Download - The INCLEN Trust

Download - The INCLEN Trust




M.C. Steinhoff, MD 1 and K. Thomas, MD 2 for the IBIS Group

The IndiaCLEN Invasive Bacterial Infection Surveillance (IBIS) study is an on-going,

multicenter project funded by the International Clinical Epidemiology Network

(INCLEN) and the United States Agency for International Development (USAID) in

India. The study is being conducted in cooperation with Johns Hopkins University and

six teaching hospitals in India: All India Institute of Medical Sciences, New Delhi;

Christian Medical College and Hospital, Vellore; Government Medical College, Nagpur;

King George’s Medical College, Lucknow; Madras Medical College, Madras; and

Trivandrum Medical College, Trivandrum.

The IBIS surveillance project has successfully generated the first data for India in the

modern era regarding the importance of pneumococcal disease in adults and children and

of Haemophilus influenzae disease in children. In India, and throughout the developing

world, pneumonia and acute respiratory infections are the most frequently documented

illness in children under five years of age. Each year, around the world, more than four

million children under five die form respiratory infections, many of which are caused by

these two bacteria.

This project was funded for three years by USAID. INCLEN is currently seeking

continued funding so as to broaden the data base regarding Streptococcus pneumoniae

and H. influenzae diseases. Since serotype-specific vaccines to prevent these diseases are

available, continued gathering of information about the serotypes of these organisms is

required to estimate the impact of these vaccines. The H. influenzae type b (Hib) vaccine

was developed in the United States and over the past five years has virtually eradicated

Hib disease from North America and Europe, and has been shown to be highly effective

in South America and West Africa. The data which the IBIS researchers have developed

show that resistance of pneumococci to penicillin appears not to be a problem in India at

present, unlike the situation in Europe, USA, and some other parts of Asia. Acute

respiratory infection or pneumonia control programs in south Asia will find the

information regarding antibiotic sensitivity useful for selecting appropriate options for the

treatment regimens. In the future, the IBIS study will help to generate important

information regarding the burden of disease caused by these vaccine preventable diseases

as well as on the changing patterns of antibiotic sensitivity of the organisms causing

invasive bacterial diseases in India, with profound ramifications for combating these

diseases throughout the entire developing world.

1 Johns Hopkins University School of Medicine, Baltimore, USA

2 Christian Medical College, Vellore, India

Objectives of the IBIS Study

There are two primary objectives for the IBIS Study. The first objective is to describe the

epidemiology of S. pneumoniae and H. influenzae invasive infections in order to obtain

data necessary for optimal antibiotic therapy, and for eventual vaccine use. The specific

data which the researchers are looking for include the frequency of positive cultures for

S. pneumoniae and H. influenzae; the antibiotic sensitivity of isolates from invasive

disease; the distribution of serotypes; and the seasonality and age distribution of

infections caused by these bacteria.

The second objective of IBIS is to strengthen the capacities of the INCLEN Clinical

Epidemiology Unites to carry out nationally important studies.


Pneumococci and H. influenzae infections are know to cause substantial morbidity and

mortality in infants and children in the developing world. 1,2 Some information from

developing countries suggests that more than 75 per cent of the deaths from acute

respiratory infection are caused by pneumonia, both bacterial (including the two bacteria

IBIS is studying) and viral. 3 In many hospitals in developing countries, bacterial cultures

are not routinely done on patients. Because of either the cost and delay of bacterial

laboratory tests or their non-availability, physicians often must treat their patients with

antibiotics without confirmation of the causative agent. Since relatively few routine

cultures are done in some developing countries, there is very limited information

regarding the burden of vaccine-preventable disease caused by these two bacteria, their

antibiotic resistance patterns, or the bacterial serotypes which are prevalent locally. 4

WHO has stated that increased surveillance for these two bacteria is necessary. 2,4

Conducting this research in India is particularly compelling when one realizes that about

20% of the world’s children live in the Indian subcontinent.

Several studies of pneumonia and meningitis show that these two organisms together

cause about 50 per cent of all hospitalized pneumonia and about 40-70 per cent of all

pyogenic meningitis. 5 However, the data regarding age specific rates of disease, and

serotype distribution, for each of these organisms are limited, especially from Africa and

Asia 2 , and apparently not available from India.

While treatment of pneumonia and meningitis with antibiotics clearly reduces the

morality rate from these severe infections, the most cost-effective and definitive solution

to these problems lies with the development of vaccines. The data garnered by IBIS

researchers will be essential to guide the development of new pneumococcal vaccines in

those countries which have the greatest burden of illness. This data is necessary to

estimate the potential effect of the existing vaccines for these infections. The design of

an optimal polysaccharide vaccine requires local current data on serotype. Current

formulations of pneumococcal vaccines are based on the very limited information on the

distribution of invasive serotypes in developing countries. Consequently, the data which

the IBIS researchers are uncovering is critical to the development of effective and locally

appropriate pneumococcal vaccines. While the development of a vaccine will

dramatically reduce mortality among children under five, it will also benefit high risk

adults, particularly the elderly.

Current Status of the Study

A series of workshops was coordinated by Christian Medical College Hospital, Vellore

and Johns Hopkins University to define a common protocol for the selection of patients

to be studied at each hospital participating in the study. In addition, a common laboratory

protocol, modified from recommended World Health Organization (WHO) procedures,

was agreed upon by the participants, and standard reagents and organisms were

distributed to the participating laboratories. Blood, cerebrospinal fluid and other

normally sterile fluids were cultured. Sputum was not cultured.

A total of 3,600 cultures, at the six INCLEN centers, have been collected during the

initial two years of IBIS. The common pneumococcal serotypes identified were types 1,

4, 5, 6, 16, and 19. Types 1 and 5 are no longer common in the developed countries

but continue to be important in India; they account for more than 25% of infections

in India and should be included in vaccines for South Asia. Of the first 57 samples of

H. influenzae, all but two were serotype “b”, suggesting the use of the Hib vaccine will

prevent 97% of all invasive Haemophilus disease seen in hospitals in India. IBIS has

shown that H. influenzae is the most common cause of childhood bacterial meningitis in

India causing 30-40% of culture positive cases, and associated with a 20% mortality.

Also of note is the lack of resistance to penicillin among 157 S. pneumoniae samples.

Pneumococcal resistance to penicillin is fairly common in the United States, Europe and

other parts of Asia, but it is heartening to see it has not yet spread to this part of South

Asia. 6 This finding has important implications for national antibiotic policy.

External quality control of the serotyping procedures has been carried out at the Statens

Seruminstitut, Copenhagen, the WHO’s reference center. The quality control tests

demonstrated a 93% concordance with the initial serotyping performed at Christian

Medical College, Vellore. This high level of concordance demonstrates the validity of

the microbiology procedures at Christian Medical College, which may, at some point in

the future, become a regional reference center. The IBIS group has also developed

simple, cost-effective techniques for the laboratory. 7,8

INCLEN is apparently the first organization to undertake a systematic, collaborative

study of preventable invasive bacterial infections in India, and the IBIS study group has

demonstrated its capacity to generate the high quality data needed to answer relevant

questions about the serotype prevalence and antibiotic pattern of S. pneumoniae

infections in India. Additionally, IBIS has already generated data needed for health

planning in India as well as the entire South Asia region. For example, some new

pneumococcal vaccines do not include antigens of serotypes 1 and 5, but these particular

serotypes account for more than 25% of the pneumococcal infections in India.

The IBIS study has demonstrated the strengths and experience of the IndiaCLEN network

and its capacity to develop nationally important information regarding vaccine

preventable disease at a relatively low cost.


Invasive Bacterial Infection

Surveillance Study

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