Pneumonia in Developing Countries: Still Unresolved Problem

Dr. Pushpa Raj Sharma

Professor, Department of Child Health

Institute of Medicine

Kathmandu, Nepal

This Presentation

• Epidemiology

• Risk factors

• Aetiological agents

• Clinical syndromes

• Investigations

• Treatment

• Future implications

• 4 months old • One day history of

excessive crying• Sent home with the

diagnosis of windy colic with anti-spasmodics

• Next day:– Grunting, respiratory

distress, fever.– Admitted, IV

ceftriaxone.

A case:

Case (contd)

• Second day:– Mother felt child is

better but continues to be tachypnoeic, chest indrawing, fever persisting.

– Vancomycin added with oxygen

Case (contd)

• Third day– Severe respiratory

distress– Pus drained through water

seal drainage– Antibiotics contd.– Discharged after 2 wk.

Strepto.pneumoniae isolated

Total live births and surviving infants in South East Asia

0

200000

400000

600000

800000

1000000

1200000

1400000

1600000

1800000

1980 1990 2000 2001 2002 2003 2004

Live births

Surviving infants

Total populaliton

Measles cases

Worlds population prospects. 2004 Revision. New York, United Nations, 2005

Leading infectious causes of mortality, 2000 estimates

Source WHO

0

0.5

1

1.5

2

2.5

3

3.5

4

Pneumonia AIDS Diarrhoea TB Malaria Measles

> 5 years old

< 5 years old

Burden of Pneumonia• Population of

approximately 667 million

• Approximately 170 million infants and children, (about one-third of all the children in developing countries).

South Asia

60240

135600

57648082320

18240

,1000

Unicef (www.childinfo.org) and Hyder et al ; Extrapolated from Black et al

DISTRIBUTION OF DISEASE

16%2.4%

6.1%

6.1%

3.7%

1.2%

7.4%

56.8%

RESPIRATORY - 32

CNS - 9

CVS - 1

DIGESTIVE -5

HEMATOLOGY - 2

NEPHROLOGY - 3

RHEUMATOLOGY -2

MISCELLAN - 8

MONTH OF Feb. 2006

Hospital Admissions Then and Now

0%

10%

20%

30%

40%

50%

60%

1982 2006

Admission of ARIcases

NEPAS J 1988; 7; 1-8

Age distribution of pneumonia in hospital

0

10

20

30

40

50

60

70

80

1 -12months

1 - 5 years 5 - 10years

> 10 years

Perc

enta

ge

Burden of Disease

• ARI episodes/child/year in U5: 5-9• Pneumonia in ARI: 1:30-50 (2-3% of all

ARI).• Most of these pneumonia are bacterial in

developing countries.• Deaths in ARI are mostly due to

pneumonia• Duration of illness who died from

pneumonia: 3.5 days (Jumla Nepal)

0%

5%

10%

15%

20%

25%

30%

Bangladesh Vietnam Benin Tanzania

Poorest 20%

Richest 20%

Acute respiratory infection prevalence in under 5 children by socioeconomic status in selected countries

Based on World Bank data 2000.

Risk Factors

• In a multivariate analysis, the variables found to be most closely associated with mortality were breastfeeding, education of the father, the number of under-fives, family income and birth weight. Having a low weight-for-age was also strongly associated with mortality but the retrospective nature of the study makes this finding difficult to interpret.

Int J Epidemiol. 1989 Dec;18(4):918-25.

Risk Factors contd.

• Current and past malnutrition were associated with acute lower respiratory infection (ALRI), even after adjusting for potential confounders (odds ratio: 2.03; 95% confidence interval: 1.202.43). Decreasing malnutrition along with timely and proper treatment of ARI may improve children's health in developing countries.

Acta Paediatr. 2000 May;89(5):608-9.

A study conducted by the World Bank found that the share of brick kilns in the valley's air pollution was 28 per cent while that of domestic fuel burning was 25 per cent, cement factory 17 per cent, vehicle emission 12 per cent and road dust 9 per cent. The study estimated that dust particles in the air cause 18,863 cases of asthma and 4,847 cases of bronchitis in Kathmandu every year.

Risk Factors: Too manyRisk Factors: Too many ………….. …………..

Emissions Along The Household Fuel Ladder Smith et al.98

Indoor Air Indoor Air PollutionPollution

Risk Factors contd

Aetiology:

• N. America and Europle(nine studies /range: 43-80%)

• Aetiology of pneumonia established in 62%:– S. pneumoniae 22%– RSV

20%– H. influenzae 7%– M. pneumoniae 15%

• Africa and S. America(eight studies/ range: 32-68%)

• Aetiology of pneumonia established in 56%: – S. pneumoniae 33%– H. influenzae 21%– RSV– M. pneumoniae

Aetiology: Viruses isolated from children with ARI (n=287)

0

10

20

30

40

50

60

Feb Apr June Aug Oct

PIV

INF

RSV

MPV

ADENO

Unpublished report: CHRP; IOM

Aetiology based on lung aspiratesStudy Country Age:yrs Total C S.Pneu H.Infl S.Aur other

Schuster,1966

Chile <10 67/125 (54%)

26/125 (21%)

19/125 (15%)

15/125 (12%)

13/125 (10%)

Rozov 1974

Brazil <7 20/37 (54%)

15/37 (41%)

3/37 (8%)

1/37 (3%0

1/37 (3%)

Silverman 1977

Nigeria <8 54/88 (61%)

31/88 (35%)

9/88 (10%)

8/88 (9%)

20/88 (23%)

Shan 1984

Papua NG

<5 48/71 (68%)

27/71 (38%)

41/71 (58%)

1/71 (1%)

23/71 (32%)

Wall 1986

Gambia <9 29/51 (57%)

26/51 (51%)

12/51 (24%)

1/51 (2%)

2/51 (4%)

Ikeogu 1988

Zimbabe <11 13/40 (32%

7/40 (18%)

3/40 (8%)

4/40 (10%)

1/40 (2%)

Total 231/412 (56%)

132/312 (42%)

96/312

(31%)

29/312

(9%)

60/312

(19%)

Aetiology: Yield from cultures of lung puncture on 755 neonates who were stillborn or died in the first 72

hours of lifeBacteria Number

Escherichia coli 71

Aerobacter aerogenes 45

Streptococcus beta haemolytic 29

Pseudomonas aeruginosa 27

Streptococcus viridans 21

Staphylococcus aureus 17

Proteus vulgaris 11

Streptococcus non haemolytic (Group D) 8

Naeye RL, Dellinger WS, Blanc WA. Fetal and maternal features of antenatal bacterial infections. J Pediatr 1971;79:733–9.

Aetiology: Burden of Hib disease in Nepal(Based on Hib Rapid Assessment Tool of WHO)

Eastern region Western region Under 5 mortality rate

Annual Hib meningitis incidence*

5.4 13.7 84

Annual number of Hib meningitis cases

196 497 3,048

Annual number of Hib Meningitis death

59 50 914

Annual number of Hib pneumonia cases

980 2,486 15,241

Annual number of Hib pneumonia deaths

147 373 2,286

*per 100,000 U5s

Paper presented at the WHO dissemination seminar by Dr. Fiona Russeli et al

SAPNA:Distribution of patients with Pneumococci cultured and identified in Nepal KCH from Nov04-Feb06

05

101520253035404550

1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd 4th 1st

2nd 3rd

Dec-04 Jan Feb March April May June July Aug Sep Oct Nov Dec-05 Jan-06 Feb

Total

Pne

umoc

occi

cultu

red an

d ide

ntifie

d

020040060080010001200140016001800

CSF Culture Isolate Blood Culture Isolate Cumulative no. of Blood Collection Cumulative no. of CSF Collected

Bacterial or Viral?

• Fever > 38.50C• Respiratory rate >50/min• Chest recession• Wheeze is not a sign of

primary bacterial LRTI (except in mycoplasma)

• Other viruses may be concurrent

• Clinical and radiological signs of consolidation rather than collapse.

• Infants and young children

• Wheeze• Fever< 38.50C• Marked recession• Hyperinflation• Respiratory rate normal

or raised• Hyperinflation and patchy

collapse in 25%• Lobar collapse when

severe

LOOKS SICKLOOKS SICK

Atypical Pneumonia

• Clark J, Archives Disease Childhood 2003Mean age of children with M pneumoniae 3.5 yrs

• Block S, Paediatric Infectious Disease Journal 1995 23% of 3-4 year old children had M pneumoniae

Signs of Pneumonia

Symptoms and Signs in Pneumonia

0

10

20

30

40

50

60

70

80

90

100

Cough

Indrawing

Convulsion

Cyanosis

Abdominal pain

crepitations

Fast breathing

Comparison of Methods for the Detection of Pneumonia in Children

Method Sensitivity Specificity

Stethoscope 53% 59%

(crepetations)

Simple clinical signs 77% 58%

(fast breathing or

chest indrawing)

Note: Pneumonia diagnosis confirmed by Chest X-ray

Comparison of total leucocyte counts in different age group with clinically diagnosed

as pneumonia

0%10%20%30%40%50%60%70%80%90%

2-5 m 6-11 m 12-23m

>24 m

<15000/cmm

>15000/cmm

Diagnostic value of total leucocyte count in radiologically positive cases:

sensitivity: 33.7% and specificity: 71.8%

0% 10% 20% 30% 40%

True negative

False negative

False positive

True positive

Indications for CXR in either primary care or hospital

• • For diagnosis of child <5 years with fever of 39°C of unknown origin

• • If complication (for example, pleural effusion) suspected

• • Atypical symptoms or unresponsive to treatment

• • For follow up of children with lobar collapse or ongoing symptoms

Laboratory studies*• Complete blood count Not helpful in distinguishing

etiology• Erythrocyte sedimentation rate Not helpful in

distinguishing etiology• C-reactive protein level Not helpful in distinguishing

etiology• Gram stain and culture Helpful if specimen is

adequate• Polymerase chain reaction Helpful with Mycoplasma

and Chlamydia infections• Rapid viral antigen testing Useful if available• Serologies Not helpful in acute settings• Imaging Chest radiograph*Not helpful in distinguishing

etiology*-Not routinely recommended.

*Pediatr Infect Dis J 2002;21:592-8, 613-4.

Clinical Diagnosis

• Tachypnoea according to the usual

WHO criteria:

<2 months: 60

2-12 months: 50

!-5 years: 40

Is Co-trimoxazole still the first line of drug for IMCI

80

8 8

75

0

20

40

60

80

% Resistance

Penicillin Chloramphenicol Erythromucin cefotaxime cotrimoxazole

Name of antibiotics tested

Pneumococcal isolates and their sensitivity to different antibiotics

Antibiotics for OPD treatment in 4months to 5 year old children

• Amoxicillin, 90 mg per kg per day orally in divided doses every 8 hours for 7 to 10 days

• A 10 Kg child will need one and half tablet per dose of 250mg/ disp.tab or three tea spoon per dose of 125mg/5ml concentration.

N Engl J Med 2002;346:429-37.

Three days versus five days treatment with amoxicillin for nonsevere

community acquired pneumonia

• Three day courses of amoxicillin are as effective as five days without increasing risk of relapse or worsened disease.

• 15 mg/kg amoxicillin every 8 hourly.

Lancet, July 23, 2002 (MASCOT Group)

BMJ  2004;328:791 (3 April), (ISCAP Group)

Time for temperature to settle in the oral and IV groups

14121086420

1.0

.8

.6

.4

.2

0.0

=IV treatment --------- = oral treatment

Pro

bab

ilit

y th

at t

he

chil

d m

eets

th

e p

rim

ary

ou

tco

me

me

asu

re a

fte

r ti

me

t

Time for temperature to be less than 380C for 24 continuous hours (days)

Wellek logrank test for equivalenceP=0.0013

ITTP=0.0001

Arch Dis Child Edu Pract 2004; 29-34

0 10 20 30 40 50

0

5

10

15

20

25

0 10 20 30 40 50

0

5

10

15

20

25

30

Time to resolution of symptomsIV group

Time to resolution of symptomsoral group

Time to resolution of symptoms in days Time to resolution of symptoms in days

Nu

mb

er o

f ch

ild

ren

Nu

mb

er o

f ch

ild

ren

Median of 9 days to full recovery in both arms of the studyArch Dis Child Edu Pract 2004; 29-34

Length of stay in hospital in the IV group

IV Group - median 2.1 days (1.8-2.9) Oral Group - median 1.77 days (1-2.2) P=<0.001

Nu

mb

er o

f ch

ild

ren

Length of hospital stay in days

0 5 10 15

0

10

20

30

40

50

0 5 10 15

0

10

20

30

40

50

Length of stay in hospital in the oral group

Length of hospital stay in days

IV Group - median 2.1 days (1.8-2.9) Oral Group - median 1.77 days (1-2.2) P=<0.001

Arch Dis Child Edu Pract 2004; 29-34

Indications for admission to hospital

Older children

• Oxygen saturation <92%• Respiratory rate > 50• Difficulty breathing• Grunting• Signs of dehydration Family not able to support

at home

> 1 year 120/182 (66%) met 1 or more criteria

Thorax. 2002;57;1-24

SWT Therapy

• No RCT’s in children

• 2 prospective observational studies• Both demonstrate that IV therapy for CAP

can be successfully be decreased to 2-4 days Al-Eidan F, Journal Antimicrobial Chemotherapy 1999

Ciommo V, Journal of evaluation in clinical practice 2002

Previous studies comparing macrolides with other groups of

antibiotics

Only 1 study in children comparing beta-lactams with macrolidesDivided children clinically into “atypical” (randomised to azithromycin or erythromycin) or “classic” pneumonia (randomised to amoxicillin or azithromycin)Results – no difference between the 2 groups

Kogan et al Pediatric Pulmonology 2003

Indication of macrolide in infant

• 3 weeks to 3 months If patient is afebrile: Azithromycin, 10 mg per kg orally on day 1, then 5 mg per kg per day on days 2 through 5or

• Erythromycin, 30 to 40 mg per kg per day orally in divided doses every 6 hours for 10 days

• Admit if patient is febrile or hypoxic

The evidence did not suggest a significant reduction with vitamin A adjunctive treatment in mortality, measures of morbidity, nor an effect on the clinical course of pneumonia in children with non-measles pneumonia. However, not all studies measured all outcomes, limiting the number of studies that could be incorporate into the meta-analyses, so that there may have been a lack of statistical power to detect statistically significant differences.

Cochrane Database Syst Rev. 2005 Jul 20;(3): CD003700.

Vitamin A and pneumonia

ZINC AND PNEUMONIA• FINDINGS: In a pooled analysis of trials, zinc

supplementation reduced the incidence of pneumonia infection by 41% and daily zinc supplementation reduced the incidence of pneumonia in Delhi children ages 6 to 30 months given vitamin A

• IMPLICATION: Zinc reduces the incidence of pneumonia but zinc in combination with vitamin A may be more effective than the administration of either micronutrient alone.

Sources: 1Bhutta ZA, et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. J Pediatr. 1999 Dec;135(6):689-97. 2Bhandari N, et al. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ. 2002 Jun 8;324(7350):1358.

• Most children in developing countries with recurrent pneumonia diagnosed by WHO criteria do not have evidence of tuberculosis, HIV infection or pulmonary anomalies, but they may be more likely to have asthma, and this should be considered as an alternative diagnosis.

Pediatr Infect Dis J. 2002 Feb;21(2):108-12

Pneumonia with associated diseases

HibHib Vaccination schedule

Recommended vaccination scheduleRecommended vaccination schedule

from 2 months old: same schedule as DTPfrom 2 months old: same schedule as DTP

6, 10, 14 weeks

2- 4- 6 months 2- 4- 6 months

booster at 18 months booster at 18 months of ageof age

12-15 months12-15 months

Plotkin S, Vacccine, 3rd ed. 1999

ACIP

Recommendation

Act-HIB™

PneumococcalPneumococcal Vaccination schedule??

Recommended vaccination scheduleRecommended vaccination schedule

from 2 months old: same schedule as DTPfrom 2 months old: same schedule as DTP

2- 4- 6 months 2- 4- 6 months 12-15 months12-15 months

PCV

PPV

Recommended in addition to the PCV for certain high risk group after two years.

5

2

1 1 1 1 1

0

1

2

3

4

5

6

7

No. of Isolates

1 39 5 7F 18F 23F Nontypable

SEROTYPES

Serotype of S. pneumoniae From Nepal KCH

Immunization for common serotypes (pneumococcus)

PCV7 (Wyeth) *

PCV12 (Wyeth) * * *

PCV10 (GSK) * * * *

Areas of continuing uncertainty

• • The most useful clinical signs and symptoms that help to predict a diagnosis of pneumonia

• • Which children require a chest x ray before treatment

• • Which test to detect the causative organism will be sensitive, specific, affordable, and quick and easy to use

• • Which antibiotic should be prescribed• • Which route should be used for administering the

antibiotic prescribed• • If the intravenous route is used when should a switch to

oral antibiotics occur

• • All children under 2 years should be given the new conjugate pneumococcal vaccine routinely or not

• • Variation in individual host response to the disease: the reason.

• The aetiology of pneumonia.

• Long term follow-up and effects of pneumonia

Areas of continuing uncertainty

SAARS and now The Avian Flue!!!!!•

2  Mar  06 – Medical News Today2  Mar  06 – Medical News TodayAuthorities in Germany have today announced detection of H5N1 avian influenza in a domestic cat. The cat was found dead over the weekend on the northern island of Ruegen. Since mid-February, more than 100 wild birds have died on the island, and tests have confirmed H5N1 infection in several.

• Formation of bulla in the lung parenchyma: difficult to ventilate.

The Avian Flu