Surveillance of Pneumococcal‐Associated Disease among Hospitalized Children in Khanh Hoa Province,...

Pneumococcal Disease in Vietnam • CID 2009:48 (Suppl 2) • S57

S U P P L E M E N T A R T I C L E

Surveillance of Pneumococcal-Associated Diseaseamong Hospitalized Children in Khanh HoaProvince, Vietnam

Dang Duc Anh,1 Paul E. Kilgore,4 Mary P. E. Slack,5 Batmunkh Nyambat,4 Le Huu Tho,2 Lay Myint Yoshida,6

Hien Anh Nguyen,1 Cat Dinh Nguyen,3 Chia Yin Chong,7 Dong Nguyen,3 Koya Ariyoshi,6 John D. Clemens,4

and Luis Jodar4,a

1National Institute of Hygiene and Epidemiology, Hanoi, and 2Khanh Hoa Health Service and 3Khanh Hoa General Hospital, Nha Trang, Vietnam;4International Vaccine Institute, Seoul, South Korea; 5Haemophilus Reference Unit, Respiratory and Systemic Infection Laboratory, HealthProtection Agency Centre for Infections, London, United Kingdom; 6Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan;and 7Infectious Diseases Unit, KK Women’s and Children’s Hospital, Singapore

Background. To understand the epidemiology of childhood bacterial diseases, including invasive pneumococcaldisease, prospective surveillance was conducted among hospitalized children in Nha Trang, Vietnam.

Methods. From April 2005 through August 2006, pediatricians at the Khanh Hoa General Hospital usedstandardized screening criteria to identify children aged !5 years who had signs and symptoms of invasive bacterialdisease. All cerebrospinal fluid (CSF) and blood specimens collected were tested by bacterial culture. Selectedculture-negative specimens were tested for Streptococcus pneumoniae by antigen detection or for Haemophilusinfluenzae, Moraxella catarrhalis, Neisseria meningitidis, and S. pneumoniae by polymerase chain reaction (PCR).

Results. A total of 987 children were enrolled (794 with pneumonia, 76 with meningitis, and 117 with othersyndromes consistent with invasive bacterial disease); 84% of children were aged 0–23 months, and 57% weremale. Seven (0.71%) of 987 blood cultures and 4 (15%) of 26 CSF cultures were positive for any bacterial pathogen(including 6 for H. influenzae type b and 1 for S. pneumoniae). Pneumococcal antigen testing and PCR identifiedan additional 16 children with invasive pneumococcal disease (12 by antigen testing and 4 by PCR). Amongchildren aged !5 years who lived in Nha Trang, the incidence rate of invasive pneumococcal disease was at least48.7 cases per 100,000 children (95% confidence interval, 27.9–85.1 cases per 100,000 children).

Conclusions. S. pneumoniae and H. influenzae type b were the most common causes of laboratory-confirmedinvasive bacterial disease in children. PCR and antigen testing increased the sensitivity of detection and provideda more accurate estimate of the burden of invasive bacterial disease in Vietnam.

Globally, nearly 2 million children aged !5 years die

each year as a result of acute respiratory tract infections

[1]. Children experience 150 million episodes of pneu-

monia per year, of which 11–20 million require hos-

pitalization [2]. Recent estimates from UNICEF suggest

that Streptococcus pneumoniae accounts for 50% of

childhood deaths due to pneumonia each year [3, 4].

With currently available interventions, it is likely that

a Present affiliation: Wyeth Vaccines, Hong Kong, Special AdministrativeRegion.

Reprints or correspondence: Dr. Paul E. Kilgore, Div. of Translational Research,International Vaccine Institute, P. O. Box 14, Gwanak, Shillim-dong, Gwanak-gu,Seoul, South Korea 151-600 ([email protected]).

Clinical Infectious Diseases 2009; 48:S57–64� 2009 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2009/4805S2-0004$15.00DOI: 10.1086/596483

a large proportion of these deaths could be prevented

through improved access to appropriate drug therapy,

as well as immunization with pneumococcal conjugate

vaccines [5–7]. Financial assistance is available to Viet-

nam through the GAVI Alliance for the purchase of

these vaccines.

There is limited information on the epidemiology

and serotype distribution of invasive pneumococcal dis-

ease (IPD) in Vietnamese children. This paucity of data

represents a substantial barrier to the introduction of

pneumococcal conjugate vaccines into routine infant

immunization programs. To help fill these gaps in in-

formation, the National Institute of Hygiene and Ep-

idemiology initiated a pilot study to describe hospital-

izations associated with invasive bacterial disease

among children in Khanh Hoa Province, Vietnam, and

to provide new insights into optimal methods for na-

at Wayne State U

niversity on March 23, 2015

http://cid.oxfordjournals.org/D

ownloaded from

http://cid.oxfordjournals.org/

S58 • CID 2009:48 (Suppl 2) • Anh et al.

Figure 1. Map of Khanh Hoa Province, Vietnam

tional surveillance of invasive bacterial disease in Vietnam.

METHODS

Study population and hospital. Before this study was initi-

ated, the research protocol was reviewed and approved by the

National Institute of Hygiene and Epidemiology and the Khanh

Hoa Provincial Health Service and International Vaccine In-

stitute Institutional Review Board. The Khanh Hoa Provincial

Health Service is responsible for oversight of the Khanh Hoa

General Hospital (KHGH), located in Nha Trang, the capital

of Khanh Hoa Province in southeastern Vietnam (figure 1). In

2006, the Khanh Hoa Province census office reported a total

population of 1,143,000 residents, with a majority living in Nha

Trang [8]. The KHGH is a provincial-level referral hospital that

provides primary and tertiary care medical services and a 24-

h clinical laboratory service that performs routine biochemical,

hematological, and microbiological tests.

Hospital-based surveillance of invasive bacterial disease.

In prestudy workshops held at KHGH, all pediatricians, emer-

gency physicians, infectious diseases specialists, and radiologists

were provided standardized procedures for screening and eval-

uation of children with pneumonia, meningitis, sepsis, and

other syndromes consistent with invasive bacterial disease, as

well as procedures for obtaining informed consent and for

collection of patient information and parent interviews. Mi-

crobiology workshops were conducted before the start of the

study, to provide standardized procedures for collection and

storage of clinical specimens, as well as procedures for testing

for pneumococcus and other invasive bacterial pathogens with

use of routine culture methods and rapid antigen tests. Hos-

pitalized children were classified as having meningitis, pneu-

monia, or other severe disease on the basis of signs and symp-

toms noted at the time of hospital admission, as well as results

of laboratory testing during their hospitalization, in accordance

with criteria developed in conjunction with the Pneumococcal

Vaccines Accelerated Development and Introduction Plan

(PneumoADIP) (see the Appendix in this supplement).

Patient enrollment and laboratory testing. Children were

eligible for entry into this study if they were aged !5 years and

exhibited signs and symptoms of suspected bacterial disease at

admission to the KHGH. After admission to the hospital, com-

pletion of informed consent forms by parents or guardians,

and enrollment in the study, patients underwent collection of

blood and CSF specimens appropriate to their presenting clin-

ical syndrome. Specimens were immediately transported to the

hospital clinical laboratory, and testing was initiated within 1

h after specimen collection. Microbiological testing services

were available 24 h per day, 7 days per week, either as a routine

or on-call service. Gram staining was performed on all CSF

specimens in accordance with standard techniques. An im-

munochromatographic test of pneumococcal antigen (NOW S.

pneumoniae Antigen Test; Binax) was performed on all collected

CSF specimens and a representative subset of blood culture

supernatant specimens collected from children enrolled from

July 2005 through August 2006. CSF specimens were plated on

blood agar (trypticase soy agar with 5% sheep blood). A second

aliquot of each CSF specimen was plated on chocolate agar and

was incubated according to standard bacterial culture proce-

at Wayne State U



ownloaded from



Figure 2. Age distribution of enrolled patients at the Khanh Hoa Gen-eral Hospital, Nha Trang, Vietnam.

dures [9]. For blood cultures, a minimum of 2 mL and a

maximum of 3 mL of blood was inoculated into commercially

prepared media (BACTEC PedsPlus/F; Becton Dickinson).

Blood cultures were manually inspected twice daily for evidence

of bacterial growth. Laboratory technicians performed routine

blood subcultures at 18–24 h, 48 h, and 7 days of incubation,

by transferring 2 drops of each culture specimen onto blood

agar and chocolate agar plates.

Bacterial colonies grown from blood and CSF specimens

underwent identification using standard biochemical test meth-

ods [10]. All bacterial isolates (stored in skim milk), blood

culture supernatant specimens, and CSF specimens were

shipped in labeled cryotubes at �80�C to the Molecular Biology

Laboratory of the Department of Clinical Medicine, Institute

of Tropical Medicine, Nagasaki University, Nagasaki, Japan, for

testing by PCR. All available CSF specimens were tested by

PCR, and a nonrandom sample of blood culture supernatant

specimens was identified for testing with use of an algorithm

that prioritized children by disease severity based on clinical

signs and symptoms, total WBC count, and chest radiograph

findings. Frozen CSF and blood culture broth supernatant spec-

imens were processed for DNA extraction with use of the

QIAamp DNA Mini Kit (Qiagen) in accordance with the man-

ufacturer’s instructions, and DNA extracts were stored at

�20�C before PCR testing. PCR was performed at the Molec-

ular Bacteriology Laboratory with multiplex detection of in-

vasive bacterial pathogens [11, 12]. Primers for detection of

Haemophilus influenzae, Moraxella catarrhalis, and S. pneu-

moniae were used for blood culture broth specimens, and prim-

ers for detection of H. influenzae, Neisseria meningitidis, and

S. pneumoniae were used for CSF specimens.

Data collection and data management. After study en-

rollment and collection of clinical specimens, all parents un-

derwent a standardized interview on the day of hospital ad-

mission. A standardized case report form was used by hospital

medical staff to collect information on signs and symptoms of

the presenting illness, medical history, physical examination,

and demographic and household characteristics. Data from the

case report form were inspected for completeness and accuracy

by Khanh Hoa Provincial Health Service epidemiologists before

data entry. The data were double entered, and automatic range

and consistency checks were performed for all data fields. The

study database was uploaded by study collaborators at the In-

ternational Vaccine Institute for final inspection, data analysis,

and reporting to the PneumoADIP.

Quality control and statistical data analyses. To maintain

data quality throughout the study period, the scientific staff of

the National Institute of Hygiene and Epidemiology and the

International Vaccine Institute performed weekly reviews of

surveillance data and provided monthly feedback on the per-

formance of the surveillance system to hospital investigators.

Study data were analyzed in univariate and bivariate fashions,

to describe clinical, epidemiological, and laboratory character-

istics of children with pneumonia, meningitis, and other severe

disease. Statistical comparisons for categorical variables were

performed using the x2 statistic and Fisher’s exact test. Cal-

culations of incidence rates for laboratory-confirmed IPD and

H. influenzae type b (Hib) disease were limited to children living

in the Nha Trang district, because this population was widely

believed to access the KHGH as their sole provider for medical

care for any severe disease. The 95% CIs for incidence estimates

were calculated using Wilson’s score method [13].

RESULTS

Study children. From 1 April 2005 through 31 August 2006,

a total of 987 children were enrolled in the study. A majority

(535 [54%]) were aged !12 months, including 148 neonates

(15%) aged !1 month (figure 2). An additional 298 (30%) were

aged 12–23 months, and 154 (16%) were aged 24–59 months.

Among the 987 study children, 559 (57%) were male, and 692

(70%) were residents of the Nha Trang district, where the study

hospital (KHGH) is located. Among all participants, there were

29 deaths (case-fatality rate, 3%), including 17 (59%) neonates

and 21 (72%) children hospitalized for pneumonia.

Children with pneumonia. Clinical pneumonia was the

most common diagnosis among study participants (table 1).

On the basis of the PneumoADIP case definitions (see the

Appendix in this supplement), 794 (80%) of the 987 children

had clinical pneumonia syndrome. Of these, 669 (84%) had

diagnosis confirmed by chest radiograph, and 323 (41%) had

severe or very severe disease.

Children with meningitis, sepsis, or other disease. Of the

remaining children, 76 (8%) had meningitis, 32 (3%) had very

severe disease, and 85 (9%) had other diseases. Fifteen children

(22%) with suspected meningitis and 11 (33%) with disease

at Wayne State U



ownloaded from



Table 1. Distribution of children enrolled in a hospital-based surveillance study, by age group and case definition, at the Khanh HoaGeneral Hospital, Nha Trang, Vietnam, April 2005–August 2006.

Age group,months

Pneumonia MeningitisOther

diseases

Allnonpneumonia

diseaseProbableCXR

confirmedProbable,

severe

CXRconfirmed,

severeProbable,

very severe

CXRconfirmed,very severe All Suspected

Probablebacterial Definite

Verysevere Other

!1 7 6 9 17 18 8 65 36 0 0 24 23 83

1–3 5 53 13 41 3 7 122 8 1 0 1 10 20

4–6 4 53 6 19 1 3 86 4 1 2 0 5 12

7–11 2 77 9 30 1 7 126 6 0 1 2 12 21

12–23 15 158 15 57 1 15 261 10 2 0 3 22 37

24–35 3 62 5 23 0 3 96 2 1 0 1 6 10

36–47 3 18 3 4 1 1 30 1 0 1 1 4 7

48–59 0 5 0 2 1 0 8 0 0 0 0 3 3

Total 39 432 60 193 26 44 794 67 5 4 32 85 193

NOTE. CXR, chest radiograph.

classified as very severe had CSF specimens obtained. There

were 8 deaths among children who received diagnoses other

than pneumonia, including 3 of the 76 children with suspected

meningitis (case-fatality rate, 4%) and 5 of the 32 children with

very severe disease (case-fatality rate, 16%). Two of the 3 chil-

dren with suspected meningitis who died underwent full clinical

and laboratory evaluation, including lumbar puncture. No chil-

dren with probable or definite meningitis died, but 2 children

with meningitis-associated disabilities were identified at hos-

pital discharge: 1 was classified as having probable bacterial

meningitis and 1 as having very severe disease.

Microbiological culture testing. Of the 987 blood cultures

performed, 7 (0.71%) had positive results, and 4 (15%) of the

26 CSF cultures had positive results (table 2). Six children had

cultures positive for Hib, including 4 with positive CSF cultures

and 2 with positive blood cultures. There was 1 child with a

blood culture positive for S. pneumoniae, but no children had

CSF cultures positive for S. pneumoniae. Four children had

cultures positive for other pathogens (2 Staphylococcus aureus,

1 Salmonella typhi, and 1 Enterobacter cloacae). Of the 11 chil-

dren with positive culture results, 10 (91%) were aged �35

months.

Pneumococcal antigen and PCR testing. Non–culture-

based tests for invasive bacterial pathogens were applied in a

pilot-test fashion, to better understand the potential benefits

of these tests in Vietnam. Pneumococcal antigen testing was

performed on a total of 11 CSF specimens (42% of the CSF

specimens that were cultured) and 64 blood culture supernatant

specimens (7% of the blood specimens that were cultured).

Because of resource constraints for laboratory testing, the use

of non–culture-based diagnostic tests was necessarily limited.

For this reason, PCR testing of blood supernatant specimens

was prioritized on the basis of the children’s total peripheral

WBC counts, measured on the day of admission and before

administration of antibiotics. PCR was performed on 23 CSF

specimens (89% of the CSF specimens that were cultured) that

contained sufficient volume for testing, and 68 blood culture

supernatants (7% of the blood specimens that were cultured)

from children with elevated WBC counts. Among children with

culture-negative CSF or blood specimens, the pneumococcal

antigen test and PCR identified an additional 16 children with

IPD, including 13 (81%) with pneumonia and 3 (19%) with

meningitis (table 2). Ten of the 13 children with pneumonia

were classified as having chest radiograph–positive pneumonia,

and an additional 3 children had chest radiograph–confirmed

severe or very severe pneumonia.

Of the 16 children with cultures negative for pneumococci

who were identified as having pneumococcal disease by antigen

testing or PCR, 12 had positive results of pneumococcal antigen

testing and 4 had positive results of PCR. Of the 4 children

who had positive results of pneumococcal PCR, 1 received a

diagnosis of chest radiograph–confirmed pneumonia and 3 re-

ceived a diagnosis of definite meningitis. Of the 12 children

who had positive results of the pneumococcal antigen test, 11

(92%) received a diagnosis of pneumonia and 1 (8%) received

a diagnosis of meningitis (figure 3).

Other invasive pathogens. Because this study enrolled chil-

dren with suspected bacterial meningitis, each patient’s speci-

mens underwent routine testing for the 3 leading invasive bac-

terial pathogens of vaccine-preventable meningitis (H.

influenzae, N. meningitidis, and S. pneumoniae). No children

with meningococcal infection were identified during the study

period. Four children with meningitis had CSF cultures positive

for Hib, and 2 had blood cultures positive for Hib (1 child

with chest radiograph–confirmed pneumonia and 1 with chest

radiograph–confirmed severe pneumonia). An additional 2

children with negative cultures had PCR results positive for

at Wayne State U



ownloaded from



Table 2. Distribution of patients by case category and laboratory test results at the Khanh Hoa General Hospital, Nha Trang, Vietnam,April 2005–August 2006.

Case categoryNo. of

patients

Specimenstested

by culture

Specimenspositive

for any organism

Specimenspositive

for pneumococcus

Specimenspositivefor Hib

Blood CSF By cultureBy PCR or

antigen testa By cultureBy PCR or

antigen testa By culture By PCRa

Pneumonia ( )n p 794Probable 39 39 0 0 0 0 0 0 0CXR confirmed 432 432 0 3 10 1 9 1 1Probable, severe 60 60 0 0 1 0 1 0 0CXR confirmed, severe 193 193 0 2 3 0 2 1 1Probable, very severe 26 26 0 1 1 0 1 … …CXR confirmed, very severe 44 44 0 1 0 0 0 … …

Meningitis ( )n p 76Suspected 67 67 15 0 3 0 3 0 0Probable bacterial 5 5 5 0 0 0 0 … …Definite 4 4 4 4 0 0 0 4 0

Other diseases ( )n p 117Very severe 32 32 2 0 0 0 0 0 0Other 85 85 0 0 0 0 0 0 0

Total 987 987 26 11 18 1 16 6 2

NOTE. CXR, chest radiograph; Hib, Haemophilus influenzae type b.a PCR and an immunochromatographic test of pneumococcal antigen (NOW Streptococcus pneumonia Antigen Test; Binax) were performed for only a subset

of patients.

Hib, including 1 with chest radiograph–confirmed pneumonia

and 1 with chest radiograph–confirmed severe pneumonia.

Estimated incidences of IPD and Hib disease. Because

health care access (especially access of the Nha Trang population

to KHGH) is excellent, we used demographic surveillance sys-

tem data from 2006 at the Khanh Hoa Provincial Health Service

to estimate minimum incidence rates for confirmed IPD (in-

cluding children with positive results of culture and nonculture

testing) and Hib disease (table 3). Among children aged !5

years who lived in Nha Trang, the estimated incidence rate of

IPD was 48.7 cases per 100,000 children (95% CI, 27.9–85.1

cases per 100,000 children). The second highest incidence rate

of invasive bacterial disease among children aged !5 years was

disease caused by Hib (22.9 cases per 100,000 children [95%

CI, 10.3–51.2 cases per 100,000 children]). Age group–specific

incidence rates for IPD and Hib disease were highest among

infants (IPD incidence, 193.4 cases per 100,000 infants [95%

CI, 97.1–384.9 cases per 100,000 infants]; Hib disease incidence,

87.9 cases per 100,000 infants [95% CI, 32.3–238.9 cases per

100,000 infants]) and among children aged 2 years (IPD in-

cidence, 49.3 cases per 100,000 children aged 2 years [95% CI,

14.0–174.0 cases per 100,000 children aged 2 years]; Hib disease

incidence, 32.9 cases per 100,000 children aged 2 years [95%

CI, 7.3–147.8 cases per 100,000 children aged 2 years]).

DISCUSSION

In this study of invasive bacterial disease among hospitalized

children in Khanh Hoa Province, 69% of children enrolled were

hospitalized for pneumonia, and 11% were hospitalized for

meningitis. An additional 20% received diagnoses of very severe

disease and other disease. A total of 29 children with laboratory-

confirmed invasive bacterial disease were identified, including

11 with culture-confirmed disease and 18 with disease identified

by antigen testing or PCR. Among the children with positive

cultures, Hib and S. pneumoniae were the most common in-

vasive bacterial isolates. Hib isolation from CSF specimens was

twice as common as isolation from blood, and Hib was the

only bacterial species recovered from CSF cultures. It is notable

that, with limited application of non–culture-based diagnostics,

16 additional children with pneumococcal disease and 2 ad-

ditional children with Hib disease were identified.

The results reported here should be interpreted in light of

some study limitations. Although standardized microbiology

laboratory procedures included routine subculture of all blood

culture specimens at defined intervals, it is possible that growth

in some cultures was not detected as quickly as may have been

the case with use of automated blood culture systems. Also, in

this pilot study, uniform testing of all CSF and blood culture

specimens by nonculture tests (antigen detection and PCR)

at Wayne State U



ownloaded from



Figure 3. Flow diagram of clinical case categories, with pneumococcal culture and non–culture-based testing categories. PCR and an immuno-chromatographic test of pneumococcal antigen (NOW Streptococcus pneumonia Antigen Test; Binax) were performed for only a selected number ofpatients.

could not be performed, because of limited test availability.

Such limited testing may result in the underascertainment of

bacterial pathogens, particularly among children who had re-

ceived antibiotic treatment before admission. Additional use of

these nonculture tests performed on blood samples has not

been validated for diagnosis of IPD or Hib disease, so the

sensitivity and specificity are unknown. Because dengue is an

important disease during summer months in Khanh Hoa Prov-

ince and because children with dengue may present with signs

and symptoms consistent with invasive bacterial disease, it is

possible that pediatricians may have misclassified cases among

children during the initial clinical evaluation. In this study,

vigorous efforts were made to raise awareness among pedia-

tricians and parents about the possibility that some hospitalized

children may present with febrile disease that mimics both

dengue and invasive bacterial disease. Despite vigorous training

and provision of standardized surveillance procedures, if sus-

pected dengue and invasive bacterial diseases were both con-

sidered in the clinical differential diagnosis, it is possible that

some pediatricians may have deferred blood or CSF collection

until the probability of either disease became clearer.

Our findings in this study are consistent with those of previous

invasive bacterial studies conducted in Vietnam. Using culture

and antigen testing, Tran et al. [14], at Children’s Hospital Num-

ber 1 in Ho Chi Minh City, Vietnam, found that Hib accounted

for 53% of bacterial meningitis cases among children aged !5

years, whereas pneumococcus was identified in 93% of bacter-

emic pneumonia cases. In Hanoi, Vietnam, Anh et al. [15] con-

ducted a population-based study of childhood bacterial men-

ingitis, in which Hib and pneumococcus were the most common

causes of bacterial meningitis in hospitalized children. In the

study by Anh et al. [15], nonculture testing (latex agglutination

test and PCR performed on CSF specimens) also increased the

yield of invasive bacterial pathogens, with a resultant increase in

the estimated incidence rate of bacterial meningitis. In Vietnam,

the widespread use of antibiotics represents a potential barrier

to the accurate estimation of the disease epidemiology associated

with invasive bacterial disease [16].

Our results suggest that the use of non–culture-based testing

may increase the overall detection of IPD and Hib, compared

with the use of culture methods alone. In this study, nonculture

testing of CSF by PCR produced greater yields than did pneu-

mococcal antigen testing. However, these results may under-

estimate the true number of CSF specimens positive for pneu-

mococcus, because the pneumococcal antigen test was

performed on fewer than half (42.3%) of the CSF specimens

with sufficient volume available for testing. PCR testing for Hib

performed on culture-negative CSF specimens identified an

additional 2 children with invasive Hib disease. This additional

PCR testing increased overall detection of laboratory-confirmed

Hib disease, compared with detection by culture alone. The

diagnostic yield by PCR of CSF specimens in this study is

consistent with the findings of Kennedy et al. [17], who found

that PCR to test for Hib and pneumococci in CSF identified

additional children who did not receive a diagnosis by either

culture or antigen testing.

This pilot study in Vietnam provides important lessons for

conduting laboratory-based surveillance of invasive bacterial

diseases among populations located in tropical or subtropical

developing countries. First, implementation of standard op-

erating procedures for microbiological diagnosis is critical for

improving the detection of pathogens in routine bacterial cul-

at Wayne State U



ownloaded from



Table 3. Incidence rates of invasive pneumococcal and Haemophilus influenzae type b (Hib)disease among children aged !5 years in the Nha Trang district, Khanh Hoa Province, Vietnam.

Age group,months

Nha Trangpopulation

Pneumococcal disease Hib disease

No. ofpatients Incidence rate (95% CI)

No. ofpatients Incidence rate (95% CI)

�11 4015 11 193.4 (97.1–384.9) 5 87.9 (32.3–238.9)12–23 4294 3 49.3 (14.0–174.0) 2 32.9 (7.3–147.8)24–35 5773 2 24.5 (5.4–109.9) 0 …36–47 5244 1 13.5 (1.8–98.3) 1 13.5 (1.8–98.3)48–59 5315 0 … 0 …

Total 24,641 17 48.7 (27.9–85.1) 8 22.9 (10.3–51.2)

NOTE. The Khanh Hoa Province population data are from Khanh Hoa Health Service Demographic SurveillanceSystem census update of 2006.

tures [18–20]. Because of the evolving epidemic of HIV infec-

tion and AIDS in Vietnam, it is possible that IPD in both

children and adults with HIV infection and/or AIDS may con-

tribute to the overall burden of disease at the national level in

Vietnam. Improved surveillance in Vietnam may also identify

cases of IPD that occur among such high-risk groups, especially

in large cities and in border areas with high levels of HIV

seroprevalence. Second, the standardized clinical assessment of

febrile diseases in children, such as meningitis, pneumonia, and

sepsis, may be challenging when clinicians must differentiate

bacterial diseases from febrile viral diseases such as dengue. In

Khanh Hoa Province, seasonal dengue epidemics often lead to

hospitalization, diagnosis, and treatment of many children with

suspected dengue fever [21, 22]. Although differentiation of

dengue fever from bacterial infections can often be done on

the basis of clinical signs and symptoms, routine blood culture

for all children hospitalized with suspected dengue may identify

additional children with invasive bacterial diseases but could

lead to an overall lower yield from blood culture testing [23].

This study provides new insights into pneumococcal and Hib

disease among children in Vietnam. On the basis of the number

of cases detected only among residents of Nha Trang, this study

found minimum overall pneumococcal disease and Hib disease

incidences among children aged !5 years of 48.7 cases per

100,000 children and 22.9 cases per 100,000 children, respectively.

Although children and families have very good access to primary

health care and to care for severe disease, this study was not

designed to enroll children who presented to outpatient clinics,

and considering the underutilization of lumber punctures, the

incidence rates found in this study may underestimate the total

burden of IPD and Hib disease. The estimated incidence rate of

childhood IPD reported in our study is within the range of

reported incidence rates from population-based studies among

nonindigenous Australians, as well as studies performed in the

United Kingdom and Israel, but are somewhat higher than the

rate reported in a Hong Kong study [24–27]. The incidence of

Hib disease reported in this study is somewhat higher than the

incidence of Hib meningitis calculated using the Hib rapid disease

burden assessment tool for Vietnam in 2006 (18 cases per 100,000

children aged !5 years) and is somewhat higher than the inci-

dence reported for Hib meningitis in Hanoi (12 cases per 100,000

children aged !5 years) [15].

This is the first systematic study of invasive bacterial disease

at a provincial-level hospital in Vietnam that incorporates clas-

sic bacterial culture methods and non–culture-based testing

methods for detection of invasive bacterial pathogens among

children presenting with major clinical syndromes, including

pneumonia, meningitis, sepsis, and other severe disease. The

lessons from this study are being used to develop additional

prospective population-based studies of IPD in Vietnamese

children, and they will be helpful for designing surveillance

systems that assess the future impact of conjugate Hib vaccine

after its introduction into the routine immunization schedule

of Vietnam. In addition, the capacity-strengthening efforts in

this study are yielding direct benefits, as national public health

scientists work to establish a national Hib and pneumococcal

reference laboratory at the National Institute of Hygiene and

Epidemiology in Hanoi. Such national laboratory capacity will

be essential to support studies that estimate the burden of IPD

in other areas of Vietnam.

Acknowledgments

We thank Sung-Hyun Song (Samchundang Pharm, Seoul, Korea), for adonation of Binax NOW kits for pneumococcal antigen testing in thisstudy; Drs. Dong Nguyen, Hoa Lan Nguyen, Hideki Yanai, Phu Quoc Viet,Thi Thi Ngo, Truong Tan Minh, and Vu Dinh Thiem, for their assistanceduring surveillance training and data collection; Thanh Hien Nguyen, fordatabase management; Min Kyoung Oh, for administrative assistance; andDr. Maria Deloria Knoll, for her critical input on data analysis duringpreparation of this article.

Financial support. PneumoADIP of Johns Hopkins University (thePneumoADIP is funded in full by the GAVI Alliance and the Vaccine Fund)and the governments of Kuwait, Sweden, and the Republic of Korea.

Supplement sponsorship. This article was published as part of a sup-plement entitled “Coordinated Surveillance and Detection of Pneumococ-cal and Hib Disease in Developing Countries,” sponsored by the GAVI

at Wayne State U



ownloaded from



Alliance’s PneumoADIP of Johns Hopkins Bloomberg School of PublicHealth, Baltimore, Maryland.

Potential conflicts of interest. B.N. has received research grants fromGlaxoSmithKline Biologicals, Sanofi-Aventis, and Wyeth Vaccines. P.E.K.has received research grants from GlaxoSmithKline Biologicals, Sanofi-Aventis, and Wyeth Vaccines; has served as a consultant for Wyeth Vaccines;and has been on the speakers’ bureau for GlaxoSmithKline Biologicals andWyeth Vaccines. L.J. has served as a consultant for and has received researchgrants from GlaxoSmithKline Biologicals and Wyeth Vaccines. All otherauthors: no conflicts.

References

1. Williams BG, Gouws E, Boschi-Pinto C, Bryce J, Dye C. Estimates ofworld-wide distribution of child deaths from acute respiratory infec-tions. Lancet Infect Dis 2002; 2:25–32.

2. Rudan I, Tomaskovic L, Boschi-Pinto C, Campbell H. Global estimateof the incidence of clinical pneumonia among children under five yearsof age. Bull World Health Organ 2004; 82:895–903.

3. Wardlaw T, Salama P, Johansson EW, Mason E. Pneumonia: the leadingkiller of children. Lancet 2006; 368:1048–50.

4. Horton R. A new global commitment to child survival. Lancet 2006;368:1041–2.

5. Rudan I, El Arifeen S, Black RE, Campbell H. Childhood pneumoniaand diarrhoea: setting our priorities right. Lancet Infect Dis 2007; 7:56–61.

6. Qazi SA. Antibiotic strategies for developing countries: experience withacute respiratory tract infections in Pakistan. Clin Infect Dis 1999; 28:214–8.

7. Levine OS, O’Brien KL, Knoll M, et al. Pneumococcal vaccination indeveloping countries. Lancet 2006; 367:1880–2.

8. People’s Committee of Khanh Hoa Province. Trang thong tin dien tu′

[E-information Web page]. Available at: http://ws1.khanhhoa.gov.vn.Accessed 14 June 2007.

9. Thomson RB Jr, Bertram H. Laboratory diagnosis of central nervoussystem infections. Infect Dis Clin North Am 2001; 15:1047–71.

10. Martin WJ. Rapid and reliable techniques for the laboratory detectionof bacterial meningitis. Am J Med 1983; 75:119–23.

11. Tzanakaki G, Tsopanomichalou M, Kesanopoulos K, et al. Simulta-neous single-tube PCR assay for the detection of Neisseria meningitidis,Haemophilus influenzae type b and Streptococcus pneumoniae. Clin Mi-crobiol Infect 2005; 11:386–90.

12. Billal DS, Hotomi M, Suzumoto M, et al. Rapid identification of non-typeable and serotype b Haemophilus influenzae from nasopharyngealsecretions by the multiplex PCR. Int J Pediatr Otorhinolaryngol2007; 71:269–74.

13. Newcombe RG. Interval estimation for the difference between inde-pendent proportions: comparison of eleven methods. Stat Med1998; 17:873–90.

14. Tran TT, Le QT, Tran TN, Nguyen NT, Pedersen FK, SchlumbergerM. The etiology of bacterial pneumonia and meningitis in Vietnam.Pediatr Infect Dis J 1998; 17(Suppl 9):S192–4.

15. Anh DD, Kilgore PE, Kennedy WA, et al. Haemophilus influenzae typeb meningitis among children in Hanoi, Vietnam: epidemiologic pat-terns and estimates of H. influenzae type b disease burden. Am J TropMed Hyg 2006; 74:509–15.

16. Larsson M, Falkenberg T, Dardashti A, et al. Overprescribing of an-tibiotics to children in rural Vietnam. Scand J Infect Dis 2005; 37:442–8.

17. Kennedy WA, Chang SJ, Purdy K, et al. Incidence of bacterial men-ingitis in Asia using enhanced CSF testing: polymerase chain reaction,latex agglutination and culture. Epidemiol Infect 2007; 135:1217–26.

18. Gilligan PH. Impact of clinical practice guidelines on the clinical mi-crobiology laboratory. J Clin Microbiol 2004; 42:1391–5.

19. Wilson ML. Assessing the quality of sputum specimens submitted formycobacterial culture: old lessons, new lessons, and the future. Am JClin Pathol 1996; 105:665–6.

20. Smith-Elekes S, Weinstein MP. Blood cultures. Infect Dis Clin NorthAm 1993; 7:221–34.

21. Phuong HL, de Vries PJ, Nagelkerke N, et al. Acute undifferentiatedfever in Binh Thuan Province, Vietnam: imprecise clinical diagnosisand irrational pharmaco-therapy. Trop Med Int Health 2006; 11:869–79.

22. Phuong HL, de Vries PJ, Nga TT, et al. Dengue as a cause of acuteundifferentiated fever in Vietnam. BMC Infect Dis 2006; 6:123.

23. Pancharoen C, Thisyakorn U. Coinfections in dengue patients. PediatrInfect Dis J 1998; 17:81–2.

24. Liddle JL, McIntyre PB, Davis CW. Incidence of invasive pneumococcaldisease in Sydney children, 1991–96. J Paediatr Child Health 1999; 35:67–70.

25. Ispahani P, Slack RC, Donald FE, Weston VC, Rutter N. Twenty yearsurveillance of invasive pneumococcal disease in Nottingham: sero-groups responsible and implications for immunisation. Arch Dis Child2004; 89:757–62.

26. Fraser D, Givon-Lavi N, Bilenko N, Dagan R. A decade (1989–1998)of pediatric invasive pneumococcal disease in 2 populations residingin 1 geographic location: implications for vaccine choice. Clin InfectDis 2001; 33:421–7.

27. Ho PL, Chiu SS, Cheung CH, Lee R, Tsai TF, Lau YL. Invasive pneu-mococcal disease burden in Hong Kong children. Pediatr Infect Dis J2006; 25:454–5.

at Wayne State U



ownloaded from


Surveillance of Pneumococcal‐Associated Disease among Hospitalized Children in Khanh Hoa Province,...

Documents

Transcript of Surveillance of Pneumococcal‐Associated Disease among Hospitalized Children in Khanh Hoa Province,...