Presentation given by Dr. Marilla Lucero in the 31st Anniversary Celebration of the Research Institute for Tropical Medicine

1. Control of Acute
Respiratory Infections in
children
(or winning the battle against childhood
pneumonia)
Marilla Lucero
RITM Research Forum
April 23, 2012

2. Pathogens causing pneumonia in
children
At least 1 respiratory pathogen was identified in 79% (122 of 154) of the patients.
Pediatrics 2004 113: 701-7

3. Childhood pneumonia is the leading
cause of death in children <5 years.
156 million new
episodes worldwide
Pneumonia is responsible for ~19%
of all deaths in children < 5 years
(70% in sub-Saharan Africa and
South-East Asia)
More than 2 million deaths/year
due to pneumonia in children
<5 years
Slide
courtesy of
Rudan I. et al. Bull World Health Org. 2008, 86(5): 408-41 GSK

4. Pneumonia kills more children than
any other illness.
Pneumonia
kills more
children
than AIDS,
malaria
and
measles
combined!
Slide
courtesy of
Adapted from Figure 4 of Black RE, et al. Lancet 2010;375:1969–1987. GSK

5. Pneumonia is the number 1 KILLER
of Filipino children 1-59 mos of
age!
HIV Deaths
0% Pertussis
0%
Pneumonia Injury
Measles
Diarrhea 1%
accounts for NCD
8%
12%
Meningitis
6%
Malaria
34% of 16% 0%
deaths in
Other infections
Filipino 23% Pneumonia
children <5 yrs 34%
old.
Slide
Black RE et al for the Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national courtesy of
causes of child mortality in 2008: a systematic analysis. Lancet 2010; 375: 1969–87 GSK

6. Our children are most
vulnerable to pneumonia !
350000
37 Filipino children 1-59
300000 months of age die from
pneumonia every day
250000 (Black et al 2010,
No. of cases
Lancet)
200000
150000
100000
50000
0
< 1 yr 1-4 yrs 5-14 yrs 15-49 yrs50-64 yrs > 65 yrs
Pneumonia and LRTI
Slide
courtesy of
FHSIS NEC-DOH 2008 Report GSK

7. Slide
courtesy of
GSK

8. Etiology of pneumonia
Pathogens causing pneumonia in children
At least 1 respiratory pathogen was identified in 79% (122 of 154) of the patients.
Pediatrics 2004 113: 701-7
Slide
courtesy of
GSK

9. Table 2.1. Review of 15 studies that reported results of 1133 lung aspirates
in hospitalized children without prior antibiotic therapy
Source: Berman S.: Acute Respiratory Infections. Infect Dis Clin North Am. 1991
Bacterial Positive Number Number of studies with isolation rates of:
Pathogens isolations (%) of studies
≤10% 11%-30% 31%-50% >50%
Total pathogens 61 15 0 1 3 11
Streptococcus 27 11 0 5 4 2
pneumoniae
Haemophilus 26 11 1 8 2 0
influenzae
Staphylococcus 17 9 4 4 1 0
aureus

10. Factors to consider in the Control of
ARI in children
Disease Burden – Developing Countries
Risk Factors – Lack of immunization,
Malnutrition etc
Etiology – Streptococcus pneumoniae,
Haemophilus influenzae

11. ARI study group (Circa 1981-1990)
Main goal: To conduct studies that would help DOH programs for
the control of childhood pneumonia
1. Etiology studies: Hospital-based studies on etiology
2. Risk Factors: Community-based studies on child-care
practices
Risk Factors for Morbidity
3. Treatment: Clinical trials on antibiotics against
pneumonia
4. Diagnosis of pneumonia in the Field: Study of signs and
symptoms of childhood pneumonia
5. Field trial of the WHO ARI control program

13. Assumptions supporting the early development
of WHO-ARI Control Program
1. High mortality from ARI – due to
a. pneumonia (70% of deaths)
b. vaccine-preventable ARI: diphtheria, pertussis
(whooping cough), and measles (30% of deaths).

14. 2. High mortality from pneumonia was due to a high incidence
of bacterial pneumonia
a. Streptococcus pneumoniae and Haemophilus influenzae
b. Sp and Hi - sensitive to co-trimoxazole, penicillin, amoxicillin,
chloramphenicol
c. pneumonia diagnosis and severity - determined by simple means
d. mothers could be trained to recognize the danger signs of
pneumonia
e. community health workers could be trained to diagnose and treat
pneumonia correctly.
3. Programs based on the treatment of pneumonia with
antimicrobial agents would reduce mortality from pneumonia
in developing countries

15. Tupasi TE, Lucero MG, Magdangal DM et al. Reviews Inf Dis 1990

17. WHO – PNEUMONIA CONTROL PROGRAM:
The ARI Bohol study 1983-1990

20. Table 5.8: Cause-specific age-standardized mortality rates for children 0-4
years by time and area, and efficacy index E (%)
Cause of death Death rate Efficacy of 2-sided
(per 1000 person-years) intervention (%) p value
(E)
All causes NIA IA
Years 1-4 14.95 17.08 22.50 0.009
Years 5-6 11.96 10.59
Pneumonia
Years 1-4 3.96 5.08 49.76 0.001
Years 5-6 3.15 2.03
Spin -off
Years 1-4 6.92 7.54 27.98 0.039
Years 5-6 5.9 4.63
Non-target
Years 1-4 4.06 4.46 -22.52 0.401
Years 5-6 2.92 3.93

24. Polysaccharide vaccine ----
Immunogenic only in adults
Polysaccharide vaccine conjugated to
protein carrier = Immunogenic in infants
Hib conjugate vaccine proven to be
efficacious in reducing Hib invasive
disease

26. CONCLUSION: THIS HEPTAVALENT PNEUMOCOCAL CONJUGATE
VACCINE APPEARS TO BE HIGHLY EFFECTIVE IN PREVENTING INVASIVE
DISEASE IN YOUNG CHILDREN.

28. Efficacy of an 11-valent pneumococcal conjugate
vaccine (11PCV) in preventing
radiographically confirmed pneumonia in children < 2
years of age:
a randomized, double-blind, placebo-controlled trial
in the Philippines
Sponsor: ARIVAC Consortium
SEROTYPES
11-valent pneumococcal conjugate vaccine (11PCV) or
saline placebo (randomized 1:1)
• 11PCV with serotypes:
1, 3, 5, 7F, 4, 6B, 9V, 14, 18C, 19F, 23F

29. Endpoint 11PCV Placebo Vaccine
Efficacy
N Rate N Rate
Radiographic 93 1040 120 1349 22.9
pneumonia (-1.1;41.2)
WHO clinical 0.1
pneumonia 934 10,448 930 10,454 (-9.4;8.7)

30. Cochrane Database of Systematic Reviews 2009, Issue 4.
Art. No.: CD004977. DOI: 10.1002/14651858.CD004977.pub2.
Lucero M, Dulalia V, Nillos L et al.
META-ANALYSIS OF PNEUMOCOCCAL CONJUGATE
VACCINES

31. POOLED VACCINE EFFICACY AGAINST INVASIVE PNEUMOCOCCAL DISEASE WAS 80%.
POOLED VACCINE EFFICACY AGAINST RADIOGRAPHIC PNEUMONIA WAS 19%.
POOLED VACCINE EFFICACY AGAINST WHO-Defined Clinical PNEUMONIA WAS 6%.

32. ARI study group (Circa 1981-1990)
Main goal: To conduct studies that would help DOH programs for
the control of childhood pneumonia
1. Etiology studies: Hospital-based studies on etiology
2. Risk Factors: Community-based studies on child-care
practices
Risk Factors for Morbidity
3. Treatment: Clinical trials on antibiotics against
pneumonia
4. Diagnosis of pneumonia in the Field: Study of signs and
symptoms of childhood pneumonia
5. Field trial of the WHO ARI control program

33. ARI study group (Circa 1991- 2000)
Main goal: To conduct studies that would help the DOH in the
control of childhood pneumonia
1. Hib conjugate vaccine immunogenicity studies
2. Pneumococcal conjugate vaccine immunogenicity studies
3. Pneumococcal conjugate vaccine trial

34. ARI study group (Circa 2001-2012)
Main goal: To conduct studies that would help the DOH in the
control of childhood pneumonia
1. Influenza studies (Surveillance, Burden of Disease)
2. Etiology studies on childhood pneumonia (RITM-TOHOKU)
3. Monitoring of novel viruses (RITM-TOHOKU)

35. RITM-TOHOKU STUDY ON VIRAL AGENTS IN CHILDHOOD
PNEUMONIA, TACLOBAN, PHILIPPINES 2007-2011

37. ARI study group (2001-2012 and beyond – FUTURE STUDIES)
Main goal: To conduct studies that would help the DOH in the
control of childhood pneumonia
1. Influenza studies (Surveillance, Burden of Disease)
2. Etiology studies on childhood pneumonia (RITM-TOHOKU)
3. Monitoring of novel viruses (RITM-TOHOKU)
4. Etiology studies – adult pneumonia (RITM-TOHOKU)
5. Other vaccine studies (RSV, Other PCVs?)
6. Monitoring of pneumococcal strains from IPD cases
7. MICROBIOME STUDIES

38. Invasive Pneumococcal Disease (IPD) Caused by Nonvaccine Serotypes
Among Alaska Native Children With High Levels of 7-Valent
Pneumococcal Conjugate Vaccine Coverage. Singleton, Henessy, Bulkow et
al.
REPLACEMENT PHENOMENON

39. ARI study group (2001-2012 and beyond – FUTURE STUDIES)
Main goal: To conduct studies that would help the DOH in the
control of childhood pneumonia
1. Influenza studies (Surveillance, Burden of Disease)
2. Etiology studies on childhood pneumonia (RITM-TOHOKU)
3. Monitoring of novel viruses (RITM-TOHOKU)
4. Etiology studies – adult pneumonia (RITM-TOHOKU)
5. Other vaccine studies (RSV, Other PCVs?)
6. Monitoring of pneumococcal strains from IPD cases
7. MICROBIOME STUDIES

40. VACCINATION AND THE PEDIATRIC MICROBIOME (2012-2014)
Collaborative study with Jay Craig Venter Institute (JCVI), Maryland
Exploratory study to define the nasopharyngeal (NP) microbiome
(collection of microbes) from birth to 12 months of age using
metagenomic DNA sequencing techiniques
What organisms comprise the microbiome? Abundances? Relative
abundance over time.
Does microbiome structure change with infants’ health?
Change of microbiome after vaccination with PCV?
Findings could lead to development of tool to identify children at risk
for disease because of an altered NP microbiome.
THANK YOU!