rate and chest wall indrawing (WHO

1990, 1991; Cashat-Cruz et al. 2005).

Data from most studies in children without malnutrition

suggest that fast breathing and chest wall indrawing have

an acceptable sensitivity and specificity. In contrast, the

predictive value of these two clinical signs for pneumonia in

severely malnourished children was generally poor sug-

gesting that a large proportion of pneumonia cases would

be missed if fast-breathing and ⁄ or chest wall indrawing are

used as the only diagnostic tool. Therefore, the recom-

mendation to use a low threshold-strategy regarding the

initiation of broad spectrum antibiotics in severely mal-

nourished children appears justified (WHO 1991, 1999).

However, findings varied considerably between studies.

These differences may be due to heterogeneity of the study

populations, large variation in sample sizes and wide

confidence intervals, and bias related to the subjectivity in

the assessment of these clinical signs.

The previous research on clinical diagnostic tools of

pneumonia in severely malnourished children has been

narrowly focused. Potentially useful diagnostic tools, such

as pulse oximetry for the detection of hypoxaemia as an

indicator of severe pneumonia, have not been sufficiently

evaluated for the diagnosis of pneumonia in children with

severe malnutrition.

Potential Limitations

Limitations of this analysis relate to the quality of the data

reported in the studies reviewed, and heterogeneity of the

populations studied. It is likely that there were children

with some degree of malnutrition in the comparison groups

(i.e. children without severe or moderate malnutrition).

Also the lack of height data limits classification as it

underreports stunting and may overestimate wasting.

Conclusions

The combination of pneumonia and malnutrition has an

enormous impact on child mortality globally. Severe




malnutrition is associated with a significant increase in

mortality risk in children with pneumonia. The currently

available data suggest that the spectrum and frequency

of causative agents of bacterial pneumonia in severely

malnourished children may differ from that observed in

children without severe malnutrition, and that a reliance

on simple clinical signs will underestimate the burden of

disease and potentially delay diagnosis. Further research

is needed to more fully investigate pneumonia aetiology

in different geographical regions, and explore the

importance of viruses and M. tuberculosis in greater detail.

Also, additional research is needed to improve the

prevention, early detection, management and outcome

of pneumonia in severely malnourished children in

resource-poor settings.

Acknowledgements

We thank Prof. AWBR Johnson for providing further data

related to his manuscript and for his constructive sugges-

tions. M.J.C is supported by an Australian Development

Scholarship provided by the Australian Agency for Inter-

national Development (AusAID). M.T is supported by a

Fellowship award by the European Society for Paediatric

Infectious Diseases (ESPID) and an International Research

Scholarship by The University of Melbourne. The Centre

for International Child Health is a WHO Collaborating

Centre for Research & Training in Child & Neonatal

Health, is supported by the RE Ross Trust (Victoria), and

is part of the AusAID Knowledge Hub for Women’s and

Children’s Health.

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Corresponding Author Trevor Duke, Centre for International Child Health, Department of Paediatrics, University of Melbourne,

Royal Children’s Hospital Melbourne, Flemington Road, Parkville, Victoria 3052, Australia. Tel.: +61 3 9345 5968; Fax: +61 3 9345

6667; E-mail: [email protected]




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Documents

royal childrens hospital

recommended clinical signs

severely malnourished children

clinical signs

malnourished children

mortality risk

child deaths

existing literature