Overview of the Disease Burden of Invasive Pneumococcal Disease in Asia

L.C. Bravoa*, the members of the Asian Strategic Alliance for Pneumococcal Disease Prevention

(ASAP) Working Groupb

a University of the Philippines Manila, Manila, Philippines

b Asian Strategic Alliance for Pneumococcal Disease Prevention (ASAP) Working Group—Brunei:

Hajah Roslin Haji Sharbawi, Elizabeth S.F. Chong; Hong Kong: Chok-Wan Chan, Kenneth K.C. Lee;

Macau: Kin-Man Lui; India: Nitin Shah, Shyam Kukreja; Indonesia: Cissy Kartasasmita, Sri Rezeki

Hadinegoro; Korea: Hoan-Jong Lee; Malaysia: Musa bin Mohd Nordin, Nik Khairulddin Nik Yusoff,

Zulkifli Ismail; Pakistan: Iqbal Ahmad Memon, Sajid Maqbool, Zulfiqar A. Bhutta; Philippines:

Anna Lisa Ong-Lim, Cecilia C. Maramba; Singapore: Chia-Yin Chong, Daniel Y.T. Goh; Sri Lanka:

Sanath P. Lamabadusuriya; Taiwan: Cheng-Hsun Chiu, Ping-Ing Lee; Thailand: Somsak Lolekha,

Usa Thisyakorn

This article was prepared based on the members’ presentations at the third meeting of

the Asian Strategic Alliance for Pneumococcal Disease Prevention (ASAP) on 15 December 2007

in Seoul, Korea. This meeting was sponsored by an educational grant from Wyeth. This article

was also presented as an abstract at the Asian Congress of Pediatric Infectious Diseases,

Surabaya, Indonesia, 2–5 July 2008 (Poster presentation number P-PNE-001).

* Corresponding author at: National Institute of Health, University of the Philippines,

Manila, 623 Pedro Gil Street, Ermita 1000 Manila, Philippines. Tel.: +632 5269167; fax:

+632 5262397

Email address: lulucbravo@yahoo.com (L.C. Bravo)

ABSTRACT

This paper represents a collaborative effort by the Asian Strategic Alliance for Pneumococcal

Disease Prevention (ASAP) Working Group to collate data on the disease burden due to invasive

pneumococcal disease (IPD) in participating Asian countries and territories; namely, Brunei,

Hong Kong, India, Indonesia, Korea, Macau, Malaysia, Pakistan, the Philippines, Singapore, Sri

Lanka, Taiwan and Thailand. A review of both published and unpublished data revealed that the

incidence of IPD in some countries is well documented by way of large, long-duration studies,

while in other countries, much of the available data have been extrapolated from international

studies or have come from small population studies of limited geographical coverage. This paper

confirms that data regarding the incidence of IPD in Asia are grossly lacking and reinforces the

need for urgent and more substantial studies.

Running title: Pneumococcal disease in Asia

Keywords: Asia, bacteremia, cost effectiveness, epidemiology, immunization, invasive

pneumococcal disease, pneumonia, meningitis, serotypes

Introduction

Pneumococcal disease can be regarded as a serious global problem based on the

number of deaths attributed to it. The World Health Organization (WHO) estimates that 1.6

million die every year from the disease, 0.7 to 1 million of which are children aged < 5 years [1];

while community-based studies of invasive pneumococcal disease (IPD) and vaccine efficacy

trials reveal that approximately 814,000 pneumococcal deaths occur each year in children aged

< 5 years in developing countries, most of them in Asia and Africa [2].

The Asian region is unique in that, while it consists of developed and newly emerging

markets, it is still home to 600 million children living in absolute poverty and large numbers of

children < 5 years old dying from malnutrition, diarrhea and acute respiratory infections (ARIs)—

mostly pneumonia, malaria and vaccine-preventable diseases [3]. Reducing healthcare

inequalities remains a challenge for the region, and substantial differences in health coverage

may exist between the poorest and wealthiest groups within a single country; for example, in

India and the Philippines, the wealthiest people are three times more likely to receive care than

the poorest [4].

Health authorities in the region have yet to act on the need to protect all young children,

regardless of social background, against the life-threatening pneumococcal disease. Although

pharmacological interventions such as antibiotics and vaccines are available for treatment and

prevention, policymakers cite the lack of data on pneumococcal disease as reason for indecision

[5,6].While the United Nations Children’s Fund (UNICEF) and WHO report provides

epidemiological evidence on the burden of pneumonia in children (Table 1) [7], information on

pathogen-specific etiology is lacking. The number of published data from the region to confirm

the impact of IPD and specific clinical presentations is also limited.

For this reason, many Asian countries still have not included pneumococcal vaccination

in their national immunization programs even though the rationale for vaccination has long been

supported by studies. In light of the additional benefits of herd immunity and with the threat of

widespread antibiotic resistance, the inclusion of this vaccine can become a cost-effective

intervention with long-term benefits [8,9].

1. Collation of available data on pneumococcal disease in Asia

The Asian Strategic Alliance for Pneumococcal Disease Prevention (ASAP) was organized

in 2007 to raise awareness of the morbidity and mortality caused by pneumococcal disease and

of the importance of preventing the disease through surveillance and advocacy. It is composed

of healthcare professionals from 13 Asian countries and territories; namely, Brunei, Hong Kong,

India, Indonesia, Korea, Macau, Malaysia, Pakistan, the Philippines, Singapore, Sri Lanka, Taiwan

and Thailand.

This paper represents the collaborative effort of ASAP members to gather local-level

data on pneumococcal disease, both published and unpublished, taking into account the

incidences of pneumococcal disease and its clinical manifestations (meningitis, pneumonia, otitis

media and septicemia) stratified according to age, mortality and case fatality rates, serotype

distribution and antibiotic resistance. With this collection of data, ASAP will then be able to

determine the importance of pneumococcal disease in the region and generate a regional

consensus on essential issues. This information will also provide an impetus for health officials

and policymakers to create strategies to manage anticipated cases and, more importantly, to

prevent disease. Summaries of data gathered by ASAP members are presented in this paper and

individual study objectives are outlined in Table 2.

2. Summaries of data from ASAP countries and territories

3.1. Brunei

The WHO reports that the mortality rate for < 5-year-olds in Brunei is 9/1000 live births.

Pneumonia and related meningitis, sepsis/septicemia and other infections are the highest causes

of neonatal deaths, contributing 7% to total deaths [10]. Records from Raja Isteri Pengiran Anak

Saleha (RIPAS) hospital, the main referral hospital in Brunei, indicate that most pneumococcal-

positive samples in children < 12 years old came from those with respiratory tract infections (268

out of the total 316 samples; RIPAS hospital, unpublished data, 2007).

3.2. Hong Kong

3.2.1. Epidemiology

A retrospective, population-based study, which included records dated between 1995

and 2004, showed that the annual incidence of IPD requiring hospitalization in children aged

≤ 2 years old was 18.3/100,000 [11]. The incidence rate was 15.6/100,000 in children aged

≤ 5 years old. More recent data from 2000 to 2005 showed that the hospitalization rate with IPD

for children ≤ 2 years old was 23.7/100,000 person-years [12] and 16.1/100,000 person-years in

children ≤ 5 years old. Based on laboratory results from the Hospital Authority in Hong Kong, the

average annual incidences among children aged < 2 years and adults aged > 65 years old were

both 7.7/100,000 (95% CI 2–13/100,000) from 2000 to 2004 [13].

2.2.2. Serotype distribution

A study conducted by Ho et al. in 79 daycare centers and kindergartens in Hong Kong

(December 1999–June 2000) determined the serotype distribution of Streptococcus pneumoniae

from both nasopharyngeal and invasive isolates in children aged < 6 years [14]. The most

common carriage serotypes found were similar to the invasive isolates—that is, 6B, 14, 19F and

23F. Furthermore, the serotypes in the 7-valent pneumococcal conjugate vaccine (PCV7)

accounted for 89.7% and 66.1% of the carriage and invasive isolates, respectively. The serotypes

in PCV7—4, 6B, 9V, 14, 18C, 19F and 23F—accounted for 89.8% of all serotypes found in invasive

isolates taken from children (age ≤ 5 years) in five Hong Kong hospitals between 1995 and 2001

[14,15].

3.2.3. Antibiotic resistance

As of 2000, the overall prevalence rate of penicillin resistance among pneumococci was

49% in Hong Kong [14]. Retrospective data gathered from patients aged ≤ 2 and ≥ 65 years

admitted to five Hong Kong hospitals with pneumococcal bacteremia between 1995 and 2001

determined that 37.4% of S. pneumoniae isolates were nonsusceptible to penicillin and 63.4%

were resistant to clarithromycin [15]. In the same study, 3.8% of S. pneumoniae isolates were

resistant to levofloxacin.

Of 383 nasopharyngeal isolates from the 79 centers in the Ho et al. study, 42.0% were

penicillin sensitive, 32.1% were intermediate and 26.1% were resistant [14]. The isolates had

high rates of resistance to cefotaxime and erythromycin at 42.8% and 77.0%, respectively. The

same study included 88 pneumococci isolated from children with IPD who were hospitalized in

five Hong Kong hospitals [14]. Isolates were obtained from the blood, cerebrospinal fluid or

brain tissue of children 0–6 years old. Among this group of isolates, 52.3% were penicillin

sensitive, 31.8% were intermediate and 15.9% were resistant. The rates of resistance to

cefotaxime and erythromycin were 33.0% and 85.2%, respectively.

More recent data from 519 S. pneumoniae isolates from nasopharyngeal aspirates of

3157 children (age < 16 years old) in Hong Kong in 2005 and 2006 were included in a surveillance

study [16]. Results showed that 64.9% and 37.2% of the isolates were not susceptible to

penicillin and cefotaxime, respectively.

3.3. India

3.3.1. Epidemiology

The Invasive Bacterial Infection Surveillance (IBIS) group and the International Clinical

Epidemiology Network (INCLEN) conducted a prospective multicenter hospital-based

surveillance study in India and reported that, of the 314 patients identified as having IPD, 32.8%

of cases occurred in children aged ≤ 5 years, including 22.6% in children ≤ 2 years and 10.2% in

2–5-year-olds [17]. Of the 304 IPD patients whose clinical outcome was known, the case fatality

rate (CFR) was 22% in children aged < 2 years, 10% in 2–12-year-olds, 26% in 13–50-year-olds

and 28% in adults > 50 years. Meningitis was found to cause approximately one-third (34%) of

the fatalities, while septicemia caused 21% and pneumonia 19%.

The IBIS group extended to other South Asian countries and established surveillance

systems in Nepal and Sri Lanka through the South Asian Pneumococcal Alliance (SAPNA) project

[18]. A semi-annual technical report from SAPNA revealed that there were 1273 enrollees to the

study from October 2006 to March 2007. S. pneumoniae has been identified as pathogen in 28 of

the participants, and 11 of them are from India [19].

3.3.2 Serotype distribution

A prospective observational study by Jebaraj et al. found 6, 19, 15, 14 and 23 to be the

most common serotypes isolated from the nasopharynges of 100 infants attending a well baby

clinic in Vellore. These serotypes comprise 55% of the pneumococcal isolates found by the study

[20]. While the IBIS–INCLEN study identified more than 25 serotypes in the total population, the

most common serotypes in children aged < 5 years were 6, 1, 19, 14 and 4 [17]. The more recent

study by the SAPNA group reported the most prevalent serotypes to be 6B, 20, 16 and 1 [19].

3.3.3. Antibiotic resistance

The IBIS–INCLEN group also performed antimicrobial susceptibility testing on 307 S.

pneumoniae isolates, finding that intermediate resistance to penicillin was noted in only 1.3% of

the isolates tested, but that resistance to cotrimoxazole and chloramphenicol was seen 56% and

17% of the isolates, respectively [17]. The Asian Network for Surveillance of Resistant Pathogens

(ANSORP), a multicountry collaborative group for antimicrobial research, has observed that India

still has the lowest pneumococcal resistance to penicillin and erythromycin in the region [21,22].

3.4 Indonesia

3.4.1. Epidemiology

Records obtained from six hospitals in Jakarta, Surabaya, Bandung, Bali, Padang, and

Makassar from January to December 2006 revealed that of the 1796 children aged < 5 years

admitted due to IPD, 1425 (79.3%) had pneumonia, 283 (15.8%) had sepsis (bacteremia) and 88

(4.9%) had meningitis. The CFR was 29.2% and 21.0% in infants aged 1–11 months and 12–23

months, respectively, while the overall CFR attributable to IPD was 23.5% (Hadinegoro, in

press),[23,24].

A hospital-based study involving pediatric patients with acute purulent meningitis

showed that in 155 cases confirmed by cerebrospinal fluid (CSF) culture, the most common

etiological agents were Salmonella sp. (12.9%), Acinetobacter sp. (7.1%), S. pneumoniae (5.8%)

and Hemophilus influenzae (5.2%) [25], whereas a more recent study showed that of the 177

positive nasopharyngeal specimens from 698 patients between 2 and 5 years of age with

nonsevere pneumonia, 120 (67.8%) had S. pneumoniae, 21 (11.9%) had Staphylococcus

epidermidis and another 21 (11.9%) had alpha-streptococcus [26].

A pneumococcal nasopharyngeal carriage study in neonates showed that 38.9% of the

108 assessed had positive isolates: 0.9% in newborns; 2.8% at 2, 4, 6 and 8 weeks; 9.3% at

10 weeks; 12.0% at 13 weeks; and 13.9% at 15 weeks. The most common sources of

transmission were siblings (57.1%) and mothers (11.9%) [27].

Records of Sanglah Hospital in Bali identified 25 cases of meningitis between 2000 and

2005; three of these patients died. Hydrocephalus, hemiplegia, monoparesis, deafness and

epilepsy were found to be the most common sequelae [28].

3.4.2. Serotype distribution and antibiotic resistance

A pneumococcal carriage study conducted in Lombok involving 484 healthy children

aged 0–25 months found pneumococcal isolates in 221 (48%) children. The most common

serogroups were 6, 23, 15, 33 and 12. Sixty-one percent of the isolates found are covered by the

current PCV7. Susceptibility testing revealed that 2.2% of the 221 specimens were

nonsusceptible to penicillin and 0% were nonsusceptible to cefotaxime [29].

3.5. Republic of Korea

3.5.1. Epidemiology

While there are no published data on the incidence rate of pneumococcal disease in

Korea, a survey of 13 hospitals found that S. pneumoniae (30%) is the most common invasive

pathogen among Korean children, especially among the immunocompromised and patients aged

3 months to 5 years (Lee HJ, unpublished data, 2007). In the same survey, the most common

clinical features of IPD in immunocompetent children were meningitis (39%) and bacteremic

pneumonia at 35%, whereas, in immunocompromised children, the most common clinical

features were bacteremia without focus (48%) and meningitis (18%).

Among the immunocompetent children, IPD was most common in children aged

< 2 years, with incidence declining as age increased. In the immunocompromised children,

however, IPD episodes did not decrease with increasing age (Fig. 1). The CFR for children with

IPD was 12% (27/222): 13% (19/144) for immunocompetent children and 10% (8/78) for

immunocompromised children (Lee HJ, unpublished data, 2007).

3.5.2. Serotype distribution

A study evaluating serotype distribution among isolates from various clinical specimens

at Seoul National University Children’s Hospital from 1991 to 2006 showed that the most

common serotypes were 19F (21.0%), 23F (17.8%), 19A (10.8%), 6B (9.3%), 6A (8.0%), 14 (7.4%)

and 9V (4.5%) [30]. Between 1991 and 2003, it was observed that the proportion of 19A isolates

increased from 0 to 26% while 19F decreased during the same period. From 2001 to 2003, just

prior to the introduction of the pneumococcal vaccine, serotypes covered by the vaccine

accounted for 57% of isolates while vaccine-related serotypes accounted for another 24%.

Although the serotype distribution of isolates changed after the introduction of pneumococcal

vaccine in 2004, similar trends were observed, i.e. the proportion of serotypes covered by the

vaccine were decreasing and the increase of 19A became more evident from 2004 to 2006 [30].

3.5.3. Antibiotic resistance

The studies conducted by ANSORP showed that S. pneumoniae isolates from Korea have

a consistently high rate of penicillin resistance (1996–1997: 55.4%; 1998–1999: 31.3%; 2000–

2001: 54.8%) [21] and erythromycin resistance (1996–1997: 74.6%; 1998–2001: 85.1%) [22].

3.6. Macau

Macau is a small city south of China and Hong Kong with only two hospitals and no

serotyping facility. A review of records dated 2001–2007 from the public acute care hospital

Centro Hospitalar Conde Säo Januário found only one IPD case—a pneumococcal meningitis case

(Kin-Man Lui, personal communication, 2007). PCVs are provided free by the government for

high-risk groups: premature infants and those with complex heart diseases.

3.7. Malaysia

3.7.1. Epidemiology

Published studies on pneumococcal infection in Malaysia have shown pneumonia to be

its most common clinical presentation, with morbidity and mortality being highest in children

aged < 2 years [31,32]. A more recent hospital-based study confirmed this finding by showing

that majority of the cases occurred in patients aged < 2 years and that definite pneumonia,

probable pneumonia, meningitis, bacteremia without focus and septic arthritis were the most

common types of IPD in Malaysian patients. Those with meningitis had the highest rate of long-

term complications [33]. Earlier studies on childhood meningitis in Malaysia showed that most

cases occurred in those < 5 years of age and that H. influenzae and S. pneumoniae were the most

common causative organisms [34,35,36]. As the H. influenzae type b (Hib) vaccine was

incorporated in the country’s national immunization program in 2002, it is presumed that S.

pneumoniae is now the leading cause of meningitis in Malaysia.

However, there are no published data to date on the incidence of invasive

pneumococcal infection post-Hib vaccination except for a paper by Suhaimi, which reported on a

single-center retrospective study conducted at Queen Elizabeth Hospital in Kota Kinabalu

evaluating the incidence of childhood meningitis both before the introduction of Hib vaccine

(January 1999–December 2001) and afterwards (January 2004–December 2006). This study

showed that the incidence of pneumococcal meningitis increased following the introduction of

Hib vaccination (3.7 vs. 8.6/100,000 per year in children aged < 5 years) [37]. Larger studies

involving more centers in Malaysia are needed to confirm this finding.

3.7.2. Serotype distribution

Several studies have documented the serotype distribution in Malaysia with differing

results. Rohani et al. reported that the most common serotypes that cause IPD in children aged

< 2 years were 1, 5, 23B, 2, 8, 14, 20, 6A, 12A, 19B and 23B [32]. Cheong et al. looked at

pneumococcal serotypes isolated from children aged < 5 years presenting with ARI in three

centers in Malaysia and the most common serotypes isolated were 19F, 6A and 23F [38]. A 4-

year prospective study was also undertaken by Jamal and colleagues in Kuala Lumpur and, out of

43 isolates in children aged < 12 years with pneumococcal disease, the most common serotypes

were 6A (25.6%), 6B (16.3%) 14 (18.6%) and 19A (18.6%) [31]. Currently, a prospective

multicenter study is underway to evaluate IPD incidence and serotype prevalence in hospitalized

children (N.K. Nik Yusoff, personal communication, 2008).

3.7.3. Antibiotic resistance

The ANSORP study showed that pneumococcal disease serotypes prevalent in Malaysia

have a considerable degree of resistance to penicillin (29.5%) and erythromycin (34.1%) [21].

3.8. Pakistan

3.8.1. Epidemiology

A previous systematic review of all national published studies by Bhutta revealed that

pneumonia and meningitis account for over 85,000 childhood deaths and cases of disability in

infancy in Pakistan and that 33% of these are attributable to infections caused by S. pneumoniae

and H. influenzae [39]. These results have recently been updated and indicate that the

proportion of meningitis cases attributable to S. pneumoniae and H. influenzae may be higher in

recent studies (Bhutta et al. unpublished observations, 2008). The 2007 Pakistan Demographic

and Health Survey indicates that 25.7% and 9.1% of all postneonatal child deaths in Pakistan

were related to pneumonia and meningitis, respectively [40]. These figures are remarkably

similar to the estimates obtained earlier by Bhutta [39].

A number of community- and hospital-based studies provide an overview of the etiology

of ARIs among children < 5 years old in Pakistan. In a census conducted in four periurban

communities, Nizami et al. isolated S. pneumoniae in 3.7% of a total of 791 oropharyngeal swab

cultures and calculated the S. pneumoniae burden in these communities to be 3.0/1000 children

[41]. Using the same technique, Rehman and colleagues identified 139 positive cultures from

500 pediatric patients at Bahawal Victoria Hospital in Bahawalpur; 36 of the 139 (25.9%) were S.

pneumoniae positive [42]. Ghafoor et al. meanwhile reported that, of the 1331 blood specimens

included in their study, H. influenzae was the leading bacterial isolate (11% of the cases)

followed by S. pneumoniae (10%) [43].

3.8.2. Serotype distribution and antibiotic resistance

Serotypes 6, 9, 15, 16, 19 and 31 comprised 60% of the S. pneumoniae isolates found in

the study by Ghafoor et al. [43]. This finding was confirmed by Mastro and colleagues who

reported a year later that the most common serotypes detected were 19F, 31, 16, 19A, 9V, 15C

and 6A. They also tested 87 strains of S. pneumoniae isolates for antimicrobial susceptibility and

found that 97% had decreased susceptibility to at least one antimicrobial agent: 31% were fully

resistant to cotrimoxazole, 39% were resistant to chloramphenicol and 9% were moderately

resistant to penicillin [44]. Recent data on antimicrobial sensitivity patterns of respiratory

isolates of S. pneumoniae and H. influenzae also confirm increasing resistance to cotrimoxazole

and penicillin.

3.9. Philippines

3.9.1. Epidemiology

Statistics from the Philippines’ Department of Health (DOH) in 2000 attributed child

mortality rates of 37.8/100,000 to pneumonia, 4.7/100,000 to meningitis and 4.5/100,000 to

septicemia, although the statistics do not describe pathogen-specific causality [45].

A few hospital- and community-based studies have examined the etiology of infections

in children aged < 5 years with pneumonia, bacteremia and meningitis. In a study by Lupisan et

al., S. pneumoniae was found to be the leading isolate among blood cultures (1.3% of the total

from an overall culture positivity of 8.9%) [46]; while Capeding et al. documented S. pneumoniae

in 3.7% of acute lower respiratory tract infections and in 35.0% of patients with confirmed

bacteremia [47].

Data on the frequency distribution of bacterial meningitis from three tertiary hospitals in

Metro Manila have shown that S. pneumoniae and Hib are the most prevalent etiological agents

(Philippine General Hospital; Philippine Children’s Medical Center; University of Santo Tomas

Hospital, unpublished data, 2002–2006). The mortality rate in patients positive for S.

pneumoniae was 23.5% compared to 5.0% for patients with Hib.

3.9.2. Serotype coverage and antibiotic resistance

A study of nasopharyngeal samples from Filipino children with ARI showed serotypes 6,

14, 19 and 23 to be the most common [48], while in a recent study among children with IPD, the

most common serotypes were 6, 18, 14 and 5 [49]. Pneumococcal antibiotic resistance is low in

the Philippines at 1% for penicillin, 5% for chloramphenicol and 18% for cotrimoxazole [50].

3.10. Singapore

3.10.1. Epidemiology

A retrospective review of more than 4000 hospital records from 1995 to 2004 in

Singapore indicated that children aged < 5 years and adults aged ≥ 65 years were most

susceptible to pneumococcal disease, with hospitalization rates of 38.4/100,00 and

56.4/100,000, respectively [51]. Pneumococcal pneumonia was the most common disease

manifestation (97.9%), followed by septicemia (1.1%) and meningitis (0.7%). The CFR for all age

groups in this study was 3.2%. Cause of death was primarily attributable to pneumococcal

meningitis, followed by septicemia and pneumococcal peritonitis, and pneumococcal

pneumonia.

A retrospective survey among all pneumococcal-positive patients (n=146; aged 3 months

to 19.5 years) admitted to Kandang Kerbau Women’s and Children’s Hospital from 1997 to 2004

showed that 46.9% of these patients were between the ages of 2 and 5 years, with a mean age

of 45 months. Pneumonia (63.3%) was also the most common form of IPD, followed by

bacteremia (17%) and meningitis (15.6%). The morbidity rate was found to be 25.2% and the

mortality rate 6.1%. Using the country’s 2005 population estimates, IPD incidence was found to

be 13.6/100 000 in children < 5 years and 16.9/100,000 in children < 2 years [52].

3.10.2. Serotype coverage and antibiotic resistance

The four most common serotypes in the pediatric population were found to be 14

(21.8%), 6B (10.2%), 23F (10.1%), 19F (5.4%) and 6A (3.4%). Overall penicillin resistance was at

44.4%, most of which were observed in serotypes 14 and 19F, whereas resistance to ceftriaxone

was 15.0% [52].

3.11. Sri Lanka

3.11.1. Epidemiology

One of the largest Sri Lankan children’s hospitals, the Lady Ridgeway Hospital for

Children (LRH) in Colombo, reported 794 pneumonia cases and 295 meningitis cases in 2003, of

which 32 and 9 died, respectively (LRH, Annual Health Bulletin, 2003 unpublished), while SAPNA

reported in 2005 that of 228 patients from LRH, 75% had pneumonia, 8% had meningitis and 4%

had septicemia. Nine of these patients were found to have IPD [53]. In SAPNA’s semi-annual

technical report, 10 of the 28 participants identified with S. pneumoniae as pathogen were from

Sri Lanka [19]

Being one of the hardest hit countries by the December 2004 tsunami, Sri Lanka has data

available on the prevalence and transmission of ARIs caused by S. pneumoniae and H. influenzae

in the evacuation camps. Nasopharyngeal swabs were collected from 324 displaced people

staying in three different camps and 21 H. influenzae isolates from 20 people and 25

S. pneumoniae isolates from 22 were identified. It is suggested that some of these infections

may have been transmitted from person to person while staying in the camps [54].

3.11.2. Serotype distribution and antibiotic resistance

The most prevalent serotypes in Sri Lanka are 23F, 19F and 14 [53, 21]. Isolates have

shown markedly increased penicillin resistance (1996–1997: 0.0%; 1998–1999: 5.9%; 2000–

2001: 14.3%) in the course of the ANSORP studies [21]. Ciprofloxacin resistance is also high at

11.8%. The SAPNA study also revealed high penicillin resistance at 22% and cotrimoxazole

resistance at 67%.

3.12. Taiwan

3.12.1 Epidemiology

In 2006, data from the Bureau of National Health Insurance suggested that the overall

incidence of IPD in Taiwan was 216/100,000. Adults aged > 65 years old had the highest

incidence (1147/100,000), followed by children aged < 5 years (422/100,000). The incidence of

pneumonia showed a reversed trend, being highest among children aged < 5 years at

45,956/100,000 [55]. This differs substantially from UNICEF–WHO report where the incidence of

pneumonia among children aged < 5 years in East Asia and the Pacific was estimated to be

23,000/100,000 [7]. The incidences of septicemia and meningitis in children aged < 5 years were

1095/100,000 and 185/100,000, respectively. The IPD mortality rate was highest in the elderly

(> 65 years), mainly due to pneumonia (30,806/10,000) [55].

In a study conducted by Siu et al. from July 1998 to June 1999, the CFR for IPD was

highest among the elderly (≥ 65 years; 42.5%) and children ≤ 5 years (7.2%) [56]. A similar trend,

but reduced CFR, was observed in an island-wide IPD surveillance study conducted from January

to November 2007—two years after PCV7 was introduced in Taiwan. The CFRs were 21.7% in the

elderly (≥ 70 years) and 2.5% in children aged ≤ 5 years (Fig. 2) (Taiwan Center for Disease

Control and Prevention [CDC], unpublished data, 2007).

3.12.2. Serotype coverage and antibiotic resistance

Serotype 14 predominated in children aged ≤ 5 years with IPD, followed by 19F, 23F, 6B

and 19A. Penicillin susceptibility testing showed S. pneumoniae to be 65–70% resistant, while

resistance to ceftriaxone was 38% (Taiwan CDC, unpublished data, 2007).

3.13. Thailand

3.13.1. Epidemiology

Two studies have reported on the etiology of ARI in young Thai children. Sunakorn et al.

performed a study between 1988 and 1989 among children admitted to the Queen Sirikit

National Institute of Child Health (formerly known as the Children’s Hospital Bangkok) and found

that the most severe ARI cases were in children aged < 2 years. Most cases were caused by Hib

and few cases by S. pneumoniae [57]. In the second study, Ekalaksananan et al. reported that

pneumonia presented most frequently in children aged < 1 year, with S. pneumoniae and H.

influenzae contributing equally to the number of cases. Viral and bacterial co-infection was also

detected [58].

The Bureau of Epidemiology of the country’s Ministry of Public Health (MOPH) reported

that, from 1999 to 2005, the incidence rate of pneumonia among children aged < 5 years was

about 1500–2000/100,000 (Bureau of Epidemiology, MOPH, unpublished data, 2006).

A population-based survey in the provinces of Sa Kaeo and Nakhon Phanom, conducted

by the MOPH and the surveillance network of the International Emerging Infections Program

(IEIP) detected a minimum IPD incidence of 4/100,000 by blood culture. The highest IPD

incidence occurred in children aged < 5 years (8.8–12.3/100,000) and in the elderly ≥ 75 years

(26/100,000); this was compounded by substantial antibiotic resistance, with vaccine serotypes

found to be especially resistant (IEIP, unpublished data, 2007). Childhood meningitis was studied

by Chotpitayasunondh who found that Hib (42.3%) and S. pneumoniae (22.2%) were the leading

causative organisms [59].

3.13.2. Serotype coverage and antibiotic resistance

In a recent study, Phongsamart et al. found that the most common S. pneumoniae

serotypes were 6B (27.8%), 23F (20.0%), 14 (10.4%) and 19F (9.6%). Seventy-four percent of

these serotypes are covered by PCV7 and 88% are covered by the 13-valent PCV (PCV13).

Seventy percent were found to be penicillin resistant [60]. In another study, Levine et al. showed

that, among rural children aged < 5 years, nasopharyngeal colonization was 60%, with 6B, 19F

and 23F being the most common serotypes isolated. About 55% of the serotypes found were

covered by PCV7 and 68% were penicillin nonsusceptible strains [61].

3. Discussion

The collection of data from the ASAP members confirms that pneumococcal disease is

an important cause of morbidity and mortality in the Asian region. Overall CFRs resulting from

IPD, as reported by studies from India, Indonesia, Singapore and Taiwan, are illustrated in

Figure 3. In many of the studies, pneumonia was identified as the most common clinical

manifestation. Interestingly, four ASAP member countries, namely, India (with 44 million

pneumonia cases), Pakistan (7 million), Indonesia (6 million) and the Philippines (3 million) were

among the 15 countries identified by both UNICEF–WHO and Rudan et al. as accounting for

three-quarters of the total childhood pneumonia cases worldwide. Both reports identified S.

pneumoniae as the leading pathogen [7,62].

The high antimicrobial resistance of S. pneumoniae in Asia contributes to both the

treatment and economic burden caused by IPD [21,22,63]. In the ANSORP studies, Korea, Taiwan

and Thailand have consistently shown high rates of penicillin resistance [21]. The judicious use of

antibiotics and promotion of vaccination have been suggested as methods to control these

resistant infections [8]. However, pneumococcal vaccination is currently not part of the national

immunization programs of any of the ASAP member countries and territories, despite it being

projected to prevent around 260,000 deaths annually as well as having the potential to mitigate

widespread antibiotic resistance [64].

Rinaldi and Chong confirmed that vaccination of infants with PCV7 would lead to a

substantial reduction in the incidence of IPD, not only among children but also in adults due to

herd protection conferred by immunization [65]. Using a decision-analytic model previously used

in the United Kingdom, Lee et al. evaluated the clinical and economic benefits of routine infant

immunization with PCV7 in Hong Kong and found that 524 cases of IPD and over 2580 cases of

otitis media were potentially prevented over a 10-year period, leading to a reduction of at least

HK$35 million (US$4.5 million) in direct medical costs. The study also took into account the

additional cost savings from the indirect prevention of 919 adult cases of IPD during the same

period. Universal PCV7 vaccination was estimated to have an incremental cost per life-year gain

of HK$44,644 (US$5718) [66].

IPD incidences in Hong Kong, Singapore and Taiwan have been documented by way of

long-duration national studies, with the objective of understanding the epidemiology of invasive

S. pneumoniae. However, the primary objectives of the studies from other ASAP member

countries were to determine the bacterial etiology of ARI, pneumonia, or meningitis; to assess

antimicrobial sensitivity; to describe the dynamics of nasopharyngeal colonization; or to

determine serotype distribution of S. pneumoniae. Data from some countries were also obtained

from very small studies with limited geographic coverage or were extrapolated from results of

international studies. In addition, it is likely that the IPD incidence in some of the studies was

underestimated given the inherent limitation of blood cultures. Moreover, not all meningitis

cases were confirmed by CSF cultures and outpatient pediatric bacteremia cases were not

reported. These differences in study objectives, methodologies and reporting criteria, as well as

the limited coverage prevent comparative analysis and the estimation of regionwide burden of

disease.

IPD is currently not a notifiable disease in any of the ASAP member countries and

territories—with the exception of Taiwan—and no comprehensive and standardized laboratory

surveillance system for IPD has been established. A surveillance system is needed to provide

valuable data on serotype distribution, antibiotic resistance and the impact of vaccination. This

also has to be supported by statistical models and clinical trial results to be able to accurately

estimate disease burden [67,68]. Currently, several surveillance projects and clinical studies are

being conducted in Asia that will be able to provide a more accurate estimate of the

epidemiology and impact of IPD in the region [67].

4. Conclusion

This review of available data confirms the substantial burden of IPD and prevalence of

antibiotic resistance of pneumococci in the Asian region. High incidence is observed in both

children aged < 2 years and adults aged > 65 years. Incidence rates vary between countries.

More substantial and specific studies and continued surveillance are therefore needed to better

assess the incidence of IPD throughout Asia and be able to develop strategies for prevention and

management. The collection of studies also highlights the need to strengthen ARI management

programs. Lastly, the overview of disease burden due to IPD emphasizes the need to deliver

effective interventions, such as early recognition and treatment, prevention through vaccination

and methods to address increasing antimicrobial resistance.

Acknowledgements

This study was supported by an unrestricted educational grant from Wyeth to ASAP. Wyeth was

not involved in the editorial direction of this paper.

With the exception of Zulfiqar A. Bhutta, all authors have received honoraria, lecture fees and

travel grants from pharmaceutical companies involved in pneumococcal and invasive Hib disease

therapeutics, and have declared past funding from Wyeth for related work.

The authors thank Tina V. Garcia of In Vivo Communications Ltd for medical writing assistance.

Table 1. Pneumonia mortality for children aged < 5 years in ASAP member countries* (adapted from UNICEF–WHO data)

Brunei India Indonesia Korea Malaysia Pakistan Philippines Singapore Sri

Lanka Thailand

Total number of

children

< 5 years (000s)

40 120,155 21,477 2521 2738 20,922 9873 226 1631 5020

Total number of

deaths among

children

< 5 years (000s)

0 2210 171 3 7 478 69 0 5 21

Mortality rate

among children

< 5 years (per

1000 live births)

9 85 38 6 12 101 34 3 14 21

Total number of

pneumonia

0 410 25 0 0 92 9 0 0 2

Brunei India Indonesia Korea Malaysia Pakistan Philippines Singapore Sri

Lanka Thailand

deaths among

children

< 5 years (000s)

Case fatality

rate in children

aged < 5 years

1% 19% 14% 2% 4% 19% 13% 9% 9% 11%

*Hong Kong SAR ceased to be a WHO member state in 1997 and thus was excluded from the world health reports. Taiwan and Macau are represented in the WHO system by China

Table 2. Summary of sources

Objectives

Brunei

Raja Isteri Pengiran Anak Saleha

(RIPAS) hospital. Unpublished

hospital data. 2007

To document hospital admissions

WHO. Mortality country fact sheet

2006. Brunei Darussalam

To provide country-specific information on size of population, life

expectancy, under-5 mortality, adult mortality, and maternal

mortality

Hong Kong

Ho PL, Que TL, et al. 2004 [15] To evaluate activities of fluoroquinolones against invasive isolates

of S. pneumoniae

Ho PL, Lam KF, et al. 2004 [14] To determine vaccine coverage of prevalent carriage and invasive

pneumococci among children aged < 6 years in Hong Kong

Ho PL et al. 2006 [11] To estimate the age-specific incidence of IPD in Hong Kong from

1995 to 2004

Ho PL et al. 2007 [12] To estimate the hospitalization rates for pneumococcal disease

among children in Hong Kong from 2000 to 2005

Ip M et al. 2007 [16] To examine the serotypes and antibiotic susceptibility of S.

pneumoniae strains from nasopharyngeal aspirates of children aged

> 1 month to 15 years with ARI

Scientific Committee on Vaccine

Preventable Diseases. 2007 [13]

To provide scientific advice on vaccine use for the population

India

Objectives

Invasive Bacterial Infections

Surveillance (IBIS) group;

International Clinical Epidemiology

Network (INCLEN). 1999 [17]

To determine pattern of diseases due to S. pneumoniae, distribution

of invasive serotypes and antimicrobial susceptibility in India

Jebaraj R et al. 1999 [20] To describe the dynamics of nasopharyngeal colonization by

pneumococci and to determine the prevalence of different

serotypes and their antimicrobial susceptibility

SAPNA. 2007 [19] To report progress of SAPNA project from October 1, 2006 to March

31, 2007

Indonesia

Ruspandji T et al. 1981 [25] To determine the etiological agent of bacterial meningitis in infants

Kartasasmita CB et al. 2001 [26] To determine nasopharyngeal bacterial carriage and antimicrobial

resistance in children aged < 5 years with community-acquired

pneumonia

Soewignjo S. et al. 2001 [29] To determine S. pneumoniae nasopharyngeal carriage prevalence,

serotype distribution and antibiotic resistance among children aged

0–25 months

Kari K et al. 2006 [28] To study the bacterial meningitis profile of patients in Sanglah

hospital in Denpasar, Indonesia.

Kartasasmita CB et al. 2006 [27] To determine prevalence of pneumococcal nasopharyngeal carriage

in neonates and possible sources of acquisition

Hadinegoro SR et al. 2008 (in press) To provide an overview of pneumococcal disease in Indonesian

children

Objectives

Nyambat B, Purniti PS, et al. 2008

[23]

To conduct a hospital review of syndromes consistent with IPD in

children in Denpasar, Indonesia

Nyambat B, Dijanto I, et al. 2008 [24] To conduct a baseline assessment on the burden of IPD syndromes

in children by reviewing hospital records in a referral center in

Surabaya, Indonesia

Korea

Lee HJ. Unpublished hospital data.

2007

To identify major pathogens of invasive diseases in Korean children

Choi EM et al. 2008 [30] To describe S. pneumoniae serotype distribution changes, with an

emphasis on serogroup 19

Malaysia

Jamal F et al. 1987 [31] To describe the clinical features and outcomes of systemic

pneumococcal infection

Cheong YM et al. 1988 [38] To describe the antibiotic susceptibility pattern and serotypes of the

pneumococcal strains

Choo KE et al. 1990 [34] To study retrospectively pyogenic meningitis in hospitalized children

in Kelantan, Malaysia, with regard to etiology, clinical features,

investigation, treatment and outcome

Tee AC. 1993 [35] To determine the relationship of presenting features and outcome

in primary childhood meningitis among patients admitted to the

pediatric department of University Hospital Kuala Lumpur from

1980 to 1989

Hussain IHM et al. 1998 [36] To determine the pattern of post neonatal childhood meningitis in

Objectives

Malaysia

Rohani MY et al. 1999 [32] To determine the distribution of serotypes that cause various types

of infections in hospitalized patients and to study antibiotic

susceptibility patterns

Lim LH et al. 2007 [33] To identify the clinical syndromes of IPD in Malaysia

Suhaimi M et al. 2007 [37] To study the effect of Hib vaccines on pneumococcal meningitis at

Queen Elizabeth Hospital, Kota Kinabalu, Sabah

Pakistan

Ghafoor A et al. 1990 [43] To present an overview of viral and bacteriologic findings and to

examine the usefulness of clinical characteristics for identification of

bacterial and viral infections

Mastro TD et al. 1991 [44] To determine the serotype distribution and antimicrobial

susceptibility of S. pneumoniae strains

Rehman A et al. 1996 [42] To study bacterial etiology of ARIs and their antimicrobial

sensitivities

Bhutta ZA. 2001 [39] To provide insight into the burden of H. influenzae and S.

pneumoniae infections in children

Nizami SQ et al. 2006 [41] To measure the incidence of ARIs and the burden of common

bacterial pathogens

Bhutta ZA et al. 2007 [40] To monitor and evaluate the needs of maternal health and family

planning programs as well as investigate factors affecting maternal

and neonatal morbidity and mortality

Philippines

Objectives

Capeding MRZ et al. 1994 [47] To determine the etiology of acute lower respiratory infection in

children under 5 years old

Lankinen KS et al. 1994 [48] To compare the sensitivity of pneumococcal culture with that of

antigen detection methods

Lupisan S. 2000 [46] To investigate the etiology of serious infections in children aged

< 5 years

admitted to a tertiary care government hospital in Bohol province

Philippine General Hospital;

University of Santo Tomas Hospital;

Philippine Children’s Medical Center.

Survey of bacterial meningitis.

Unpublished hospital data. 2002–

2006

To determine the etiology of bacterial meningitis

Capeding 2007 [49] To describe the pneumococcal serotypes seen among Filipino

children admitted in a tertiary care center in the Philippines due to

infectious diseases

Carlos C. 2007 [50] To determine the antimicrobial resistance patterns of common

pathogens in 2007

Singapore

Low S et al. 2007 [51] To describe the epidemiology of pneumococcal disease based on

hospitalization rates for all age groups for the evaluation of

prevention and control strategies

Chong CY et al. 2008 [52] To assess the adequacy of PCV7 and future expanded vaccine

Objectives

formulations in relation to the predominant IPD serotypes; to

determine the epidemiology of IPD, antibiotic susceptibility patterns

and the morbidity and mortality of children with community-

acquired IPD

Sri Lanka

Lady Ridgeway Hospital. Annual

Health Bulletin. Unpublished internal

hospital data. 2003

To provide hospital statistics on patient admissions

SAPNA. Newsletter. Jan–March 2005

[53]

To provide updates on the SAPNA project

SAPNA. 2007 [19] To report progress of SAPNA project from October 1, 2006 to March

31, 2007

Watanabe H et al. 2007 [54] To determine the status of ARIs caused by S. pneumoniae and H.

influenzae in tsunami evacuation camps in Sri Lanka

Taiwan

Siu LK et al. 2002 [56] To understand the epidemiology of invasive S. pneumoniae in

Taiwan

Department of Health Statistics;

Department of Health, Executive

Yuan, Republic of China. 2006 [55]

To collect essential information on several areas such as population,

economy, education, labor and healthcare among others.

Taiwan Centers for Disease Control

and Prevention (CDC). Unpublished

data. 2007.

To collect information necessary for the notification and control of

disease outbreaks, syndromes and communicable diseases

Objectives

Thailand

Sunakorn P et al. 1990 [57] To detect the etiology of severe ARIs in children aged < 5 years and

to correlate this with clinical findings

Chotpitayasunondh T. 1994 [59] To conduct a retrospective study on the etiology and clinical

features of bacterial meningitis in children

Ekalaksananan T et al. 2001 [58] To determine the etiology of ARIs in children < 5 years admitted to

Srinagarind Hospital

Bureau of Epidemiology,

Department of Disease Control,

Ministry of Public Health.

Unpublished data. 2006

To collect information on the incidence and distribution of diseases

in Thailand

Levine S et al. 2006 [61] To determine S. pneumoniae carriage prevalence, serotype

distribution and antimicrobial resistance patterns among patients

with respiratory illness; to summarize national data on invasive

pneumococcal isolates

Phongsamart W et al. 2007 [60] To determine the serotype coverage of PCV7, PCV9, PCV11 and

PCV13 among isolates causing IPD in Thai children < 5 years to guide

decisions on the use of PCV

International Emerging Infections

Program (IEIP) surveillance network.

Unpublished data. 2007

To collect useful information on the burden of vaccine-preventable

pneumococcal disease

ARI, acute respiratory infection; IPD, invasive pneumococcal disease; PCV7, pneumococcal conjugate

vaccine.

0

10

20

30

40

50

60N

o. o

f ep

iso

des

Age

Immunocompetent

Immunocompromised

<2 years 2-5 years >5-16 years

Figure 1. Age distribution of IPD in immunocompetent and immunocompromised children in Korea (Lee HJ,

unpublished data, 2007).

Figure 2. Case fatality rates in two IPD surveillance studies in Taiwan before and after the introduction of

the 7-valent pneumococcal conjugated vaccine (Taiwan CDC 2007), [56].

Figure 3. Overall case fatality rates due to IPD as reported by studies from different ASAP

member countries (Hadinegoro, in press), [18, 23, 24, 52].

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