INDIAN JOURNAL OF IJPP

PRACTICAL PEDIATRICS
IJPP is a quarterly subscription journal of the Indian Academy of Pediatrics
committed to presenting practical pediatric issues and management
updates in a simple and clear manner
Indexed in Excerpta Medica, CABI Publishing.

Vol.8 No.4 OCT.-DEC. 2006

Dr. A. Balachandran Dr. K.Nedunchelian
Editor-in-Chief Executive Editor

CONTENTS
FROM THE EDITOR'S DESK 271

TOPIC OF INTEREST - VACCINES

Various immunization practices 272
- Parthasarathy A

Newer vaccines (II) 281

- Dutta AK, Kush Jhunjhunwala

Additional vaccines - Current trends (Typhoid, MMR, Varicella) 292

- Niranjan Shendurnikar, Mukesh Kumar Singh

Passive immune prophylaxis for infections 301

- Baldev S. Prajapati, Rajal Prajapati

Immunization in special situations 309

- Shyam Kukreja, Sandeep Aggarwal

Journal Office: Indian Journal of Practical Pediatrics, Krsna Apartments, Block II, 1A, 50, Halls Road,
Egmore, Chennai - 600 008. INDIA. Tel.No. : 044-28190032 E.mail : ijpp_iap@rediff mail.com
Address for ordinary letters: The Editor-in-Chief, Indian Journal of Practical Pediatrics, Post Bag No.524,
Chennai 600 008.
Address for registered/insured/speed post/courier letters/parcels and communication by various
authors: Dr. A. Balachandran, Editor-in-Chief, Indian Journal of Practical Pediatrics, F Block, No. 177,
Plot No. 235, 4th Street, Anna Nagar East, Chennai - 600 102. Tamil Nadu, INDIA.
1
RADIOLOGIST TALKS TO YOU
The Central nervous system - Anatomical basis of radiology 315
- Vijayalakshmi G, Elavarasu E, Porkodi, Malathy K, Venkatesan MD

PICTURE QUIZ 318

CASE STUDY
Cutis verticis gyrata 319
- Sri Venkateswaran K, Purushothaman, Raveendranath V,
Saradambal N, Sujatha L, Susheela Rajendran
Cavernous sinus thrombosis - A case report 322
- Arunkumar J, Lakshmi S, Kumarasamy K, Ravisekar CV,
Venkataraman P, Vasanthamallika TK
Hereditary Sensory Autonomic Neuropathy type IV -
A very rare condition 325
- Nilesh Jain, Vyas BR, Shalini Jain
IAP TASK FORCE REPORT
Guidelines and Management of enteric fever in children 329
AUTHOR INDEX 341

SUBJECT INDEX 342

NEWS AND NOTES 280,291,300,314,317,321,324

FOR YOUR KIND ATTENTION

* The views expressed by the authors do not necessarily reflect those of the sponsor or publisher.
Although every care has been taken to ensure technical accuracy, no responsibility is accepted for errors
or omissions.
* The claims of the manufacturers and efficacy of the products advertised in the journal are the
responsibility of the advertiser. The journal does not own any responsibility for the guarantee of the
products advertised.
* Part or whole of the material published in this issue may be reproduced with
the note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission.
- Editorial Board

Published and owned by Dr. A. Balachandran, from Krsna Apartments, Block II, 1A,
50, Halls Road, Egmore, Chennai - 600 008 and printed by Mr. D. Ramanathan, at Alamu Printing Works,
9, Iyyah Street, Royapettah, Chennai - 600 014. Editor : Dr. A. Balachandran.

2
 EDITORS DESK
Greetings from the Journal Committee of the
IJPP. This issue will cover the remaining topics
on Vaccines. The journal committee once again
thanks Dr. Nitin K Shah for accepting to be the
Guest Editor and formulating the topics. We hope
our readers, both practicing pediatricians and
postgraduates will find these topics useful in day
to day practice.
The topic on Various immunization
practices is contributed by Dr. A. Parthasarathy.
He has discussed in detail, the issues on various
schedules of immunization in special situations.
He has also highlighted certain facts in adolescent
immunization and cleared the common myths.
The article on Newer vaccines is written
by Dr.A.K.Dutta, et al. They have covered certain
newer vaccines which are currently available and
also vaccines under development for the future
such as rotavirus, malaria and HIV vaccines.
Additional vaccines - current trends by
Dr.Niranjan Shendurnikar, et al. narrates those
vaccines not covered under National Immunization
Schedule but recommended by IAP. They have
summarized the pertinent issues with the additional
vaccines which are of clinical relevance and
patient-doctor concern to optimize vaccine
acceptance and cost effectiveness.
Kindly note the address of new premises ;
Krsna Apartments, Block II, 1A,
50, Halls Road, Egmore, Chennai - 600 008
WISH YOU
A HAPPY AND PROSPEROUS
NEW YEAR - 2007
3
Passive immune prophylaxis is used as post
exposure prophylaxis. In this article Dr.Baldev S
Prajapati, et al. mention the advantages and
disadvantages of human and animal products of
immunoglobulins, the various preparations
available, indications, doses etc.
Immunization in special situations by Dr.
Shyam Kukreja and Dr. Sandeep Aggarwal covers
some clinical circumstances which need
modifications of existing immunization practices.
How to tackle the situations like outbreaks,
adolescence, patients with malignancy,
immunotherapy and HIV infections are clarified
in this review.
We thank Dr. Vijayalakshmi, et al for their
contribution to the Radiologist talks to you
column. They have commenced from this issue
the other imaging modalities like CT and MRI.
To begin with the anatomical basis of radiology
of central nervous system is highlighted in this
issue.
We are happy to publish the Guidelines and
management of enteric fever in children which
is being brought under IAP - Presidents Action
Plan 2006.
We thank all the contributors for case study
and picture quiz columns in this issue.
 VACCINES II
THE VARIOUS IMMUNIZATION
PRACTICES
* Parthasarathy A
Abstract: Issues in various schedules of
immunization like Expanded Programme on
Immunization (EPI) and National Immunization
Schedule are discussed. Immunization in special
clinical circumstances like preterm, schedule for
lapsed immunization, rationale of scheduling
individual vaccines, spacing of multiple doses
of an antigen and current concepts of
combination vaccines are also covered. Certain
myths and facts in pediatric and adolescent
immunization are highlighted.
Key words: Immunization schedules, Special
Clinical Circumstances, Myths, Facts
The World Health Organization periodically
issues guidelines for best global immunization
practices. Various professional bodies also keep
updating the immunization practices with
reference to their individual countries. Centre for
Disease Control and Prevention, Atlanta, USA
issues guidelines every year updating the current
recommendations. In India since 1985, the Indian
Academy of Pediatrics is publishing Guide Book
on Immunization which is updated every 2/3 years.
However, controversies still exist among members
of the various professional bodies on issues like
* Sr. Clinical Professor of Pediatrics (Retd.),
Madras Medical College and
Deputy Superintendant,
Institute of Child Health and Hospital for Children
Chennai 600 008.
4
the various schedules for individual vaccines, use
of combination vaccines, simulta-neous
administration of multiple vaccines etc.
I. The various immunization
schedules
The Rationale: The purpose of administering a
vaccine is to offer optimal protection to the
vaccinee. For obtaining the optimal protection,
proper scheduling is mandatory based on
immunological responses. Among the live
vaccines BCG needs only a single dose. Others
like OPV, MMR and Varicella require a minimum
of 3/2/2 doses respectively for life long immunity
in a primary and repeat dose schedule since these
vaccines have no booster effect. Measles, MMR
and Varicella vaccines once thought to be highly
immunogenic in a single dose schedule are now
found to be immunogenic only when a repeat dose
is given. Hence the emerging concept of 2 doses
for MMR and Varicella vaccines and 3 or more
doses for OPV. On the other hand inactivated
subunit vaccines always need to be administered
in a prime boost schedule with the exception of
Hepatitis B vaccine which does not need booster
dose because of its capability of eliciting
anamnestic response following viral exposure.
Generally 3 primary doses are recommended for
inactivated vaccines and for vaccines containing
toxoid / subunit components followed by boosters.
However, Hib vaccine, Pneumococcal vaccine,
etc need either 3/2/1 primary dose(s) depending
upon the age of immunization followed by 1 or 2
boosters, since they act by the mechanism of
natural boosting.
 For certain vaccines like the DTP/DT/TT
etc the dose is the same i.e 0.5 ml for all ages.
For Hepatitis B vaccine, the dose is 0.5 ml and
1 ml respectively for children upto 10 years and
above 10 years. For Varicella vaccine a single dose
of 0.5 ml upto 12 years and 2 doses for those
above 13 years. Hepatitis A is administered in
0 (prime) and 6 months (boost) schedule with
0.5ml/1ml of pediatric or adult formulation. The
dose is 0.25ml/0.5ml for vaccines like Influenza
for children 6 months to 3 years and above 3
years respectively. Hence the schedules also vary
for these vaccines at different settings.1,2
The EPI Schedule
The schedule recommended for the
Expanded Program on Immunization(EPI) by
World Health Organization may be modified by
the ministries of Health in individual countries
based on local recommendations. This is the basis
of the National Immunization Schedule 1985
(Table 1) now in practice in India and the IAP
Immunization Time Table 2004 (Table 2) which
includes certain additional vaccines as well as
additional doses for routine vaccines. However it
should be clearly understood that, when additional
vaccines are desirable, routine vaccines are
mandatory.1,2
The vaccines administered in the National
Immunization Schedule (which once introduced
cannot be withdrawn and should be given free of
cost to all beneficiaries) should be
epidemiologically relevant, immunologically
appropriate, technically sound, economically
viable and socio culturally acceptable. Logistic

Table 1. National immunization schedule 1985 3,4

Age Vaccines
Birth BCG, OPV-0 (for institutional deliveries)
6 weeks DTP1, OPV1 (BCG, if not given at birth)
10 weeks DTP2, OPV2
14 weeks DTP3, OPV3
9 months Measles
16-24 months DTP, OPV
5-6 years DT*
10 years TT*
16 years TT
For pregnant women
Early in pregnancy TT1 (if not immunized early in childhood) or booster if
already fully immunized
One month after TT1 TT2**
NOTE
* A second dose of DT or TT vaccine should be given at an interval of one month if there is no clear
history or documented evidence of previous immunization with DTP.
** A second dose of TT vaccine should be given at an interval of one month if there is no clear history or
documented evidence of previous immunization with DTP, DT or TT vaccines. (Source: National Child
Survival and Safe Motherhood program Module, Ministry of Health and Family Welfare, Govt. of India
New Delhi ; 1994)

5
Table 2. IAP Immunization time table 2004 6
Vaccine Age recommended
1. BCG From birth to 2 weeks
2. OPV At birth; 6, 10 & 14 weeks; 15-18 months; 5 years
3. DTPwc/DTPa 6, 10 & 14 weeks; 15-18 months; 5 years
4. Hepatitis B Birth, 6 & 14 weeks or Birth, 1 & 6 months or 6,10 & 14 weeks.
5. Hib 6, 10 & 14 weeks; 15-18 months
6. Measles 9 months+
7. MMR 15-18 months
8. Typhoid 2 years+ (Revaccination 3-4 years)
9. Td 10 & 16 years
10. 2 doses of TT Pregnant women
Newer Vaccines
1. Varicella Above 1 year
2. Hepatitis A Above 1 year

Note:
1. The IAP endorses the continued use of whole cell pertussis vaccine because of its proven efficacy and
safety. Acellular pertussis vaccine may undoubtedly have fewer side-effects (like fever, local reactions
at injection site and irritability), but this minor advantage does not offset the inordinate costs involved
in the routine use of this vaccine.
2. With the marked decline of paralytic polio cases in our country, inactivated polio vaccine (IPV) should
replace OPV in a phased manner.
3. If the mother is known to be HBs Ag negative, HB vaccine can be given along with DTP at 6, 10, 14
weeks. If the mothers HBs Ag status is not known, it is advisable to start vaccination soon after birth to
prevent perinatal transmission of the disease. If the mother is HBsAg positive (and especially HBeAg
positive), the baby should be given Hepatitis B Immune Globulin (HBIG) within 24 hours of birth, along
with HB vaccine.
4. Combination vaccines can be used to decrease the number of injections being given to the baby and to
decrease the number of clinic visits. Under no circumstances, however, should combination vaccines
be viewed as being more effective than vaccines given separately. The manufacturers instructions
should be followed strictly whenever mixing vaccines in the same syringe prior to injection.
5. At present, the only typhoid vaccine available in our country is the Vi Polysaccharide Vaccine.
Revaccination may be carried out every 3-4 years.
6. Under special circumstances (eg. Epidemics), measles vaccine may be given earlier than
9 months followed by MMR at 12-15 months.
7. MMR, Varicella and Hepatitis A vaccines can be given after one year of age at any time.
8. During pregnancy, the interval between the two doses of TT/Td should be at least one month.

6
considerations have to be taken into account before
scheduling these vaccines. Though the Indian
Academy of Pediatrics recommends, 3 doses of
Hepatitis B vaccine in 3 different schedules viz
birth, 6 and 14 weeks; Birth, 1 month and
6 months; or 6, 10 and 14 weeks; (since the
vaccine is immunogenic in all these schedules),
the Govt. of India has chosen to introduce
Hepatitis B vaccine in 6,10 and 14 weeks schedule
only, due to logistic considerations. However in
private practice, members of IAP practice the
IAP immunization time table. In Government
health facilities only the National Immunization
Schedule is followed.
II. Immunization in special
circumstances 3,4,5,7
1. Immunization in preterm infants
In general, all vaccines may be administered
as per schedule according to the chronological
age irrespective of birth weight or period of
gestation. Very low birth weight babies can
be given immunizations after initial
stabilization.
2. Children receiving corticosteroids
Children receiving oral corticosteroids in high
doses (eg. Prednisolone 1-2 mg/kg/day) for
more than 14 days should not receive live
virus vaccines until steroids have been
discontinued for at least one month. Killed
vaccines are safe in such situations. Patients
Table 3. Vaccination schedule for a non immunized child 3,4,5
Age Less than 5 years
First visit BCG, OPV, DTP, HB
2nd visit OPV, DTP, HB
(1 month later)
3rd visit OPV, DTP, HB, Measles or
(1 month later) MMR, Typhoid
1 year later OPV, DTP
Every 3 years Typhoid booster
7
on topical or inhaled steroid therapy should
not be denied their age appropriate vaccines.
3. Children awaiting splenectomy
Children with loss of splenic function either
with congenital asplenia or after splenectomy
are at high risk of serious infections with
encapsulated organisms. If surgical
splenectomy is being planned, immunization
with Pneumococcal, Hib and Meningococcal
vaccines should be initiated at least 2 weeks
prior to splenectomy.
4. The schedule for lapsed immunization
For children who have missed the routine
immunization during infancy or children who
report late for immunizations, the schedule
suggested is given in Table 3.
5. Adolescent immunization
schedule 3,4,5
Adolescent immunization is also mandatory
for those children who have not been adequately
immunized already and for those adolescents
who leave abroad for education or employment
(Table 4).
Thus it may be seen from the above
discussion, that the various schedules are very
much needed for infant, childhood and adolescent
routine immunization and immunization under
special circumstances. However, consensus
should be the mainstay of these schedules rather
More than 5 years
TT/Td, HB
TT/Td, HB
HB, MMR, Typhoid
-
Typhoid booster
Table 4. Adolescent immunization schedule 6,10,11
Vaccine Age
1. Tetanus diphtheria toxoid
Boosters at 10 and 16 years
2. Rubella vaccine (or) 1 dose to girls at 12-13 years of age, if MMR was not given earlier (or)
MMR vaccine 1 dose at 12-13 years of age, if not given earlier
3. Hepatitis B vaccine 3 doses at 0,1 and 6 months, if not given earlier
4. Typhoid vaccine Vi-polysaccharide vaccine every 3 years
5. Varicella vaccine* 1 dose upto 13 years and 2 doses (at 4-8 weeks interval)
after 13 years of age (if not given earlier)
6. Hepatitis A vaccine* 2 doses - 0 and 6 months(if not given earlier)
* Mandatory for adolescents going abroad or staying in hostels.

than raising unnecessary controversies and
confusing doctors especially when the practice of
immunization has become an integral part of day
to day practice.
It should also be noted that in these days of
easy internet access parents go through so many
web sites on immunization including the
controversial sites and hence the practicing
pediatric physicians have to update their
knowledge keeping abreast of the current concepts
and latest recommendations.
IV. Rationale of scheduling
individual vaccines 3,4,5,8,9
a. BCG: BCG vaccine elicits Cell mediated
immunity (CMI). Maternal CMI is not
transferred to the fetus. Therefore BCG can
be given at birth.
b. OPV: OPV is given by mouth; it establishes
local infection in a proportion of children.
Maternal antibody in the infants circulation
is a very weak inhibitory factor; hence OPV
also can be given at birth.
c. Hepatitis B: Hepatitis B surface antigen is an
excellent immunogen overcoming to a large
extent, the inhibiting effect of maternal
antibody; hence that too can be given at birth.
The HB birth dose along with HBIG is
mandatory for babies born to HBsAg positive
mother followed by 2 more doses at 6 and
14 weeks. Babies born to HBsAg negative
mothers can receive the vaccine either at
6, 10, 14 weeks schedule or at birth, 1 and 6
month schedule. The vaccine is highly
immunogenic in whichever schedule that is
followed. No doubt the third dose given at
6 months produces highest geometric mean
titer (GMT) and GMT is directly proportion-
ate to long term protection. However in view
of the anamnestic response by which HBsAg
acts, natural boosting occurs on virus
exposure even when the vaccine is given at
a minimum of 4 weeks interval thus ensuring
long term protection (Fig.1). In countries
where universal HB immunization is practiced
HB vaccine is advocated either at 4, 6, 8
weeks interval only, comprising of a total of
3 doses. No booster doses are recommended.
Immunogenicity at different schedules is
comparable as mentioned below :
0, 1, and 6 months 96 98%
0, 1, and 2 months 96%
0, 6, and 14 weeks 95 96%
6, 10, and 14 weeks 97 %
2, 4, and 6 months 99%

8

Fig. 1. Anamnestic response following HB
vaccination administered at 4 weeks interval 8,9
Note: The required protective value is 10 mIU.When
given at a minimum of 4 weeks interval the antibody
response elicited is >100 mIU.When the antibody
level declines below the protective level over a period
of time, even a transient infection automatically
elevates the antibody level to well above the
protective titer due to anamnestic response. The upper
curve denotes the anamnestic response when some
protective antibodies are still present and the lower
curve denotes the anamnestic response when the
antibody titre falls below the protective level.
d. DTaP / DTwP / Hib vaccines :
These vaccines can be given earliest at
6 weeks of age since they are capable of eliciting
optimum immune response evoking protective
titres
e. Measles vaccine:
Live measles vaccine may be completely
inhibited in the presence of detectable maternal
antibodies upto 9 months in the infants circulation.
Therefore measles vaccine is given after a delay
of 9 months from birth, followed by MMR after
12 months.
f. MMR and Varicella vaccines :
These vaccines can be given earliest at
12 months of age. They can be given together or
if given separately, should be administered at
4 weeks mandatory interval.
9
V. Combination vaccines -Current
concepts 10,11
1. Combination vaccines have become the
order of the day in developed countries and in
developing countries like India, the concept is
picking up. For instance in India, today, we can
adopt a 3-4-7 strategy with the available
combination vaccines especially for a baby born
to HBsAg negative mother. We need to administer
only 3 vaccine formulations viz BCG at birth,
combined DTP-HB-Hib at 6, 10 and 14 weeks
along with oral polio vaccine at birth, 6, 10 and
14 weeks before the baby reaches 4 months of
age and thus prevent 7 diseases viz tuberculosis,
poliomyelitis, diphtheria, pertussis, tetanus,
hepatitis B and Hib infection.
Current status of new combination vaccines
Already developed DTPw + Hib
DTPw + Hepatitis B
DTPw + Hib + Hep B
DTPa + IPV
DTPa + Hib
DTPa + Hib +
Hep B + IPV
Hepatitis A + Hepatitis B
MMR + Varicella
Under development DTPa + Hib + IPV +
Hep B + Hep A
Available for DTPw + Hib
use in India DTPw + Hep B
DTPw + Hib +
Hepatitis B
Hepatitis A + Hepatitis B
2. The immunogenicity of individual vaccine
components is excellent even when given in
combination formulation12,13. Fig.2 depicts the
individual antigen immunogencity.
It could be seen from the above illustration
that all the vaccine components elicit excellent
 Diptheria(>0.01 IU/ml)
Tetanus (>0.1 IU/ml)
Pertussis (>3.92 EU/ml) - AF Antifimbrial
Pertussis (>2.24 EU/ml) - AP Antipertactin
Hib (>0.15 g/ml)
Hib (> 1.00 g/ml)
Hepatitis B (>10 IU/ml)
Fig.2. Immunogenicity of individual antigens
immune response when given in combination
formulation.
In India two brands of DTwP-HB-Hib
combination vaccine formulations are available viz.
(1) lyophilized formulation and (2) fully liquid
formulation. Similarly there are two brands of
DTwP-Hib combination vaccine formulations viz.
(1) lyophilized formulation and (2) fully liquid
formulation. The lyophilized Hib component in
pellet form is mixed extraneously using the
recommended DTPw formulation as a diluent.
These are studies to show that administering
DTPw and Hib in combination results in reduced
mean PRP antibody levels compared to giving
the same components separately. However, even
in those studies with statistically significant
reduction, antibody levels were still high and 90%
of children (typically 95%) developed greater than
1 mcg/ml of antibody to PRP-T / CRM 197
component of Hib. Plotkin in his review has
described that, this reduced immunogenicity of
Hib when given in combination with DTPw
appears to be of no clinical importance.
Recent data shows that addition of Hib
component to either the DTPw / DTPw HB
lyophilized / liquid formulations does not affect
the safety and immunogenicity of either the
PRP-T / CRM197 Hib component.
10
100%
100%
97%
81%
100%
90%
100%
VI. Spacing of multiple doses of same
antigen 5
4 weeks interval is mandatory for spacing
multiple doses of same antigen. Recommended
age of initiation and maintaining interval between
multiple doses of the same antigen provide optimal
protection. Though recommended minimum
interval of 4 weeks (28 days) is mandatory,
vaccine doses administered less than 4 days before,
can also be counted as a valid dose. Rabies vaccine
is an exception and should be given in 0, 3, 7, 14
and 28 days schedule.
It is therefore mandatory that the
recommended schedules are followed to obtain
optimum immunogenicity. It is always advisable
to refer to the manufactures recommendations
especially before administering newer vaccines.
Points to remember
1. EPI Schedule is the sheet anchor of
childhood immunization.
2. Modifications as needed may be adapted
as per local government / professional body
recommendations.
3. Different schedules have to be followed
under special clinical circumstances.
VII. Myths and facts 12,13
The following myths and facts need to be emphasized on the basis of available evidence.
S.No. Myth
1. Too many vaccines might overload
the immune system
2. Combination vaccines may be less
effective than vaccines administrated
separately
3. Thimerosal used as preservative in
multi dose vaccine formulations is
neurotoxic
4. Aluminium salts used as adjuvants in Since the discovery of DTPw combination
certain vaccines may be harmful to
the child
4. The fear compounded about the doubtful
immunogenicity of individual antigens in
combination formulations, is not true.
5. Recommended interval of atleast 4 weeks
between multiple doses of same antigen is
mandatory.
6. Simultaneous administration of multiple
antigens does not suppress the immune
system.
7. Various myths and vaccination scares are
not true.
Fact
The immune system can simultaneously respond
to over 10 million antigens at any one time
Natural infections present more antigens
(2)
eg Hib-50 or more , Hep B-4 or more
Whole cell Pertussis vaccine contains over
3000 antigens, yet no overload
The DTPw-HB-Hib combination formulation
has
- excellent immunological response
- superior safety and less reactogenicity
The DTPa-HB-Hib combination formulation has
enhanced safety and lowered the reactogenicity
With 2.5 mcg for each vaccine administration,
Thimerosal which is ethyl mercury, does not
produce any neurotoxicity as once feared
formulation in 1943, DTPw-HB and DTPw-HB
Hib in 1998, Alum salts have been successfully
used as adjuvants without any significant
adverse effect
References
1. American Academy of Pediatrics. Scheduling
Immunization. In: Pickering LK, (Ed), 2000
Red Book: Report of the Committee on
th
Infectious Diseases. 25 Edn, Elk Grove
Village IL, American Academy of Pediatrics;
2000: pp54-79.
2. American Academy of Pediatrics. Hepatitis A.
In: Pickering LK, (Ed),. 2000 Red Book:
Report of the Committee on Infectious
th
Diseases. 25 Edn, Elk Grove Village IL,
American Academy of Pediatrics; 2000:
pp282-283.
11
3. American Academy of Pediatrics. Hepatitis B.
In: Pickering LK, (Ed),. 2000 Red Book:
Report of the Committee on Infectious
th
Diseases. 25 Edn. Elk Grove Village IL,
American Academy of Pediatrics; 2000:
pp294-300.
4. American Academy of Pediatrics. Immunizing
agents. In: Pickering LK, (Ed), 2000 Red
Book; Report of the Committee on Infectious
th
Diseases, 25 Edn. Elk Grove Village IL,
American Academy of Pediatrics; 2000;p9.
5. Immunization Special Circumstances, IAP
nd
Guide Book on Immunization, 2 Edn:
Parthasarathy A, Dutta AK, Bhave S (Eds), IAP
Publication, Mumbai 2001: 14, 17, 47-49.
6. Adolescent Immnuzation Schedule, IAP Guide
Book on Immunization. Dubey AP, Surjith
Singh: (Eds). Indian Academy of Pediatrics,
Mumbai 2004;8: pp37-42.
7. Immunization in Special clinical circum-
stances. Innunization in Clinical Practice :
Naveen Thacker, Nitin K Shah, (Eds) Jaypee
Bros. Medical Publishers, New Delhi,
2004;pp10-11.
8. Claire-Anne, Siegrist. Understanding immune
response to Vaccine: Immunization in
childhood. Annales Nestle 2000; 58:75-81.
9. Global Program for Vaccines and
Immunization. Expanded Program on
Immunization Policy on Hepatitis B
Immunization schedule. WHO GPV/GEN/20.
10. American Academy of Pediatrics. Hepatitis A.
In: Pickering LK (Ed): 2000 Red Book: Report
of the Committee on Infections Diseases.
th
25 Edn, Elk Grove Village IL, Americal
Academy of Pediatrics, 2000; pp280-282.
11. American Academy of Pediatrics. Varicella
infection, Recommendations for Immunization
In: Pickering LK (Ed), 2000 Red Book.: Report
of the Committee in Infectious Diseases.
th
25 Edn, Elk Grove Village IL, American
Academy of Pediatrics, 2000: pp634-638.
12. Francis Andre. In Proceedings on
Combination Vaccines: Glaxo SmithKline
publication 2001.
13. Parthasarathy A. Combination Vaccines. The
choice ahead in Pediatric Index. Kumar A,
Mohan M, Mohan H (Eds) Meditech
Publishers and Distributors, New Delhi 2001;
1:3;13-18.

NEWS AND NOTES

COMGAN
SECOND INTERNATIONAL PEDIATRIC NEPHROLOGY TRAINING COURSE
All India Institute of Medical Sciences, New Delhi
9-11, March 2007
Day 1 : Targeted towards specialists, those interested in nephrology, PG students
Day 2, 3 : Intended for specialists, pediatricians, PG students
Registration Fee Till 15-01-2007 Thereafter
Days 1-3 Rs. 1,500 Rs. 2,000
Days 2, 3 Rs. 1,000 Rs. 1,500
Postgraduate students : 50% concession
Demand draft in favour of Pediatric Nephrology Training Coure payable at New Delhi
Chairperson : Arvind Bagga Secretary : Pankaj Hari
Department of Pediatarics, All India Institute of Medical Sciences, Ansari Nagar,
New Delhi - 110 029, India. Phone : 011-26593472; 26588700; ext. 4858
E-mail : arvindbagga@hotmail.com, pankajhari@hotmail.com

12
 VACCINES II
NEWER VACCINES - II
* Dutta AK
** Kush Jhunjhunwala
Abstract: This article deals with few vaccines,
which are already available(acellular pertussis
Tdap and rota virus vaccines), and other
vaccines, which are under development (malaria
and HIV vaccines). Multi component acellular
pertussis vaccines are effective and have less
adverse effects than whole cell vaccines. Tdap is
expected to protect the adolescents against
pertussis and gives protection against tetanus
and diphtheria. The usefulness of presently
available rotavirus vaccine can be established
only after the enumeration of serotypes of
rotavirus strain in India. Malaria vaccines
developed to target different stages of malarial
parasite are found to have varied response in
trials. A safe and effective vaccine remains
elusive with regard to HIV vaccine.
Key words: Acellular pertussis vaccine, Tdap,
Rotavirus, Malaria, HIV Vaccines.
The worlds oldest vaccine invented and
perfected by Sir Edward Jenner has become
obsolete after serving the mankind for over a
century and half. It is needless to state that
vaccination is one of the most cost effective
methods of prevention of disease. In spite of the
* Director, Professor and Head of the Department,
** Senior Resident,
Lady Hardinge Medical College and associated
Kalawati Saran Children Hospital,
New Delhi- 110 001.
13
introduction of universal immunization program
in the world followed by EPI program, still
1.8 million deaths occur in the world due to
common vaccine preventable diseases like measles,
tetanus, whooping cough, and diphtheria.
Approximately 7,45,000 deaths occur in the world
due to measles alone. A large number of vaccine
preventable deaths occur in India due to poor
coverage of vaccine in National Immunization
Program. A large number of newer vaccines are
available in the world including India and many
more vaccines are in the process of development.
The present article will deal with few of the
available vaccines and significant ones in the
process of development.
1) Acellular pertussis vaccine
Diphtheria, tetanus and pertussis are still a
major cause of mortality and morbidity in the
world. Although the whole cell pertussis vaccine
has good immunogenicity, there is a fear of serious
adverse reactions associated with it in the form of
encephalopathy, persistent screaming episodes,
convulsions and hyperpyrexia.
Better understanding of the biology of
B.pertussis and the isolation of components that
appear to be important in the pathogenesis of
disease led to the development of purified
component, known as acellular pertussis vaccine,
in Japan in 1981. The encouraging results of the
Japanese experience stimulated thorough efforts
in developed world to develop other acellular
pertussis vaccines.1, 2, 3
Today, in the world almost a dozen
formulations of acellular pertussis vaccines have
been evaluated for the efficacy and safety and
are being extensively used. These vaccines vary
from one another with respect to their source,
number of components, quantity of each
component, method of purification, method of
toxin inactivation, incorporation of adjuvant and
excipients.
At present there is only one acellular pertussis
containing DTaP available in India. The acellular
pertussis with DT formulation contains pertussis
toxins, viz. pertactin and filamentous
hemagglutinin.
Many large scale acellular pertussis vaccine
efficacy trials have been conducted in various parts
of the world and the results have shown that the
vaccine is safer than the whole cell vaccine in
terms of common as well as serious adverse
reactions.
The efficacy of the whole cell pertussis
vaccine is in the range of 85-95% and that of the
acellular vaccine ranges from 75-90%.1 Whole
cell pertussis vaccine is very effective and
inexpensive. The choice of vaccine depends on
balancing considerations of relative efficacy,
adverse effects and most important is the cost.
However for second booster dose and especially
if it is delayed due to some reasons, acellular
pertussis vaccine would be more safe in terms of
serious adverse reactions.
Doses and Schedule
Three primary doses beginning at 6 weeks
as per the national schedule of the country can be
used safely. In USA 2-4-6 months schedule and
in some countries 2-3-4 months or 3-5-7 months
schedule are in use. The duration of immunity
with the entire schedule using acellular pertussis
vaccine has been found to be equal or more than
that of whole cell pertussis vaccine. Following
3 doses primary schedule, the immunity lasts for
2-4 years, and with two more booster doses, at
14
18-24 months and 5 years, the immunity would
last longer up to 10-15 years. There is evidence
to show that herd immunity is produced using
acellular pertussis vaccine.
Safety and adverse events
Acellular pertussis vaccine has been found
to reduce both the common adverse events e.g.
fever, pain, irritability as well as the uncommon
adverse events e.g. seizures, shock like episodes
by two third compared to the whole cell vaccine.
It has been observed that with latter doses of
acellular pertussis vaccine the rate of adverse
reaction remains less than that seen with the whole
cell vaccine. Acellular pertussis vaccine in reduced
dose has the advantage of use in adults as an
essential tool for control of pertussis.1, 4
Cochrane Review
Six efficacy trials and 45 safety trials were
included. Acellular pertussis vaccines with three
or more pertussis antigens were more effective
than those with one or two antigens. They were
also more effective than one type of whole cell
pertussis vaccine, but less effective than two other
types of whole cell vaccines. Differences in trial
design precluded pooling of the efficacy data and
results should be interpreted with caution. Most
systemic and local adverse events were
significantly less common with acellular than with
whole cell pertussis vaccines.
Conclusions
Multi-component acellular pertussis vaccines
are effective and show less adverse effects than
whole cell pertussis vaccines. However in countries
where cost is a concern, whole cell pertussis
vaccine can be safely used taking into considertion
the risk, benefit of the disease versus adverse
reaction to whole cell vaccine.5
2) Tdap vaccine
Tdap is a formulation for use in adolescents
and contains reduced content of diphtheria toxoid
and acellular pertussis; and normal content of
tetanus toxoid. Pertussis, an acute, infectious
illness, remains endemic in major part of the world
despite routine childhood pertussis vaccination for
more than half a century and high coverage levels
in children for more than a decade.
Recent estimates from the WHO suggest that
in 2002 about 18,351,000 cases of pertussis
occurred worldwide, the vast majority of which
were in developing countries, and that about
294,000 patients died from this disease. It is further
estimated that in 2002 global vaccination against
pertussis averted more than 37 million cases and
587,000 deaths.6 According to a Central Bureau
of Health Intelligence (CBHI) study, the number
of reported cases of pertussis in India has increased
recently, by 50 percent from 1997 to 2003.
A primary reason for the continued
circulation of Bordetella pertussis is that immunity
to pertussis wanes approximately 5 - 10 years after
completion of childhood pertussis vaccination,
leaving adolescents and adults susceptible to
pertussis.7
In 2004, there were more than 25,000 cases
of pertussis in the United States. More than 8,000
of these cases were among adolescents 11-18
years of age. Up to two in 100 adolescents with
pertussis are hospitalized or have complications.7
The spectrum of disease caused by
B.pertussis in adolescents ranges from mild illness
with cough to classic pertussis; infection also can
be asymptomatic.
During the year 2005, two products
containing reduced contents of diphtheria, acellular
pertussis; and normal content of tetanus toxoid
(Tdap) for use in adolescents (and 1 product for
use in adults) were licensed in the United States.
In pre-licensure studies, Tdap administered as a
single booster dose to adolescents was shown to
be safe and effective against tetanus, diphtheria,
15
and pertussis. 7 Currently pediatric DTaP is
routinely advocated for children aged <7 years,
pediatric diphtheria and tetanus toxoids vaccine
(DT) for children aged <7 years with
contraindications or precautions for pertussis
components, and adult tetanus and diphtheria
toxoids vaccine (Td) routinely for persons aged
>7 years. The formulation of choice for
vaccination of persons aged >7 years has been
Td rather than pediatric DT, as the lower
diphtheria toxoid antigen content of Td induces
an adequate immune response and lower rates of
adverse reactions in adults than the pediatric DT.7
In India, since children usually get DT at the age
of five years, and as the incidence of pertussis is
rising alarmingly in the age group of 5-15 years,
Tdap has been recommended for a lower age
group as compared to that in US. Thus, in India
Tdap has been registered for use in children over
the age of 4 years, who have already received
their primary DTP doses in the first and second
year of life. Currently, there is a globally-approved
acellular pertussis boosting vaccine for all age
groups available in India, in the form of Tdap.
Composition of vaccine
Each dose of Tdap contains aluminum
hydroxide (<0.39 mg aluminum) as the adjuvant,
4.5 mg NaCl, <100 g residual formaldehyde and
<100 g polysorbate 80 (Tween 80) per 0.5mL
dose. Tdap contains no thiomerosal or other
preservative. Tdap is available in two
presentations: a pre-filled disposable syringe
without a needle and a single dose vial. The
pertussis antigen composition of the adolescent
and adult Tdap formulations is similar to pediatric
DTaP, but some of the pertussis antigens are
reduced in quantity.6,7
Dosage and administration
The dose of Tdap is 0.5 mL, administered
intramuscularly (IM), preferably into the deltoid
muscle.
Safety
The primary safety study, conducted in the
United States, was a randomized, observer-
blinded, controlled study in which 3,080
adolescents aged 1018 years received a single
dose of Tdap. No immediate events (within 30
minutes of vaccination) were reported.
Adverse effects:
Mild
Pain and redness or swelling
Mild fever/ headache/ tiredness/ nausea,
vomiting diarrhea.
Other mild problems reported include chills,
body aches, sore joints, rash and swollen
lymph nodes.
Moderate to severe
Severe pain at the injection site / severe
redness or swelling / fever more than 102F
A severe allergic reaction could occur after
any vaccine. These are estimated to occur
less than one in a million doses.
Specific recommendations to reduce pertussis
morbidity in adolescents and maintain the standard
of care for tetanus and diphtheria protection in
adolescents aged 11 to 18 years are as follows:
Adolescents should receive a single dose of
Tdap instead of tetanus and diphtheria toxoids
vaccine (Td) for booster immunization
against tetanus, diphtheria, and pertussis if
they have completed the recommended
childhood diphtheria and tetanus toxoids and
whole cell pertussis vaccine (DTP)/diphtheria
and tetanus toxoids and acellular pertussis
vaccine (DTaP) vaccination series and have
not received Td or Tdap. The recommended
age for Tdap vaccination is 11 to 12 years.
Those adolescents, who received Td, but not
Tdap, should receive a single dose of Tdap
16
to confer protection against pertussis,
provided they have completed the
recommended childhood DTP/DTaP
vaccination series. To reduce the risk for local
and systemic reactions after Tdap
vaccination, there should be an interval of at
least 5 years between Td and Tdap.8,9
Contraindications
For use of Tdap or Td are a history of serious
allergic reaction (i.e. anaphylaxis) to any
component of the vaccine; and history of
encephalopathy of undetermined cause within
7 days of administration of a vaccine with pertussis
components. Adolescents with the latter
contraindication should receive Td instead of
Tdap.
Simultaneous vaccination with Tdap and
other vaccines
If two or more vaccines are indicated, they
should be administered during the same visit (i.e.,
simultaneous vaccination). Each vaccine should
be administered using a separate syringe at a
different anatomic site.
Can pediatric DTaP be used in adolescents
or can adolescent Tdap be used in the
primary series in children?
No. The capital and lowercase abbreviation letters
denote relatively larger and smaller content of
antigens. Tdap would be expected to have inferior
immunogenicity of diphtheria and pertussis
components in young children, and DTaP would
be expected to have increased reactogenicity in
adolescents. The primary objective of vaccinating
adolescents with Tdap is to protect the vaccinated
adolescents against pertussis while maintaining the
standard of care for protection against tetanus and
diphtheria. A secondary objective of adolescent
Tdap vaccination is to reduce the reservoir of
pertussis within the population at large and
potentially reduce the incidence of pertussis in
other age groups, including infants who have the
highest risk for complications from pertussis. The
extent to which the secondary objective can be
achieved through adolescent vaccination is
unknown.
3) Rotavirus Vaccine
Rotavirus kills approximately half a million
children in the developing countries of the world
and accounts for about one third of hospitalization
for childhood diarrhea throughout the world.10
The first rotavirus vaccine made from
human-rhesus reassortant strains was introduced
in USA but soon suffered a serious setback due
to the possible causal relationship with
development of intussusception following
vaccination.10
At present there are two available rotavirus
vaccines in the world. The first one is the mono-
valent vaccine derived from the most common
human rotavirus strain G1P(8), that has been
attenuated. The mono-valent vaccine strain
replicates well in the gut , is shed by more then
50 % of patients receiving the vaccine after the
first dose and like natural rotavirus infection
provides cross protection against most of the other
serotypes.
This vaccine is given in two doses starting
at 6 weeks of age at an interval of 1-2 months.
The protective efficacy of the vaccine against wild
type of G1P(8) strain induced severe rotavirus
diarrhea is 90%. The efficacy of the vaccine
against strain sharing only P(8) antigen {(G3P (8),
G4P (8) and G9P (8)} is 87.3%. Type G2P (4)
rotavirus which does not share either the G or the
P antigen with the vaccine strain was detected in
less number of cases and against it the vaccine
showed efficacy of 41.0%.10,11
The incidence of severe gastroenteritis of any
etiology that requires rehydration according to
17
WHO plan B or C was 30.9/1000 infant years in
the vaccine group as compared with 51.7 per 1000
infant years in the placebo group for an overall
rate reduction of 40.0 percent among vaccine
recipient. Similarly the rate of hospitalization for
diarrhea of any cause was significantly reduced
by 42.0% in the vaccine group.
The second vaccine is a penta-valent vaccine
based on a bovine strain, WC3 that contains five
human bovine reassortant viruses. The bovine
virus grows less well in the human intestine so
that aggregate titer required to immunize a child
is greater. The bovine vaccine strains are
infrequently shed in the stools. Three oral doses
are required at an interval of one month. The
efficacy of this vaccine is similar to human mono-
valent strain. Both the vaccines are safe and no
causal relationship with intussusception has been
observed in large trials.10
Conclusion : Current evidence shows that rhesus
rotavirus vaccine (particularly RRV-TV) and the
human rotavirus 89-12 are efficacious in
preventing diarrhea caused by rotavirus and all-
cause diarrhea. Bovine rotavirus vaccine were also
efficacious, but safety data are not available. Trials
of new rotavirus vaccines will hopefully improve
the evidence base. Randomised controlled trials
should be performed simultaneously in high,
12
middle and low income countries.
The rotavirus surveillance network in India
is now trying to establish the epidemiology of
rotavirus disease in India. The data would be of
immense help to identify the serogroups involved
and whether the available rotavirus vaccine would
be beneficial in Indian subcontinent or not.
4) Malaria Vaccine
Malaria continues to claim an estimated 2 to
3 million lives annually and is known to account
for untold morbidity in approximately 300 to 500
million people infected annually. Approximately
2.48 million cases are reported annually from
South Asia of which 75% cases are contributed
by India alone.12
At-risk groups include those in whom
immunity has not yet developed (travellers, young
children in endemic areas, etc.) and those in whom
immunity has diminished (pregnant women, and
people from endemic areas who have ceased to
be routinely exposed to infection). Malaria is often
cited as a substantial impediment to economic and
social development in endemic regions.
Malaria is considered a re-emerging disease,
due largely to the spread of drug-resistant parasite
strains, decay of health-care infrastructure and
difficulties in implementing and maintaining vector
control programs in many developing countries.
Historically, vaccines have been one of the
most cost-effective and easily administered means
of controlling infectious diseases, yet no licensed
vaccine exists for malaria. Accumulating basic and
clinical research suggest that effective vaccines
for malaria can be developed and could
significantly reduce morbidity and mortality, and
potentially reduce the spread of infection.
The idea that a vaccine against malaria is feasible
is supported by the following findings:
Immunity can be acquired as a result of
natural exposure.
Most of the severe disease in endemic area
occurs in young children before they have
developed immunity.
Passive transfer of purified immunoglobulin
from immune people has been shown to be
protective.
A pre-erythrocytic vaccine would protect against
the infectious form injected by a mosquito
(sporozoite) and/or inhibit parasite development
in the liver. An erythrocytic or blood stage vaccine
would inhibit parasite multiplication in the red cells,
thus preventing (or diminishing) severe disease
18
during the blood infection. A sexual stage vaccine
does not protect the person being vaccinated, but
instead interrupts the cycle of transmission by
inhibiting the further development of parasites once
they, along with antibodies produced in response
to the vaccine, are ingested by the mosquito.13
A pre-erythrocytic vaccine would ideally not
only prevent sporozoites from invading
hepatocytes but also induce cytotoxic cell mediated
immunity against any infected hepatocytes. The
lead candidate among the tried vaccine is the RTS
recombinant protein vaccine, targeting the
circumsporozoite antigen that is expressed on both
sporozoites and the infected hepatocytes. This
antigen is fused with the hepatitis B surface
antigen and expressed as a recombinant protein
in yeast and used with a powerful adjuvant AS02.
Though the vaccine is safe and immunogenic, the
protective efficacy is only 30-60%. This RTS,
S/ASO2 pre-erythrocytic vaccine holds out hope
of achieving sterilizing immunity and is eminently
suited for immunization of travelers.14,15
DNA vaccine and prime-boost approaches
Perhaps the most viable multi-component
attack on malaria is offered by DNA vaccines,
which can be genetically tailored to induce both
cell-mediated and humoral immune responses.
Multi-component DNA vaccines offer the best
prospects for protection against malaria because
they can be tailored to include a variety of
numbers, types, and arrangements of epitopes (the
sites within a molecule to which a specific antibody
binds). DNA vaccines, unlike conventional
vaccines, have high immunogenicity, unlike multi-
component synthetic peptide vaccines like
SPF-66. DNA vaccines are also cost-effective.
SPF-66 was a vaccine designed to contain
sequences from three blood stage antigens,
combined with the tetra-peptide repeats of the
circumsporozoite protein. Unfortunately in large
phase III trials this vaccine lacked significant
efficacy. Vaccine directed at antigens of the
merozoites important for the red blood cells
invasion include those against the apical membrane
antigens(AMAI) and merozoite surface antigens
(MSP1, MSP2). These have been shown to be
highly effective in animal models, but are poorly
immunogenic in humans, while high antibody titers
are required to prevent invasion.
Transmission blocking or so-called altruistic
vaccines rely on preventing fertilization of the
sexual stage of the parasite in the gut of the
mosquito vector. Two candidate antigens under
development are Pfs28 and Pfs25 containing
sexual stage (ookinete) antigens expressed by
P.falciparum and P. vivax, respectively.
Recombinant vaccines
Through a collaborative program between
investigators at Oxford University and SB Bio
(SmithKline) detailed characterization of the
cellular immune response to the RTS,S/SBAS2
vaccine is underway. Planned clinical trials include
prime-boost studies of RTS, S boosted with a
recombinant modified vaccinia virus Ankara
encoding the CS protein.13
Two P. falciparum candidate vaccines are
under investigation. One, an ~41 kd protein called
FALVAC-1. It has been expressed in a baculovirus
expression system in collaboration with National
Institute of Immunology, New Delhi, India.
A second candidate, FALVAC-2, is under
development. CDC has entered into a
Collaborative Research and Development
Agreement (CRADA) with the Bharat Biotech,
International Limited (BBIL), Hyderabad, India,
for production of GMP-grade candidate vaccine
antigens.
Genomic and proteomic approaches
In 1996, a collaborative International effort
was undertaken to sequence the complete genome
of P. falciparum. The most promising development
19
in the field is publication of the genomes of Homo
sapiens, Plasmodium falciparum and Anopheles
gambiae - the three corners of the fatal triangle of
African malaria. This would certainly open up
immense possibilities. Use of sophisticated
procedures like micro arrays, gene analyses and
proteomics will throw up a large number of vaccine
candidates. It is now estimated that essentially all
of the parasites approximately 6000 genes are
available in existing databases. Thus, the malaria
community and vaccine developers have access
to virtually all of the genes encoding the antigens
and proteins expressed by this organism.13
Cochrane review
Four types of malaria vaccines, SPF-66 and
MSP/RESA vaccines (against the asexual stages
of the Plasmodium parasite) and CS-NANP and
RTS, S vaccines (against the sporozoite stages),
have been tested in randomized controlled trials
in endemic areas
Eighteen efficacy trials involving 10,971
participants were included. There were ten trials
of SPF-66 vaccine, four trials of CS-NANP
vaccines, two trials of RTS,S vaccine, and two of
MSP/RESA vaccine. Results with SPf66 in
reducing new malaria infections (P. falciparum)
were heterogeneous: it was not effective in four
African trials (Peto odds ratio (OR) 0.96, 95%
confidence interval (CI) 0.81 to 1.14), but in five
trials outside Africa the number of first attacks
was reduced (Peto OR 0.77, 95% CI 0.67 to
0.88). Trials to date have not indicated any serious
adverse events with SPf66 vaccine.
In three trials of CS-NANP vaccines, there
was no evidence for protection by these vaccines
against P. falciparum malaria (Peto OR 1.12, 95%
CI 0.64 to 1.93).
In a small trial in non-immune adults in the
USA, RTS,S gave strong protection against
experimental infection with P. falciparum. In a
trial in an endemic area of the Gambia in semi-
immune people, there was a reduction in clinical
malaria episodes in the second year of follow up,
corresponding to a vaccine efficacy of
66% (CI 14% to 85%).
In a trial in Papua New Guinea, MSP/RESA
had no protective effect against episodes of clinical
malaria. There was evidence of an effect on
parasite density, but this differed according to
whether the participants had been pretreated with
sulfadoxine/pyrimethamine or not. The prevalence
of infections with the parasite subtype of MSP2
in the vaccine was reduced compared with the
other subtype (Peto OR 0.35, CI 0.23 to 0.53).
Conclusion: There is no evidence for protection
by SPf66 vaccines against P. falciparum in Africa.
There is a modest reduction in attacks of
P.falciparum malaria following vaccination with
SPf66 in other regions. Further research with
SPf66 vaccines in South America or with new
formulations of SPf66 may be justified. There
was not enough evidence to evaluate the use of
CS-NANP vaccines.
The RTS,S vaccine showed promising result,
as did the MSP/RESA vaccine, but it should
include the other main allelic form of MSP2. The
MSP/RESA trial demonstrated that chemotherapy
during a vaccine trial may reduce vaccine efficacy,
and trials should consider very carefully whether
this practice is justified.16,17
5) HIV Vaccine
The HIV-1 pandemic has grown to become
one of the greatest infectious disease threats to
human health and social stability that the world
has ever encountered. Nearly 40 million persons
are living with HIV-1 infection and more than
21 million people have already died from HIV-
induced disease. Regarding the status of AIDS in
India, since the first report of the HIV infection
20
among sex workers in Chennai in 1986, India has
the second largest number of people living with
HIV/AIDS in the world, with an adult population
prevalence of approximately 5.13 millions. Though
HIV infection in India is concentrated among poor,
marginalized groups, HIV is spreading quickly into
the general population. Approximately 90 percent
of reported AIDS cases occur in sexually active
and economically productive individuals aged
15 to 44 years. HIV infection among women and
children is on the rise. The reported doubling time
of HIV epidemic in India is nearly two years.18
HAART allows the stabilisation of the
patients symptoms and viremia, but they do not
cure the patient of HIV, nor of the symptoms of
AIDS. High levels of HIV-1, viremia often
HAART resistant, return once treatment is
stopped. Moreover, it would take more than the
lifetime of an individual to be cleared from HIV
infection using HAART. Antivirals are also too
expensive for developing countries, which have
the highest rates of HIV-infection. Only a vaccine
will be able to halt the pandemic. This would
possibly cost less, thus being affordable for
developing countries, and would not require daily
treatments. However, after over 20 years of
research, HIV-1 remains a difficult target for a
vaccine.19
Current Strategies for an HIV Vaccine
Traditional
Immunization with live attenuated viruses
Possible limitations In vivo mutation may
render vaccine pathogenic, no animal
model for pathogenicity.
Immunization with inactivated viruses with
adjuvant
Possible limitations - Brief duration of
immunity, absence of cytotoxic
T lymphocytes
Newer approaches
Immunization with recombinant HIV protein
with adjuvant
Possible limitations -Brief duration of
immunity, absence of cytotoxic T cells,
restricted number of isolates recognized
Immunization with synthetic HIV peptides
with adjuvents
Possible limitations -Restricted number of
immunogenic epitopes
Combined approaches (e.g. recombinant
vaccinia virus and recombinant protein)
Possible limitations -No consistent protection
in the animal model
Intramuscular inoculation of the virus agent
Possible limitations -Little experience with the
approach
Use of vaccine for immune potentiation in
HIV infected patients
Possible limitations -No evidence of
effectiveness
The classical vaccination approaches that
have been successful in the control of various viral
diseases by priming the adaptive immunity to
recognize the viral envelope proteins have failed
in the case of HIV-1, as the epitopes of the viral
envelope are too variable. Furthermore, the
functionally important epitopes of the gp120
protein are masked by glycosylation, trimerisation
and receptor-induced conformational changes
making it difficult to block with neutralising
antibodies.Thus the vaccine failed to protect
because the circulating HIV strain hides its epitopes
in a variety of ways that genetically engineered
gp120 proteins do not mimic successfully. In
February 2003, VaxGen announced that their
AIDSVAX vaccine was a failure in North America
as there was not a statistically significant reduction
of HIV infection within the study population. In
November 2003, it also failed clinical trials in
Thailand for the same reason.20, 21
21
Based on the observation that in the initial
part of the infection, T cells are involved in the
identification and killing of HIV infected cells,
various vaccine are underway that stimulate
T cells responses. Methods attempted include
recombinant proteins, synthetic peptides,
recombinant viral vectors, recombinant bacterial
vectors, recombinant particles, DNA vaccines to
induce production of a specific antigen, and whole-
killed and live-attenuated HIV, however, initial
results cast doubts about the vaccine
immunogenicity. Another vacine now in the early
stage of a proof of concept, or phase 2B trial,
contain replication-defective adenovirus type 5
that transmit the HIV genes gag, pol, and nef
(which codes for internal HIV protein and may
stimulate cellular immunity), this vaccine looks
far more promising.20, 21
Other novel approaches will soon be tested
in nonhuman-primate models of AIDS, among
them the direct intramuscular inoculation of viral
genes. Such an immunization procedure generates
potent antibody and cell-mediated immune
responses and protects against challenge with live
influenza virus.
Clinical trials for the HIV vaccines
A total of 17 vaccine candidates are in phase
I trials and four in phase I/II. There is only one in
phase III (the NIH/Department of Defenses
ALVAC vCP 1521 canary pox vector/AIDSVAX
prime-boost vaccine trial now under way in
Thailand). ALVAC-HIV: a genetically
engineered HIV vaccine composed of a live,
weakened canary pox virus (ALVAC) into
which parts of genes for non-infectious
components of HIV have been inserted. When
ALVAC infects a human cell, the inserted HIV
genes direct the cell to make HIV proteins. These
proteins are packaged into HIV-like particles that
bud from the cell membrane. These particles are
not infectious but fool the immune system into
mounting an immune response to HIV. ALVAC
can infect but not grow in human cells, an important
safety feature.
Up to May 2003 over 60 phase I/II trials of
candidate vaccines have been conducted
worldwide. Most initial approaches focused on
the HIV envelope protein. At least thirteen
different gp120 and gp160 envelope candidates
have been evaluated, in the US predominantly
through the AIDS Vaccine Evaluation Group.
Overall, they have been safe and immunogenic
in diverse populations, have induced neutra-
lizing antibody in nearly 100% recipients, but
rarely induced CD8+ cytotoxic T lymphocytes
(CTL). 19,20
On January 26, 2005, a large phase IIb clinical
trial of a novel HIV vaccine has begun enrolling
volunteers at sites in North America, South
America, the Caribbean and Australia. The
organizers are seeking 1,500 participants. The trial
is co-funded by the National Institute of Allergy
and Infectious Diseases (NIAID), part of the
National Institutes of Health (NIH), and the
pharmaceutical company Merck & Co. Inc. In
previous smaller trials, this vaccine was found to
be safe and to induce cellular immune responses
against HIV in more than half of volunteers.
NIAID and Merck expect the trial be
completed in four-and-a-half years, with results
anticipated in 2010.19
Novel approaches, including modified
vaccinia Ankara (MVA), adeno-associated virus,
Venezuelan Equine Encephalitis (VEE) replicons,
and codon-optimized DNA have proven to be
strong inducers of CTL in macaque models, and
have provided at least partial protection in some
models. Most of these approaches are, or will
soon, enter clinical studies.19,20,22
In India, Pune-based National AIDS
Research Institute (NARI) is set to begin the
phase 1 trial that involves administration of
22
Modified Vaccinia Ankara (MVA) HIV-1 subtype
C vaccine for the first time to humans in India.
The tests in the western city of Pune will involve
30 HIV-free volunteers between 18 and 45 of
both sexes.
Due to an enormous amount of pre-clinical
work over the last several years, many other
vaccines are being studied and include important
concepts worth watching. These include the
Venezuelan equine encephalitis virus vectors
(encoding gag from clade C), the heat-killed
recombinant Saccharomyces cerevisiae
(expressing gag from Clade B), the IL-2/Ig cytokine
adjuvanted DNA of the VRC in collaboration with
Harvard, the IL-12 cytokine adjuvanted Gag
subtype B vaccine of Wyeth and the DNA prime/
MVA boost strategy being developed by Harriet
Robinson at Emory. But as in 1984, still a safe
and effective preventive vaccine remains elusive.
Points to remember
Acellular pertussis and Tdap vaccines have
definite role as newer vaccines.
With regard to rotavirus, malaria & HIV
vaccines an ideal vaccine is yet to be
developed.
References
1. Edwards K, at el. Pertussis Vaccine. In:
Vaccines, 3rd Edn, Philadelphia, W B Saunders
1999; pp293-344.
2. Noble GR, Bernier RH, Esber EC, Hardegree
MC. Acellular and whole cell pertussis vaccine
in Japan: Report of a visit by an US Scientist.
JAMA 1987; 257:1351-1356.
3. Kimura M, Kuno-Sakai H. Current epidemio-
logy of pertussis in Japan. Pediatr Infect Dis J
1990;9:705-709.
4. Koto T, Goshima T, Nakajima M, Kaku M,
Ajimoto Y, Mayashi F. Protection against
pertussis by acellular vaccine Acta Pediatr Jpn
1989;31:698-701.
 5. Tinnion ON, Hanlon M. Acellular vaccines for
preventing whooping cough in children. The
Cochrane Database of Systematic Reviews
1999, Issue 2. Art. No.: CD001478. DOI:
10.1002/14651858.CD001478.
6. Pichichero ME, Casey JR. Acellular pertussis
vaccines for adolescents. Pediatr Infect Dis J
2005; 24:S117S126.
7. CDC. Diphtheria, tetanus, and pertussis:
recommendations for vaccine use and other
preventive measures. Recommendations of the
Immunization Practices Advisory committee
(ACIP). MMWR 1991; 40(No. RR-10):1-28.
8. Long SS. Academy issue policy on adolescent
pertussis vaccine-American Academy of
pediatrics: 26(12)e2005188-AAP news.htm -
httm://www.aap.org
9. Tdap vaccine: CDC; vaccine information
s t a t e m e n t : h t t p : / / w w w. c d c . g o v / n i p /
publications/VIS/defaults.htm#tdap
10. Glass R, Parashar U. The promise of new
Rotavirus Vaccine. N Engl J Med 2005;
354:75-77.
11. Bresee JS, Umesh, Parashar D, Marc-Alain
Widdowson, Jon R. Gentsch. Rotavirus in Asia:
The Value of Surveillance for Informing
Decisions about the Introduction of New
Vaccines; J Infect Dis 2005;192 (suppl 1):S1-
S5.
12. Kundu R, Ganguly N, Ghosh TK, Choudhury P,
Shah RC. Diagnosis and management of malaria
in children: recommendations and IAP plan of
NEWS AND NOTES
XIV INTERNATIONAL CONFERENCE OF
THE INDIAN ASSOCIATION OF PALLIATIVE CARE
Date : 10th to 12th February 2007
Registration fees : Rs. 2,000.
Contact :
Dr. Sajid S. Qureshi, Pediataric Surgical Oncologist, Tata Memorial Hospital, Mumbai.
E-mail : sajidshafique@rediffmail.com; Tel No. 24177276 / 7000
23
action, Indian Pediatr 2005;42(11):1101-
1114.
13. Raghunath D. Malarial Vaccine:Are we
anywhere close? JPGM 2004;50: 51-54.
14. Read Andrew. Quoted in Malaria - from Infants
to Genomics to Vaccines, by Long CA,
Hoffman SL. Science 2002; 297:345-347.
15. Richie TL, Saul A. Progress and challenges for
malaria vaccines. Nature 2002; 415:694-701
16. Karen Fleming Michael. Steady progress;
Malaria vaccines show progress thanks to
Armys efforts, assessed at dc military.com
17. Graves P, Gelband H. Vaccines for preventing
malaria. The Cochrane Database of Systematic
Reviews 2003, Issue 1. Art. No.: CD000129.
DOI: 10.1002/1465 1858.CD000129
18. Norman L. Letvin. Vaccines against Human
Immunodeficiency Virus Progress and
Prospects. N Engl J Med 1993;329:1400-
1405.
19. HIV vaccine: from Wikipedia, the free
encyclopedia; http://en.wikipedia.org
20. Steinbrook R., Drazen JM. AIDS - Will the
Next 20 Years Be Different? N Engl J Med
2001;344:1781-1782.
21. Cohen Jon. The search for an AIDS vaccine and
on effective global response shots in the dark:
The Wayward search for an AIDS vaccine. N
Engl J Med 2001;344:1801-1802.
22. HIV vaccine: National institute of allergy and
infectious disease ( NIAID), assessed at :http:/
/www.niaid.nih.gov/information/search.htm.
 VACCINES II
ADDITIONAL VACCINES - CURRENT
TRENDS
* Niranjan Shendurnikar
** Mukesh Kumar Singh
Abstract : Additional vaccines (vaccines not
covered under National Immunization Schedule
but recommended by IAP) like Typhoid, MMR
and varicella vaccines are covered in this article.
In developing countries, Vi polysaccharide and
Ty 21a typhoid vaccines are equally effective.
Another option for less than 2 years old children
is Vi-conjugate vaccine. Reviving whole cell
typhoid vaccine manufacture could be considered
in view of its cost effectiveness, usefulness even
in infants and toddlers and possibility of reducing
the side effects by excluding paratyphoid bacilli
and administering it intradermally. Indian
Academy of Pediatrics recommends M/MMR
vaccine strategy with measles vaccine at
9 months of age and MMR at 15 months of age.
The varicella vaccine is effective in preventing
all forms of varicella infection.
Keywords : Typhoid, MMR, Varicella Vaccines.
Typhoid Vaccines
Need for typhoid vaccines
Besides sanitation, immunization is an
additional effective tool for the prevention of
typhoid fever. With the global emergence of multi-
* Associate Professor
** Assistant Professor
Department of Pediatrics
Medical College, Baroda 390001
24
drug resistance and of strains with reduced
susceptibility to fluoroquinolones, prevention is
of paramount importance.1 Immunization is useful
for prevention of typhoid in travellers from
developed countries to typhoid-endemic countries,
in preventing and controlling epidemics, and for
children in endemic settings aged 2 to19 years.2
Vaccine availability
The old parenteral whole-cell typhoid-
paratyphoid A and B (TAB) vaccine was effective
against typhoid and paratyphoid fevers but has
been largely discontinued because of frequent
side-effects and the cumbersome manufacturing
process.3,4 Currently, two vaccines for typhoid
fever, one based on Vi polysaccharide and the
other oral one based on whole-cell live attenuated
bacteria, are licensed. There is no licensed vaccine
for paratyphoid fever. The liquid formulation of
the live oral vaccine for younger children is
currently marketed in only a few countries.1 The
live oral Ty21a vaccine in the capsule formulation
is also no longer available in India.
Whole-cell typhoid vaccine and vaccine efficacy
In a meta-analysis of randomized controlled
trials evaluating the efficacy of the various typhoid
vaccines, the three-year cumulative efficacy was
73% (95% confidence interval 65% to 80%) for
two doses of whole cell vaccines (based on seven
trials); 51% (35% to 63%) for three doses of
Ty21a vaccine (four trials); and 55% (30% to
71%) for one dose of Vi vaccine (one trial). For
whole cell and Ty21a vaccines, regimens of fewer
doses were less effective. Efficacy was shown to
be significant for five years for whole cell vaccines,
four years for Ty21a vaccine, and two years for
Vi vaccine. After vaccination, fever occurred in
15.7% (11.5% to 21.2%) of whole cell vaccine
recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine
recipients, and 1.1% (0.1% to 12.3%) of
Vi vaccine recipients. This meta-analysis
concluded that whole-cell vaccines are more
effective than the Ty21a and Vi vaccines, but are
more frequently associated with adverse effects.
Whether the added efficacy of the whole cell
vaccines outweighs their toxicity will depend on
the setting in which immunization is used.3
The acetone-killed whole-cell vaccine was
reported to have a protective efficacy of 79 88%
in various studies. The Vi and oral typhoid vaccines
are safe but the protective efficacy is much less
(between 50 70%) compared to the effective
vaccines available for other diseases.5
Whole cell vaccines
The whole-cell vaccine is quite inexpensive
and it is effective even in infants and toddlers. Its
side-effects can be decreased if the vaccine
contains only S.typhi (and not paratyphoid bacilli
too) and if it is administered by the intradermal
route (as recommended for revaccinations) rather
than subcutaneously. The adverse effects of the
whole-cell vaccine are no worse than the local or
systemic reactions to DTP vaccine, are not serious,
and are short-lived and well-tolerated. Reviving
the manufacture of the whole-cell vaccine could
be considered.4
Vi polysaccharide vaccine
This is the only typhoid vaccine available
widely in India currently. This vaccine is licensed
for use in individuals older than two years and is
given in a single subcutaneous or intramuscular
dose. The vaccine is moderately effective for
about three years after vaccination. Revaccination
is recommended every three years. However, 58%
25
of participants in a field trial in South Africa still
had protective levels of antibodies ten years after
vaccination.6 This vaccine has shown about 70%
protective efficacy in a population vaccinated
before or during an outbreak in China.7
Ty21a vaccine
This live oral vaccine in enteric-coated or
liquid formulation is approved for use in individuals
six years of age and older. Three doses are
recommended each given two days apart.1 The
oral typhoid vaccine is recommended as four initial
doses in the USA and only three in Europe -
a potential point of confusion. Antimicrobials
should be avoided for seven days before or after
vaccination.
The oral vaccine is moderately effective for
up to about three years after vaccination.
Revaccination is recommended every three years
in endemic areas and every five years for travellers
to developing countries. Travellers to typhoid-
endemic areas such as South Asia need to be
vaccinated even if they plan to stay for less than
two weeks. Herd immunity was shown during field
trials in Chile.1
In a study to determine the acceptability of
oral typhoid vaccine among Thai children, the
rates of successfully being able to swallow all three
capsules (one capsule every other day) were
84.4%, 94.9%, and 100% in the age groups
4-6 years, 7-9 years, and 10-12 years
respectively.8
Choosing a typhoid vaccine
The effectiveness of both the vaccines in
developing countries is similar. Ty21a has the
advantage that it is given orally and therefore might
be easier for immunizing groups of children, as in
schools. The Ty21a vaccine, especially the enteric-
coated capsule formulation, is not licensed for use
in 25 year-old children. Vi vaccine has a relative
advantage that it can be used for these preschool
children, in settings where typhoid fever is
common in this age-group. The vaccine, however,
is not licensed for use in children younger than
two years.1
Adverse events
Post-marketing surveillance in the U.S. for
licensed typhoid fever vaccines from the Vaccine
Adverse Effects Reporting System (VAERS) from
1990 to 2002 revealed that unexpected frequently
reported symptoms included dizziness and pruritus
for Vi polysaccharide vaccine and fatigue and
myalgia for Ty21a. Gastroenteritis for Ty21a and
abdominal pain after Vi vaccine were previously
recognized events. Occasional nonfatal anaphylaxis
was reported after both vaccines. VAERS reports
do not indicate any unexpected serious side effects
that compromise use of these vaccines as
prophylaxis for travellers.9
Vi-conjugate vaccine
Unlike polysaccharide vaccines, conjugate
vaccines can be effective in children younger than
two years and elicit immunologic memory.
Vietnamese children between the ages of two and
five years given Vi-conjugate vaccine had 91.1%
protection against typhoid 27 months after
vaccination, with geometric mean titers of 7.61
ELISA units for those vaccinated at age two to
three years. 10 The efficacy of this conjugate
vaccine persisted after 46 months of vaccination;
over the entire period, the protection was 89%
(95% CI: 76%97%).11 As yet, it has not been
tested in infants. This vaccine could be used for
children younger than two years and be
incorporated into the Expanded Program on
Immunization (EPI) schedules in the future.
Combination vaccines
In a multicenter study to evaluate the first
combined vaccine against typhoid fever and
hepatitis A in healthy subjects aged 15-50 years,
26
more than 95% of the subjects were positive for
anti-Vi antibodies and more than 86% were
positive for anti-HAV antibodies as early as
14 days after immunization. The combined
vaccine offers more convenience and rapid
seroconversion for travellers.12 Clinical studies in
healthy adults have also documented the safety
and immunogenicity of concomitant administration
of an inactivated hepatitis A vaccine and either a
typhoid fever (Vi) vaccine or a combination of Vi
and yellow fever vaccines.13
MMR Vaccine
Is a second dose necessary?
Research over the merits of two doses of
MMR vaccine versus a single dose is not new. In
Finland, a two-dose MMR vaccination program
was begun in 1982. The program with high
coverage (9798%) has eliminated these three
diseases from Finland. In a study following the
kinetics of measles virus antibodies in MMR-
vaccinated cohorts, the primary dose induced
99.4% seroconversion for measles with a geo-
metric mean haemagglutination inhibition(HI)
antibody titer (GMT) of 1/269 (219). After
12 years, 80% of the original children remained
available for sampling. The 12-year follow-up
samples showed a measles seropositivity rate of
100% as assayed with the HI test with a mean
HI antibody titer of 1/39 (54). The authors
postulated that vaccination-induced measles virus
antibodies decline in the absence of natural
booster infections.14
It is important to follow how long the
protection achieved by the present vaccine
programs will last after elimination of indigenous
measles.14 It must be borne in mind that at any
given time, the epidemiology will vary among
countries and the situation in developing countries
cannot be extrapolated from that in the developed
countries.
 Even in the industrialized countries, two
doses of the trivalent MMR vaccine are currently
advocated. The MMR triple (i.e. combined)
vaccine is used in over 90 countries worldwide
and no country recommends immunization for
measles, mumps and rubella in separate
vaccinations.15 The first dose of MMR vaccine
is given routinely at 12-15 months. The second
dose is usually given between three and five years
of age during the school immunization booster
program. Two doses of MMR are required in
order to ensure that all children receive the
vaccination as some may miss it when they are
12-15 months old for a variety of reasons. It is
also important as it confers immunity on those
who did not respond to the first vaccination, which
can be as many as 5-10% (primary vaccine
failure).15,16 The majority of individuals who fail
to respond to the first dose of MMR respond to a
second dose. For children who did receive and
responded to the first vaccination, the second
simply boosts their antibodies to measles, mumps
and rubella just as they start attending school and
increasing social contact with other children.15
During a 1998-99 outbreak of mumps among
children of a religious community in North East
London, a case-control study was conducted to
assess the effectiveness of the mumps component
of the MMR vaccine. Two doses of vaccine were
more effective (88% (95% CI: 6296%)) than a
single dose (64% (95% CI: 4078%)). The authors
concluded that the two-dose vaccination program
remains the best method for controlling mumps
infection in the community.17
Measles and mumps, but not rubella,
outbreaks have been reported amongst populations
highly vaccinated with a single dose of MMR
vaccine. Repeated experience has shown that a
two-dose regime of measles vaccine is required
to eliminate measles. A study paper reported the
effect of the first and second MMR doses on
specific antibody levels in a variety of
populations.18
27
Two to four years after receiving a first dose
of MMR vaccine at age 1218 months, it was
found that a large proportion of pre-school children
had measles (19.5%) and mumps (23.4%) IgG
antibody below the putative level of protection.
Only a small proportion (4.6%) had rubella
antibody below the putative protective level.
A total of 41% had negative or equivocal levels to
one or more antigens. The proportion who had
measles antibody negative (but not rubella or
mumps) was significantly higher in children
vaccinated at 12 months of age than at 1317
months. After a second dose of MMR, the
proportion who were negative to one or more
antigens dropped to <4%. Examination of National
serosurveillance data found that following an MR
vaccine campaign in cohorts that previously
received MMR, both measles and rubella antibody
levels were initially boosted but declined to pre-
vaccination levels within 3 years. This study
supports the policy of administering a second dose
of MMR vaccine to all children. However,
continued monitoring of long-term population
protection will be required and this study suggests
that in highly vaccinated populations, total measles
(and rubella) IgG antibody levels may not be an
accurate reflection of protection. Further studies
including qualitative measures, such as avidity, in
different populations are merited and may
contribute to the understanding of MMR
population protection.18
MMR being a combination vaccine, the
question of a single dose versus two doses can be
addressed only in the context of each of the three
diseases separately. Measles vaccine is known to
have lower seroconversion rate when administered
before 12 months of age, hence a two-dose
measles vaccine schedule (with MMR vaccine at
15 18 months) should be the best approach.
Efficacy of a single dose of mumps vaccine is
around 95%.19 However, in the Indian scenario,
where MMR vaccine or mumps vaccine is not
part of the National Immunization Program
currently, coverage with even a single dose of
mumps vaccine is negligible. It is too far-fetched
to debate over the issue of a second dose.
However there exists the possibility of eradication
of mumps with two doses of mumps vaccine.16
A single dose of rubella vaccine (RA 27/3 strain)
provides seroconversion in more than 95%
children with vaccine efficacy of about 90% for
lifelong protection. The Indian Academy of
Pediatrics recommends M/MMR vaccine strategy
with measles vaccine at 9 months of age to be
followed by MMR vaccine at 15- 18 months.19
As of now, MMR is not included in EPI and
parents must bear the expense for their childs
immunization.
Mumps vaccine virus strain and aseptic
meningitis
The live attenuated mumps virus component
in MMR vaccine could be one of the several strains;
these different strains (Urabe, Leningrad-Zagreb
and Jeryl-Lynn used in India at some time or the
other) have good immunogenicity, though it is
claimed that side-effects are least with the Jeryl-
Lynn strain, particularly in reference to aseptic
meningitis. There is an association between the
Urabe strain of mumps vaccine and aseptic
meningitis.16 Studies have estimated the incidence
of aseptic meningitis to be 49-100, 20-30 and 1.0
per 100,000 doses for the Urabe, L-Zagreb and
Jeryl-Lynn strains respectively20 i.e. it is negligible
for all strains. Moreover, this is a benign disease
with complete recovery even if untreated. A recent
study done in Egypt covering more than 100,000
children being given MMR with the L-Zagreb
mumps virus strain showed that there was not a
single case of aseptic meningitis on prospective
follow-up. All MMR vaccines are considered as
equally safe and immunogenic by IAP.
MMR vaccine scares
Epidemiologic studies do not support a
causative link between MMR vaccine and autism,
28
Inflammatory Bowel Disease and Guillian-Barre
Syndrome.16 From multiple population-based
studies and extensive review committee reports,
it has been summarized that neither immunization
nor thimerosal exposure has been conclusively
linked to autism.
Contested reports associating the MMR
vaccine with autism had resulted in diminished
confidence and public acceptance of the vaccine
in the UK. In a postal survey of parental attitudes,
both MMR-accepting and refusing parents were
supportive of immunization, yet the high level of
concern about the safety of the vaccine expressed
even by parents who had immunized their children
is worrying in its implications for public confidence
and trust in health care.
The weight of evidence lies in favor of triple
MMR vaccination and a 95% uptake of this
vaccine would confer immunity that would protect
not only the immunized child but also those too
young to be immunized and those in utero.15
Varicella Vaccine
Effectiveness of the vaccine and duration of
protection
Varicella vaccine is effective in preventing
any form of the disease in 90-95% of vaccinees
whereas protection against moderate to severe
disease is provided to >95% of vaccinees. The
seroconversion rate in children aged 112 years
was 95% after a single dose. After 13 years of
age, seroconversion rates were 7882% after the
first dose and 99% after two doses. The immunity
to varicella lasts for at least 1020 years.
Secondary vaccine failure may result from waning
vaccine-induced immunity over the years.
Exposure to natural infection in the community
will continue to provide a boosting effect.5
The six-year cumulative varicella antibody
persistence rate was 99.5% (95% CI: 98.9%-
100.0%) in a manufacturer-funded study of
healthy children aged between 1 to 12 years given
the Oka varicella vaccine. The annual
breakthrough rate through seven years ranged
from 0.2% to 2.3% per year; the estimated
cumulative event rate was 6.5%. Comparison of
the observed average annual breakthrough rate
with the age-adjusted expected annual incidence
rate of varicella in unvaccinated children
corresponded to an estimated vaccine efficacy of
93.8% to 94.6%. Eighty vaccinated children were
exposed to varicella in the household, resulting in
8 (10%) cases of infection. When compared with
the historical attack rate of 86.8% in unvaccinated
susceptible persons exposed to varicella in the
household, this yields an estimated vaccine
efficacy of 88.5% (95% CI: 80.9%, 96.1%).
Varicella cases in vaccinated children generally
were mild.21
Results from a study indicate that the
effectiveness of the varicella vaccine used in actual
clinical practice (as against in a clinical trial) is
excellent, at least in the short term. Against
moderately severe and severe disease, the vaccine
was 97 % effective (95% CI - 93 to 99%). Virtually
all the vaccinated children in whom chickenpox
subsequently developed (all of whom were
infected with wild-type virus) had very mild
disease.22 These findings are consistent with those
of a study by the Center for Disease Control and
Prevention that show a marked decline in the
incidence of chickenpox in areas where the vaccine
is widely used, as well as with reports of the
effectiveness of the vaccine after outbreaks in day-
care centers.
Breakthrough varicella
Live attenuated varicella vaccine (Oka strain)
was approved for administration to healthy children
in the United States in 1995. Over the past
10 years, varicella vaccine has been given to
millions of U.S. children, usually at ages between
12 and 18 months. The main unanticipated
observation has been a growing number of
29
outbreaks of varicella among immunized children
(breakthrough varicella). The most cited risk
factors for breakthrough varicella include the
following: (i) 3 to 5-year interval since
immunization and (ii) immunization at the
youngest ages, especially 12 months. Explanations
for breakthrough varicella include a lessened
immune response among the youngest recipients
of the vaccine. Another possibility is genetic
variation among circulating VZV strains.
Breakthrough disease among vaccine recipients
appears to be more common in the United States
than in Japan.23
A study documented an outbreak of varicella
among largely immunized 4-year-olds at a day-
care centre in New Hampshire. Moderately severe
varicella spread from the index case to 15 others,
indicating that the vaccine was only 44% effective
in this outbreak. Children who had been vaccinated
three years or more before the outbreak were at
greater risk for vaccine failure than those
vaccinated more recently.24 There are still not
enough data to recommend a second dose of
varicella vaccine for younger children. However
this may become the reality after more experience
is gained as happened in case of MMR.
Varicella vaccine: Other issues
Rates of herpes zoster are much lower
(2.4 cases per 1,00,000 population) in vaccinees
than in those who develop zoster following
wild virus infection (68 cases per 1,00,000
population).5
For post-exposure prophylaxis, susceptible
immunocompetent children and household
contacts can be given varicella vaccine within
2-3 days of the appearance of the rash in the index
case.19
In a randomized, double-blind, placebo-
controlled study, it was concluded that varicella
vaccine may not be effective in preventing varicella
when administered after household exposure,
although it is highly effective in ameliorating the
disease in those who acquire it under these
circumstances. The risk of developing moderate
to severe disease was eight times greater in the
placebo group (RR = 8), indicating an 80%
protective effect against moderate/severe
disease.25
Varicella vaccine administered in a two-dose
regimen was generally well-tolerated and highly
immunogenic in US and Canadian children
(12 months to <18 years) with nephrotic
syndrome, including those on low-dose, alternate-
day prednisolone.
A study at the Johns Hopkins Childrens
Center, Baltimore to determine whether the
vaccine was immunogenic in children with chronic
renal insufficiency identified fifty such children
with no detectable varicella zoster virus antibody.
Each child was given two doses of vaccine 48
weeks apart, rather than the typical one dose, and
subsequent rates of seroconversion were
measured. During three years of follow-up all
children (including 16 who received kidney
transplants later) retained a concentration of
antibodies considered to be protective against
chicken pox.
The Centers for Disease Control and
Prevention recommends varicella immunization
for those HIV-1-infected children without clinical
or laboratory evidence of clinically significant
immune suppression.
Combination vaccines and newer vaccines
A new MMRV combination vaccine was
studied in 480 children aged 1223 months. The
response rate to the first dose was 96% for
measles, 99% for mumps, 95.1% for rubella, and
91.2% for varicella. The response rate after the
second dose was 98.6% for measles, 100% for
mumps, 94.8% for rubella, and 99.2% for
30
varicella. These results compared favorably with
the licensed MMR and varicella vaccines. The
combined vaccine was well-tolerated with the only
exception being a slight increase in measles-like
rash after the initial dose.26
The gelatin content in the varicella vaccine
may be associated with hypersensitivity reactions.
A new gelatin-free varicella vaccine tested in
Japanese studies has been reported to be safe,
with similar immunogenicity to the earlier gelatin-
containing vaccine.27
Summary
Universal coverage with efficacious vaccines
is still a distant dream in most developing countries
today. Theoretically, however, science is equipped
with the means to prevent, control and eventually
even eradicate certain infectious diseases. In the
future, widespread coverage with vaccines is likely
to present newer challenges to the scientific and
medical communities due to the changes it brings
about in the epidemiology of infectious diseases.
In summary, these pertinent issues with the
additional vaccines are of clinical relevance and
patient-doctor concern to optimize vaccine
acceptance and cost-effectiveness.
Points to remember
The efficacy of the available typhoid
vaccines is reported to be similar in
developing countries.
The two-dose vaccination program remains
the best method for controlling measles and
mumps infection in the community, using
MMR as a part of national schedule.
Varicella vaccine is effective in preventing
any form of the disease in 90-95% of
vaccinees, whereas protection against
moderate to severe disease is more than
95% of vaccinees.
References
1. Bhan MK, Bahl R, Bhatnagar S. Typhoid and
paratyphoid fever. Lancet 2005; 366: 749-762.
2. World Health Organization. Background
document: The diagnosis, treatment and
prevention of typhoid fever. WHO/V&B/03.07.
Geneva: World Health Organization, 2003.
3. Engels EA, Falagas ME, Lau J, Bennish ML.
Typhoid fever vaccines: a meta-analysis of
studies on efficacy and toxicity. Br Med J
1998; 316: 110-116.
4. Kukreja S, Chitkara AJ. Immunization against
Typhoid Fever. In: Thacker N, Shah N. (eds.)
Immunization in Clinical Practice. 1st edn
Jaypee Brothers Medical Publishers (P) Ltd.,
New Delhi. 2005; pp 119-124.
5. Vashishtha VM. Symposium on Pediatric
Vaccines. Pediascene 2003; 51: 4-15.
6. Keddy KH, Klugman KP, Hansford CF,
Blondeau C, Bouveret le Cam NN. Persistence
of antibodies to the Salmonella typhi Vi
capsular polysaccharide vaccine in South
African school children ten years after
immunization. Vaccine 1999; 17: 110-113.
7. Yang HH, Kilgore PE, Yang LH, et al. An
outbreak of typhoid fever, Xing-An County,
Peoples Republic of China, 1999: estimation
of the field effectiveness of Vi polysaccharide
typhoid vaccine. J Infect Dis 2001; 183: 1775-
1780.
8. Mekmullica J, Pancharoen C. Acceptability of
oral typhoid vaccine in Thai children. Southeast
Asian J Trop Med Public Health 2003; 34:334-
336.
9. Begier EM, Burwen DR, Haber P, Ball R.
Vaccine Adverse Event Reporting System
Working Group. Postmarketing safety
surveillance for typhoid fever vaccines from
the Vaccine Adverse Event Reporting System,
July 1990 through June 2002. Clin Infect Dis
2004; 38: 771-779.
10. Lin FY, Ho VA, Khiem HB, et al. The efficacy
of a Salmonella typhi Vi conjugate vaccine in
two-to-five-year-old children. N Engl J Med
2001; 344: 1263-1269.
31
11. Mai NL, Phan VB, Vo AH, et al. Persistent
efficacy of Vi conjugate vaccine against
typhoid fever in young children. N Engl J Med
2003; 349: 1390-1391.
12. Beran J, Beutels M, Levie K, et al. A single
dose, combined vaccine against typhoid fever
and hepatitis A: consistency, immunogenicity
and reactogenicity. J Travel Med 2000; 7: 246-
252.
13. Dumas R, Forrat R, Lang J, Farinelli T, Loutan
L. Safety and immunogenicity of a new
inactivated hepatitis A vaccine in concurrent
administration with a typhoid fever vaccine or
a typhoid fever + yellow fever vaccine. Adv
Ther 1997; 14: 160-167.
14. Davidkin I, Valle M. Vaccine-induced measles
virus antibodies after two doses of combined
measles, mumps and rubella vaccine: a 12-year
follow-up in two cohorts. Vaccine 1998; 16:
2052-2057.
15. McGreevy D. Risks and benefits of the single
versus the triple MMR vaccine: how can health
professionals reassure parents? JRSH 2005;
125: 84-86.
16. Dubey AP, Banerjee S. Measles, Mumps,
Rubella (MMR) Vaccine. Indian J Pediatr
2003; 70: 579-586..
17. Harling R, White JM, Ramsay ME, Macsween
KF, van den Bosch C. The effectiveness of the
mumps component of the MMR vaccine: a
case control study. Vaccine 2005; 23: 4070-
4074.
18. Pebody RG, Gay NJ, Hesketh LM, Vyse A,
Morgan-Capner P, Brown DW et al.
Immunogenicity of second dose measles
mumpsrubella (MMR) vaccine and
implications for serosurveillance. Vaccine
2002; 20: 1134-1140.
19. Shah NK, Shendurnikar N, Thacker N,
Vashishtha VM. Current Issues and Options in
Childhood Vaccines. In: Thacker N,
Shendurnikar N. (Eds.) Childhood
Immunization Issues and Options. 1st Edn
Thacker N, IAP Kutch Branch. pp 11 22.
20. American Academy of Pediatrics. Rubella. In:
Pickering LK, ed. 2003 Red Book: Report of
th
the Committee on Infectious Diseases. 26
Edn. Elk Grove Village, IL. American Academy
of Pediatrics 2003; pp536-541.
21. Rupert Vessey SJ, Chan CY, Kuter BJ, et al.
Childhood vaccination against varicella:
Persistence of antibody, duration of protection,
and vaccine efficacy. J Pediatr 2001;139: 297-
304.
22. Vazquez M, LaRussa PS, Gershon AA,
Steinberg SP, Freudigman K, Shapiro ED. The
Effectiveness of the Varicella Vaccine in
Clinical Practice. N Engl J Med 2001;
344:955-960.
23. Grose C. Varicella vaccination of children in
the United States: Assessment after the first
decade 19952005. J Clini Virol 2005; 33:
89-95.
NEWS AND NOTES
24. Galil K, Lee B, Strine T, et al. Outbreak of
varicella at a day-care center despite
vaccination. N Engl J Med 2002; 347: 1909
1915.
25. Mora M, Harelb L, Kahanc E, Amirb J.
Efficacy of postexposure immunization with
live attenuated varicella vaccine in the
household settinga pilot study. Vaccine
2004; 23: 325-328.
26. Kerr C. Good response rate for MMRV
vaccine. The Lancet Infectious Diseases 2003;
3: 748
27. Ozakia T, Nishimuraa N, Mutoa T, et al. Safety
and immunogenicity of gelatin-free varicella
vaccine in epidemiological and serological
studies in Japan. Vaccine 2005; 23: 1205-
1208.

SYMPOSIUM ON DIAGNOSIS AND TREATMENT OF

GASTROINTESTINAL INFECTIONS
Chandigarh, January 13-14, 2007
Enquiries to : Dr. Chetana Vaishnavi, Department of Gastroenterology, P.G.I.M.E.R.,
Chandigarh.
Email : vaishnav@rediffmail.com; evaishnavi@sify.com

PALS PROVIDER COURSE

New Delhi, January 20-21, 2007
Enquiries to : Dr. Suresh Gupta, Department of Pediatrics, Sir Ganga Ram Hospital,
New Delhi 110 060.
Email : drguptasuresh@yahoo.co.in

ICPP 3
INTERNATIONAL COURSE ON PEDIATRIC PULMONOLOGY
April 12-14, 2007
Hotel Royal Riviera, Saint-lean Cap-Ferrat
Information :
ICPP Secretariat, 27, Rue Massena 06000 Nice, France
Tel. +33(0)497038597 Fax: +33(0)497038598 E-mail : cipp@cipp-meeting.com

32
 VACCINES II
PASSIVE IMMUNE PROPHYLAXIS
FOR INFECTIONS
* Baldev S. Prajapati
** Rajal Prajapati
Abstract : Passive immune prophylaxis is used
mainly as post exposure prophylaxis. Advantages
and disadvantages of human and animal products
of immunoglobulins are discussed. Preparations
available, indications, dose, etc. of immuno-
globulins against various diseases are dealt with.
Keywords : Passive immune prophylaxis,
Indications, Disease specific immunoglobulins
Preformed antibodies as a therapeutic tool is
used for immediate protection against certain
infections. They are used either to prevent or to
treat the infectious diseases. Use of preformed
antibodies to prevent the infection is called passive
immunoprophylaxis and its use to treat the
infection is called passive immunotherapy. Passive
immunoprophylaxis is used in a susceptible
individual mainly as post exposure prophylaxis.
Animal derived hyperimmune globulins are
mainly of equine origin and is available in the form
of antitoxins. Animal derived products are known
for their serious side effects. Human derived
preparations are safer and used as prophylaxis for
measles, rubella, hepatitis-A, hepatitis-B, varicella,
tetanus, rabies etc. Respiratory syncytial viral
immunoglobulin (RSV-IVIG) is recently
* Associate Professor
** Associate Professor
Sheth L G General Hospital
Smt. NHL Municipal Medical College, Ahmedabad
33
introduced for prevention of RSV infection
especially in high risk patients like preterm babies
and those who are suffering from broncho-
pulmonary dysplasia.
Preparations (Table 1)
There are two sources of immuno-
globulin preparations available for human
administration and they are human and animal
derived products. Animal derived hyperimmune
globulins, generally of equine origin are available
in the form of sera. Due to their known serious
reactions and availability of safer human
immunoglobulin preparations, the animal derived
antisera or antitoxins are now in less use. Products
derived from human plasma include human
immune serum globulin (ISG). Intravenous
immunogloblin IVIG and specific hyperimmune
ISG.
Human immune serum globulin (ISG)
Human immune serum globulin is derived
by alcohol fractionation of pooled human plasma.
It contains 95% IgG (in 16.5% solution), with
trace quantities of IgM and IgA. A plasma pool of
more than 1000 donors provides a wide diversity
of antibodies in each lot. Plasma pool needs to be
screened for a variety of viruses to minimize the
potential for transmission of infections. The utility
of ISG is limited due to several reasons. It must
be given by deep IM route. It is painful. The
maximum volume that can be given per site is
1 to 3 ml in a small child and 5 ml in a large child
or an adult, with a maximum total volume of
20 ml. Peak antibodies are not attained till
Table 1. Available preparations for passive immunoprophylaxis
Human Normal Immunoglobulin
10% and 16.5% preparations for IM use in 1 ml and 2 ml ampoules.
Bharglob, Globunal, Gamafine, Gammalin, Sii Gama globulin.
Intravenous Immunoglobulin IVIG and specific hyperimmune Ig G
Intraglobin
5 ml (250 mg), 10 ml (500 mg), 20 ml (1gms), ampoules.
50 ml (2.5 gms), 100 ml (5 gms),200 ml (10 gms) in infusion bottles.
Pentaglobin :
5 ml, 10 ml, 20 ml ampoules.
5 ml, 100 ml infusion bottles.
Sandoglobulin : 1gms, 3 gms and 6 gms vials.
Gamma IV : 0.5gms, 2.5 gms and 5 gms infusion bottles.
Hepatitis B Immunoglobulin
Hepabig, Hepaglob
0.5 ml (100 IU),
1 ml (200 IU) vials for IM use.
Hepatect 2 ml ampoule (100 IU) for IV use.
Varicella Zoster Immunoglobulin.
Varitect 5 ml, 20 ml, 50 ml.
VZIG 125 units per vial.
Rabies Immunoglobulin
Human Rabies Immunoglobulin (HRIG)
Berirab 300 IU (2 ml)
750 IU (5 ml)
Imogam 300IU (2 ml)
Equine Rabies Immunoglobulin (ERIG)
Imorab 1000 IU (5 ml vial)
Tetanus Human Immunoglobulin
Tetglob 250 IU, 500 IU, 1000 IU in vials
Immunotetan 250 IU, 500 IU
Tetnal 250 IU
Sii TIG 250 units for IM and IV
Tetanus Antitoxin
Tetanus antitoxin Haffkine 1500 IU (1 ml)
10,000 IU (3.4 ml)
20,000 IU (5 ml)
Tetanus Antitoxin B.C. 1500 IU (1 ml)
Anti-TET 10,000 IU (3.3 ml)
Tetanus antitoxin Bengal Immunity
750 IU, 5000 IU, 10,000 IU, 20,000 IU, 50,000 IU
RSV-IVIG
Respi Gam 50 mg/ml.
Anti Rh D Immunoglobulin Rhiggal, Rhesogram, sii Anti D,Masteram-P, Vinobulin. 100 ug, 250 ug,
300 ug, 350 ug, 2ml vial for IM.
34
2 to 3 days and are limited by the injected volume.
Serum IgG half life is approximately 4 weeks.1
The WHO has laid down definite standards
for its preparation. It should contain at least
90 percent intact IgG, it should be as free as
possible from IgG aggregates, all IgG sub classes
should be present, there should be a low IgA
concentration, the level of antibody against at least
two bacterial species and two viruses should be
ascertained etc.2
Live vaccines should not be given for
12 weeks after an injection of ISG and if a live
vaccine has already been given, ISG should be
deferred for 2 weeks.2
Intravenous immunoglobulin (IVIG)
Large plasma pools from more than 1000
donors (in some cases more than 15,000 donors)
are fractionated as for ISG and then further
processed by a variety of techniques such as
polyethylene glycol fractionation, ion exchange,
chromatography, ultrafiltration, exposure to low
pH and others to make IVIG suitable for
IV administration. Products vary in their sources
of plasma pools and processing methods. While
each lot must contain a minimal antibody titre to
certain marker organisms (measles, polio and
tetanus) antibody titres to other bacterial and viral
pathogens vary greatly between preparations and
lots. In addition to it, processing steps may alter
functional capabilities of IgG or change relative
distribution of immunoglobulin subclasses, changes
not reflected in proposed antibody titres.
Therefore, IVIG should not be considered as a
uniform generic product. Different preparations
are packed as liquid or lyophilized formulations
and in different total IgG concentrations, from
5% to 10%.1
Specific hyperimmune human
immunoglobulin
The specific hyperimmune human immuno-
globulin should contain atleast five times the
35
antibody potential of the standard preparation per
unit volume. These preparations are made from
the plasma of patients who have recently recovered
from an infection or are obtained from individuals
who have been purposefully immunized against
the specific infection under consideration.
Therefore, they have a high antibody concentration
against a specific organism and provide immediate
protection.2
Specific hyperimmune human immuno-
globulin is administered by intramuscular injection.
These preparations suitable for intravenous
administration have also become available.3 The
IM injections are painful. Peak blood levels are
reached in 2 days after IM injection. The half life
is 20-35 days.2
Adverse reactions are local as well as
systemic. Pain and sterile abscess like reactions
are relatively common especially when large
volumes are injected by IM route. Systemic
reactions may be immediate or late. Immediate
reactions occur during or within minutes of
administration and they are anaphylactic in type.
Late reactions may occur within hours or days,
are usually less severe and include urticaria,
arthralgia, pyrexia etc.2
Animal derived antisera or antitoxins
Originally passive immunization was achieved
by administration of antisera or antitoxins prepared
from animals such as horses. These preparations
have high incidence of serious reactions like
anaphylaxis and serum sickness. Due to their
serious complications and availability of safer
human immunoglobulin preparations, the current
trend is unfavouring their regular use. Still these
preparations are mainstay of passive immunization
against diphtheria, gas gangrene, and snake bite
etc.2
Indications for passive immunoprophylaxis
Measles: Passive immunization with
immunoglobulin is effective for prevention and
attenuation of measles within 6 days of exposure.4
Susceptible household and hospital contacts who
are less than 12 months of age and pregnant
women should receive immunoglobulin in a dose
of 0.25 ml/kg (maximum 15 ml) IM as soon as
possible after exposure, but within 5 days.
Immunocompromised persons should receive
immunoglobulin 0.5 ml/kg IM regardless of
immunization status. Infants less than 6 months
of age born to non immune mothers should receive
immunoglobulin. Infants less than 6 months of
age born to immune mothers are considered
protected by maternal antibodies. Measles vaccine
should be deferred following administration of
immunoglobulin, depending on the dose and
duration of therapy.5
Rubella : The susceptible pregnant women
exposed to rubella in early pregnancy for whom
abortion is not an option, immunoglobulin should
be administered in the dose of 0.55 ml/kg which
reduces the attack rate but does not eliminate the
risk of fetal infection. The use of IVIG may be an
alternative but not studied in details.6
Hepatitis A: Indications for IM administration of
ISG include preexposure and postexposure
prophylaxis (Table-2). IVIG is likely to be effective
against hepatitis A infection, but appropriate dose,
efficacy and duration of protection have not been
defined. ISG is recommended for preexposure
prophylaxis for all susceptible travellers to
countries where HAV is endemic. For individuals
age 2 and older, HAV immunization is preferred
if the interval before departure is more than
1 month after first dose. ISG as post exposure
prophylaxis is indicated in household and sexual
contacts of HAV cases, newborn infants of HAV
infected mothers, child care centre staff,
employees, children and their household contacts
during an outbreak and outbreaks in institutions
and hospitals. The use of ISG more than 2 weeks
after exposure is not indicated. ISG is not
recommended routinely in sporadic non-
household exposure e.g. protection of hospital staff
or school mates.6

Table 2. ISG Prophylaxis for HAV7

Age Exposure
Pre-exposure Prophylaxis (Travellers to Endemic areas)
< 2 years Expected < 3 months
Expected 3-5 months
Expected long term
> 2 yeas Expected < 3 months
Expected 3-5 months
Expected long term
Post-Exposure prophylaxis
> 2 years < 2 weeks since exposure
> 2 weeks since exposure
All ages < 2 weeks since exposure
> 2 weeks since exposure
Dose
0.02 ml/kg
0.06 ml/kg
0.06 ml/kg at departure and every
5 months thereafter.
HAV vaccine or ISG 0.02 ml/kg
HAV vaccine or ISG 0.06 ml/kg
HAV vaccine
ISG 0.02 ml/kg and HAV vaccine
HAV vaccine
ISG 0.02 ml/kg + HAV vaccine
No prophylaxis

36
Hepatitis B: Prophylactic treatment can
effectively prevent infection after exposure to
HBV. It is indicated in the following situations.
Perinatal exposure of an infant born to a
HBsAg-positive mother.
Inadvertent percutaneous or permucosal
exposure to blood.
Sexual exposure to a HBsAg-positive person.
Exposure of an infant less than 12 months of
age to a primary care giver who has acute
hepatitis B.
The mainstay of postexposure immuno-
prophylaxis is hepatitis B vaccination, but in some
settings passive immunization with HBIG provides
increased protection. HBIG is prepared from
plasma known to contain a high titre of antibodies
and provides temporary protection for 3 to 6
months in certain postexposure settings. The
standard dose of HBIG for postexposure
prophylaxis of infants born to HBsAg positive
mother is 0.5 ml while in all other situations it is
0.06 ml/kg. For prevention of perinatal
transmission, hepatitis B vaccination and one dose
of HBIG given concurrently but at separate sites
using separate syringes, administered within 12
to 24 hours after birth, is highly effective in
prevention of both acute and chronic HBV
infection.7,8,9,10
Varicella-Zoster: Varicella-zoster immunoglobulin
(VZIG), prepared from high titre immune human
serum, reduces the attack rate of varicella when
it is given just after exposure (Table-3). Break
through infections occur, but the extent of
exanthem and risk of varicella pneumonia are
diminished. VZIG given after the appearance of
varicella rash does not alter the disease process.
The dosage is 1 vial (125 U)/10 kg body weight
(maximum 5 vials) given intramuscularly. VZIG
should be given to susceptible high risk individuals
within 96 hours and if possible within 48 hours
after close contact to a person with varicella or
herpes zoster. VZIG prophylaxis is recommended
for immunocompromised children and newborn
infants exposed to maternal varicella. VZIG should
be given to infants born to mothers with onset of
varicella 5 days or less before delivery or within
2 days after delivery. VZIG is not indicated for
healthy, full term infants exposed postnatally,
including those whose mothers rash developed
more than 48 hours after delivery.10.11.12

Table 3. Use of Varicella-Zoster Immunoglobulin (VZIG) for prophylaxis 10

Individuals at risk :
Immunocompromised children with no history of varicella.
Pregnant women with no history of varicella and no antibodies to varicella zoster.
Infants born to mothers who develops varicella 5 days before or 2 days after delivery.
Criterias of close exposure :
Varicella
House-hold contact, close in-door contacts like schoolmates, playmates etc.
Hospital contact, newborn exposure to maternal varicella.
Herpes Zoster
Intimate, direct contact with infected individual.
Administration of VZIG :
VZIG must be given within 96 hours and possibly with 48 hours after exposure.
Dose : 1 vial (125 units)/10 kg body weight (maximum 5 vials) by IM injection.

37
 The administration of VZIG administration
does not eliminate the possibility of disease in high
risk patients. The incidence of varicella despite
VZIG prophylaxis is significantly higher after
household exposures. VIZG to immuno-
compromised children lowered the risk of severe
varicella significantly, but 11% of these children
still developed pneumonia. Because passive
antibody titres of VZIG decline by
2 weeks in some patients and by 4 weeks in most
patients, a second dose should be given if a new
exposure occurs more than two weeks later. VZIG
does not reduce the risk of VZV reactivation in
high risk population or alter the clinical course of
herpes zoster when given after the onset of
symptoms.12
Rabies: Once rabies develops, it is almost
invariably fatal in humans, and prevention is the
only option. With the availability of safe and
effective modern tissue culture vaccines and
immunoglobulins, the prevention of rabies is
almost assured.
Rabies immunoglobulins (RIGs) are special
neutralizing antibodies that immediately neutralize
virus on contact. RIGs give a coating to the virus
so that it can not enter the nerve endings resulting
in reduction or total obliteration of inoculated virus.
Replication of virus is also prevented by RIG.
Administration of RIGs as part of routine post
exposure prophylaxis is intended to provide a
passive source of antibodies before endogenous
development of antibodies by the vaccine.
Pregnancy and lactation are not contraindication.
The need for RIG appears to be on the rise,
because of the ubiquity of human exposure to
rabies virus from uncontrolled canine sources in
developing countries.10,12,13
Indications for use of RIGs13
All category III bites as per WHO
classification.
38
Licks on mucous membrane by wild or pet
animals.
Category II and III bites in immunologically
compromised patients such as AIDS,
varicella, patients on long term steroid therapy,
patients on chemotherapy, radiation therapy
etc.
Before wound suturing for local infiltration.
Those with past history of complete post
exposure prophylaxis using modern tissue
culture vaccines do not need to be given RIG
irrespective of the class of bites.
Human rabies immunoglobulin (HRIG).10,13: It is
a freeze dried preparation containing IgG
immunoglobulins obtained from plasma or serum
of donors immunized against rabies and contains
specific antibodies neutralizing the rabies virus.
Though HRIG represents the gold standard for
passive immunoprophylaxis, its cost is exorbitantly
high. Its supply is also erratic. Advantages of
HRIG include purity, presence of minimal or no
foreign protein and absence of immediate
hypersensitivity reaction. Disadvantages of HRIG
include cost, chances of transmission of potential
plasma borne infections, erratic supply,
development of some rare side effects like angio
edema, nephrotic syndrome and anaphylactic
shock etc. Patients sensitive to other human
immunoglobulins products may be sensitive to
HRIG also. The dose of HRIG is 20 units/kg body
weight to a maximum of 2000 units.
Equine rabies immunoglobulin (ERIG).10,13: It is
produced by immunizing horses with low dose of
rabies vaccines. The modern automated
ultrafiltration technology saves the time and makes
it safer. Easy availability and low cost are its
advantages. Due to presence of foreign protein,
there are chances of immediate hypersensitivity
reaction. It is the main disadvantage of this
product. It is given in dose of 40 units/kg body
weight with maximum of 4000 units.
 Administration of RIGs : As much as
anatomically feasible the RIG should be infiltrated
through, into and around the wound. The
remaining portion of the calculated amount of
RIG, if any, is to be injected in the deltoid region
in older children and adults or anterolateral aspect
of thigh in newborns, infants and young children.
It should be given at a site different from the one
where the vaccine is administered. For injecting
RIG and vaccine separate syringes should be used.
If the administration of RIG is delayed, it can be
administered up to the seventh day after the first
dose of vaccine. Caution is needed while injecting
RIG in certain tissues like finger pulp as excess of
fluid can result in increased compartment pressure
leading to necrosis. For small children calculated
dosage of RIG may be insufficient to infiltrate all
the wounds. In this situation, RIG should be diluted
with sterile normal saline 2 to 3 fold to permit
thorough effective infiltration of all the wounds.
In case of ERIG skin sensitivity testing is essential,
but not required for HRIG.12,13
Tetanus: Tetanus prevention consists of
postexposure administration of vaccine and
antitoxin following a tetanus-prone injury. Need
is determined by type of injury and history of
immunization. Although wounds with major tissue
injury are most tetanus prone, any type of wound,
if contaminated, can lead to tetanus. Tetanus
toxoid vaccine is given immediately if history of
tetanus immunization is not available, is unsure,
or 60 months have elapsed since previous booster
dose. Simultaneous passive immunoprophylaxis
is also indicated in these circumstances.10,14
Two types of preparations are available for
this purpose, Tetanus Human Immunoglobulin
(TIG) and Tetanus Antitoxin (Anti tetanus serum
ATS). TIG is a freeze-dried preparation containing
immunoglobulin mainly IgG obtained from plasma
or serum from immunized human donors. It is
more efficacious, longer acting and safer than
39
equine antitoxin (ATS). The half life of TIG is
4 weeks and significant blood levels are maintained
upto 14 weeks. As a prophylactic, TIG is given in
dose of 250 to 500 IU by IM route. It does not
cause serum sickness like reactions. If TIG is not
available, the use of IVIG may be considered.
ATS is another preparation used for this
purpose. The standard dose is 1500 IU, injected
subcutaneously after negative skin sensitivity test.
It gives protection for about 7 to 10 days. Being a
foreign protein, ATS is rapidly excreted from the
body and there may be very little antibody at the
end of two weeks. It may not cover tetanus
incubation period in all cases. Therefore, it is less
reliable and not favored for routine use.
The infants born to the mothers who have
not previously received 2 doses of tetanus toxoid
are exposed to the risk of neonatal tetanus. They
can be protected by 250 IU of TIG or 750 IU of
ATS, if given within 6 hours of birth.
RSVIVIG: Administration of respiratory syncytial
viral IV immunoglobulin (RS-IVIG) is
recommended in dose of 750 mg/kg for protecting
high risk children against serious complications
from RSV disease. Immunoprophylaxis reduces
the frequency and total days of hospitalization for
RSV infection in high risk infants. These agents
are administered monthly from beginning
(October-December) to end (March-May) of RSV
season. Another IM preparation is also available
and given in dose of 15 mg/kg. Candidates for
immunoprophylaxis include children with lung
diseases like bronchopulmonary dysplasia and
premature babies to be discharged from hospital
during RSV season.15,16
Points to remember
Passive immunoprophylaxis has vital role
in prevention of certain infections in
susceptible individuals, used mainly as post
exposure prophylaxis.

Animal derived products are known for
serious reactions. Human derived
preparations are safer and are commonly
used now-a-days.
Various immunoglobulins are used as
passive prophylaxis for susceptible
individuals against measles, rubella,
hepatitis-A, hepatitis-B, varicella, tetanus,
rabies, RSV, etc. Certain preparations are
recently introduced for clinical use and
some are expected in the near future.
References
1. Fischer GW. Prevention of infectious
diseases. In: Long SS, Pickering LK, Prober
CG (Eds), Principles and Practice of Pediatric
st
Infectious Diseases, 1 Edn. New York,
Churchill Livingstone 1997; pp44-49.
2. Immunoglobulins. In: Parks Textbook of
th
Preventive and Social Medicine, 18 Edn. (Ed)
Park K. Jabalpur. M/s. Banarasidas Bhanot
2005; pp97-98.
3. Cohn JE, Strong LE, Hughes Jr. Wl, Mulford
DJ, et al. Introduction and research objectives,
Bull WHO. 1982;60(1):43-47.
4. Subbarao EK, Andrews-Mann L, Amin S, et al.
Postexposure prophylaxis for measles in a
neonatal intensive care unit. J Pediatr 1990;
117: 782-785.
5. Maldonado YA. Rubeola virus (Measles and
subacute sclerosing panencephalitis). In: Long
SS, Pickering LK, Prober CG (Eds) Principles
st
and Practice of Infectious Diseases, 1 Edn,
New York, Churchill Livingstone, 1997;
pp1251-1262.
6. Maldonado Y. Ruibella. In: Behrman RE,
Kleigman RM, Jenson HB, Eds, Nelson
th
Textbook of Pediatrics, 16 Edn, New Delhi,
Harcourt (India) Private Limited, 2000; pp951-
954.
7. Snyder JD, Pickering LK. Viral Hepatitis In:
Behrman RE, Kliegman RM, Jenson HB.
40
th
(Eds), Nelson textbook of Pediatrics, 16 Edn.
New Delhi, Harcourt (India) Private Limited,
2000;pp768-776.
8. Mahoney FJ, Hepatitis B Virus. In: Long SS,
Pickering LK, Prober CG, Eds, Principles and
Practice of Pediatric Infectious Diseases,
st
1 Edn, New York, Churchill Livingstone.
1997; pp1193-1202.
9. Parthas Immunization digest. Parthasarathy A,
st
Lokeshwar MR, Shah NK, 1 Edn, New Delhi,
Jaypee Brothers, 2005; pp41-42.
10. Dubey AP, Singh S (Eds) IAP Guide Book on
rd
Immunization (3 Edn) 2005;pp20-21.
11. Arvin AM: Varicella-Zoster Virus In: Long SS,
Pickering LK, Prober CG, Eds, Principles and
st
Practice of Infectious Diseases, 1 Edn, New
York, Churchill Livingstone 1997; pp1144-
1154.
12. Centres for Diseases Control and Prevention:
Varicella Zoster Immunoglobulin for the
prevention of Chicken Pox: recommendations
of the immunization practices advisory
committee. Ann Intern Med 1984; 100: 859-
865.
13. Ghosh TK. Prevention of Rabies by vaccination
and immunoglobulin therapy: Some
controversies and solutions In: Ghosh TK,
Kalra A, (Eds), Infectious diseases In Children
and newer vaccines. Part-II Agra, 2003: pp171-
176.
14. Prajapati BS. Prajapati RB. Rabies
Immunoglobulins in Practice. Bulletin of
Infectious Diseases Chapter of IAP.
15. Rathore MH: Clostridium Tetani. In: Long SS,
Pickering LK, Prober CG, Eds, Principles and
Practice of Pediatric Infectious Diseases,
st
1 Edn, New York, Churchill Livingstone 1997;
pp1081-1084.
16. McIntosh K: Respiratory syncytial virus In:
Behrman RE, Kleigman RM, Jenson HB (Eds),
th
Nelson Textbook of Pediatrics, 16 Edn, New
Delhi, Harcourt (India) Pvt. Ltd. 2000; pp991-
993.
 VACCINES II

IMMUNIZATION IN SPECIAL recommending a vaccine. In this chapter

SITUATIONS vaccination in children in the following special
situations are being discussed:
* Shyam Kukreja
** Sandeep Aggarwal 1. Patients with HIV infection
2. Patients with maligancy
Abstract : In some clinical circumstances there
arises a need to modify the already existing 3. Patients on steroids
immunization practices. How to go about in 4. Patients on immunoglobulins
situations like disease outbreaks, adolescence, 5. During disease outbreak
patients with HIV infection, malignancy and
6. Adolescents
patients on steroid therapy/immunoglobulin are
discussed in this article. 7. Travellers
1. Patients with HIV infection
Keywords : Special situation, Immunization
HIV infected patients being immuno-
Immunization is an attempt to replace the
compromised are more susceptible to a wide range
anticipated natural primary (first) contact between
of pathogens thereby necessitating prevention.
the human body and pathogenic organism with a
They are also potentially at risk of getting
safer artificial contact so that the subsequent
disseminated infection following administration of
natural contact between the two takes place in a
live vaccines. In addition to the risk of severe
state of heightened immunity. Immunization forms
complications from live attenuated vaccine in
the backbone of preventive strategies in public
patient with more advanced HIV infection, there
health medicine. Recommendations for
is a risk of activating the immune systems by
immunization practices are based on scientific
vaccination which could potentially increase the
knowledge of vaccine characteristics, principles
viral replication and thereby increase HIV viral
of immunization and epidemiology of specific
load. This theoretical possibility has been
disease. These recommendations become normally
demonstrated in some studies where there was a
applicable to most individuals in the community.
transient increase of HIV RNA concentrations
There are several special clinical circumstances
after immunization with influenza and
that are commonly and uncommonly encountered
pneumococcal vaccines but other studies have
in pediatric practice where some variations from
shown no such increase.1,2 There is no evidence
the norm are to be kept in mind while
to indicate that this transient increase in HIV RNA
load enhances progression of disease. Lastly HIV
* Head, Dept. of Pediatrics,
Max Balaji Hospital, New Delhi infected individuals may develop sub-optimal
** Pediatrician responses to immunization, especially if they have
Max Balaji Hospital, New Delhi immune suppression. Screening to detect HIV
41
infection before initiating routine immunization in
asymptomatic children is not recommended.
Asymptomatic children should be immunized in
accordance with recommended childhood
immunization schedule. Children with
asymptomatic or symptomatic HIV infection
should receive all the killed and conjugate vaccines
and toxoids such as DPT, Hep B and Hib according
to the recommended schedule. Patients with HIV
infection have a high risk of infections with
Hemophilus influenzae type b (Hib) and
pneumococcus. So HIV infected patients should
receive Hib and conjugate pneumococcal vaccines.
Most evidence supports the idea that immunization
with these vaccines should be given early in the
course of HIV infection. Annual immunization
with influenza vaccine is also recommended in
HIV infected children. The use of this vaccine
has been questioned in patients with more
advanced HIV infection because of the risk of
severe disease and likelihood of a poor response
to immunization with influenza vaccine in patients.
Most experts prefer to give influenza vaccine
thinking that benefits do exceed the risk. The
safety of immunization with live attenuated vaccine
is a matter of concern as discussed earlier; hence
it is necessary to weigh the risk and benefits before
deciding to administer the live vaccine to the child.
Measles vaccine should be given to asymptomatic
HIV infected children3 and symptomatic but not
severely immuno-compromised HIV infected
children. Severely immuno-compromised HIV
Patients with CD4 lymphocyte count less than
15% should not receive measles vaccine. Currently
varicella vaccine is recommended for HIV infected
children who have CD4 T lymphocyte count more
than 25% percent (those with no evidence of
immuno-suppression). WHO currently
recommends BCG immunization for all children
in developing countries at high risk for tubercular
infection including HIV infected children. BCG is
given at birth and no HIV infected child is
symptomatic or immuno-deficient at birth. Hence
42
BCG is safe and must be given to all newborns.
However BCG immunization is not recommended
in developed countries with a low risk of
contracting tuberculosis. The most commonly
used live vaccine is oral polio vaccine. Rider and
colleagues reported from Zaire that no serious side
effects were reported in infants with HIV infection
who were given trivalent Sabin vaccine. However,
use of inactivated poliovirus vaccine (IPV) is
generally recommended as this does not carry the
risk for development of paralytic disease.
Table 1 summarizes the recommendations
for immunizing HIV infected children. In general
children with symptomatic HIV infection have
poor immunologic response to vaccine. Hence
when these children are exposed to vaccine
preventable disease, they should be considered
susceptible regardless of the history of
immunization and should receive if indicated,
passive immuno-prophylaxis or chemoprophylaxis.
2. Patients with malignancy
Leukemia is the most common form of
childhood malignancy. Most of these cases occur
before the age of 10 years. Other tumors like
Hodgkins and Non Hodgkins lymphoma occur
more frequently in the age group over 10 years.
Hib and pneumococci are important causes of
infection in patients with hematological
malignancies.4 Patients with Hodgkins disease are
frequently splenectomized as part of their diagnosis
and therapy making these patients particularly
vulnerable to disseminated pneumococcal
infection. Also these patients are at increased risk
of invasive Hib disease.4 Antibody response is
likely to be best when these patients are
immunized at least 2 weeks before splenectomy
or before initiation of chemotherapy. During
chemotherapy, antibody responses to vaccination
are impaired. Immunization is effective if carried
out 3 months after cessation of chemotherapy or
radiation therapy. The immune response to killed
Table 1. Recommendations for immunizing a child with HIV infection
Vaccine WHO ACIP/AAP WHO ACIP/AAP
recommendations recommendations recommendations recommendations
for asymptomatic for asymptomatic for symptomatic for symptomatic
child child child child
BCG Yes (for areas with No No No
High incidence of TB)
DTP/ DTaP Yes Yes Yes Yes
OPV Yes No No No
Measles/ MMR Yes Yes Yes Yes
IPV - Yes - Yes
Hepatitis B Yes Yes Yes Yes
Hib - Yes - Yes
Pneumococcal - Yes - Yes
Influenza - Yes - Yes
Varicella - Consider - Consider
Hepatitis A - Yes - Yes
AAP America Academy of Pediatrics, ACIP Advisory Committee on Immunization Practices,
WHO World Health Organization

vaccines like diphtheria and tetanus toxoid in
children undergoing maintenance chemotherapy
is similar to those of healthy children.5 Oral polio
vaccine can induce paralytic polio and should be
avoided in children undergoing chemotherapy for
cancer. Primary varicella zoster virus (VZV)
infection causes high mortality in children with
malignancy. The available vaccine for protection
is live attenuated VZ vaccine. The vaccine has
been shown to be effective and safe in children
with leukemia who are in remission. The
frequency of side effects from the vaccine is low
and the breakthrough disease can be treated with
acyclovir. The sero-conversion rates are 88% after
one dose and 98% after two doses. The immunity
is stable for more than 5 years. The risk for herpes
zoster after vaccination was lower than in patients
who had natural varicella. Cancer patients who
are infected with measles have a high mortality
rate. Immunization with measles vaccine is
43
contraindicated owing to severe side effects in
cancer patients undergoing chemotherapy.
However it can be given 3 months after cessation
of chemotherapy or before initiating
chemotherapy.
3. Patients on steriod therapy
The degree of immuno-suppression in a child
receiving corticosteroids is influenced not only by
the duration, route and dose of steroids but also
by the underlying disease and other concurrent
therapy the patient is receiving. The vaccines other
than live viral vaccines may safely be given, and
the following guidelines 6 are useful for
administration of live vaccines in recipients of
steroids.
a) Topical therapy or local injection of
corticosteroids: Usually does not result in immuno-
suppression that would contraindicate
administration of live viral vaccines.
b) Physiological maintenance dose of
corticosteroids: Such children can receive live
vaccine.
c) Low or moderate dose of systemic
corticosteroids or an alternate day therapy:
Children receiving less than 2 mg/kg per day of
prednisolone can receive the live viral vaccine
during corticosteroid therapy.
d) High dose of systemic corticosteroids given
daily for less than 14 days: Children receiving less
than 2 mg/kg per day of prednisolone for duration
of less than 14 days can receive live viral vaccine
immediately after discontinuation of therapy. If
there is no urgency it is preferable to delay
immunization until 2 weeks after corticosteroids
have been discontinued.
e) High dose of systemic corticosteroids given daily
or an alternate day for 14 days or more: Children
receiving more than 2 mg/kg per day of
prednisolone should not receive live virus vaccine
until corticosteroids have been discontinued for
at least 1 month.
Children with a disease that by itself is considered
to suppress immune response and who are
receiving corticosteroids: These children should
not be given live vaccines.
4. Immunization of children who recently
received immunoglobulin
Administration of immunoglobulin (IG)
preparation has not been demonstrated to cause
significant inhibition of the immune responses to
inactivated vaccines and toxoids. Concurrent
administration of recommended dose of hepatitisB
immunoglobulin (HBIG), tetanus immunoglobulin
(TIG) or human rabies immune globulin (HRIG)
and the corresponding inactivated vaccine or
toxoid for post exposure prophylaxis does not
impair the efficacy of vaccine and provides
immediate and long term immunity.
44
Live viral vaccine may have demonstrated
reduced immunogenicity when given shortly
before or during few months after receipt of IG.
This has shown to inhibit the response to measles
vaccine.7,8 Measles vaccine should be deferred
for 3 months after Tetanus IG, HRIG, HBIG, IG
administration; for 6-7 months after blood / plasma
administration and 10-11 months after IVIG
administration in the dose of 2gm / kg as in
Kawasaki disease or ITP.6
Immunoglobulin preparation also contains
rubella, mumps and varicella antibodies. High dose
of passively acquired antibodies can inhibit the
response to live rubella vaccination for as long as
3 months.9,10 Administration of rubella vaccine
should be postponed for at least 3 months. The
effect of IG preparation on the response to live
mumps and live varicella vaccine is not studied;
postponement of mumps and varicella vaccines
for 3 months and 5 months respectively is
recommended because of possible interference by
administration of IG.
Immunoglobulin administration should be
delayed for 2 weeks after MMR and 3 weeks
after varicella vaccine for adequate antibody
response to occur.
5. Immunization of adolescents
Adolescence should be considered an
appropriate age for top up immunization as well
as administration of certain vaccines which may
not have been given earlier. Table 2 shows
vaccination schedule for adolescents
6. Vaccination during outbreak
Measles outbreak: During outbreak, monovalent
measles vaccine may be given to infants as young
as 6 months of age. Seroconversion rates are
significantly lower in children immunized before
the age of 9 months. These infants should receive
another dose of measles vaccine or preferably
Table 2. Vaccination schedule for
adolescents 11
Vaccine Age
Tetanus toxoid and Booster at 10 and 16 yrs
diphtheria (dT)
MMR 1 dose if not given earlier
Hepatitis B 3 doses (0, 1, 6 months)
if not given earlier
Typhoid vaccine Vi vaccine given every
3 years (other typhoid
vaccines not available)
Varicella vaccine* 1 dose up to 13 years
2 doses after 13 years
(if not given earlier)
Hepatitis A vaccine* 2 doses, 6 months apart
(if not given earlier)
*If the child has suffered from chicken pox and
Hepatitis A (serological evidence) in the past the
respective vaccine need not be given.
MMR after the age of 1 year. During outbreak,
susceptible children above the age of 1 year should
be given a dose of MMR. If MMR vaccine is not
affordable or not available, then monovalent
measles vaccine may be given.
Meningococcal outbreak: Because secondary
cases can occur several weeks or more after the
onset of disease in index case, meningococcal
vaccine may be offered as a possible adjunct to
chemoprophylaxis when an outbreak is caused by
a sero-group contained in the vaccine.6
Japanese B encephalitis outbreak: Vaccination
is the method of choice for prevention of JE. This
should ideally be used to prevent the outbreak.
Contrary to common belief, this vaccine is not
meant to be used as an outbreak vaccine. In India
after introduction of vaccine in high-risk areas of
Andhra Pradesh, cases of JE decreased from 300
cases in 2002 to 25 in 2003. The inactivated
mouse brain vaccine is troubled by issues regarding
45
its safety, high cost, non-availability in large
quantity and efficacy. The SA 14-14-2 vaccine
produced by China is a live attenuated, cheap and
effective vaccine. The vaccine is likely to be used
in India in endemic areas to prevent outbreaks of
Japanese B encephalitis in recent future.
7. Immunization for travellers 11
The risk of travellers contracting infectious
disease depends on the region/country to be
visited, duration of trip and nature and conditions
of travel. Uniform recommendations are not
possible because the epidemiology of disease differ
in various geographical areas. The physician should
try to update routine immunization and provide
destination specific immunizations. For instance,
vaccines commonly recommended for Indian
travellers include yellow fever vaccine for those
intending to go to destinations in South America
and sub-Saharan Africa (except for infants less
than 9 months and pregnant women) and
meningococcal vaccine for those intending to go
on a Haj pilgrimage. Similarly, visitors coming to
India from Western Europe/North America are
usually advised vaccination against typhoid and
Hepatitis A, especially if the stay is likely to be
prolonged.
Points to remember
All killed vaccines can be given in HIV
infected children, irrespective of the clinical
status. While giving live attenuated
vaccines, it is necessary to weigh the risks
and benefits.
Patients with malignancies should receive
vaccines like pneumococcal, influenzae and
hepatitis B vaccines before starting therapy,
including splenectomy.
Patients on prednisolone in a dose of
2 mg/kg for a period of more than 2 weeks
should be given live vaccines one month
after discontinuation of the steriods.
 Vaccines recommended for adolescents
should be administered.
Immunization for travellers and during out
breaks need the knowledge of local
epidemiology of the VPDs.
References
1. OBrien W, Grovit-Ferbas K, Namazi A, et al.
Human immunodeficiency virus-type 1
replication can be increased in peripheral blood
of seropositive patients after influenza
vaccination. Blood 1995;86:1082-1089.
2. Staprans S, Hamilton B, Follansbee S, et al.
Activation of virus replication after vaccination
of HIV-1 infected individuals. J Exp Med
1995;182:1727-1737.
3. Mclaughlin M, Thomas P, Onorato I et al. Live
virus vaccines in human immunodeficiency
virus infected children: A retrospective survey.
Pediatrics 1988;82:229-233.
4. Feldman S, Gigliotti F, Shenep J, et al. Risk of
Haemophilus influenza type b disease in
children with cancer and response of
immunocompromised leukemia children to a
conjugate vaccine. J Infect Dis 1990;161:926-
931.
5. Van der Does-van den Berg A, Hermans J,
Nagel J and van Steeins G. Immunity to
diphtheria, pertussis, tetanus, and poliomyelitis
NEWS AND NOTES
ANNUAL CONVENTION OF KERALA STATE NNF
FEBRUARY 17-18, 2007
Contact :
Dr. Naveen Jain,
Consultant Neonatologist,
Kerala Institute of Medical Sciences,
Trivandrum.
Mobile : 93878 14568,
E-mail : naveen_19572@hotmail.com
46
in children with acute lymphocytic leukemia
after cessation of chemotherapy. Pediatrics
1981;67:222-229.
6. American Academy of Pediatrics 2003 Red
Book: Report of the committee on infectious
th
disease 26 Edn, Elk Grove Village IL,
American Academy of Pediatrics.
7. Dengler T, Strnad N, Zimmermann R, et al.
Pneumococcal vaccination after heart and liver
transplantation. Immune response in
immunosuppressed patients and in healthy
controls. Dtsch Med Wochenschr 1996;121:
1519-1525.
8. American Academy of Pediatrics. Measles. In
Peter G (ed.) 1997 Red Book: Report of the
th
Committee on Infectious Disease, 24 Edn, Elk
Grove Village IL, American Academy of
Pediatrics, 1997; pp 344-357.
9. Mauch T, Crouch N, Freese D, et al. Antibody
response of pediatric solid organ transplant
recipients to immunization against influenza
virus. J Pediatr 1995;127:957-960.
10. American Academy of Pediatrics. Rubella. In:
Peter G (ed.) 1997 Red Book: Report of the
th
Committee on Infectious Disease, 24 Ed, Elk
Grove Village, IL, American Academy of
Pediatrics, 1997; pp 456-462.
11. IAP Guide Book on immunization IAP
committee on Immunization 2003-2004.
 RADIOLOGIST TALKS TO YOU
THE CENTRAL NERVOUS SYSTEM-
ANATOMICAL BASIS OF
RADIOLOGY
* Vijayalakshmi G
** Elavarasu E
** Porkodi
** Malathy K
*** Venkatesan MD
In this issue we will start the study of the
central nervous system. Ultrasound, CT and MRI
are useful. Let us study the appearances in the
various sections obtained by these imaging
modalities. For this, we will combine the study of
anatomy, physiology and embryology. This kind
of approach will help us understand the various
pathologies of CNS seen in children.
Water forms the major part of the body and
also determines the appearances of body structure
in all types of imaging. The brain is suspended
within a waterbath of CSF. The distribution of
this extracellular fluid varies in the different
anatomical spaces that are enclosed in the cranium,
varying from a thin film in the normal subdural
space to larger collections in the ventricles and
basal cisterns.
As we trace the formation and flow of CSF
we will note the anatomical landmarks that we
see in cranial CT. CSF is formed in the choroid
* Addl.Professor
** Asst. Professor
*** Professor
, Department of Radiology,
Chenglepet Medical College Hospital, Chenglepet
47
plexuses in the ventricles. The triangular,
symmetrical dark grey structures seen on either
side of the midline are the lateral ventricles
(Fig 1). The choroid plexus is easy to note in the
adult and older child as it shows calcification
which appears as a white spot in the posterior
part of the body of the lateral ventricle. From the
lateral ventricle the CSF flows down through the
foramen of Munro into the third ventricle. This is
the small round midline fluid space (Fig 2). It then
passes through the aqueduct of Sylvius which is
very thin and not discernible in CT axial images.
CSF in the fourth ventricle is seen as a midline
round fluid space. The CSF filled central ventricles
are easily identifiable and any change or distortion
in these help in diagnosis.
If you recall embryology, the cranial part of
the neural tube which forms the brain develops
dilatations that are the future ventricles. The
cerebral cortex and the corpus striatum form
from the telencephalon and therefore are related
to the telencephalic vesicles or the lateral
ventricles. So look for these structures on either
side of the lateral ventricles. The corpus striatum
or basal ganglia consist of the medial caudate
nucleus abutting the lateral wall of the lateral
ventricle. The lateral part of the basal ganglia which
is the lenticular nucleus is separated from the
caudate nucleus by the internal capsule (Fig 1).
On either side of the third ventricle are the
thalami or the diencephalic structures. Caudal to
these is the midbrain. The CSF cavity here is the
aqueduct which is not discernible. Therefore look
for the colliculi (Fig.3) on the dorsal aspect that
will help you identify this part. This is shaped like
a double U.
 L
c
l t 3

Fig 1. Section showing lateral (L)ventricles with Fig 2. Section showing slit-like, midline third
cerebrum, caudate nucleus(c) and lentiform ventricle (3) and thalamus (t) on either side.
nucleus (l)

p
m

Fig 3. Section showing midbrain (m). The Fig 4. The fourth ventricle with the pons (p)
colliculi are on the posterior aspect and the and the cerebellum(c ).
cerebral peduncles extend anteriorly.

48
 3 3 L

Fig 5. Dilated third ventricle . Note the dilated Fig 6. All ventricles are dilated. L-temporal
temporal horns on either side. horn of lateral ventricle.

The fourth ventricle is related to the pons
and the medulla oblongata which are the
rhombencephalic structures (Fig.4). The folding
of the neural tube brings the pons to lie anterior
to the fourth ventricle while the medulla is placed
posteriorly. This is an important relation which
will help you to know the site of lesions and
therefore the pathology.
From the fourth ventricle the CSF flows
through the foramina of Magendie and Luschka
into the subarachnoid space . From the
subarachnoid space the fluid is absorbed through
the arachnoid villi into the dural venous sinuses.
The villi consist of projections of fused arachnoid
membrane and endothelium of the sinuses which
act as valves allowing the CSF to flow into the
venous sinuses.
If the flow of CSF down this conduit is
stopped at any point, the proximal part of the
system dilates. Look at the normal size of the
ventricles (in Fig. 1 to 4) See the concave lateral
border in the case of the lateral ventricles. When
the lateral ventricle dilates the outer edge bulges.
The normal third ventricle which is thin and slit
like assumes a round shape (Fig.5) when there is
distal obstruction, as in aqueduct stenosis. When
the fourth ventricle also becomes dilated and
more spherical, we can call it tetraventricular
hydrocephalus (Fig.6). This happens when thick
basal exudates block the outlets of the fourth
ventricle or disturb the flow through the arachnoid
villi.
The central, fluid filled ventricles are readily
identified and aid in knowing the level of the section
and therefore the site of any lesions.

NEWS AND NOTES

APLS : THE PEDIATRIC EMERGENCY MEDICINE COURSE
New Delhi, March 24-25, 2007
Enquiries to : Dr. Suresh Gupta, Department of Pediatrics, Sir Ganga Ram Hospital,
New Delhi 110 060. Email : drguptasuresh@yahoo.co.in

49
 PICTURE QUIZ

11 year old girl has presented with progressive abdominal distension, cachexia, anemia, short stature
with massive splenomegaly and moderate hepatomegaly. Bone marrow aspirate revealed the characteristic
cells, which is diagnostic (shown in the picture). What is the diagnosis?
Compiled by:
*Aditi Devidas Kamble, **Sandeep S. Patil
*Lecturer, **Resident
Department of Pediatrics
Govt. Medical College, Aurangabad-431001.

Answer on page: 328

50
 CASE STUDY
CUTIS VERTICIS GYRATA
*Sri Venkateswaran K
**Purushothaman
***Raveendranath V
**Saradambal N
****Sujatha L
*****Susheela Rajendran
Introduction
Cutis verticis gyrata is a descriptive term to
describe skin lesions with a folded and loose
appearance. It can be primary due to a genetic
defect or secondary to various disorders like
myxedema, pachydermoperiostosis, neuro-
fibromas, naevi etc.1 Associated central nervous
system defects have been described in Cutis
verticis gyrata.2,3 Herewith we are reporting a case
of congenital melanocytic nevus presenting as
Cutis verticis gyrata (CVG) for its morphological
appearance.
Case report
A boy of 12 years presented with an irregular
mass consisting of ridges and furrows on the scalp
present since birth with gradual increase in size.
He had no neurological complaints and there was
no family history. On examination cerebriform,
* Associate Professor, Dept. of Dermatology
** Prof. and Head, Dept. of Plastic Surgery
*** Internee
** Prof. and Head, Dept. of Pathology
**** Tutor, Dept. of Radiodiagnosis
***** Prof. and Head & Medical Superintendent
Dept. of Pediatrics
Vinayaka Missions Medical College, Karaikal
51
non tender, firm, hyperpigmented tumorous
lesion of 12 cm size was present in the occipital
and parietal area of the scalp (Fig.1,2). There was
alopecia over the mass. No similar lesions elsewere
in the body. A clinical diagnosis of Cutis verticis
gyrata was made.
Skull X- ray revealed an intact cranial vault.
CT of the brain and skull showed a soft tissue
swelling in the occipital area of the scalp with a
normal brain study (Fig.3). A diagnosis of
melanocytic nevus presenting as CVG was made.
The mass was surgically excised in toto (Fig.4)
and the skull was covered with split skin graft by
plastic surgeon. Histopathology of the biopsy of
the lesion showed dermal melanocytic nevus cells
(Fig. 5).
Discussion
The importance of congenital melanocytic nevus
presenting as Cutis verticis gyrata is to exlude
neurological abnormalities and prevention of
malignant transformation. Patients with
congenital melanocytic nevi may have associated
leptomeningeal melanocytosis with or without
central nervous system melanomas3. Patients with
large congenital melanocytic nevi in a posterior
axial location are at greater risk for manifesting
with neurocutaneous melanosis4. Nervous system
associations such as cerebral mass5, encephalo-
cele, melanomas, neurologic findings, lipomatosis
have been described.
Giant nevi may have different morphological
appearances. Four children presenting with hard,
ligneous progressively hypopigmented and alopecic
 Fig.1. Cutis verticis gyrata lesion over Fig 3. CT Scan skull showing extracranial
scalp soft tissue shadows

Fig.2. Close up view of lesion in fig 1 Fig.4 Excised specimen

Fig.5. Histopathology showing naevus cells in dermis 40X

52
giant nevi with features suggestive of desmoplasia
have been reported6. Giant Melanocytic Naevus
with progressive sclerodermoid reaction in a
newborn has also been described.7 In our case it
was a cutis verticis gyrata like appearance.
Whether the evolution of this unique
appearance of the lesion in our patient mimicking
the contours of the brain is related to the
embryological origin of the neuroectoderm is not
known . It is well known that in some dermal
naevi there are neuroid changes in the deeper
parts.The differentiation of these neuroid naevi
from solitary neurofibroma may be difficult in
routinely stained sections but distinction may be
possible by immunohistochemistry employing
myelin basic protein which is positive only in
neurofibroma.8 These findings support the belief
that dermal melanocytic nevi are hamartomas of
both melanocytic and neural cells. In the etiology
of melanocytic naevi it is proposed that during
embryogenesis a morphogenic error in the
neuroectoderm results in the dysregulated growth
and distribution of melanoblasts from the neural
crest to the leptomeninges and the integument.9
References
1. Mathur NB, Maria A, Khandpur S, Bala S. Giant
congenital melanocytic nevus with cutis vertis
gyrate.Indian Pediatr 2001;38:553-556
NEWS AND NOTES
NATIONAL TYPE 1 DIABETIC MEET FOR PARENTS OF
DIABETIC CHILDREN OF ALL AGES
Kanpur, UP, January 27-28, 2007
Enquiries to :
Dr. Rashmi Kapoor, Pediatric Intensivist,
Regency Hospital Ltd., A-2, Sarvodaya Nagar, Kanpur, UP.
Phone No. -0512-2236201, 02 Mobile - 9839027449
E-mail : rashmireg@rediffmail.com
53
2. Shermak MA, Perlman EJ, Carson BS,
Dufresne CR.Giant congenital nevocellular
nevus overlying an encephalocele.J Craniofac
Surg 1996;7(5):376-383.
3. Cabrere H, Gomez ML, Garcia S. Lipomatous
melanocytic nevomatosis.J Eur Acad Dermatol
Venerol 2002;16(4):377-379.
4. Martinez-Granero MA, Pascual-Castroviejo I,
Roche Herrere MC, Urgelles Fajardo E.
Neurocutaneous melanosis and congenital
melanocytic nevi.Neurolgia 1997;12(7): 287-
292.
5. Schaffer JV, MC Niff JM, Bolognia JL.
Cerebral mass due to neurocutaneous
Melanosis:eight years later.Pediatr Dermatol
2001;18(5):367-377.
6. Maldonada R, Orozco L. Desmoplastic
hairless hypopigmented nevus:a variant of
congenital melanocytic nevi. Br J Dermatol
2003;148(6) 1253-1255.
7. Pattee SF, Hansen RC, Bangert JL, Joganic EF.
Giant congenital nevus with progressive
sclerodermoid reaction. Pediatr Dermatol
2001;18(4):320-324.
8. Elder D, Elenitsas R. Benign pigmented lesions
and malignant melanoma. In: Levers
th
Histopathology of skin 8 Edn. Lippincott-
Raven, Philadelphia 1997; p 636.
9. Marghoob AA. Congenital melanocytic nevi-
evaluation and management. Dermatol Clin N
Am 2002;20:607-616.
 CASE STUDY
CAVERNOUS SINUS THROMBOSIS
A CASE REPORT
* Arunkumar J
** Lakshmi S
** Kumarasamy K
** Ravisekar CV
** Venkataraman P
*** Vasanthamallika TK
Introduction
Intracranial septic venous thrombosis is very
rare in the post antibiotic era. It may complicate
meningitis, epidural or subdural abscess or spread
from extracranial veins. A review of literature
between 1940 and 1988 has identified only 88
cases. The treatment is controversial and the
outcome is fatal in approximately 30% and nearly
half have chronic neurological sequelae including
oculomotor weakness, blindness, ptosis, proptosis,
hemiparesis and hypopituitarism.1
Case report
A four year old boy presented with history
of furuncle over the bridge of the nose. He also
had swelling in the right periorbital region and low
grade fever. Subsequently, the child became toxic
with increase of swelling, pain and limitation of
movements of both eye balls. He then developed
right sided ptosis, mild proptosis, chemosis of
* Postgraduate
** Asst. Professor
*** Addl. Professor
Institute of Child Health and Hospital for Children,
Chennai - 8.
54
conjunctiva and bilateral lateral rectus palsy
(Fig.1). The pupils and rest of the CNS
examination were normal except for meningeal
signs.
Based on these, a diagnosis of cavernous
sinus thrombosis was made and the child was
investigated. Routine investigations revealed
polymorphonuclear leucocytosis. CSF was
normal and blood, pus and CSF culture were
negative. CT scan showed dilated superior
ophthalmic vein on the right side. Contrast MRI
confirmed the thrombus in the cavernous sinus
(Fig.2).
The child showed remarkable improvement
with antibiotics (vancomycin and ceftriaxone for
three weeks and metronidazole for two weeks)
and steroids (dexamethasone 0.2mg/kg/dose iv
every 8 hours for seven days) and was discharged
with bilateral resolving lateral rectus palsy and
partial ptosis on the right side.
Anticoagulants were not initiated as its role
is controversial and for the fear of spread of
infection as the child had septic foci in the face2.
Discussion
Septic facial lesion remain the most frequent
predisposing infection for intracranial venous
thrombosis, the others being infection of sinuses
and jaw. Staphylococcus aureus is the most
common pathogen isolated in nearly two thirds
followed by pneumococci, H. influenzae and
anaerobes. Gram negative rods and fungi may be
isolated in chronic forms.3

Fig. 1. Clinical picture with bilateral squint
and residual ptosis right eye
The principal symptoms are fever and
periorbital edema initially affecting one eye.
Within 24-48 hours the other eye becomes
involved through spread from intercavernous
sinuses. The classical physical features include
ptosis, proptosis, chemosis, oculomotor palsies and
painful limitation of movements of eyeball.
Depending on the involvement of sixth, third
or fifth cranial nerve and sympathetic plexus there
may be focal deficits. Contralateral hemiparesis
results if internal carotid artery is thrombosed.
The differential diagnosis includes other
causes of periorbital edema: orbital cellulitis,
carotico-cavernous fistula, idiopathic
granulomatous inflammation of the superior orbital
fissure and cavernous sinus (Tolosa Hunt
Syndrome), periarteritis nodosa associated with
cerebral venous sinus thrombosis (Cogans
Syndrome) and tumors. But orbital cellulitis is
the most common mimic and it can be
differentiated by the characteristic bilaterality of
cavernous sinus thrombosis.
CT scan is the diagnostic study of choice.1
Contrast CT will demonstrate irregular filling
defects and convex bulging of the lateral sinus
walls on coronal sections and dilation of superior
ophthalmic vein. MR venography or cerebral
angiography with venous phase studies may be
necessary to confirm the diagnosis.4 Blood or
CSF culture may reveal the offending organism.
The mainstay of therapy is early intravenous
55
administration of antibiotics in high dosage
directed against the most likely pathogens. A
penicillinase resistant penicillin combined with a
third generation cephalosporin is a good empirical
choice. Metronidazole may be added to enhance
anaerobic coverage.
Corticosteroids are universally used in
patients treated non surgically.3,5 This does not
prove that steroids influence the morbidity or
mortality of cavernous sinus thrombosis but their
use as an adjunctive therapy might partially prevent
cranial nerve dysfunction caused by
inflammation.3,6
There are insufficient data regarding the
indication of anticoagulant therapy2 because the
condition is rare. Anticoagulation should be
considered only when there is no evidence of
cortical venous infarction either clinically or on
imaging. Early addition of heparin to the primary
treatment with antibiotics (within seven days of
hospitalization) may reduce the morbidity and
mortality in this disease.1 However there is a
potential danger of hemorrhagic cerebral infarction
and enhance spread of infection.
Cavernous sinus surgical exposure and
drainage is not recommended because of the high
risk of damage to vital nerves.
Fig. 2. MRI showing thrombus in the right
cavernous sinus
 Recent advances in interventional neuro
radiology and endovascular techniques enable the
local delivery of thrombolytic agents to selective
venous channels where thrombosis occur and these
newer techniques will undoubtedly be used with
increasing frequency in the future for the treatment
of cortical venous thrombosis.
References
1. Southwick FS, Swastz MN. Inflamatory
thrombosis of major dural venous sinuses and
cortical veins. In: Wilkins RH, Rengachary SS
(EDs) Neurosurgery, 2nd Edn,Vol III, McGraw-
Hill, USA 1996;PP3307-3308.
2. Bhatia K. Jones NS. Septic cavernous sinus
thrombosis secondary to sinusitis: are
anticoagulants indicated? J Laryngol Otol
2002; 116 (9) : 667 676.
3. Migirov L, Eyal A, Kroneberg J. Treatment of
cavernous sinus thrombosis. I Med Assn J
2002; 4: 468469.
4. Verma A, Solbring MV. Infection of the nervous
system. In: Bradley WG, Daroff RB, Fenichel
GM, Jankovic J (Eds). Neurology in clinical
th
practice, 4 Edn, Vol II, Elsevier, USA. 2004;
pp 1488 1489.
5. Johanson DL, Markle BM, Wiedermann BL,
Hanahan L. Treatment of intracranial
abscesses associated with sinusitis in children
and adolescents. J Pediatr 1988; 113: 15 23.
6. Southwick FS, Richardson EP, Swartz MN.
Septic thrombosis of the dural venous sinuses.
Medicine 1986; 65: 82 106.

NEWS AND NOTES

9th ASIAN AND OCEANIAN CONGRESS OF CHILD NEUROLOGY

Philippines, January 24-27, 2007
Enquiries to :
Secretariat, Philippine Neurological Society,
RM 1006, 10th floor, North Tower, Cathedral Heights Building,
St. Lukes Medical Center, E. Rodriguez St., Quezon City, Philippines.
Email : secretariat@aoccn2007.org and pna@surfshop.net.ph

5th NATIONAL CME IN NEONATOLOGY

New Delhi, February 10-11, 2007
Enquiries to :
Dr. Ramesh Agarwal,
Department of Pediatrics,
All India Institute of Medical Sciences,
New Delhi 110 029.

56
 CASE STUDY
HEREDITARY SENSORY
AUTONOMIC NEUROPATHY TYPE IV-
A VERY RARE CONDITION
* Nilesh Jain
** Vyas BR
*** Shalini Jain
Introduction
Hereditary Sensory Autonomic Neuropathy
(HSAN) is classified into five types according to
natural history, mode of inheritance and
electrophysiological characteristics. HSAN type IV
is a rare autosomal recessive disorder. Very few
cases have been reported in literature. The main
features are insensitivity to pain, anhidrosis, mental
retardation and self-mutilating behaviour, present
since birth1. The diagnosis primarily relies on
history and examination but can be confirmed by
absence of sensory evoked potential and absence
of unmyelinated axons in sural nerve biopsy.
Mutation of Neurotrophic Tyrosine Receptor
Kinase - 1(NTRK-1) causes defect in nerve
growth factor (NGF) signalling, leading to death
of various NGF dependent neurons.2 Recurrent
trauma as well as episodes of fever require medical
treatment.
Case Report
A 3 year old male child presented with history
of generalized convulsions associated with fever,
self inflicted injury with mutilation of lower lip,
* Asst. Professor, Dept. of Pediatrics
** Assoc. Professor, Dept. of Pediatrics
*** Tutor, Dept. of Anaesthesiology
M.P. Shah Medical College,
Guru Gobind Singh Hospital, Jam Nagar, Gujarat.
57
nose, fingers and toes leading to multiple scar
formation, dry skin, mental retardation and near
blindness. There was no history of tingling,
burning, numbness and sensation of pins and
needles. The child was born full term to second
degree consanguineous parents. Antenatal,
intranatal and postnatal periods were uneventful.
The child was able to walk without support but
could neither climb stairs with assistance nor walk
sideways. He was able to speak 8-10 words but
could not form simple sentences. He was toilet
trained and dry during the day. There was history
of repeated biting and scratching of lips, fingers
and nose without sensation of pain during
scratching and injury causing deep ulcer formation,
fibrosis and deformity. He had inadequate sweating
and repeated episodes of unexplained fever and
two such episodes were accompanied by seizures.
There was no similar history in the family.
On examination, he had corneal opacities in
both eyes. The nose was deformed, lower lip was
mutilated and fingers of both hands were
deformed especially index and ring fingers of right
hand with hyper pigmentation. Feet and toes were
also hyper pigmented and had multiple scars. The
skin was rough and dry. Sweating was not
observed in the child. Fungiform papillae were
seen over the tongue. Eyebrows, teeth and nails
were normal.
Blood pressure was normal. No sphincter
disturbances were present. Pain and temperature
sensations were absent all over body, however
touch sense was preserved. Corneal reflex was
present and deep tendon reflexes were sluggish.
There was no cerebellar sign and gait was normal.
 Intradermal injection of 1:10000 histamine
failed to show axon flare.
Study of conduction velocity showed absence
of evoked potential from sensory nerves. The
motor action potential and conduction velocities
were normal. The normal values in children
more than 2 years are 50-70 m/s in arms and 40-
60 m/s in legs as in adults. Sural nerve biopsy
showed absence of unmyelinated axons, decrease
in number of small myelinated axons and normal
distribution of large myelinated axons. Serum uric
acid level was normal.
Discussion
HSAN is a group of hereditary sensory and
autonomic neuropathy, classified by Dyck into
five types (Table 1). Hereditary sensory and
autonomic neuropathy type-IV (HSAN-IV) is a
very rare autosomal recessive disorder. The
frequency of this disease is unknown. HSAN-IV
is also known as congenital insensitivity to pain
with anhidrosis (CIPA, MIM#256800) and Familial
dysautonomia type two. It was first described by
Swanson in 1963.3
The diagnosis is commonly based on clinical,
neuropathological findings and histamine test.
Recently molecular analysis of NTRK-1, the gene
mutated in this disease is available.
Clinical features4 : The constant features (100%)
are anhydrosis, episodes of unexplained fever,
severe mental retardation, insensitivity to pain,
self-mutilating behaviour. The frequent features
include multiple fractures with slow healing skin
infections, bruises, corneal ulcerations, and
aggressive behaviour. Impaired immune response,
proteinuria, renal failure, anemia, hyperkeratosis,
dry skin and early primary teeth loss have also
been reported.
HSAN-IV is caused by mutation of
neurotrophic tyrosine receptor kinase I gene
58
(NTRK 1) located on 1q21-q22 which encodes a
receptor tyrosine kinase (RTK) for the nerve
growth factor (NGF).
Intradermal injection of 1:10000 histamine
fails to show axon flare.
Diagnosis is confirmed by neruropathological
finding showing the absence of unmyelinated
axons, decrease in number of small myelinated
axons and normal distribution of large myelinated
axons. Sweat glands have a normal structure but
are not innervated. Electrophysiological studies
reveal reduction in sensory action potential.
Differential Diagnosis: Familial dysautono-mia,
HSAN III and HSAN IV have many features in
common. However in HSAN III, insensitivity to
pain is not prominent, corneal reflex is absent and
fungiform papillae of the tongue are not seen.
Affected children with ectodermal dysplasia are
anhidrotic because sweat glands are absent. The
nervous system is intact, and sensation to pain is
present.
Another differential diagnosis for self-
mutilation is Lesch Nyhan disease. Affected
children have compulsive self mutilation and
mental retardation but pain and temperature
sensations are present.
Treatmet : No specific therapy is available for
HSAN-IV. However, constant vigilance and
protective milieu to prevent injuries to the skin
and bones are essential. Extraction of teeth has
been performed in some children to prevent
mutilation. An important goal of therapy is to
prevent foot ulcers. Recurrent traumatic
complications, as well as severe episodes of fever
require frequent medical treatment. Fracture must
be suspected whenever bruising or swelling are
identified. Proper and rapid immobilization is
mandatory. It is estimated that about 20% deaths
occur due to hyperthermia or sepsis.
Table 1. Hereditary sensory and autonomic neuropathies. Modified by Dyck
(1994)
Neurons (Axons)
HSAN Onset Inheri- Motor Loci Gene Salient clinical features
tance A- A- C
alpha delta

Type 1 >2 AD + ++ ++ LS 9q22 SPTLC1 Lancinating pain, plantar

decades ulcers. Feet are more
involved than hand

Type 2 Co AR ++ ++ + G Unknown Unkown Infantile hypotonia. Arms

and legs are equally
involved. Touch and
pressure are more affected
than pain and temperature

Type 3 Co AR ++ ++ ++ G 9q31 IKVKAP Feeding difficulties and

poor control of autonomic
function

Type 4 Co AR N + + G 1q21 NTRK1 Absence of pain and tempe-

rature sensation; touch and
vibration are intact in some
cases. Anhidrosis and
mental retardation are
prominent features.

Type 5 Co AR N N/+ N/+ G Unknown Unknown Pain sensation lost

selectively.

Co = Congenital LS = Lumbo sacral G = Generalised

Reference insensitivity to pain with anhidrosis (CIPA), a

1. Fenichel GM. Sensory and autonomic
disturbances. In: Clinical Pediatric Neurology
th
4 Edn. W.B. Saunders Company, Philadelphia
2001;pp 216-218.
2. Indo Y. Molecular basis of congenital
insensitivity to pain with anhidrosis (CIPA):
mutations and polymorphisms in TRDA
(NTRK) gene encoding the receptor tyrosine
kinase for nerve growth factor. Hum Mutat
2001;18:462-471.
3. Swanson AG. Congenital insensitivity to pain
with anhidrosis. Arch neurol 1963; 8:299-306.
4. Toscano E, Delta Casa R, Mardy S, et al.
Multisystem involvement in congenital
59
nerve growth factor receptor (TrkA) related
disorder. Neuropediatrics. 2000;31:39-41.
5. Levi-Montalcini R. the nerve grwoth factor.
Thirty-five years later. EMBO J 1987; 6:1145-
1154.
6. Asaumi K, Nakanishi T, Asahara H, Inoue H,
Takigawa M. Espression of neurotrophins and
their receptors (Trk) during fracture healing.
Bone 2000; 26:625-633.
7. Dyck PJ, Chance P, Lebo R, Camey JA.
Hereditary motor and sensory neuropathies. In:
Dyck PJ, Thomas PK, Griffin JW, Low PA,
Poduslo JF (Eds). Peripheral Neuropathy
Vol 2 WB Saunders, 1993;pp1094-1123.
8. Greco A, Filla R, Tubine B, Romano L, Penso
D, Piertotti MA. A novel NTRK1 Mutation
associated to insensitivity to pain with
anhidrosis. IS J Hum Genet 1999; 64:1207-
1210.
9. Indo Y, Mardy S, Miura Y, et al. Congenital
insensitivity to pain with anhidrosis (CIPA):
novel mutations of the TRKA (NTRK1) gene,
a putative uniparental disomy, and a linkage
of the mutant TRKA and PKLR genesis in a
family with CIPA and pyruvate kinase
deficiency. Hum Mutat 2001;18:308-318.
10. Shatzky S, Moses S, Levy J, et al . Congenital
insensitivity to pain with anhidrosis (CIPA) in
Israli-Bedouins. Genetic heterogeneity, novel
mutations in the TRKA/NFG receptor gene
clinical findings and results of nerve
conduction studies. Am J Med Genet
2000;92:353-360.

PICTURE QUIZ
Answer for the picture quiz : Gauchers Disease
ADVT.

MAHAMAHAM PEDICON - 2007

KUMBAKONAM
XXXII ANNUAL STATE CONFERENCE OF IAP-TAMILNADU STATE CHAPTER
ORGANISED BY IAP-TTKPN DIST. BRANCH
DATE : 10th - 12th OF AUGUST 2007
Org. Chairman Org. Secretary Treasurer Jt. Org. Secretary
Dr. R. Virudha Giri Dr. R. Palanivelu Dr. S. Lakshmi Narayanan Dr. G. Sambasivam
94433 82982 94433 64111 94431 60800 94431 34711
Theme : Childrens Safety and Nutritional Security - Nations Priority
Delegate fee upto 31-03-06 31-05-06 15-07-06 Spot
IAP 1500 2000 2500 3000
Non - IAP 1750 2250 2750 3500
Post Graduate 1250 1500 1750 2000
Accompanying person 1250 1750 2250 2500
The delegate fee as DD / Cheque drawn in favour of Mahamaham Pedicon - 2007 payable at
Kumbakonam, (Please add Rs. 50 for outstation cheques) along with registration form may be
sent to :
Dr. R. Palanivelu, Organising Secretary, 39, Chellam Nagar, Kumbakonam - 612 001.
Phone : 0435 - 2431712 Cell : 94433 64111

60
 IAP TASK FORCE REPORT

GUIDELINES AND MANAGEMENT Diagnosis of Enteric Fever

OF ENTERIC FEVER IN CHILDREN
The correct and rapid diagnosis of enteric
(UNDER IAP ACTION PLAN 2006)
fever is of paramount importance for instituting
Chairperson appropriate therapy and also for avoiding
Dr Nitin K Shah, President, Indian Academy unnecessary therapy.
of Pediatrics Complete Blood Count (CBC)
Writing Committee
For practical purposes the CBC in enteric
Dr Ritabrata Kundu, Professor of Pedaitrics,
fever is unremarkable. The hemoglobin is normal
Institute of Child Health, Kolkata
in the initial stages but drops with progressing
Dr Nupur Ganguly, Assistant Professor of
illness. Severe anemia is unusual and should make
Pedaitrics, Institute of Child Health, Kolkata
one suspect intestinal hemorrhage or hemolysis
Dr Tapan Kr Ghosh, Scientific Coordinator,
or an alternative diagnosis like malaria. The WBC
Institute of Child Health, Kolkata
count is normal in most cases and leukocytosis
Dr Vijay N Yewale, Consultant Pediatrician, makes the diagnosis less probable. Leukopenia
Dhapi, Navi Mumbai perceived to be an important feature of typhoid
Dr Raju C Shah, National President 2005 fever and has been reported in only 20-25%
Dr Nitjn K Shah, National President 2006 cases. 1 The differential count is usually
Recommendation Committee unremarkable except for eosinopenia. Eosinopenia
Dr A Balachandran often absolute may be present in 70-80% cases.2,3
Dr Ajay Kalra Presence of absolute eosinopenia offers a clue to
Dr Anju Aggarwal diagnosis but does not differentiate enteric fever
Dr Ashok Kapse from other acute bacterial or viral infections.
Dr Deepak Ugra Conversely a normal eosino-phil count does make
Dr Nigam P Narain typhoid fever a less likely possibility. Platelet
Dr Nitin K Shah counts are normal to begin with and fall in some
Dr Nupur Ganguly cases by the second week of illness. Overall
Dr Panna Chowdhury prevalence of thrombocytopenia is around 10-
Dr Raju C Shah 15%.4
Dr Ritabrata Kundu
Cultures
Dr Shivananda
Dr Shyam Kukreja Blood Culture :
Dr Tanu Singhal Blood cultures are the gold standard
Dr Tapan Kr Ghosh diagnostic method for diagnosis of enteric fever.5
Dr Vijay N Yewale The sensitivity of blood culture is highest in the
61
first week of the illness and reduces with
advancing illness.6 Overall sensitivity is around
50 % but drops considerably with prior antibiotic
therapy.5 Failure to isolate the organism may be
caused by several factors which includes
inadequate laboratory media, the volume of blood
taken for culture, the presence of antibiotics and
the time of collection. For blood culture it is
essential to inoculate media at the time of drawing
blood.
Salmonella can be easily cultured in most
microbiologic laboratories with use of routine
culture media (Hartleys media, Blood agar and
MacConkey agar). Automated blood culture
systems such as BACTEC certainly enhance the
recovery rate. Sufficient amount of blood should
be collected for culture as the median bacterial
count in the peripheral blood is only 0.3 CFU/ml
(inter quartile range 0.1 to 10; range, 0.1 to 399).7
At least 10 ml of blood in adults and 5ml in
children should be collected. Dilution should be
appropriate in order to adequately neutralize the
bactericidal effect of serum and a ratio of 1:5 to
1:10 of blood to broth is recommended. Clot
cultures, wherein the inhibitory effect of serum is
obviated have not been found to be of superior
sensitivity as compared to blood cultures in several
clinical studies.8-10 In the laboratory, blood culture
bottles should be incubated at 370 C and checked
for turbidity, gas formation and other evidence of
growth after 1, 2, 3 and 7 days. For days 1,2 and
3 only bottles showing signs of positive growth
are cultured on agar plates. On day 7 all bottles
should be sub-cultured before being discarded as
negative.
There are considerable advantages of routine
blood cultures in investigation of suspected enteric
fever. Not only are they 100% specific, but they
also provide information on the antimicrobial
sensitivity of the isolate. This is vital in todays
scenario of multidrug resistance. Moreover
alternative methods for diagnosis particularly
62
serology are rather unsatisfactory as will be
discussed later. Blood cultures may actually turn
out to be cheaper and very cost effective in the
long run, as positive cultures unequivocally
establish the diagnosis of enteric fever and all other
investigations for PUO can be safely deferred.
Bone Marrow Culture :
Salmonella typhi is an intracellular pathogen
in the reticuloendothelial cells of the body including
the bone marrow.5 Studies have revealed that the
median bacteremia in the bone marrow is 9 CFU/
ml (IQR, 1 to 85; range, 0.1 to 1,5805) compared
to 0.3 CFU/ml (IQR, 0.1 to 10; range, 0.1 to
399) in blood. This bone marrow: peripheral blood
ratio which is around 4.8 (IQR, 1 to 27.5) in the
first week of the illness increases to 158 (IQR, 60
to 397) during the third week owing to
disappearance of bacteria from the peripheral
blood.7 The overall sensitivity of bone marrow
cultures ranges from 80 95 % and is good even
in late disease and despite prior antibiotic
therapy.5,11-13
The invasive nature of bone marrow
aspiration deters from its use as a first line
investigation for diagnosis of typhoid fever. It is
however a very useful and valid investigation in
evaluation of PUO wherein the marrow should
be inoculated in the culture bottle at the bedside.
Stool, Urine and Other Cultures :
Stool specimen should be collected in a sterile
wide mouthed container. Specimens should
preferably be processed within 2 hours after
collection. If there is a delay the specimen should
be stored in a refrigerator at 40 C or in a cool box
with freezer packs. The sensitivity of stool culture
depends on the amount of feces cultured, and the
positivity rate increases with the duration of the
illness. Rectal swabs should be avoided as these
are less successful. Stool cultures are positive in
30% of patients with acute enteric fever.5 For the
detection of carriers, several samples should be
examined because of irregular shedding of
salmonella. Urine cultures are not recommended
for diagnosis in view of poor sensitivity.5,14 Other
methods such as duodenal string and skin snip
culture of rose spots have been reported to be
more efficacious than blood cultures but are
mainly of academic importance.14-16
Antimicrobial Sensitivity Testing
The crucial issue here pertains to
fluoroquinolone susceptibility testing.
Fluoroquinolones were introduced in 1989 and
during the past decade there has been a progressive
increase in the MICs of ciprofloxacin in
Salmonella typhi and paratyphi.5 Since the current
MICs are still below the National Committee for
Clinical Laboratory Standards (NCCLS) suscepti-
bility breakpoint, laboratory reports will continue
to report Salmonella typhi/paratyphi as
ciprofloxacin/ofloxacin sensitive.17 However use
of fluoroquinolones in this scenario is associated
with a high incidence of clinical failure.5,17 It has
also been demonstrated that resistance to nalidixic
acid is a surrogate marker for high ciprofloxacin
MICs, predicts fluoroquinolone failure and can
hence be used to guide antibiotic therapy (i.e, if
culture results show resistance to nalidixic acid
irrespective of the results of ciprofloxacin/
ofloxacin sensitivity, quinolones should not be used
or if used high doses should be given).18 Since
MIC testing is not within the scope of most
laboratories, nalidixic acid susceptibility testing is
mandatory to help guide choice of antibiotics.
Serologic Tests
WIDAL test :
This test first described by F Widal in 1896,
detects agglutinating antibodies against the O and
H antigens of Salmonella typhi and H antigens of
paratyphi A and B.6,19 The O antigen is the
somatic antigen of Salmonella typhi and is shared
63
by Salmonella paratyphi A, paratyphi B, other
Salmonella species and other members of the
Enterobacteriaceae family.20 Antibodies against the
O antigen are predominantly IgM, rise early in
the illness and disappear early.20 The H antigens
are flagellar antigens of Salmonella typhi,
paratyphi A and paratyphi B. Antibodies to H
antigens are both IgM and IgG, rise late in the
illness and persist for a longer time.19,20 Usually,
O antibodies appear on day 6-8 and H antibodies
on days 10-12 after the onset of disease. The test
is usually performed on an acute serum (at first
contact with the patient). A convalescent serum
should preferably also be collected so that paired
titrations can be performed.
Conventionally, a positive WIDAL test result
implies demonstration of rising titers in paired
blood samples 10-14 days apart.19 Unfortunately
this criterion is purely of academic interest.
Decisions about antibiotic therapy cannot wait for
results from two samples. Moreover antibiotics
may dampen the immune response and prevent a
rise in titers even in truly infected individuals.
Therapeutic decisions have to be generally based
on results of a single acute sample. In endemic
areas, baseline anti O and anti H antibodies are
present in the population owing to repeated
subclinical infections with Salmonella typhi/
paratyphi, infections with other Enterobacteria-
ceae and other tropical diseases such as dengue
and malaria.19-21 These antibody titers vary with
age, socio economic strata, urban or rural areas
and prior immunization with the TAB vaccine.
Establishing appropriate cut offs for distinguishing
acute from past infections is thus important for
the population where the test is applied. In one
study from Central India, anti O and anti H titer
of more than 1: 80 was seen in 14% and 8%
respectively of a study sample of 1200 healthy
blood donors. 22
While interpreting the results of the WIDAL
test, both H and O antibodies have to be taken
into account. There is controversy about the
predictive value of O and H antibodies for
diagnosis of enteric fever. Certain authorities claim
that O antibodies have superior specificity and
positive predictive value (PPV) because these
antibodies decline early after an acute infection.23
Other studies report a poorer positive predictive
value of O antibodies probably due to rise of these
antibodies in other salmonella species, gram-
negative infections, in unrelated infection and
following TAB vaccination 21. For practical
purpose and for optimal result this test should be
done after 5-7 days of fever by tube method and
level of both H and O antibodies of 1 in 160
dialution (four fold rise) should be taken as cut
off value for diagnosis. H anitbodies once positive
can remain positive for a long time.
The WIDAL test as a diagnostic modality
has suboptimal sensitivity and specificity.19-21 It
can be negative in up to 30% of culture proven
cases of typhoid fever. Sub optimal sensitivity
results from negativity in early infection, prior
antibiotic therapy and failure to mount an immune
response by certain individuals.19 Poor specificity,
an even greater problem and is a consequence of
preexisting baseline antibodies in endemic areas,
cross reactivity with other Gram-negative
infections and non-typhoidal salmonella,
anamnestic reactions in unrelated infections and
prior TAB or oral typhoid vaccination. The purity
and standardization of antigens used for the
WIDAL test is a major problem and often results
in poor specificity and poor reproducibility of test
results.19 The slide WIDAL test should also be
discouraged owing to high rate of false positives.20
Nowithstanding these problems, the WIDAL
test may be the only test available in certain
resource poor set ups for diagnosis of enteric. In
Vietnam, using a cutoff of >1/200 for the O
agglutinin or >1/100 for H agglutinin test
performed on acute-phase serum the WIDAL test
could correctly diagnose 74% of blood culture
64
positive typhoid fever, however 14% results would
be false positive and 10% false negative.21 Hence,
it is important to realize the limitations of the
WIDAL test and interpret the results carefully in
light of endemic titers so that both over diagnosis
and under diagnosis of typhoid fever and the
resulting consequences are avoided.24
Other Serologic Tests
In view of the limitations of the WIDAL test
and need for a cheap and rapid diagnostic method,
several attempts to develop alternative serologic
tests have been made. These include rapid dipstick
assays, dot enzyme immunoassays and
agglutination inhibition tests.25-27
Enzyme Immunoassay (EIA) test or
Typhidot? test A dot enzyme immunoassay that
detects IgG and IgM antibodies against a 50 KD
Outer Membrane Protein distinct from the somatic
(O), flagellar (H) or capsular (Vi) antigen of
Salmonella typhi is commercially available as
Typhidot.27 The sensitivity and specificity of this
test has been reported to vary from 70%-100%
and 43% - 90% respectively.28-33 This dot EIA
test offers simplicity, speed, early diagnosis and
high negative and positive predictive values. The
detection of IgM reveals acute typhoid in the early
phase of infection, while the detection of both
IgG and IgM suggests acute typhoid in the middle
phase of infection. In areas of high endemicity
where the rate of typhoid transmission is high the
detection of specific IgG increase. Since IgG can
persist for more than 2 years after typhoid
infection34 the detection of specific IgG can not
differentiate between acute and convalescent
cases. Further more, false positive results
attributable to previous infection may occur. On
the other hand IgG positivity may also occur in
the event of current reinfection. In cases of
reinfection there is a secondary immune response
with a significant boosting of IgG over IgM, such
that the later can not be detected and its effect
masked. A possible strategy for solving this
problem is to enable the detection of IgM by
ensuring that it is unmasked 35. The original
Typhidot test was modified by inactivating the
total IgG in the serum samples. Studies with
modified test, Typhidot M, have shown that
inactivation of IgG removes competitive binding
and allows the access of the antigen to the specific
IgM when it is present.
The Typhidot M that detects only IgM
antibodies of Salmonella typhi has been reported
to be slightly more specific in a couple of
studies.26,33
IDL Tubex test The Tubex test is easy to
perform and takes approximately 2 minutes
time36. The test is based on detecting antibodies
to a single antigen in S. typhi only. The 09 antigen
used in this test is very specific found in only sero
group D salmonellae. A positive result always
suggest a salmonellae infection but not which
group D salmonella is responsible. Infection by
other serotypes like S. paratyphi A give negative
result. This test detects IgM antibodies but not
IgG which is further helpful in the diagnosis of
current infections.
IgM dipstick test26 The test is based on the
binding of S. typhi specific IgM antibodies to S.
typhi lipopolysaccharide (LPS) antigen and the
staining of the bound antibodies by an antihuman
IgM antibody conjugated to colloidal dye particles.
This test will be useful in places where culture
facilities are not available as it can be performed
without formal training and in the absence of
specialized equipments. One should keep in mind
that specific antibodies appear a week after the
onset of symptoms so the sensitivity of this test
increases with time.
Antigen detection tests Enzyme
immunoassays, counterimmune electro-phoresis
and co-agglutination tests to detect serum or
urinary somatic/flagellar/Vi antigens of Salmonella
typhi have been evaluated.37-40 Sensitivity of
65
Vi antigen has been found to be superior to
somatic and flagellar antigen and has been
reported as ranging from 50% to 100% in different
studies.37-40 Similarly specificity estimates have
been reported to vary from 25% to 90%.37-40 The
suboptimal and variable sensitivity and specificity
estimates, inability to detect Salmonella paratyphi
infection and Vi antigen negative strains of S typhi
are serious limitations of the Vi antigen detection
tests.
Molecular Methods
The limitations of cultures and serologic tests
advocate for development of alternative diagnostic
strategies. PCR as a diagnostic modality for
typhoid fever was first evaluated in 1993 when
Song et al successfully amplified the flagellin gene
of S typhi in all cases of culture proven typhoid
fever and from none of the healthy controls.41
Moreover some patients with culture negative
typhoid fever were PCR positive suggesting that
PCR diagnosis of typhoid may have superior
sensitivity than cultures. Over the next 10 years a
handful of studies have reported PCR methods
targeting the flagellin gene, somatic gene, Vi
antigen gene, 5S-23S spacer region of the
ribosomal RNA gene, invA gene and hilA gene
of Salmonella typhi for diagnosis of typhoid
fever.42-50 These studies have reported excellent
sensitivity and specificity when compared to
positive (blood culture proven) and healthy
controls. The turnaround time for diagnosis has
been less than 24 hours.
These reports should be viewed within the
context of certain limitations. Clinical utility of PCR
tests has been inadequately evaluated.
Performance of the test in individuals with febrile
illnesses other than typhoid, in those with past
history of typhoid, carriers of S typhi, and those
vaccinated with typhoid vaccine is not known.
Patients with a clinical diagnosis of typhoid fever
who are culture negative but PCR positive may
in fact be false positives. Comparison of PCR to
bone marrow cultures as a gold standard may be
a superior way of evaluating the sensitivity and
specificity of these tests, but has not been done.
The tests claim to detect as few as 10 organisms,
but it should be remembered that in typhoid the
median bacteremia is 0.3 CFU/ml of blood.7 Using
small volumes of blood for DNA extraction may
significantly lower the sensitivity of these tests.
The cost and requirement for sophisticated
instruments is also a potential drawback of
molecular methods.
Conclusion
The complete blood count is the logical first
investigation. Presence of a normal or low
leukocyte count with eosinopenia points to possible
enteric. It also helps in evaluation of alternative
diagnoses such as malaria, dengue and other
bacteremias. Blood cultures remain the most
effective investigations for diagnosis of enteric till
date. They should be sent early in the course of
the illness and prior to starting antibiotic therapy.
Susceptibility testing for nalidixic acid should be
routinely done for all isolates to aid choice of
antibiotics. Bone marrow culture is a highly
sensitive diagnostic test even in late stages of the
illness and with prior antibiotic therapy. It should
be performed in all patients with prolonged pyrexia
if routine investigations have failed to establish a
diagnosis. The WIDAL test has several limitations
and should be requested for in the second week
of the illness and its results interpreted with caution.
Data on baseline titers in the local population
should be generated by appropriate studies to help
in determining appropriate cut offs for the WIDAL.
The modified WIDAL test, Typhidot, Tubex and
Vi antigen tests need to be evaluated further before
their routine use can be recommended. Molecular
methods are still experimental.
Bibliography
1. Abdool Gaffar MS, Seedat YK, Coovadia YM,
Khan Q. The white cell count in typhoid fever.
Trop Geogr Med. 1992; 44: 23-27.
66
2. Deshmukh CT, Nadkarni UB, Karande SC. An
analysis of children with typhoid fever admitted
in 1991. J Postgrad Med 1994; 40: 204-207.
3. Pandey KK, Srinivasan S, Mahadevan S, Nalini
P, Rao RS. Typhoid fever below five years.
Indian Pediatr 1990; 27: 153-156.
4. Chiu CH, Tsai JR, Ou JT, Lin TY. Typhoid fever
in children: a fourteen-year experience. Acta
Pediatr Taiwan 2000; 41: 28-32.
5. Parry CM, Hien TT, Dougan G, White NJ, Farrar
JJ. Typhoid Fever. N Engl J Med 2002; 347:
1770-1782.
6. Ananthanarayan R, Panikar CKJ. Textbook of
Microbiology. Chennai: Orient Longman
1999; 244249.
7. Wain J, Pham VB, Ha V, et al Quantitation of
bacteria in bone marrow from patients with
typhoid fever: relationship between counts and
clinical features. J Clin Microbiol 2001; 39:
1571-1576.
8. Hoffman SL, Edman DC, Punjabi NH, Lesmana
M, Cholid A, Sundah S, Harahap J. Bone
marrow aspirate culture superior to
streptokinase clot culture and 8 ml 1:10 blood-
to-broth ratio blood culture for diagnosis of
typhoid fever. Am J Trop Med Hyg 1986; 35:
836-839.
9. Simanjuntak CH, Hoffman SL, Darmowigoto
R, Lesmana M, Soeprawoto, Edman DC.
Streptokinase clot culture compared with
whole blood culture for isolation of Salmonella
typhi and S. paratyphi A from patients with
enteric fever. Trans R Soc Trop Med Hyg 1988;
82:340-341.
10. Escamilla J, Florez-Ugarte H, Kilpatrick ME.
Evaluation of blood clot cultures for isolation
of Salmonella typhi, Salmonella paratyphi-A
and Brucella melitensis. J Clin Microbiol
1986; 24: 388-390.
11. Farooqui BJ, Khurshid M, Ashfaq MK, Khan
MA. Comparative yield of Salmonella typhi
from blood and bone marrow cultures in
patients with fever of unknown origin. J Clin
Pathol 1991; 44 : 258-259.
12. Duthie R, French GL. Comparison of methods
for the diagnosis of typhoid fever. J Clin Pathol
1990; 43: 863-865.
13. Akoh JA. Relative sensitivity of blood and bone
marrow cultures in typhoid fever. Trop Doct
1991; 21:174-176.
14. Gilman RH, Terminel M, Levine MM,
Hernandez-Mendoza P, Hornick RB. Relative
efficacy of blood, urine, rectal swab, bone-
marrow, and rose-spot cultures for recovery
of Salmonella typhi in typhoid fever. Lancet
1975; 31; 1(7918):1211-1213.
15. Vallenas C, Hernandez H, Kay B, Black R,
Gotuzzo E. Efficacy of bone marrow, blood,
stool and duodenal contents cultures for
bacteriologic confirmation of typhoid fever in
children.Pediatr Infect Dis 1985 ; 4 : 496-498.
16. Benavente L, Gotuzzo E, Guerra J, Grados O,
Guerra H, Bravo N. Diagnosis of typhoid fever
using a string capsule device. Trans R Soc Trop
Med Hyg 1984; 78: 404-406.
17. Crump JA, Barrett TJ, Nelson JT, Angulo FJ.
Reevaluating fluoroquinolone breakpoints for
Salmonella enterica serotype typhi and for non-
typhi salmonellae. Clin Infect Dis 2003; 37:75-
81.
18. Kapil A, Renuka, Das B. Nalidixic acid
susceptibility test to screen ciprofloxacin
resistance in Salmonella typhi. Indian J Med
Res 2002; 115: 49-54.
19. Olopoenia LA, King AL. Widal agglutination
test - 100 years later: still plagued by
controversy. Postgrad Med J 2000; 76: 80-
84.
20. Rodrigues C. The Widal test more than 100
years old: abused but still used. J Assoc
Physicians India 2003; 51:7-8.
21. Parry CM, Hoa NT, Diep TS, Wain J, Chinh
NT, Vinh H, Hien TT, White NJ, Farrar JJ. Value
of a single-tube Widal test in diagnosis of
typhoid fever in Vietnam. J Clin Microbiol
1999; 37: 2882-2886.
22. Shukla S, Patel B, Chitnis DS. 100 years of
WIDAL test and its reappraisal in an endemic
area. Indian J Med Res 1997; 105: 53-57.
67
23. Schoeder SA. Interpretation of serologic tests
for typhoid fever. J Am Med Assoc 1968; 206:
839-840.
24. Nsutebu EF, Ndumbe PM, Koulla S. The
increase in occurrence of typhoid fever in
Cameroon: overdiagnosis due to misuse of the
Widal test? Trans R Soc Trop Med Hyg. 2002;
96: 64-67.
25. Jesudason M, Esther E, Mathai E. Typhidot test
to detect IgG & IgM antibodies in typhoid fever.
Indian J Med Res 2002; 116:70-72.
26. Hatta M, Goris MG, Heerkens E, Gooskens J,
Smits HL Simple dipstick assay for the
detection of Salmonella typhi-specific IgM
antibodies and the evolution of the immune
response in patients with typhoid fever. Am J
Trop Med Hyg. 2002; 66: 416-421.
27. Gasem MH, Smits HL, Goris MG, Dolmans
WM. Evaluation of a simple and rapid dipstick
assay for the diagnosis of typhoid fever in
Indonesia. J Med Microbiol 2002; 51: 173-
177.
28. Khan E, Azam I, Ahmed S, Hassan R. Diagnosis
of typhoid fever by Dot enzyme immunoassay
in an endemic region. J Pak Med Assoc 2002;
52: 415-417.
29. Cardona-Castro N, Agudelo-Florez P.
Immunoenzymatic dot-blot test for the
diagnosis of enteric fever caused by
Salmonella typhi in an endemic area. Clin
Microbiol Infect 1998; 4: 64-69.
30. Handojo I, Dewi R. The diagnostic value of the
ELISA-Ty test for the detection of typhoid
fever in children. Southeast Asian J Trop Med
Pub Hlth 2000; 31: 702-707.
31. Bhutta ZA, Mansurali N. Rapid serologic
diagnosis of pediatric typhoid fever in an
endemic area: a prospective comparative
evaluation of two dot-enzyme immunoassays
and the Widal test. Am J Trop Med Hyg 1999;
61(4): 654-657.
32. Jackson AA, Ismail A, Ibrahim TA, Kader ZS,
Nawi NM. Retrospective review of dot enzyme
immunoassay test for typhoid fever in an
endemic area. Southeast Asian J Trop Med Pub
Hlth 1995; 26: 625-630.
33. Choo KE, Davis TM, Ismail A, Tuan Ibrahim
TA, Ghazali WN. Rapid and reliable serological
diagnosis of enteric fever: comparative
sensitivity and specificity of Typhidot and
Typhidot-M tests in febrile Malaysian
children. Acta Tropica 1999; 72: 175-183.
34. Saha SK, Talukdar SY, Islam M, Saha S. A highly
ceftriaxone resistant Salmonella typhi in
Bangladesh. The Ped Infect Dis J 1999; 18 :
297-303.
35. Bhutta ZA. Impact of age and drug resistance
on mortality in typhoid fever. Arch Dis Child
1996; 75 : 214-217.
36. Lim PL, Tam FC, Cheong YM, Jegathesan M.
One-step 2-minute test to detect typhoid-
specific antibodies based on particle separation
in tubes. J Clin Microbiol 1998; 36: 2271-
2278.
37. Rao PS, Prasad SV, Arunkumar G, Shivananda
PG. Salmonella typhi Vi antigen co-
agglutination test for the rapid diagnosis of
typhoid fever. Indian J Med Sci 1999; 53:7-9.
38. Sharma M, Datta U, Roy P, Verma S, Sehgal S.
Low sensitivity of counter-current immuno-
electrophoresis for serodiagnosis of typhoid
fever. J Med Microbiol 1997; 46: 1039-1042.
39. Pandya M, Pillai P, Deb M. Rapid diagnosis of
typhoid fever by detection of Barber protein
and Vi antigen of Salmonella serotype typhi. J
Med Microbiol 1995; 43:185-188.
40. Chaicumpa W, Ruangkunaporn Y, Burr D,
Chongsa-Nguan M, Echeverria P. Diagnosis of
typhoid fever by detection of Salmonella typhi
antigen in urine. J Clin Microbiol. 1992; 30 :
2513-2515.
41. Song JH, Cho H, Park MY, Na DS, Moon HB,
Pai CH. Detection of Salmonella typhi in the
blood of patients with typhoid fever by
polymerase chain reaction. J Clin Microbiol
1993; 31:1439-1443.
42. Sanchez-Jimenez MM, Cardona-Castro N.
Validation of a PCR for diagnosis of typhoid
fever and salmonellosis by amplification of the
68
hilA gene in clinical samples from Colombian
patients. J Med Microbiol 2004; 53: 875-878.
43. Cocolin L, Manzano M, Astori G, Botta GA,
Cantoni C, Comi G. A highly sensitive and fast
non-radioactive method for the detection of
polymerase chain reaction products from
Salmonella serovars, such as Salmonella typhi,
in blood specimens. FEMS Immunol Med
Microbiol 1998; 22: 233-239.
44. Chaudhry R, Laxmi BV, Nisar N, Ray K, Kumar
D. Standardisation of polymerase chain
reaction for the detection of Salmonella typhi
in typhoid fever. J Clin Pathol 1997; 50: 437-
439.
45. Zhu Q, Lim CK, Chan YN. Detection of
Salmonella typhi by polymerase chain reaction.
J Appl Bacteriol 1996; 80: 244-251.
46. Hashimoto Y, Itho Y, Fujinaga Y, Khan AQ,
Sultana F, Miyake M, Hirose K, Yamamoto H,
Ezaki T. Development of nested PCR based on
the ViaB sequence to detect Salmonella typhi.
J Clin Microbiol 1995; 33: 775-777.
47. Hirose K, Itoh K, Nakajima H, Kurazono T,
Yamaguchi M, Moriya K, Ezaki T, Kawamura
Y, Tamura K, Watanabe H. Selective
amplification of tyv (rfbE), prt (rfbS), viaB, and
fliC genes by multiplex PCR for identification
of Salmonella enterica serovars typhi and
Paratyphi A. J Clin Microbiol 2002; 40: 633-
636.
48. Haque A, Ahmed N, Peerzada A, Raza A, Bashir
S, Abbas G. Utility of PCR in diagnosis of
problematic cases of typhoid. Jpn J Infect Dis
2001; 54: 237-239.
49. Massi MN, Shirakawa T, Gotoh A, Bishnu A,
Hatta M, Kawabata M. Quantitative detection
of Salmonella enterica serovar typhi from
blood of suspected typhoid fever patients by
real-time PCR. Int J Med Microbiol 2005;
295:117-120.
50. Prakash P, Mishra OP, Singh AK, Gulati AK,
Nath G. Evaluation of nested PCR in diagnosis
of typhoid fever. J Clin Microbiol 2005; 43:
431-432.
Diagnosis of Enteric Fever
1. Contrary to the popular belief leukopenia
perceived as an important diagnostic feature of
typhoid fever is reported only in limited cases.
2. Blood culture is the gold standard for
diagnosis of typhoid fever. Blood culture can turn
out to be cheaper and cost effective in the long
run as positive culture unequivocally establishes
the diagnosis and also gives the sensitivity pattern,
thereby helping in the choice of antibiotics.
3. Since MIC is not within the scope of most
laboratories nalidixic acid sensitivity is a surrogate
marker of fluoroquinolone sensitivity and nalidixic
acid susceptibility testing is mandatory to help to
guide the choice of antibiotics.
4. Sensitivity of marrow culture is 80 95
% even in late disease and prior to antibiotic
therapy. Marrow should be inoculated in the
culture bottle at bed side.
5. Widal is the most widely used test in the
diagnosis of typhoid fever in our country. It has
poor sensitivity due to its negativity in early
infection, prior antibiotic therapy may influence it
and certain individual fail to mount an immune
response to the disease. It should be done after 5-
7 days of fever by tube method and level of 1 in
160 for both H and O antibodies are usually taken
as diagnostic.
6. Widal test also has poor specificity due
to preexisting base line antibodies in endemic areas.
Cross reactivity with other Gram negative
infection and nontyphoidal salmonella, prior
typhoid vaccination and anamnestic reaction in
unrelated infection. Data on base line titers of O
and H antibodies should be generated in
determining the appropriate cut of for Widal test.
7. Slide Widal test should be discouraged
due to high rate of false positivity.
8. It is important to realize the limitations of
the Widal test and interpret the results carefully
69
in light of endemic titers so that both overdiagnosis
and underdiagnosis of enteric and the resulting
consequences are avoided.
9. Typhoid test detects IgG and IgM against
outer membrane protein of Salmonella typhi. As
IgG can persist over a long time it is difficult to
distinguish between acute infection and
convalescent cases.
10.This test has been improved in modified
typhidot M test which detects only IgM antibodies.
11. Other serological tests IDL tubex and
IgM dipstick test detects only IgM antibodies to
different S typhi antigens.
12.Molecular methods like PCR are still in
experimental stage not used in day to day practice.
13.The modified Widal test, Typhidot,
Tubex and Vi antigen tests need to be evaluated
further before their routine use can be
recommended.
Treatment of Enteric Fever
The timely appropriate management of typhoid
fever, can considerably reduce both morbidity and
mortality. General supportive measures like use
of antipyretics, maintenance of hydration,
appropriate nutrition and prompt recognition and
treatment of complications are extremely important
for a favorable outcome. The child should
continue to have normal diet and no food should
be restricted.
In areas of endemic disease 90% or more of
typhoid cases can be managed at home with
proper oral antibiotics and good nursing care1.
Close medical follow up is necessary to look for
development of complications or failure to respond
to therapy.
Patients with persistent vomiting, inability to
take oral feed, severe diarrhea and abdominal
distension usually require parenteral antibiotic
therapy preferably in a hospital.
Antimicrobial Therapy
Since 1990s Salmonella typhi has developed
resistance simultaneously to all the drugs used in
first line treatment (chloramphenicol,
cotrimoxazole and ampicillin) and are known as
Multi Drug Resistant typhoid fever (MDRTF).
There are some reports of re-emergence of fully
susceptible strain to first line drugs2. But these
reports are few and unless antibiotic sensitivity
testing shows the organisms to be fully susceptible
to first line drugs they are not advocated for
empirical therapy in typhoid.
Fluoroquinolones are widely regarded as the
most effective drug for the treatment of typhoid
fever3. But unfortunately some strains of S. typhi
have shown reduced susceptibility to
fluoroquinolones 4,5. On routine disc testing with
the recommended break points, organisms
showing suspectibility to fluoroquino-lones shows
poor clinical response to actual treatment. These
organisms when tested by disc testing with
nalidixic acid shows resistance to it. So in other
words resistance to nalidixic acid is a surrogate
marker which predicts fluoroquinolones failure and
can be used to guide antibiotic therapy. The
resistance to fluoroquino-lones may be total or
partial. The nalidixic acid resistant S typhi
(NARST) is a marker of reduced susceptibility to
fluoroquinolones.
With the development of fluoroquinolones
resistance third generation cephalosporins were
used in treatment but sporadic reports of resistance
to these antibiotics also followed 6.
Recently azithromycin are being used as an
alternative agent for treatment of uncomplicated
typhoid fever 7.
Aztreonam and imipenem are also potential
third line drugs which are used recently3.
There is now considerable amount of
evidence from the long term use of fluroquinolones
in children that neither they cause bone or joint
toxicity nor impairment of growth.
70
Ciprofloxacin, ofloxacin, perfloxacin and
fleroxacin are common fluoroquinolones proved
to be affective and used in adults. In children the
first two are only used in our country and there is
no evidence of superiority of any particular
fluroquinolones. Norfloxacin and nalidixic acid
do not achieve adequate blood concentration after
oral administration and should not be used.
Fluoroquinolones have the advantage of lower
rates of stool carriage than the first line drugs8.
However, fluoroquinolones are not approved by
Drug Controller General of India to be used under
18 years of age unless the child is resistant to all
other recommended antibiotics and is suffering
from life threatening infection.
Of the third generation cephalosporins oral
cefixime has been widely used in children9,10,11.
Amongst the third generation cepha-losporins in
injectable form ceftriaxone, cefotaxime and
cefoperazone are used of which ceftriaxone is most
convenient.
Fluoroquinolones like ofloxacin or
ciprofloxacin are used in a dose of 15mg per kg
of body weight per day to a maximum of 20mg/
kg/day.
Of the oral third generation cephalosporins,
oral cefixime is used in a dose of 15-20 mg per kg
per day in two divided doses. Parenteral third
generation cephalosprins include ceftriaxone 50-
75mg per kg per day in one or two doses;
cefotaxime40 80 mg per kg per day in two or
three doses and cefoperazone 50-100 mg per kg
per day in two doses.
Azithromycin is used in a dose of 10mg per
kg given once daily for 14 days.
Fluoroquinolones are the most effective drug
for treatment of typhoid fever. For nalidixic acid
sensitive S. typhi (NASST) 7 days course are
highly effective. Though shorter courses are
advocated but they should be reserved for
containment of epidemics. For nalidixic acid
resistant S. typhi (NARST) 10-14 days course For complicated typhoid the choice of drug
with maximal permitted dosage is recommended. is parenteral third generation cephalosporin eg,
Courses shorter than seven days are not ceftriaxone. In sever life threatening infection
satisfactory. fluoroquinolones may be used as a last resort.
Aztreonam and imepenem may also be used.
In case of uncomplicated typhoid oral third
generation cephalosporine eg, cefixime should be Combination therapy though practiced all
the drug of choice as emperic therapy. If by over needs substantiation with adequate data from
5 days there is no clinical improvement and the studies.
culture report is inconclusive add a second line
Below (Tables 1, 2) are given various
drug eg, azithromycine or any other drug effective
antibiotics in the management of both complicated
against S typhi depanding up on the sensitivity
and uncomplicated typhoid with different
pattern of the area.
sensitivity patterns.
Table 1. Treatment of Uncomplicated Typhoid
SUSCEPTIBILITY FIRST LINE ORAL DRUG SECOND LINE ORAL DRUG
Antibiotic Daily Dose Days Antibiotic Daily Dose Days
(mg/kg) (mg/kg)

Fully Sensitive 3rd Gen. 15-20 14 Chloramphenicol 50- 75 14-21

Cephalosporin Amoxicillin 75-100 14
e.g.Cefixime TMP-SMX 8 TMP
40 SMX 14
Multidrug Resistant 3rd Gen. 15-20 14 Azithromycin 10-20 14
Cephalosporine
e.g.Cefixime
Table 2. Treatment of severe Typhoid

SUSCEPTIBILITY FIRST LINE PARENTERAL SECOND LINE PARENTERAL

DRUG DRUG
Antibiotic Daily Dose Days Antibiotic Daily Dose Days
(mg/kg) (mg/kg)
Fully Sensitive Ceftriaxone 50-75 14 Chloramphenicol 100 14-21
or Ampicillin 100 14
Cefotoxime TMP-SMX 8 TMP
40 SMX 14
Multidrug Resistant Ceftriaxone 50-75 14 Aztreonam 50-100 14
or
Cefotoxime
Imepenem are potential second line drug and fluoroquinolones can be used in life threating infection
resistant to other recommended antibiotics.
71
The Antibiotic Therapy of Typhoid Fever
Multidrug resistamt typhoid cases, resistant
to 1st line drugs, namely chloramohenicol,
co-trimoxazole and ampicillin are reported
since 1990. They need to be treated with 2nd
line drugs like 3rd generation cephalospotins.
Most of the typhoid cases can be managed
at home with oral antibiotics and good nursing
care.
For severe cases with persistent vomiting,
inability to take oral feeds, severe diarrhea,
abdominal distensions parenteral antibiotic,
will be needed preferably in a hospital.
Though some strain have shown reemergence
of sensitivity to first line drugs still it is too
early for their recommendation in emperic
therapy.
The nalidixic acid resistant S. typhi (NARST)
is a marker of reduced susceptibility to
fluoroquinolones.
Third generation cephalosporin, both oral and
injectables are recommended first line
treatment. Of the oral 3rd generation
cephalosporins, cefixime and cefpodoxime
proxelil are used commonly and of parenteral
preparation ceflriaxone, cefotaxime, and
cefoperazone are used, of which ceftriaxone
is most convenient. Oral 3rd generation
cephalosporin is to be used in higher dose in
typhoid fever.
Azithromycin is used as an alternative agent
in treatment of uncomplicated typhoid fever.
Aztreonam and Imepenem are potential
second line drugs
For life threatening infection resistant to all
other recommended antiobiotics
fluoquinolones may be used.
72
Bibliography
1. Punjabi NH. Typhoid fever. In:Rakel RE, editor
Conns Current therapy. Fifty second edition.
Philadelphia : WB Saunders; 2000:161-165.
2. Sood S, Kapil A, Das B, Jain Y, Kabra SK. Re-
emergence of chloramphenicol sensitive
Salmonella typhi. Lancet 1999; 353:1241-
1242.
3. Parry CM, Hien TT, Dougan G, White NJ, Farrar
JJ. Typhoid fever. N Engl J Med 2002;
347:1770-1782.
4. Gupta A, Swarnkar NK, Choudhary SP.
Changing antibiotic Sensitivity in enteric fever.
J Trop Ped 2001; 47:369-371.
5. Dutta P, Mitra U, Dutta S, De A, Chatterjee M
K, Bhattacharya S K. Ceftriaxone therapy is
ciprofloxacin treatment failure typhoid fever
in children. In J Med Res 2001; 113:210-213.
6. Saha SK, Talukder SY, Islam M. Saha S. A
highly Ceftriaxone resistant Salmonella typhi
in Bangladesh. Pediatr Infect Dis J 1999;
18(3):297-303.
7. Background document : The diagnosis,
treatment and prevention of Typhoid fever.
Communicable Disease Surveillance and
Response, Vaccines and Biologicals. World
Health Organisation. May 2003. WHO/V &
B/03.07.
8. Gotuzzo E, Carrillo C. Quinolones in typhoid
fever. Infect D is Clin Pract 1994; 3:345-351.
9. Bhutta ZA, Khanl, Molla AM. Therapy of
multidrug resistant typhoidal salmonellosis in
childhood : a randomized controlled
comparism of therapy with oral cefixime
versus IV ceftriaxone. Pediatr Infect Dis J
1994:13:990-994.
10. Girgis N1, Tribble DR, Sultan Y, Farid Z. Short
course chemotherapy with cefixime in children
with multidrug resistant Salmonella typhi
septicalmia. J Trop Ped 1995; 41:364-365.
11. Girgis NI, Sultan Y, Hammad O, Farid Z.
Comparison of the efficacy, safety and cost of
cefixime, ceftriaxone and aztreonam in the
treatment of multidrug resistant Salmonella
typhi septicalmia in children. Ped Infect Dis
J 1995; 14:603-605.

Ajit Saxena (250)
Alka Sophia Rao (262)
Anjul (252)
Anuradha D (87)
Arunkumar J (322)
Arun Kumar Manglik (146)
Arun MK (35)
Ashish Bavdekar (232)
Ashok Pareek (99)
Balachandran A (160)
Balaji V (252)
Baldev S Prajapati (301)
Behera M K (181)
Bharat Prajapati (190)
Bhaskar Raju B (79)
Bhavneet Bharti (6)
Chandralekha K (87)
Chhangani NP (99)
Deenadayalan .M (92, 265)
Deepali Mankad (74)
Deshmukh LS (178)
Dinesh Kumar J (87)
Dutta AK (281)
Editorial Board IJPP (95) Parthasarathy A (272)
Elavarasu E (246, 316)
Faisal Haque (250)
Farzana.Beg (250)
Fazal Nabi (74)
Ganesh R. (79,92,265)
Gautam Ghosh (146)
Gowrishankar NC (160)
Gurinder Arora (116)
Imteyaz Ahmad Khan (250)
Indra Shekhar Rao M (208)
Janani Sankar (262)
Krishan Chugh (116)
AUTHOR INDEX
Krishna Kumar(61)
Kulandai Kasthuri R (139)
Kumarasamy K (322)
Kush Jhunjhunwala (281)
Lakshmi (322)
Lalitha AV (16)
Lalitha Janakiraman (92,265)
Mahadevan S (134)
Mahesh Babu (110)
Mahesh Baldwa (155)
Malathi Sathiyasekaran (79)
Malathy K (246, 316)
Meena Jayashankar (87)
Meharban Singh (167)
Mukesh kumar singh (292)
Muralinath S (262)
Nammalwar BR (262)
Natarajan B. (85,176)
Naveen Thacker (221)
Nilesh Jain (325)
Niranjan shendurnikar (292)
Nitin K Shah (197)
Pangrikar AG (178)
Sujatha L (319)
Porkodi (246, 316)
Pradip Vincent (256)
Pramod Sharma (99)
Purushothaman (319)
Radha Rajagopalan (252)
Raghupathy P. (123)
Rajal Prajapati (301)
Rajeshwari (252)
Raju C Shah (190)
Ramakrishnan TV (43)
Ramalingam A (85,176)
Ramesh S (256)
73
Rana K S (181)
Randeep Singh (99)
Rashmi Kapoor (27)
Raveendranath V (319)
Ravisekar CV (322)
Renu P Kurup (61)
Sandeep Aggarwal (309)
Santosh T Soans (35)
Saradambal N (319)
Sathyaprakash.M (92)
Shalini Jain (325)
Sheila Bhave (232)
Shivbalan So (79,160)
Shrishu R Kamath (51,252)
Shyam Kukreja (309)
Siraj N Huda (250)
Sood A (181)
Sridharan S (256)
Sri Venkateswaran K (319)
Subba Rao SD (16)
Subramanyam L (160)
Suchitra Ranjit (51,252)
Susheela Rajendran (319)
Sunit Singhi (6)
Tapan Kumar Ghosh (239)
Vasanthamallika TK (322)
Venkatesan MD (246, 316)
Venkataraman P (322)
Vijayakumar M (262)
Vijayalakshmi G (85,176,246, 315)
Vijayasekaran D. (160)
Vipin M. Vashishtha (220)
Vyas BR (325)
 SUBJECT INDEX

Abdominal epilepsy (178) Immunization : Special situations (309)

Acquired velopalatopharyngeal palsy (181) Klippel Trenaunay Syndrome (87)
Acute asthma (116) Mckusick Kaufman Syndrome (256)
Acute poisoning (146) Medico legal issues (155)
Acute stridor (27) Milroys Disease (250)
Additional vaccines (292) Mixed Connective Tissue Disease (92)
Adverse events following Immunization (208) Necrotizing fascitis (252)
Approach : Respiratory distress (110) Newer Vaccines (197,281)
Avian Influenza (Bird flu) (95) Nutrition (167)
Cardio Pulmonary Resuscitation (16) Passive immune prophylaxis (301)
Cardiogenic shock (61) Pediatric Emergency Room (6)
Cavernous sinus thrombosis (322) Pediatric Pulmonary Function Test (160)
Chikungunya (266) Picture Quiz (99,265,318)
Cholelithiasis (79) Polio eradication (220)
Critical care Transport (74) Rabies Vaccines (239)
Cutis verticis gyrata (319) Radiology :
Dengue hemorrhagic fever, shock Acute abdomen (85)
syndromes (51) Hepatomegaly and hepatic masses (176,246)
Endocrine emergencies (123) Central Nervous System (315)
Enteric Fever - Guidelines Management (330) Scorpion sting (134)
EPI/IAP Immunization Schedule (190) Snake bite (139)
Hepatitis vaccines Current concepts (232) Status epilepticus (35)
Hereditary sensory autonomic neuropathy (325) Trauma: Resuscitation (43)
Immunization practices (272) Ultrasound (262)

74
 INDIAN JOURNAL OF PRACTICAL PEDIATRICS
SUBSCRIPTION TARIFF
IJPP
JOURNAL OFFICE Official Journal of the Indian Academy of Pediatrics
Krsna Apartments, Block II, 1A, A quarterly medical journal committed to practical
50, Halls Road, Egmore, pediatric problems and management update
Chennai 600 008. For office use
Phone: +91-44-28190032, 42052900.
Email: ijpp_iap@rediffmail.com Ref. No.
Cash / DD for Rs.
Enter ONE year
Subscription DD No.
for TEN years
Receipt No. & Date

Name ..................................................................................................................................

Address ................................................................................................................................

...............................................................................................................................................

City ...............................................................State ................................................................

Pin .............................. Phone (R) ...................................... (O)............................................

Mobile ...................................... Email ...................................................................................

Designation ................................................. Qualification........................................................

I am enclosing a DD No. .. dated drawn on .................

favoring Indian Journal of Practical Pediatrics for Rs

Signature
Subscription rate

Individual Annual Rs.300/- Send your subscription, only by crossed demand draft,
Ten Years Rs.3000/- drawn in favour of INDIAN JOURNAL OF PRACTICAL
PEDIATRICS, payable at Chennai and mail to
Institution Annual Rs.400/- Dr.A.BALACHANDRAN, Editor-in-Chief, F Block,
Ten Years Rs.4000/-
No.177, Plot No.235, 4th Street, Anna Nagar East,
Chennai - 600 102, Tamilnadu, India.
Foreign Annual US $ 50/-
 INDIAN JOURNAL OF PRACTICAL PEDIATRICS
ADVERTISEMENT TARIFF
Official Journal of the Indian Academy of Pediatric - A quarterly medical journal
committed to practical pediatric problems and management update

Name ...................................................... FULL PAGE

Address .................................................. B/W Colour*

............................................................... Ordinary 5,000 10,000
............................................................... Back cover - 15,000
...............................................................
Second cover - 12,000
City .........................................................
Third cover - 12,000
State ............................... Pin................

* Positives of the advertisements should be given by the company.

Signature
Kinldy send your payment by crossed demand draft only drawn in favour of
Indian Journal of Practical Pediatrics and art work / matter to

MANAGING EDITOR
Indian Journal of Practical Pediatrics
Krsna Apartments, Block II, 1A,
50, Halls Road, Egmore, Chennai - 600 008. India
Phone : 044-2819 0032, 044-42052900
Email : ijpp_iap@rediffmail.com

76
 Indian Journal of
Practical Pediatrics IJPP
Subscription Journal of the
Indian Academy of Pediatrics

JOURNAL COMMITTEE NATIONAL ADVISORY BOARD

Editor-in-Chief President, IAP

Dr. A.Balachandran Dr.Nitin K Shah
Executive Editor
President 2007, IAP
Dr. K.Nedunchelian
Managing Editor Dr.Naveen Thacker
Dr. Malathi Sathiyasekaran Editor, Indian Pediatrics
Associate Editors
Dr. Panna Choudhury
Dr. N.C.Gowrishankar
Dr. P.Ramachandran Members

Dr. C.V.Ravisekar Dr. Arati Deka

Dr. S. Thangavelu Dr. B.K.Bhuyan
Dr. V. Sripathi
Dr. C.Kamaraj
Executive Members
Dr.Kul Bhushan Sharda
Dr. G. Durai Arasan
Dr. Mahesh Kumar Goel
Dr. Janani Sankar
Dr. S.Lakshmi Dr. M.A.Mathew
Dr. V.Lakshmi Dr. Mukesh Kumar Khare
Dr. (Major) K.Nagaraju Dr. Subhash Singh Slathia
Dr. T. Ravikumar Emeritus Editors
Dr. S.Shanthi
Dr. A.Parthasarathy
Dr. So.Shivbalan
Dr. B.R.Nammalwar
Dr. C.Vijayabhaskar
Dr. M.Vijayakumar
Dr. Deepak Ugra
(Ex-officio)

77
 Indian Academy
of Pediatrics
IAP Team - 2006 Kailash Darshan,
Kennedy Bridge,
Mumbai - 400 007.
President Karnataka
Dr.Nitin K Shah Dr.M.Govindaraj
President-2007 Dr.R.Nisarga
Dr.Naveen Thacker Dr.Santosh T Soans
President-2005 Kerala
Dr.Raju C Shah Dr.Guhan Balraj
Vice President Dr.M.A.Mathew
Dr.VN.Tripathi Dr.T.U.Sukumaran
Secretary General Madhya Pradesh
Dr.Deepak Ugra Dr.Mukesh Kumar Khare
Treasurer Dr.C.P.Bansal
Dr.Rohit C Agrawal Maharashtra
Editor-in-Chief, IP Dr.Anand K Shandilya
Dr.Panna Choudhury Dr.Tanmay Amladi
Editor-in-Chief, IJPP Dr.Vijay N Yewale
Dr.A.Balachandran Dr.Yashwant Patil
Joint Secretary Manipur
Dr.Bharat R Agarwal Dr.K.S.H.Chourjit Singh
Members of the Executive Board Orissa
Andhra Pradesh Dr.B.K.Bhuyan
DR K Umamaheswara Rao Punjab
Dr.P.Venkateshwara Rao Dr.Kul Bhushan Sharda
Dr.P.Sudershan Reddy Rajasthan
Assam Dr.Prem Prakash Gupta
Dr.Arati Deka Dr.Ashok Gupta
Bihar Tamilnadu
Dr.Sachidanand Thakur Dr.K.Chandrasekaran
Chhattisgarh Dr.M.P.Jeyapaul
Dr.Pradeep Sihare Dr.K.Nedunchelian
Delhi Uttar Pradesh
Dr.Ajay Gambhir Dr.Mahesh Kumar Goel
Dr.Sunil Gomber Dr.V.N.Tripathi
Gujarat Dr.Vineet K Saxena
Dr.Baldev S Prajapati West Bengal
Dr.Satish V Pandya Dr.Nabendu Choudhuri
Haryana Dr.Sutapa Ganguly
Dr.Verender N Mehendiratta Services
Jammu and Kashmir Brig. Vipin Chandar
Dr.Subhash Singh Slathia IAPs Spl. Representative
Jharkhand Dr.Anupam Sachdeva
Dr.Bijay Prasad A.A.A.
Dr.Kamlesh K Shrivastava
78
 FOR IMMEDIATE ACTION

Please intimate your correct mailing address (including postal PIN code) with contact telephone
numbers and email ID for updating mailing list of IJPP.
If you are not responding we presume your mailing address is correct. Kindly respond without
fail, so that we can ensure prompt delivery of the journal.

Subscription Number : ..........................................................................................................

Name : ..........................................................................................................

Address

Door No. Street Name : ..........................................................................................................

Village / Town / City : ..........................................................................................................

Taluk / District : ..........................................................................................................

State : ..........................................................................................................

Pin Code : ..........................................................................................................

Contact Phone Numbers: .........................................................................................................

Email ID : ..........................................................................................................