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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.
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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.

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EDITORS DESK

Greetings from the Journal Committee of the Passive immune prophylaxis is used as post
IJPP. This issue will cover the remaining topics exposure prophylaxis. In this article Dr.Baldev S
on Vaccines. The journal committee once again Prajapati, et al. mention the advantages and
thanks Dr. Nitin K Shah for accepting to be the disadvantages of human and animal products of
Guest Editor and formulating the topics. We hope immunoglobulins, the various preparations
our readers, both practicing pediatricians and available, indications, doses etc.
postgraduates will find these topics useful in day Immunization in special situations by Dr.
to day practice. Shyam Kukreja and Dr. Sandeep Aggarwal covers
The topic on Various immunization some clinical circumstances which need
practices is contributed by Dr. A. Parthasarathy. modifications of existing immunization practices.
He has discussed in detail, the issues on various How to tackle the situations like outbreaks,
schedules of immunization in special situations. adolescence, patients with malignancy,
He has also highlighted certain facts in adolescent immunotherapy and HIV infections are clarified
immunization and cleared the common myths. in this review.
The article on Newer vaccines is written We thank Dr. Vijayalakshmi, et al for their
by Dr.A.K.Dutta, et al. They have covered certain contribution to the Radiologist talks to you
newer vaccines which are currently available and column. They have commenced from this issue
also vaccines under development for the future the other imaging modalities like CT and MRI.
such as rotavirus, malaria and HIV vaccines. To begin with the anatomical basis of radiology
Additional vaccines - current trends by of central nervous system is highlighted in this
Dr.Niranjan Shendurnikar, et al. narrates those issue.
vaccines not covered under National Immunization We are happy to publish the Guidelines and
Schedule but recommended by IAP. They have management of enteric fever in children which
summarized the pertinent issues with the additional is being brought under IAP - Presidents Action
vaccines which are of clinical relevance and Plan 2006.
patient-doctor concern to optimize vaccine We thank all the contributors for case study
acceptance and cost effectiveness. and picture quiz columns in this issue.

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

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VACCINES II

THE VARIOUS IMMUNIZATION the various schedules for individual vaccines, use
PRACTICES of combination vaccines, simulta-neous
administration of multiple vaccines etc.
* Parthasarathy A
I. The various immunization
Abstract: Issues in various schedules of schedules
immunization like Expanded Programme on
Immunization (EPI) and National Immunization The Rationale: The purpose of administering a
Schedule are discussed. Immunization in special vaccine is to offer optimal protection to the
clinical circumstances like preterm, schedule for vaccinee. For obtaining the optimal protection,
lapsed immunization, rationale of scheduling proper scheduling is mandatory based on
individual vaccines, spacing of multiple doses immunological responses. Among the live
of an antigen and current concepts of vaccines BCG needs only a single dose. Others
combination vaccines are also covered. Certain like OPV, MMR and Varicella require a minimum
myths and facts in pediatric and adolescent of 3/2/2 doses respectively for life long immunity
immunization are highlighted. in a primary and repeat dose schedule since these
vaccines have no booster effect. Measles, MMR
Key words: Immunization schedules, Special and Varicella vaccines once thought to be highly
Clinical Circumstances, Myths, Facts immunogenic in a single dose schedule are now
found to be immunogenic only when a repeat dose
The World Health Organization periodically
is given. Hence the emerging concept of 2 doses
issues guidelines for best global immunization
for MMR and Varicella vaccines and 3 or more
practices. Various professional bodies also keep
doses for OPV. On the other hand inactivated
updating the immunization practices with
subunit vaccines always need to be administered
reference to their individual countries. Centre for
in a prime boost schedule with the exception of
Disease Control and Prevention, Atlanta, USA
Hepatitis B vaccine which does not need booster
issues guidelines every year updating the current
dose because of its capability of eliciting
recommendations. In India since 1985, the Indian
anamnestic response following viral exposure.
Academy of Pediatrics is publishing Guide Book
Generally 3 primary doses are recommended for
on Immunization which is updated every 2/3 years.
inactivated vaccines and for vaccines containing
However, controversies still exist among members
toxoid / subunit components followed by boosters.
of the various professional bodies on issues like
However, Hib vaccine, Pneumococcal vaccine,
* Sr. Clinical Professor of Pediatrics (Retd.), etc need either 3/2/1 primary dose(s) depending
Madras Medical College and upon the age of immunization followed by 1 or 2
Deputy Superintendant,
Institute of Child Health and Hospital for Children boosters, since they act by the mechanism of
Chennai 600 008. natural boosting.

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For certain vaccines like the DTP/DT/TT the ministries of Health in individual countries
etc the dose is the same i.e 0.5 ml for all ages. based on local recommendations. This is the basis
For Hepatitis B vaccine, the dose is 0.5 ml and of the National Immunization Schedule 1985
1 ml respectively for children upto 10 years and (Table 1) now in practice in India and the IAP
above 10 years. For Varicella vaccine a single dose Immunization Time Table 2004 (Table 2) which
of 0.5 ml upto 12 years and 2 doses for those includes certain additional vaccines as well as
above 13 years. Hepatitis A is administered in additional doses for routine vaccines. However it
0 (prime) and 6 months (boost) schedule with should be clearly understood that, when additional
0.5ml/1ml of pediatric or adult formulation. The vaccines are desirable, routine vaccines are
dose is 0.25ml/0.5ml for vaccines like Influenza mandatory.1,2
for children 6 months to 3 years and above 3
years respectively. Hence the schedules also vary The vaccines administered in the National
for these vaccines at different settings.1,2 Immunization Schedule (which once introduced
cannot be withdrawn and should be given free of
The EPI Schedule cost to all beneficiaries) should be
The schedule recommended for the epidemiologically relevant, immunologically
Expanded Program on Immunization(EPI) by appropriate, technically sound, economically
World Health Organization may be modified by 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)

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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.

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considerations have to be taken into account before on topical or inhaled steroid therapy should
scheduling these vaccines. Though the Indian not be denied their age appropriate vaccines.
Academy of Pediatrics recommends, 3 doses of
3. Children awaiting splenectomy
Hepatitis B vaccine in 3 different schedules viz
birth, 6 and 14 weeks; Birth, 1 month and Children with loss of splenic function either
6 months; or 6, 10 and 14 weeks; (since the with congenital asplenia or after splenectomy
vaccine is immunogenic in all these schedules), are at high risk of serious infections with
the Govt. of India has chosen to introduce encapsulated organisms. If surgical
Hepatitis B vaccine in 6,10 and 14 weeks schedule splenectomy is being planned, immunization
only, due to logistic considerations. However in with Pneumococcal, Hib and Meningococcal
private practice, members of IAP practice the vaccines should be initiated at least 2 weeks
IAP immunization time table. In Government prior to splenectomy.
health facilities only the National Immunization 4. The schedule for lapsed immunization
Schedule is followed. For children who have missed the routine
II. Immunization in special immunization during infancy or children who
circumstances 3,4,5,7 report late for immunizations, the schedule
suggested is given in Table 3.
1. Immunization in preterm infants
In general, all vaccines may be administered 5. Adolescent immunization
as per schedule according to the chronological schedule 3,4,5
age irrespective of birth weight or period of Adolescent immunization is also mandatory
gestation. Very low birth weight babies can for those children who have not been adequately
be given immunizations after initial immunized already and for those adolescents
stabilization. who leave abroad for education or employment
2. Children receiving corticosteroids (Table 4).

Children receiving oral corticosteroids in high Thus it may be seen from the above
doses (eg. Prednisolone 1-2 mg/kg/day) for discussion, that the various schedules are very
more than 14 days should not receive live much needed for infant, childhood and adolescent
virus vaccines until steroids have been routine immunization and immunization under
discontinued for at least one month. Killed special circumstances. However, consensus
vaccines are safe in such situations. Patients should be the mainstay of these schedules rather

Table 3. Vaccination schedule for a non immunized child 3,4,5


Age Less than 5 years More than 5 years
First visit BCG, OPV, DTP, HB TT/Td, HB
2nd visit OPV, DTP, HB TT/Td, HB
(1 month later)
3rd visit OPV, DTP, HB, Measles or HB, MMR, Typhoid
(1 month later) MMR, Typhoid
1 year later OPV, DTP -
Every 3 years Typhoid booster Typhoid booster

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

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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
Fig. 1. Anamnestic response following HB
vaccination administered at 4 weeks interval 8,9
only 3 vaccine formulations viz BCG at birth,
combined DTP-HB-Hib at 6, 10 and 14 weeks
Note: The required protective value is 10 mIU.When
along with oral polio vaccine at birth, 6, 10 and
given at a minimum of 4 weeks interval the antibody
response elicited is >100 mIU.When the antibody
14 weeks before the baby reaches 4 months of
level declines below the protective level over a period age and thus prevent 7 diseases viz tuberculosis,
of time, even a transient infection automatically poliomyelitis, diphtheria, pertussis, tetanus,
elevates the antibody level to well above the hepatitis B and Hib infection.
protective titer due to anamnestic response. The upper
Current status of new combination vaccines
curve denotes the anamnestic response when some
protective antibodies are still present and the lower Already developed DTPw + Hib
curve denotes the anamnestic response when the DTPw + Hepatitis B
antibody titre falls below the protective level. DTPw + Hib + Hep B
DTPa + IPV
d. DTaP / DTwP / Hib vaccines : DTPa + Hib
These vaccines can be given earliest at DTPa + Hib +
6 weeks of age since they are capable of eliciting Hep B + IPV
optimum immune response evoking protective Hepatitis A + Hepatitis B
titres MMR + Varicella
Under development DTPa + Hib + IPV +
e. Measles vaccine: Hep B + Hep A
Live measles vaccine may be completely Available for DTPw + Hib
inhibited in the presence of detectable maternal use in India DTPw + Hep B
antibodies upto 9 months in the infants circulation. DTPw + Hib +
Therefore measles vaccine is given after a delay Hepatitis B
of 9 months from birth, followed by MMR after Hepatitis A + Hepatitis B
12 months.
2. The immunogenicity of individual vaccine
f. MMR and Varicella vaccines : components is excellent even when given in
These vaccines can be given earliest at combination formulation12,13. Fig.2 depicts the
12 months of age. They can be given together or individual antigen immunogencity.
if given separately, should be administered at It could be seen from the above illustration
4 weeks mandatory interval. that all the vaccine components elicit excellent

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Diptheria(>0.01 IU/ml) 100%
Tetanus (>0.1 IU/ml) 100%

Pertussis (>3.92 EU/ml) - AF Antifimbrial 97%

Pertussis (>2.24 EU/ml) - AP Antipertactin 81%


Hib (>0.15 g/ml) 100%
Hib (> 1.00 g/ml) 90%
Hepatitis B (>10 IU/ml) 100%

Fig.2. Immunogenicity of individual antigens

immune response when given in combination VI. Spacing of multiple doses of same
formulation. antigen 5
In India two brands of DTwP-HB-Hib 4 weeks interval is mandatory for spacing
combination vaccine formulations are available viz. multiple doses of same antigen. Recommended
(1) lyophilized formulation and (2) fully liquid age of initiation and maintaining interval between
formulation. Similarly there are two brands of multiple doses of the same antigen provide optimal
DTwP-Hib combination vaccine formulations viz. protection. Though recommended minimum
(1) lyophilized formulation and (2) fully liquid interval of 4 weeks (28 days) is mandatory,
formulation. The lyophilized Hib component in vaccine doses administered less than 4 days before,
pellet form is mixed extraneously using the can also be counted as a valid dose. Rabies vaccine
recommended DTPw formulation as a diluent. is an exception and should be given in 0, 3, 7, 14
and 28 days schedule.
These are studies to show that administering
DTPw and Hib in combination results in reduced It is therefore mandatory that the
mean PRP antibody levels compared to giving recommended schedules are followed to obtain
the same components separately. However, even optimum immunogenicity. It is always advisable
in those studies with statistically significant to refer to the manufactures recommendations
reduction, antibody levels were still high and 90% especially before administering newer vaccines.
of children (typically 95%) developed greater than
1 mcg/ml of antibody to PRP-T / CRM 197 Points to remember
component of Hib. Plotkin in his review has
described that, this reduced immunogenicity of 1. EPI Schedule is the sheet anchor of
Hib when given in combination with DTPw childhood immunization.
appears to be of no clinical importance.
2. Modifications as needed may be adapted
Recent data shows that addition of Hib as per local government / professional body
component to either the DTPw / DTPw HB recommendations.
lyophilized / liquid formulations does not affect
the safety and immunogenicity of either the 3. Different schedules have to be followed
PRP-T / CRM197 Hib component. under special clinical circumstances.
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VII. Myths and facts 12,13
The following myths and facts need to be emphasized on the basis of available evidence.
S.No. Myth Fact
1. Too many vaccines might overload The immune system can simultaneously respond
the immune system 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
2. Combination vaccines may be less The DTPw-HB-Hib combination formulation
effective than vaccines administrated has
separately - excellent immunological response
- superior safety and less reactogenicity
The DTPa-HB-Hib combination formulation has
enhanced safety and lowered the reactogenicity
3. Thimerosal used as preservative in With 2.5 mcg for each vaccine administration,
multi dose vaccine formulations is Thimerosal which is ethyl mercury, does not
neurotoxic produce any neurotoxicity as once feared
4. Aluminium salts used as adjuvants in Since the discovery of DTPw combination
certain vaccines may be harmful to formulation in 1943, DTPw-HB and DTPw-HB
the child Hib in 1998, Alum salts have been successfully
used as adjuvants without any significant
adverse effect

4. The fear compounded about the doubtful References


immunogenicity of individual antigens in 1. American Academy of Pediatrics. Scheduling
combination formulations, is not true. Immunization. In: Pickering LK, (Ed), 2000
5. Recommended interval of atleast 4 weeks Red Book: Report of the Committee on
th
Infectious Diseases. 25 Edn, Elk Grove
between multiple doses of same antigen is
Village IL, American Academy of Pediatrics;
mandatory. 2000: pp54-79.
6. Simultaneous administration of multiple 2. American Academy of Pediatrics. Hepatitis A.
antigens does not suppress the immune In: Pickering LK, (Ed),. 2000 Red Book:
system. Report of the Committee on Infectious
th
Diseases. 25 Edn, Elk Grove Village IL,
7. Various myths and vaccination scares are American Academy of Pediatrics; 2000:
not true. pp282-283.

11
3. American Academy of Pediatrics. Hepatitis B. response to Vaccine: Immunization in
In: Pickering LK, (Ed),. 2000 Red Book: childhood. Annales Nestle 2000; 58:75-81.
Report of the Committee on Infectious 9. Global Program for Vaccines and
th
Diseases. 25 Edn. Elk Grove Village IL, Immunization. Expanded Program on
American Academy of Pediatrics; 2000: Immunization Policy on Hepatitis B
pp294-300. Immunization schedule. WHO GPV/GEN/20.
4. American Academy of Pediatrics. Immunizing 10. American Academy of Pediatrics. Hepatitis A.
agents. In: Pickering LK, (Ed), 2000 Red In: Pickering LK (Ed): 2000 Red Book: Report
Book; Report of the Committee on Infectious of the Committee on Infections Diseases.
th th
Diseases, 25 Edn. Elk Grove Village IL, 25 Edn, Elk Grove Village IL, Americal
American Academy of Pediatrics; 2000;p9. Academy of Pediatrics, 2000; pp280-282.
5. Immunization Special Circumstances, IAP 11. American Academy of Pediatrics. Varicella
nd
Guide Book on Immunization, 2 Edn: infection, Recommendations for Immunization
Parthasarathy A, Dutta AK, Bhave S (Eds), IAP In: Pickering LK (Ed), 2000 Red Book.: Report
Publication, Mumbai 2001: 14, 17, 47-49. of the Committee in Infectious Diseases.
th
6. Adolescent Immnuzation Schedule, IAP Guide 25 Edn, Elk Grove Village IL, American
Book on Immunization. Dubey AP, Surjith Academy of Pediatrics, 2000: pp634-638.
Singh: (Eds). Indian Academy of Pediatrics, 12. Francis Andre. In Proceedings on
Mumbai 2004;8: pp37-42. Combination Vaccines: Glaxo SmithKline
7. Immunization in Special clinical circum- publication 2001.
stances. Innunization in Clinical Practice : 13. Parthasarathy A. Combination Vaccines. The
Naveen Thacker, Nitin K Shah, (Eds) Jaypee choice ahead in Pediatric Index. Kumar A,
Bros. Medical Publishers, New Delhi, Mohan M, Mohan H (Eds) Meditech
2004;pp10-11. Publishers and Distributors, New Delhi 2001;
8. Claire-Anne, Siegrist. Understanding immune 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 introduction of universal immunization program


in the world followed by EPI program, still
* Dutta AK 1.8 million deaths occur in the world due to
** Kush Jhunjhunwala common vaccine preventable diseases like measles,
Abstract: This article deals with few vaccines, tetanus, whooping cough, and diphtheria.
which are already available(acellular pertussis Approximately 7,45,000 deaths occur in the world
Tdap and rota virus vaccines), and other due to measles alone. A large number of vaccine
vaccines, which are under development (malaria preventable deaths occur in India due to poor
and HIV vaccines). Multi component acellular coverage of vaccine in National Immunization
pertussis vaccines are effective and have less Program. A large number of newer vaccines are
adverse effects than whole cell vaccines. Tdap is available in the world including India and many
expected to protect the adolescents against more vaccines are in the process of development.
pertussis and gives protection against tetanus The present article will deal with few of the
and diphtheria. The usefulness of presently available vaccines and significant ones in the
available rotavirus vaccine can be established process of development.
only after the enumeration of serotypes of 1) Acellular pertussis vaccine
rotavirus strain in India. Malaria vaccines
developed to target different stages of malarial Diphtheria, tetanus and pertussis are still a
parasite are found to have varied response in major cause of mortality and morbidity in the
trials. A safe and effective vaccine remains world. Although the whole cell pertussis vaccine
elusive with regard to HIV vaccine. has good immunogenicity, there is a fear of serious
adverse reactions associated with it in the form of
Key words: Acellular pertussis vaccine, Tdap, encephalopathy, persistent screaming episodes,
Rotavirus, Malaria, HIV Vaccines. convulsions and hyperpyrexia.
The worlds oldest vaccine invented and Better understanding of the biology of
perfected by Sir Edward Jenner has become B.pertussis and the isolation of components that
obsolete after serving the mankind for over a appear to be important in the pathogenesis of
century and half. It is needless to state that disease led to the development of purified
vaccination is one of the most cost effective component, known as acellular pertussis vaccine,
methods of prevention of disease. In spite of the in Japan in 1981. The encouraging results of the
Japanese experience stimulated thorough efforts
* Director, Professor and Head of the Department,
in developed world to develop other acellular
** Senior Resident, pertussis vaccines.1, 2, 3
Lady Hardinge Medical College and associated
Kalawati Saran Children Hospital, Today, in the world almost a dozen
New Delhi- 110 001. formulations of acellular pertussis vaccines have
13
been evaluated for the efficacy and safety and 18-24 months and 5 years, the immunity would
are being extensively used. These vaccines vary last longer up to 10-15 years. There is evidence
from one another with respect to their source, to show that herd immunity is produced using
number of components, quantity of each acellular pertussis vaccine.
component, method of purification, method of
Safety and adverse events
toxin inactivation, incorporation of adjuvant and
excipients. Acellular pertussis vaccine has been found
to reduce both the common adverse events e.g.
At present there is only one acellular pertussis fever, pain, irritability as well as the uncommon
containing DTaP available in India. The acellular adverse events e.g. seizures, shock like episodes
pertussis with DT formulation contains pertussis by two third compared to the whole cell vaccine.
toxins, viz. pertactin and filamentous It has been observed that with latter doses of
hemagglutinin. acellular pertussis vaccine the rate of adverse
reaction remains less than that seen with the whole
Many large scale acellular pertussis vaccine
cell vaccine. Acellular pertussis vaccine in reduced
efficacy trials have been conducted in various parts
dose has the advantage of use in adults as an
of the world and the results have shown that the
essential tool for control of pertussis.1, 4
vaccine is safer than the whole cell vaccine in
terms of common as well as serious adverse Cochrane Review
reactions.
Six efficacy trials and 45 safety trials were
The efficacy of the whole cell pertussis included. Acellular pertussis vaccines with three
vaccine is in the range of 85-95% and that of the or more pertussis antigens were more effective
acellular vaccine ranges from 75-90%.1 Whole than those with one or two antigens. They were
cell pertussis vaccine is very effective and also more effective than one type of whole cell
inexpensive. The choice of vaccine depends on pertussis vaccine, but less effective than two other
balancing considerations of relative efficacy, types of whole cell vaccines. Differences in trial
adverse effects and most important is the cost. design precluded pooling of the efficacy data and
However for second booster dose and especially results should be interpreted with caution. Most
if it is delayed due to some reasons, acellular systemic and local adverse events were
pertussis vaccine would be more safe in terms of significantly less common with acellular than with
serious adverse reactions. whole cell pertussis vaccines.
Conclusions
Doses and Schedule
Multi-component acellular pertussis vaccines
Three primary doses beginning at 6 weeks are effective and show less adverse effects than
as per the national schedule of the country can be whole cell pertussis vaccines. However in countries
used safely. In USA 2-4-6 months schedule and where cost is a concern, whole cell pertussis
in some countries 2-3-4 months or 3-5-7 months vaccine can be safely used taking into considertion
schedule are in use. The duration of immunity the risk, benefit of the disease versus adverse
with the entire schedule using acellular pertussis reaction to whole cell vaccine.5
vaccine has been found to be equal or more than
that of whole cell pertussis vaccine. Following 2) Tdap vaccine
3 doses primary schedule, the immunity lasts for Tdap is a formulation for use in adolescents
2-4 years, and with two more booster doses, at and contains reduced content of diphtheria toxoid

14
and acellular pertussis; and normal content of and pertussis. 7 Currently pediatric DTaP is
tetanus toxoid. Pertussis, an acute, infectious routinely advocated for children aged <7 years,
illness, remains endemic in major part of the world pediatric diphtheria and tetanus toxoids vaccine
despite routine childhood pertussis vaccination for (DT) for children aged <7 years with
more than half a century and high coverage levels contraindications or precautions for pertussis
in children for more than a decade. components, and adult tetanus and diphtheria
toxoids vaccine (Td) routinely for persons aged
Recent estimates from the WHO suggest that
>7 years. The formulation of choice for
in 2002 about 18,351,000 cases of pertussis
vaccination of persons aged >7 years has been
occurred worldwide, the vast majority of which
Td rather than pediatric DT, as the lower
were in developing countries, and that about
diphtheria toxoid antigen content of Td induces
294,000 patients died from this disease. It is further
an adequate immune response and lower rates of
estimated that in 2002 global vaccination against
adverse reactions in adults than the pediatric DT.7
pertussis averted more than 37 million cases and
In India, since children usually get DT at the age
587,000 deaths.6 According to a Central Bureau
of five years, and as the incidence of pertussis is
of Health Intelligence (CBHI) study, the number
rising alarmingly in the age group of 5-15 years,
of reported cases of pertussis in India has increased
Tdap has been recommended for a lower age
recently, by 50 percent from 1997 to 2003.
group as compared to that in US. Thus, in India
A primary reason for the continued Tdap has been registered for use in children over
circulation of Bordetella pertussis is that immunity the age of 4 years, who have already received
to pertussis wanes approximately 5 - 10 years after their primary DTP doses in the first and second
completion of childhood pertussis vaccination, year of life. Currently, there is a globally-approved
leaving adolescents and adults susceptible to acellular pertussis boosting vaccine for all age
pertussis.7 groups available in India, in the form of Tdap.
In 2004, there were more than 25,000 cases Composition of vaccine
of pertussis in the United States. More than 8,000
Each dose of Tdap contains aluminum
of these cases were among adolescents 11-18
hydroxide (<0.39 mg aluminum) as the adjuvant,
years of age. Up to two in 100 adolescents with
4.5 mg NaCl, <100 g residual formaldehyde and
pertussis are hospitalized or have complications.7
<100 g polysorbate 80 (Tween 80) per 0.5mL
The spectrum of disease caused by dose. Tdap contains no thiomerosal or other
B.pertussis in adolescents ranges from mild illness preservative. Tdap is available in two
with cough to classic pertussis; infection also can presentations: a pre-filled disposable syringe
be asymptomatic. without a needle and a single dose vial. The
pertussis antigen composition of the adolescent
During the year 2005, two products and adult Tdap formulations is similar to pediatric
containing reduced contents of diphtheria, acellular DTaP, but some of the pertussis antigens are
pertussis; and normal content of tetanus toxoid reduced in quantity.6,7
(Tdap) for use in adolescents (and 1 product for
use in adults) were licensed in the United States. Dosage and administration
In pre-licensure studies, Tdap administered as a The dose of Tdap is 0.5 mL, administered
single booster dose to adolescents was shown to intramuscularly (IM), preferably into the deltoid
be safe and effective against tetanus, diphtheria, muscle.

15
Safety to confer protection against pertussis,
provided they have completed the
The primary safety study, conducted in the recommended childhood DTP/DTaP
United States, was a randomized, observer- vaccination series. To reduce the risk for local
blinded, controlled study in which 3,080 and systemic reactions after Tdap
adolescents aged 1018 years received a single vaccination, there should be an interval of at
dose of Tdap. No immediate events (within 30 least 5 years between Td and Tdap.8,9
minutes of vaccination) were reported.
Contraindications
Adverse effects:
For use of Tdap or Td are a history of serious
Mild allergic reaction (i.e. anaphylaxis) to any
Pain and redness or swelling component of the vaccine; and history of
Mild fever/ headache/ tiredness/ nausea, encephalopathy of undetermined cause within
vomiting diarrhea. 7 days of administration of a vaccine with pertussis
components. Adolescents with the latter
Other mild problems reported include chills, contraindication should receive Td instead of
body aches, sore joints, rash and swollen Tdap.
lymph nodes.
Simultaneous vaccination with Tdap and
Moderate to severe
other vaccines
Severe pain at the injection site / severe
redness or swelling / fever more than 102F If two or more vaccines are indicated, they
should be administered during the same visit (i.e.,
A severe allergic reaction could occur after
simultaneous vaccination). Each vaccine should
any vaccine. These are estimated to occur
be administered using a separate syringe at a
less than one in a million doses.
different anatomic site.
Specific recommendations to reduce pertussis
morbidity in adolescents and maintain the standard Can pediatric DTaP be used in adolescents
of care for tetanus and diphtheria protection in or can adolescent Tdap be used in the
adolescents aged 11 to 18 years are as follows: primary series in children?
No. The capital and lowercase abbreviation letters
Adolescents should receive a single dose of
denote relatively larger and smaller content of
Tdap instead of tetanus and diphtheria toxoids
antigens. Tdap would be expected to have inferior
vaccine (Td) for booster immunization
immunogenicity of diphtheria and pertussis
against tetanus, diphtheria, and pertussis if
components in young children, and DTaP would
they have completed the recommended
be expected to have increased reactogenicity in
childhood diphtheria and tetanus toxoids and
adolescents. The primary objective of vaccinating
whole cell pertussis vaccine (DTP)/diphtheria
adolescents with Tdap is to protect the vaccinated
and tetanus toxoids and acellular pertussis
adolescents against pertussis while maintaining the
vaccine (DTaP) vaccination series and have
standard of care for protection against tetanus and
not received Td or Tdap. The recommended
diphtheria. A secondary objective of adolescent
age for Tdap vaccination is 11 to 12 years.
Tdap vaccination is to reduce the reservoir of
Those adolescents, who received Td, but not pertussis within the population at large and
Tdap, should receive a single dose of Tdap potentially reduce the incidence of pertussis in

16
other age groups, including infants who have the WHO plan B or C was 30.9/1000 infant years in
highest risk for complications from pertussis. The the vaccine group as compared with 51.7 per 1000
extent to which the secondary objective can be infant years in the placebo group for an overall
achieved through adolescent vaccination is rate reduction of 40.0 percent among vaccine
unknown. recipient. Similarly the rate of hospitalization for
diarrhea of any cause was significantly reduced
3) Rotavirus Vaccine by 42.0% in the vaccine group.
Rotavirus kills approximately half a million The second vaccine is a penta-valent vaccine
children in the developing countries of the world based on a bovine strain, WC3 that contains five
and accounts for about one third of hospitalization human bovine reassortant viruses. The bovine
for childhood diarrhea throughout the world.10 virus grows less well in the human intestine so
The first rotavirus vaccine made from that aggregate titer required to immunize a child
human-rhesus reassortant strains was introduced is greater. The bovine vaccine strains are
in USA but soon suffered a serious setback due infrequently shed in the stools. Three oral doses
to the possible causal relationship with are required at an interval of one month. The
development of intussusception following efficacy of this vaccine is similar to human mono-
vaccination.10 valent strain. Both the vaccines are safe and no
causal relationship with intussusception has been
At present there are two available rotavirus observed in large trials.10
vaccines in the world. The first one is the mono-
valent vaccine derived from the most common Conclusion : Current evidence shows that rhesus
human rotavirus strain G1P(8), that has been rotavirus vaccine (particularly RRV-TV) and the
attenuated. The mono-valent vaccine strain human rotavirus 89-12 are efficacious in
replicates well in the gut , is shed by more then preventing diarrhea caused by rotavirus and all-
50 % of patients receiving the vaccine after the cause diarrhea. Bovine rotavirus vaccine were also
first dose and like natural rotavirus infection efficacious, but safety data are not available. Trials
provides cross protection against most of the other of new rotavirus vaccines will hopefully improve
serotypes. the evidence base. Randomised controlled trials
should be performed simultaneously in high,
12
This vaccine is given in two doses starting middle and low income countries.
at 6 weeks of age at an interval of 1-2 months.
The protective efficacy of the vaccine against wild The rotavirus surveillance network in India
type of G1P(8) strain induced severe rotavirus is now trying to establish the epidemiology of
diarrhea is 90%. The efficacy of the vaccine rotavirus disease in India. The data would be of
against strain sharing only P(8) antigen {(G3P (8), immense help to identify the serogroups involved
G4P (8) and G9P (8)} is 87.3%. Type G2P (4) and whether the available rotavirus vaccine would
rotavirus which does not share either the G or the be beneficial in Indian subcontinent or not.
P antigen with the vaccine strain was detected in 4) Malaria Vaccine
less number of cases and against it the vaccine
showed efficacy of 41.0%.10,11 Malaria continues to claim an estimated 2 to
3 million lives annually and is known to account
The incidence of severe gastroenteritis of any for untold morbidity in approximately 300 to 500
etiology that requires rehydration according to million people infected annually. Approximately

17
2.48 million cases are reported annually from during the blood infection. A sexual stage vaccine
South Asia of which 75% cases are contributed does not protect the person being vaccinated, but
by India alone.12 instead interrupts the cycle of transmission by
inhibiting the further development of parasites once
At-risk groups include those in whom
they, along with antibodies produced in response
immunity has not yet developed (travellers, young
to the vaccine, are ingested by the mosquito.13
children in endemic areas, etc.) and those in whom
immunity has diminished (pregnant women, and A pre-erythrocytic vaccine would ideally not
people from endemic areas who have ceased to only prevent sporozoites from invading
be routinely exposed to infection). Malaria is often hepatocytes but also induce cytotoxic cell mediated
cited as a substantial impediment to economic and immunity against any infected hepatocytes. The
social development in endemic regions. lead candidate among the tried vaccine is the RTS
recombinant protein vaccine, targeting the
Malaria is considered a re-emerging disease,
circumsporozoite antigen that is expressed on both
due largely to the spread of drug-resistant parasite
sporozoites and the infected hepatocytes. This
strains, decay of health-care infrastructure and
antigen is fused with the hepatitis B surface
difficulties in implementing and maintaining vector
antigen and expressed as a recombinant protein
control programs in many developing countries.
in yeast and used with a powerful adjuvant AS02.
Historically, vaccines have been one of the Though the vaccine is safe and immunogenic, the
most cost-effective and easily administered means protective efficacy is only 30-60%. This RTS,
of controlling infectious diseases, yet no licensed S/ASO2 pre-erythrocytic vaccine holds out hope
vaccine exists for malaria. Accumulating basic and of achieving sterilizing immunity and is eminently
clinical research suggest that effective vaccines suited for immunization of travelers.14,15
for malaria can be developed and could
DNA vaccine and prime-boost approaches
significantly reduce morbidity and mortality, and
potentially reduce the spread of infection. Perhaps the most viable multi-component
attack on malaria is offered by DNA vaccines,
The idea that a vaccine against malaria is feasible
which can be genetically tailored to induce both
is supported by the following findings:
cell-mediated and humoral immune responses.
Immunity can be acquired as a result of Multi-component DNA vaccines offer the best
natural exposure. prospects for protection against malaria because
Most of the severe disease in endemic area they can be tailored to include a variety of
occurs in young children before they have numbers, types, and arrangements of epitopes (the
developed immunity. sites within a molecule to which a specific antibody
Passive transfer of purified immunoglobulin binds). DNA vaccines, unlike conventional
from immune people has been shown to be vaccines, have high immunogenicity, unlike multi-
protective. component synthetic peptide vaccines like
SPF-66. DNA vaccines are also cost-effective.
A pre-erythrocytic vaccine would protect against
the infectious form injected by a mosquito SPF-66 was a vaccine designed to contain
(sporozoite) and/or inhibit parasite development sequences from three blood stage antigens,
in the liver. An erythrocytic or blood stage vaccine combined with the tetra-peptide repeats of the
would inhibit parasite multiplication in the red cells, circumsporozoite protein. Unfortunately in large
thus preventing (or diminishing) severe disease phase III trials this vaccine lacked significant
18
efficacy. Vaccine directed at antigens of the in the field is publication of the genomes of Homo
merozoites important for the red blood cells sapiens, Plasmodium falciparum and Anopheles
invasion include those against the apical membrane gambiae - the three corners of the fatal triangle of
antigens(AMAI) and merozoite surface antigens African malaria. This would certainly open up
(MSP1, MSP2). These have been shown to be immense possibilities. Use of sophisticated
highly effective in animal models, but are poorly procedures like micro arrays, gene analyses and
immunogenic in humans, while high antibody titers proteomics will throw up a large number of vaccine
are required to prevent invasion. candidates. It is now estimated that essentially all
of the parasites approximately 6000 genes are
Transmission blocking or so-called altruistic available in existing databases. Thus, the malaria
vaccines rely on preventing fertilization of the community and vaccine developers have access
sexual stage of the parasite in the gut of the to virtually all of the genes encoding the antigens
mosquito vector. Two candidate antigens under and proteins expressed by this organism.13
development are Pfs28 and Pfs25 containing
sexual stage (ookinete) antigens expressed by Cochrane review
P.falciparum and P. vivax, respectively.
Four types of malaria vaccines, SPF-66 and
Recombinant vaccines MSP/RESA vaccines (against the asexual stages
of the Plasmodium parasite) and CS-NANP and
Through a collaborative program between RTS, S vaccines (against the sporozoite stages),
investigators at Oxford University and SB Bio have been tested in randomized controlled trials
(SmithKline) detailed characterization of the in endemic areas
cellular immune response to the RTS,S/SBAS2
vaccine is underway. Planned clinical trials include Eighteen efficacy trials involving 10,971
prime-boost studies of RTS, S boosted with a participants were included. There were ten trials
recombinant modified vaccinia virus Ankara of SPF-66 vaccine, four trials of CS-NANP
encoding the CS protein.13 vaccines, two trials of RTS,S vaccine, and two of
MSP/RESA vaccine. Results with SPf66 in
Two P. falciparum candidate vaccines are reducing new malaria infections (P. falciparum)
under investigation. One, an ~41 kd protein called were heterogeneous: it was not effective in four
FALVAC-1. It has been expressed in a baculovirus African trials (Peto odds ratio (OR) 0.96, 95%
expression system in collaboration with National confidence interval (CI) 0.81 to 1.14), but in five
Institute of Immunology, New Delhi, India. trials outside Africa the number of first attacks
A second candidate, FALVAC-2, is under was reduced (Peto OR 0.77, 95% CI 0.67 to
development. CDC has entered into a 0.88). Trials to date have not indicated any serious
Collaborative Research and Development adverse events with SPf66 vaccine.
Agreement (CRADA) with the Bharat Biotech,
International Limited (BBIL), Hyderabad, India, In three trials of CS-NANP vaccines, there
for production of GMP-grade candidate vaccine was no evidence for protection by these vaccines
antigens. against P. falciparum malaria (Peto OR 1.12, 95%
CI 0.64 to 1.93).
Genomic and proteomic approaches
In 1996, a collaborative International effort In a small trial in non-immune adults in the
was undertaken to sequence the complete genome USA, RTS,S gave strong protection against
of P. falciparum. The most promising development experimental infection with P. falciparum. In a

19
trial in an endemic area of the Gambia in semi- among sex workers in Chennai in 1986, India has
immune people, there was a reduction in clinical the second largest number of people living with
malaria episodes in the second year of follow up, HIV/AIDS in the world, with an adult population
corresponding to a vaccine efficacy of prevalence of approximately 5.13 millions. Though
66% (CI 14% to 85%). HIV infection in India is concentrated among poor,
marginalized groups, HIV is spreading quickly into
In a trial in Papua New Guinea, MSP/RESA the general population. Approximately 90 percent
had no protective effect against episodes of clinical of reported AIDS cases occur in sexually active
malaria. There was evidence of an effect on and economically productive individuals aged
parasite density, but this differed according to 15 to 44 years. HIV infection among women and
whether the participants had been pretreated with children is on the rise. The reported doubling time
sulfadoxine/pyrimethamine or not. The prevalence of HIV epidemic in India is nearly two years.18
of infections with the parasite subtype of MSP2
in the vaccine was reduced compared with the HAART allows the stabilisation of the
other subtype (Peto OR 0.35, CI 0.23 to 0.53). patients symptoms and viremia, but they do not
cure the patient of HIV, nor of the symptoms of
Conclusion: There is no evidence for protection AIDS. High levels of HIV-1, viremia often
by SPf66 vaccines against P. falciparum in Africa. HAART resistant, return once treatment is
There is a modest reduction in attacks of stopped. Moreover, it would take more than the
P.falciparum malaria following vaccination with lifetime of an individual to be cleared from HIV
SPf66 in other regions. Further research with infection using HAART. Antivirals are also too
SPf66 vaccines in South America or with new expensive for developing countries, which have
formulations of SPf66 may be justified. There the highest rates of HIV-infection. Only a vaccine
was not enough evidence to evaluate the use of will be able to halt the pandemic. This would
CS-NANP vaccines. possibly cost less, thus being affordable for
developing countries, and would not require daily
The RTS,S vaccine showed promising result, treatments. However, after over 20 years of
as did the MSP/RESA vaccine, but it should research, HIV-1 remains a difficult target for a
include the other main allelic form of MSP2. The vaccine.19
MSP/RESA trial demonstrated that chemotherapy
during a vaccine trial may reduce vaccine efficacy, Current Strategies for an HIV Vaccine
and trials should consider very carefully whether
Traditional
this practice is justified.16,17
Immunization with live attenuated viruses
5) HIV Vaccine
Possible limitations In vivo mutation may
The HIV-1 pandemic has grown to become render vaccine pathogenic, no animal
one of the greatest infectious disease threats to model for pathogenicity.
human health and social stability that the world
Immunization with inactivated viruses with
has ever encountered. Nearly 40 million persons
adjuvant
are living with HIV-1 infection and more than
21 million people have already died from HIV- Possible limitations - Brief duration of
induced disease. Regarding the status of AIDS in immunity, absence of cytotoxic
India, since the first report of the HIV infection T lymphocytes

20
Newer approaches Based on the observation that in the initial
Immunization with recombinant HIV protein part of the infection, T cells are involved in the
with adjuvant identification and killing of HIV infected cells,
various vaccine are underway that stimulate
Possible limitations -Brief duration of
T cells responses. Methods attempted include
immunity, absence of cytotoxic T cells,
recombinant proteins, synthetic peptides,
restricted number of isolates recognized
recombinant viral vectors, recombinant bacterial
Immunization with synthetic HIV peptides vectors, recombinant particles, DNA vaccines to
with adjuvents induce production of a specific antigen, and whole-
Possible limitations -Restricted number of killed and live-attenuated HIV, however, initial
immunogenic epitopes results cast doubts about the vaccine
Combined approaches (e.g. recombinant immunogenicity. Another vacine now in the early
vaccinia virus and recombinant protein) stage of a proof of concept, or phase 2B trial,
Possible limitations -No consistent protection contain replication-defective adenovirus type 5
in the animal model that transmit the HIV genes gag, pol, and nef
(which codes for internal HIV protein and may
Intramuscular inoculation of the virus agent
stimulate cellular immunity), this vaccine looks
Possible limitations -Little experience with the far more promising.20, 21
approach
Other novel approaches will soon be tested
Use of vaccine for immune potentiation in
in nonhuman-primate models of AIDS, among
HIV infected patients
them the direct intramuscular inoculation of viral
Possible limitations -No evidence of genes. Such an immunization procedure generates
effectiveness potent antibody and cell-mediated immune
The classical vaccination approaches that responses and protects against challenge with live
have been successful in the control of various viral influenza virus.
diseases by priming the adaptive immunity to Clinical trials for the HIV vaccines
recognize the viral envelope proteins have failed
in the case of HIV-1, as the epitopes of the viral A total of 17 vaccine candidates are in phase
envelope are too variable. Furthermore, the I trials and four in phase I/II. There is only one in
functionally important epitopes of the gp120 phase III (the NIH/Department of Defenses
protein are masked by glycosylation, trimerisation ALVAC vCP 1521 canary pox vector/AIDSVAX
and receptor-induced conformational changes prime-boost vaccine trial now under way in
making it difficult to block with neutralising Thailand). ALVAC-HIV: a genetically
antibodies.Thus the vaccine failed to protect engineered HIV vaccine composed of a live,
because the circulating HIV strain hides its epitopes weakened canary pox virus (ALVAC) into
in a variety of ways that genetically engineered which parts of genes for non-infectious
gp120 proteins do not mimic successfully. In components of HIV have been inserted. When
February 2003, VaxGen announced that their ALVAC infects a human cell, the inserted HIV
AIDSVAX vaccine was a failure in North America genes direct the cell to make HIV proteins. These
as there was not a statistically significant reduction proteins are packaged into HIV-like particles that
of HIV infection within the study population. In bud from the cell membrane. These particles are
November 2003, it also failed clinical trials in not infectious but fool the immune system into
Thailand for the same reason.20, 21 mounting an immune response to HIV. ALVAC
21
can infect but not grow in human cells, an important Modified Vaccinia Ankara (MVA) HIV-1 subtype
safety feature. C vaccine for the first time to humans in India.
The tests in the western city of Pune will involve
Up to May 2003 over 60 phase I/II trials of 30 HIV-free volunteers between 18 and 45 of
candidate vaccines have been conducted both sexes.
worldwide. Most initial approaches focused on
the HIV envelope protein. At least thirteen Due to an enormous amount of pre-clinical
different gp120 and gp160 envelope candidates work over the last several years, many other
have been evaluated, in the US predominantly vaccines are being studied and include important
through the AIDS Vaccine Evaluation Group. concepts worth watching. These include the
Overall, they have been safe and immunogenic Venezuelan equine encephalitis virus vectors
in diverse populations, have induced neutra- (encoding gag from clade C), the heat-killed
lizing antibody in nearly 100% recipients, but recombinant Saccharomyces cerevisiae
rarely induced CD8+ cytotoxic T lymphocytes (expressing gag from Clade B), the IL-2/Ig cytokine
(CTL). 19,20 adjuvanted DNA of the VRC in collaboration with
Harvard, the IL-12 cytokine adjuvanted Gag
On January 26, 2005, a large phase IIb clinical subtype B vaccine of Wyeth and the DNA prime/
trial of a novel HIV vaccine has begun enrolling MVA boost strategy being developed by Harriet
volunteers at sites in North America, South Robinson at Emory. But as in 1984, still a safe
America, the Caribbean and Australia. The and effective preventive vaccine remains elusive.
organizers are seeking 1,500 participants. The trial
is co-funded by the National Institute of Allergy Points to remember
and Infectious Diseases (NIAID), part of the
Acellular pertussis and Tdap vaccines have
National Institutes of Health (NIH), and the
definite role as newer vaccines.
pharmaceutical company Merck & Co. Inc. In
previous smaller trials, this vaccine was found to With regard to rotavirus, malaria & HIV
be safe and to induce cellular immune responses vaccines an ideal vaccine is yet to be
against HIV in more than half of volunteers. developed.
NIAID and Merck expect the trial be References
completed in four-and-a-half years, with results
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phase 1 trial that involves administration of 1989;31:698-701.

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14. Read Andrew. Quoted in Malaria - from Infants
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preventive measures. Recommendations of the
Malaria vaccines show progress thanks to
Immunization Practices Advisory committee
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(ACIP). MMWR 1991; 40(No. RR-10):1-28.
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18. Norman L. Letvin. Vaccines against Human
9. Tdap vaccine: CDC; vaccine information Immunodeficiency Virus Progress and
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 / Prospects. N Engl J Med 1993;329:1400-
publications/VIS/defaults.htm#tdap 1405.
10. Glass R, Parashar U. The promise of new 19. HIV vaccine: from Wikipedia, the free
Rotavirus Vaccine. N Engl J Med 2005; encyclopedia; http://en.wikipedia.org
354:75-77. 20. Steinbrook R., Drazen JM. AIDS - Will the
11. Bresee JS, Umesh, Parashar D, Marc-Alain Next 20 Years Be Different? N Engl J Med
Widdowson, Jon R. Gentsch. Rotavirus in Asia: 2001;344:1781-1782.
The Value of Surveillance for Informing 21. Cohen Jon. The search for an AIDS vaccine and
Decisions about the Introduction of New on effective global response shots in the dark:
Vaccines; J Infect Dis 2005;192 (suppl 1):S1- The Wayward search for an AIDS vaccine. N
S5. Engl J Med 2001;344:1801-1802.
12. Kundu R, Ganguly N, Ghosh TK, Choudhury P, 22. HIV vaccine: National institute of allergy and
Shah RC. Diagnosis and management of malaria infectious disease ( NIAID), assessed at :http:/
in children: recommendations and IAP plan of /www.niaid.nih.gov/information/search.htm.

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
VACCINES II

ADDITIONAL VACCINES - CURRENT drug resistance and of strains with reduced


TRENDS susceptibility to fluoroquinolones, prevention is
of paramount importance.1 Immunization is useful
* Niranjan Shendurnikar for prevention of typhoid in travellers from
** Mukesh Kumar Singh developed countries to typhoid-endemic countries,
Abstract : Additional vaccines (vaccines not in preventing and controlling epidemics, and for
covered under National Immunization Schedule children in endemic settings aged 2 to19 years.2
but recommended by IAP) like Typhoid, MMR Vaccine availability
and varicella vaccines are covered in this article.
In developing countries, Vi polysaccharide and The old parenteral whole-cell typhoid-
Ty 21a typhoid vaccines are equally effective. paratyphoid A and B (TAB) vaccine was effective
Another option for less than 2 years old children against typhoid and paratyphoid fevers but has
is Vi-conjugate vaccine. Reviving whole cell been largely discontinued because of frequent
typhoid vaccine manufacture could be considered side-effects and the cumbersome manufacturing
in view of its cost effectiveness, usefulness even process.3,4 Currently, two vaccines for typhoid
in infants and toddlers and possibility of reducing fever, one based on Vi polysaccharide and the
the side effects by excluding paratyphoid bacilli other oral one based on whole-cell live attenuated
and administering it intradermally. Indian bacteria, are licensed. There is no licensed vaccine
Academy of Pediatrics recommends M/MMR for paratyphoid fever. The liquid formulation of
vaccine strategy with measles vaccine at the live oral vaccine for younger children is
9 months of age and MMR at 15 months of age. currently marketed in only a few countries.1 The
The varicella vaccine is effective in preventing live oral Ty21a vaccine in the capsule formulation
all forms of varicella infection. is also no longer available in India.
Keywords : Typhoid, MMR, Varicella Vaccines. Whole-cell typhoid vaccine and vaccine efficacy
Typhoid Vaccines In a meta-analysis of randomized controlled
trials evaluating the efficacy of the various typhoid
Need for typhoid vaccines
vaccines, the three-year cumulative efficacy was
Besides sanitation, immunization is an 73% (95% confidence interval 65% to 80%) for
additional effective tool for the prevention of two doses of whole cell vaccines (based on seven
typhoid fever. With the global emergence of multi- trials); 51% (35% to 63%) for three doses of
Ty21a vaccine (four trials); and 55% (30% to
* Associate Professor
** Assistant Professor 71%) for one dose of Vi vaccine (one trial). For
Department of Pediatrics whole cell and Ty21a vaccines, regimens of fewer
Medical College, Baroda 390001 doses were less effective. Efficacy was shown to

24
be significant for five years for whole cell vaccines, of participants in a field trial in South Africa still
four years for Ty21a vaccine, and two years for had protective levels of antibodies ten years after
Vi vaccine. After vaccination, fever occurred in vaccination.6 This vaccine has shown about 70%
15.7% (11.5% to 21.2%) of whole cell vaccine protective efficacy in a population vaccinated
recipients, 2.0% (0.7% to 5.3%) of Ty21a vaccine before or during an outbreak in China.7
recipients, and 1.1% (0.1% to 12.3%) of
Ty21a vaccine
Vi vaccine recipients. This meta-analysis
concluded that whole-cell vaccines are more This live oral vaccine in enteric-coated or
effective than the Ty21a and Vi vaccines, but are liquid formulation is approved for use in individuals
more frequently associated with adverse effects. six years of age and older. Three doses are
Whether the added efficacy of the whole cell recommended each given two days apart.1 The
vaccines outweighs their toxicity will depend on oral typhoid vaccine is recommended as four initial
the setting in which immunization is used.3 doses in the USA and only three in Europe -
a potential point of confusion. Antimicrobials
The acetone-killed whole-cell vaccine was
should be avoided for seven days before or after
reported to have a protective efficacy of 79 88%
vaccination.
in various studies. The Vi and oral typhoid vaccines
are safe but the protective efficacy is much less The oral vaccine is moderately effective for
(between 50 70%) compared to the effective up to about three years after vaccination.
vaccines available for other diseases.5 Revaccination is recommended every three years
in endemic areas and every five years for travellers
Whole cell vaccines to developing countries. Travellers to typhoid-
The whole-cell vaccine is quite inexpensive endemic areas such as South Asia need to be
and it is effective even in infants and toddlers. Its vaccinated even if they plan to stay for less than
side-effects can be decreased if the vaccine two weeks. Herd immunity was shown during field
contains only S.typhi (and not paratyphoid bacilli trials in Chile.1
too) and if it is administered by the intradermal In a study to determine the acceptability of
route (as recommended for revaccinations) rather oral typhoid vaccine among Thai children, the
than subcutaneously. The adverse effects of the rates of successfully being able to swallow all three
whole-cell vaccine are no worse than the local or capsules (one capsule every other day) were
systemic reactions to DTP vaccine, are not serious, 84.4%, 94.9%, and 100% in the age groups
and are short-lived and well-tolerated. Reviving 4-6 years, 7-9 years, and 10-12 years
the manufacture of the whole-cell vaccine could respectively.8
be considered.4
Choosing a typhoid vaccine
Vi polysaccharide vaccine
The effectiveness of both the vaccines in
This is the only typhoid vaccine available developing countries is similar. Ty21a has the
widely in India currently. This vaccine is licensed advantage that it is given orally and therefore might
for use in individuals older than two years and is be easier for immunizing groups of children, as in
given in a single subcutaneous or intramuscular schools. The Ty21a vaccine, especially the enteric-
dose. The vaccine is moderately effective for coated capsule formulation, is not licensed for use
about three years after vaccination. Revaccination in 25 year-old children. Vi vaccine has a relative
is recommended every three years. However, 58% advantage that it can be used for these preschool

25
children, in settings where typhoid fever is more than 95% of the subjects were positive for
common in this age-group. The vaccine, however, anti-Vi antibodies and more than 86% were
is not licensed for use in children younger than positive for anti-HAV antibodies as early as
two years.1 14 days after immunization. The combined
vaccine offers more convenience and rapid
Adverse events seroconversion for travellers.12 Clinical studies in
Post-marketing surveillance in the U.S. for healthy adults have also documented the safety
licensed typhoid fever vaccines from the Vaccine and immunogenicity of concomitant administration
Adverse Effects Reporting System (VAERS) from of an inactivated hepatitis A vaccine and either a
1990 to 2002 revealed that unexpected frequently typhoid fever (Vi) vaccine or a combination of Vi
reported symptoms included dizziness and pruritus and yellow fever vaccines.13
for Vi polysaccharide vaccine and fatigue and
MMR Vaccine
myalgia for Ty21a. Gastroenteritis for Ty21a and
abdominal pain after Vi vaccine were previously
Is a second dose necessary?
recognized events. Occasional nonfatal anaphylaxis
was reported after both vaccines. VAERS reports Research over the merits of two doses of
do not indicate any unexpected serious side effects MMR vaccine versus a single dose is not new. In
that compromise use of these vaccines as Finland, a two-dose MMR vaccination program
prophylaxis for travellers.9 was begun in 1982. The program with high
coverage (9798%) has eliminated these three
Vi-conjugate vaccine
diseases from Finland. In a study following the
Unlike polysaccharide vaccines, conjugate kinetics of measles virus antibodies in MMR-
vaccines can be effective in children younger than vaccinated cohorts, the primary dose induced
two years and elicit immunologic memory. 99.4% seroconversion for measles with a geo-
Vietnamese children between the ages of two and metric mean haemagglutination inhibition(HI)
five years given Vi-conjugate vaccine had 91.1% antibody titer (GMT) of 1/269 (219). After
protection against typhoid 27 months after 12 years, 80% of the original children remained
vaccination, with geometric mean titers of 7.61 available for sampling. The 12-year follow-up
ELISA units for those vaccinated at age two to samples showed a measles seropositivity rate of
three years. 10 The efficacy of this conjugate 100% as assayed with the HI test with a mean
vaccine persisted after 46 months of vaccination; HI antibody titer of 1/39 (54). The authors
over the entire period, the protection was 89% postulated that vaccination-induced measles virus
(95% CI: 76%97%).11 As yet, it has not been antibodies decline in the absence of natural
tested in infants. This vaccine could be used for booster infections.14
children younger than two years and be
It is important to follow how long the
incorporated into the Expanded Program on
protection achieved by the present vaccine
Immunization (EPI) schedules in the future.
programs will last after elimination of indigenous
Combination vaccines measles.14 It must be borne in mind that at any
given time, the epidemiology will vary among
In a multicenter study to evaluate the first countries and the situation in developing countries
combined vaccine against typhoid fever and cannot be extrapolated from that in the developed
hepatitis A in healthy subjects aged 15-50 years, countries.

26
Even in the industrialized countries, two Two to four years after receiving a first dose
doses of the trivalent MMR vaccine are currently of MMR vaccine at age 1218 months, it was
advocated. The MMR triple (i.e. combined) found that a large proportion of pre-school children
vaccine is used in over 90 countries worldwide had measles (19.5%) and mumps (23.4%) IgG
and no country recommends immunization for antibody below the putative level of protection.
measles, mumps and rubella in separate Only a small proportion (4.6%) had rubella
vaccinations.15 The first dose of MMR vaccine antibody below the putative protective level.
is given routinely at 12-15 months. The second A total of 41% had negative or equivocal levels to
dose is usually given between three and five years one or more antigens. The proportion who had
of age during the school immunization booster measles antibody negative (but not rubella or
program. Two doses of MMR are required in mumps) was significantly higher in children
order to ensure that all children receive the vaccinated at 12 months of age than at 1317
vaccination as some may miss it when they are months. After a second dose of MMR, the
12-15 months old for a variety of reasons. It is proportion who were negative to one or more
also important as it confers immunity on those antigens dropped to <4%. Examination of National
who did not respond to the first vaccination, which serosurveillance data found that following an MR
can be as many as 5-10% (primary vaccine vaccine campaign in cohorts that previously
failure).15,16 The majority of individuals who fail received MMR, both measles and rubella antibody
to respond to the first dose of MMR respond to a levels were initially boosted but declined to pre-
second dose. For children who did receive and vaccination levels within 3 years. This study
responded to the first vaccination, the second supports the policy of administering a second dose
simply boosts their antibodies to measles, mumps of MMR vaccine to all children. However,
and rubella just as they start attending school and continued monitoring of long-term population
increasing social contact with other children.15 protection will be required and this study suggests
During a 1998-99 outbreak of mumps among that in highly vaccinated populations, total measles
children of a religious community in North East (and rubella) IgG antibody levels may not be an
London, a case-control study was conducted to accurate reflection of protection. Further studies
assess the effectiveness of the mumps component including qualitative measures, such as avidity, in
of the MMR vaccine. Two doses of vaccine were different populations are merited and may
more effective (88% (95% CI: 6296%)) than a contribute to the understanding of MMR
single dose (64% (95% CI: 4078%)). The authors population protection.18
concluded that the two-dose vaccination program MMR being a combination vaccine, the
remains the best method for controlling mumps question of a single dose versus two doses can be
infection in the community.17 addressed only in the context of each of the three
Measles and mumps, but not rubella, diseases separately. Measles vaccine is known to
outbreaks have been reported amongst populations have lower seroconversion rate when administered
highly vaccinated with a single dose of MMR before 12 months of age, hence a two-dose
vaccine. Repeated experience has shown that a measles vaccine schedule (with MMR vaccine at
two-dose regime of measles vaccine is required 15 18 months) should be the best approach.
to eliminate measles. A study paper reported the Efficacy of a single dose of mumps vaccine is
effect of the first and second MMR doses on around 95%.19 However, in the Indian scenario,
specific antibody levels in a variety of where MMR vaccine or mumps vaccine is not
populations.18 part of the National Immunization Program
27
currently, coverage with even a single dose of Inflammatory Bowel Disease and Guillian-Barre
mumps vaccine is negligible. It is too far-fetched Syndrome.16 From multiple population-based
to debate over the issue of a second dose. studies and extensive review committee reports,
However there exists the possibility of eradication it has been summarized that neither immunization
of mumps with two doses of mumps vaccine.16 nor thimerosal exposure has been conclusively
A single dose of rubella vaccine (RA 27/3 strain) linked to autism.
provides seroconversion in more than 95%
children with vaccine efficacy of about 90% for Contested reports associating the MMR
lifelong protection. The Indian Academy of vaccine with autism had resulted in diminished
Pediatrics recommends M/MMR vaccine strategy confidence and public acceptance of the vaccine
with measles vaccine at 9 months of age to be in the UK. In a postal survey of parental attitudes,
followed by MMR vaccine at 15- 18 months.19 both MMR-accepting and refusing parents were
As of now, MMR is not included in EPI and supportive of immunization, yet the high level of
parents must bear the expense for their childs concern about the safety of the vaccine expressed
immunization. even by parents who had immunized their children
is worrying in its implications for public confidence
Mumps vaccine virus strain and aseptic and trust in health care.
meningitis
The weight of evidence lies in favor of triple
The live attenuated mumps virus component MMR vaccination and a 95% uptake of this
in MMR vaccine could be one of the several strains; vaccine would confer immunity that would protect
these different strains (Urabe, Leningrad-Zagreb not only the immunized child but also those too
and Jeryl-Lynn used in India at some time or the young to be immunized and those in utero.15
other) have good immunogenicity, though it is
claimed that side-effects are least with the Jeryl- Varicella Vaccine
Lynn strain, particularly in reference to aseptic Effectiveness of the vaccine and duration of
meningitis. There is an association between the protection
Urabe strain of mumps vaccine and aseptic
meningitis.16 Studies have estimated the incidence Varicella vaccine is effective in preventing
of aseptic meningitis to be 49-100, 20-30 and 1.0 any form of the disease in 90-95% of vaccinees
per 100,000 doses for the Urabe, L-Zagreb and whereas protection against moderate to severe
Jeryl-Lynn strains respectively20 i.e. it is negligible disease is provided to >95% of vaccinees. The
for all strains. Moreover, this is a benign disease seroconversion rate in children aged 112 years
with complete recovery even if untreated. A recent was 95% after a single dose. After 13 years of
study done in Egypt covering more than 100,000 age, seroconversion rates were 7882% after the
children being given MMR with the L-Zagreb first dose and 99% after two doses. The immunity
mumps virus strain showed that there was not a to varicella lasts for at least 1020 years.
single case of aseptic meningitis on prospective Secondary vaccine failure may result from waning
follow-up. All MMR vaccines are considered as vaccine-induced immunity over the years.
equally safe and immunogenic by IAP. Exposure to natural infection in the community
will continue to provide a boosting effect.5
MMR vaccine scares
The six-year cumulative varicella antibody
Epidemiologic studies do not support a persistence rate was 99.5% (95% CI: 98.9%-
causative link between MMR vaccine and autism, 100.0%) in a manufacturer-funded study of
28
healthy children aged between 1 to 12 years given outbreaks of varicella among immunized children
the Oka varicella vaccine. The annual (breakthrough varicella). The most cited risk
breakthrough rate through seven years ranged factors for breakthrough varicella include the
from 0.2% to 2.3% per year; the estimated following: (i) 3 to 5-year interval since
cumulative event rate was 6.5%. Comparison of immunization and (ii) immunization at the
the observed average annual breakthrough rate youngest ages, especially 12 months. Explanations
with the age-adjusted expected annual incidence for breakthrough varicella include a lessened
rate of varicella in unvaccinated children immune response among the youngest recipients
corresponded to an estimated vaccine efficacy of of the vaccine. Another possibility is genetic
93.8% to 94.6%. Eighty vaccinated children were variation among circulating VZV strains.
exposed to varicella in the household, resulting in Breakthrough disease among vaccine recipients
8 (10%) cases of infection. When compared with appears to be more common in the United States
the historical attack rate of 86.8% in unvaccinated than in Japan.23
susceptible persons exposed to varicella in the
household, this yields an estimated vaccine A study documented an outbreak of varicella
efficacy of 88.5% (95% CI: 80.9%, 96.1%). among largely immunized 4-year-olds at a day-
Varicella cases in vaccinated children generally care centre in New Hampshire. Moderately severe
were mild.21 varicella spread from the index case to 15 others,
indicating that the vaccine was only 44% effective
Results from a study indicate that the in this outbreak. Children who had been vaccinated
effectiveness of the varicella vaccine used in actual three years or more before the outbreak were at
clinical practice (as against in a clinical trial) is greater risk for vaccine failure than those
excellent, at least in the short term. Against vaccinated more recently.24 There are still not
moderately severe and severe disease, the vaccine enough data to recommend a second dose of
was 97 % effective (95% CI - 93 to 99%). Virtually varicella vaccine for younger children. However
all the vaccinated children in whom chickenpox this may become the reality after more experience
subsequently developed (all of whom were is gained as happened in case of MMR.
infected with wild-type virus) had very mild
disease.22 These findings are consistent with those Varicella vaccine: Other issues
of a study by the Center for Disease Control and
Rates of herpes zoster are much lower
Prevention that show a marked decline in the
(2.4 cases per 1,00,000 population) in vaccinees
incidence of chickenpox in areas where the vaccine
than in those who develop zoster following
is widely used, as well as with reports of the
wild virus infection (68 cases per 1,00,000
effectiveness of the vaccine after outbreaks in day-
population).5
care centers.
Breakthrough varicella For post-exposure prophylaxis, susceptible
immunocompetent children and household
Live attenuated varicella vaccine (Oka strain) contacts can be given varicella vaccine within
was approved for administration to healthy children 2-3 days of the appearance of the rash in the index
in the United States in 1995. Over the past case.19
10 years, varicella vaccine has been given to
millions of U.S. children, usually at ages between In a randomized, double-blind, placebo-
12 and 18 months. The main unanticipated controlled study, it was concluded that varicella
observation has been a growing number of vaccine may not be effective in preventing varicella

29
when administered after household exposure, varicella. These results compared favorably with
although it is highly effective in ameliorating the the licensed MMR and varicella vaccines. The
disease in those who acquire it under these combined vaccine was well-tolerated with the only
circumstances. The risk of developing moderate exception being a slight increase in measles-like
to severe disease was eight times greater in the rash after the initial dose.26
placebo group (RR = 8), indicating an 80%
protective effect against moderate/severe The gelatin content in the varicella vaccine
disease.25 may be associated with hypersensitivity reactions.
A new gelatin-free varicella vaccine tested in
Varicella vaccine administered in a two-dose Japanese studies has been reported to be safe,
regimen was generally well-tolerated and highly with similar immunogenicity to the earlier gelatin-
immunogenic in US and Canadian children containing vaccine.27
(12 months to <18 years) with nephrotic
syndrome, including those on low-dose, alternate- Summary
day prednisolone.
Universal coverage with efficacious vaccines
A study at the Johns Hopkins Childrens is still a distant dream in most developing countries
Center, Baltimore to determine whether the today. Theoretically, however, science is equipped
vaccine was immunogenic in children with chronic with the means to prevent, control and eventually
renal insufficiency identified fifty such children even eradicate certain infectious diseases. In the
with no detectable varicella zoster virus antibody. future, widespread coverage with vaccines is likely
Each child was given two doses of vaccine 48 to present newer challenges to the scientific and
weeks apart, rather than the typical one dose, and medical communities due to the changes it brings
subsequent rates of seroconversion were about in the epidemiology of infectious diseases.
measured. During three years of follow-up all In summary, these pertinent issues with the
children (including 16 who received kidney additional vaccines are of clinical relevance and
transplants later) retained a concentration of patient-doctor concern to optimize vaccine
antibodies considered to be protective against acceptance and cost-effectiveness.
chicken pox.
Points to remember
The Centers for Disease Control and
Prevention recommends varicella immunization The efficacy of the available typhoid
for those HIV-1-infected children without clinical vaccines is reported to be similar in
or laboratory evidence of clinically significant developing countries.
immune suppression.
The two-dose vaccination program remains
Combination vaccines and newer vaccines the best method for controlling measles and
mumps infection in the community, using
A new MMRV combination vaccine was MMR as a part of national schedule.
studied in 480 children aged 1223 months. The
response rate to the first dose was 96% for Varicella vaccine is effective in preventing
measles, 99% for mumps, 95.1% for rubella, and any form of the disease in 90-95% of
91.2% for varicella. The response rate after the vaccinees, whereas protection against
second dose was 98.6% for measles, 100% for moderate to severe disease is more than
mumps, 94.8% for rubella, and 99.2% for 95% of vaccinees.

30
References 11. Mai NL, Phan VB, Vo AH, et al. Persistent
efficacy of Vi conjugate vaccine against
1. Bhan MK, Bahl R, Bhatnagar S. Typhoid and typhoid fever in young children. N Engl J Med
paratyphoid fever. Lancet 2005; 366: 749-762. 2003; 349: 1390-1391.
2. World Health Organization. Background
12. Beran J, Beutels M, Levie K, et al. A single
document: The diagnosis, treatment and
dose, combined vaccine against typhoid fever
prevention of typhoid fever. WHO/V&B/03.07.
and hepatitis A: consistency, immunogenicity
Geneva: World Health Organization, 2003.
and reactogenicity. J Travel Med 2000; 7: 246-
3. Engels EA, Falagas ME, Lau J, Bennish ML. 252.
Typhoid fever vaccines: a meta-analysis of
studies on efficacy and toxicity. Br Med J 13. Dumas R, Forrat R, Lang J, Farinelli T, Loutan
1998; 316: 110-116. L. Safety and immunogenicity of a new
inactivated hepatitis A vaccine in concurrent
4. Kukreja S, Chitkara AJ. Immunization against
administration with a typhoid fever vaccine or
Typhoid Fever. In: Thacker N, Shah N. (eds.)
a typhoid fever + yellow fever vaccine. Adv
Immunization in Clinical Practice. 1st edn
Ther 1997; 14: 160-167.
Jaypee Brothers Medical Publishers (P) Ltd.,
New Delhi. 2005; pp 119-124. 14. Davidkin I, Valle M. Vaccine-induced measles
5. Vashishtha VM. Symposium on Pediatric virus antibodies after two doses of combined
Vaccines. Pediascene 2003; 51: 4-15. measles, mumps and rubella vaccine: a 12-year
follow-up in two cohorts. Vaccine 1998; 16:
6. Keddy KH, Klugman KP, Hansford CF,
2052-2057.
Blondeau C, Bouveret le Cam NN. Persistence
of antibodies to the Salmonella typhi Vi 15. McGreevy D. Risks and benefits of the single
capsular polysaccharide vaccine in South versus the triple MMR vaccine: how can health
African school children ten years after professionals reassure parents? JRSH 2005;
immunization. Vaccine 1999; 17: 110-113. 125: 84-86.
7. Yang HH, Kilgore PE, Yang LH, et al. An 16. Dubey AP, Banerjee S. Measles, Mumps,
outbreak of typhoid fever, Xing-An County, Rubella (MMR) Vaccine. Indian J Pediatr
Peoples Republic of China, 1999: estimation 2003; 70: 579-586..
of the field effectiveness of Vi polysaccharide
typhoid vaccine. J Infect Dis 2001; 183: 1775- 17. Harling R, White JM, Ramsay ME, Macsween
1780. KF, van den Bosch C. The effectiveness of the
mumps component of the MMR vaccine: a
8. Mekmullica J, Pancharoen C. Acceptability of
case control study. Vaccine 2005; 23: 4070-
oral typhoid vaccine in Thai children. Southeast
4074.
Asian J Trop Med Public Health 2003; 34:334-
336. 18. Pebody RG, Gay NJ, Hesketh LM, Vyse A,
9. Begier EM, Burwen DR, Haber P, Ball R. Morgan-Capner P, Brown DW et al.
Vaccine Adverse Event Reporting System Immunogenicity of second dose measles
Working Group. Postmarketing safety mumpsrubella (MMR) vaccine and
surveillance for typhoid fever vaccines from implications for serosurveillance. Vaccine
the Vaccine Adverse Event Reporting System, 2002; 20: 1134-1140.
July 1990 through June 2002. Clin Infect Dis 19. Shah NK, Shendurnikar N, Thacker N,
2004; 38: 771-779. Vashishtha VM. Current Issues and Options in
10. Lin FY, Ho VA, Khiem HB, et al. The efficacy Childhood Vaccines. In: Thacker N,
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two-to-five-year-old children. N Engl J Med Immunization Issues and Options. 1st Edn
2001; 344: 1263-1269. Thacker N, IAP Kutch Branch. pp 11 22.
31
20. American Academy of Pediatrics. Rubella. In: 24. Galil K, Lee B, Strine T, et al. Outbreak of
Pickering LK, ed. 2003 Red Book: Report of varicella at a day-care center despite
th
the Committee on Infectious Diseases. 26 vaccination. N Engl J Med 2002; 347: 1909
Edn. Elk Grove Village, IL. American Academy 1915.
of Pediatrics 2003; pp536-541.
25. Mora M, Harelb L, Kahanc E, Amirb J.
21. Rupert Vessey SJ, Chan CY, Kuter BJ, et al.
Efficacy of postexposure immunization with
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household settinga pilot study. Vaccine
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304.
22. Vazquez M, LaRussa PS, Gershon AA, 26. Kerr C. Good response rate for MMRV
Steinberg SP, Freudigman K, Shapiro ED. The vaccine. The Lancet Infectious Diseases 2003;
Effectiveness of the Varicella Vaccine in 3: 748
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344:955-960. and immunogenicity of gelatin-free varicella
23. Grose C. Varicella vaccination of children in vaccine in epidemiological and serological
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89-95.
NEWS AND NOTES

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 introduced for prevention of RSV infection


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

Table 2. ISG Prophylaxis for HAV7


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

36
Hepatitis B: Prophylactic treatment can using separate syringes, administered within 12
effectively prevent infection after exposure to to 24 hours after birth, is highly effective in
HBV. It is indicated in the following situations. prevention of both acute and chronic HBV
infection.7,8,9,10
Perinatal exposure of an infant born to a
Varicella-Zoster: Varicella-zoster immunoglobulin
HBsAg-positive mother.
(VZIG), prepared from high titre immune human
Inadvertent percutaneous or permucosal serum, reduces the attack rate of varicella when
exposure to blood. it is given just after exposure (Table-3). Break
Sexual exposure to a HBsAg-positive person. through infections occur, but the extent of
exanthem and risk of varicella pneumonia are
Exposure of an infant less than 12 months of diminished. VZIG given after the appearance of
age to a primary care giver who has acute varicella rash does not alter the disease process.
hepatitis B. The dosage is 1 vial (125 U)/10 kg body weight
The mainstay of postexposure immuno- (maximum 5 vials) given intramuscularly. VZIG
prophylaxis is hepatitis B vaccination, but in some should be given to susceptible high risk individuals
settings passive immunization with HBIG provides within 96 hours and if possible within 48 hours
increased protection. HBIG is prepared from after close contact to a person with varicella or
plasma known to contain a high titre of antibodies herpes zoster. VZIG prophylaxis is recommended
and provides temporary protection for 3 to 6 for immunocompromised children and newborn
months in certain postexposure settings. The infants exposed to maternal varicella. VZIG should
standard dose of HBIG for postexposure be given to infants born to mothers with onset of
prophylaxis of infants born to HBsAg positive varicella 5 days or less before delivery or within
mother is 0.5 ml while in all other situations it is 2 days after delivery. VZIG is not indicated for
0.06 ml/kg. For prevention of perinatal healthy, full term infants exposed postnatally,
transmission, hepatitis B vaccination and one dose including those whose mothers rash developed
of HBIG given concurrently but at separate sites 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 Licks on mucous membrane by wild or pet
does not eliminate the possibility of disease in high animals.
risk patients. The incidence of varicella despite Category II and III bites in immunologically
VZIG prophylaxis is significantly higher after compromised patients such as AIDS,
household exposures. VIZG to immuno- varicella, patients on long term steroid therapy,
compromised children lowered the risk of severe patients on chemotherapy, radiation therapy
varicella significantly, but 11% of these children etc.
still developed pneumonia. Because passive
Before wound suturing for local infiltration.
antibody titres of VZIG decline by
2 weeks in some patients and by 4 weeks in most Those with past history of complete post
patients, a second dose should be given if a new exposure prophylaxis using modern tissue
exposure occurs more than two weeks later. VZIG culture vaccines do not need to be given RIG
does not reduce the risk of VZV reactivation in irrespective of the class of bites.
high risk population or alter the clinical course of Human rabies immunoglobulin (HRIG).10,13: It is
herpes zoster when given after the onset of a freeze dried preparation containing IgG
symptoms.12 immunoglobulins obtained from plasma or serum
of donors immunized against rabies and contains
Rabies: Once rabies develops, it is almost
specific antibodies neutralizing the rabies virus.
invariably fatal in humans, and prevention is the
Though HRIG represents the gold standard for
only option. With the availability of safe and
passive immunoprophylaxis, its cost is exorbitantly
effective modern tissue culture vaccines and
high. Its supply is also erratic. Advantages of
immunoglobulins, the prevention of rabies is
HRIG include purity, presence of minimal or no
almost assured.
foreign protein and absence of immediate
Rabies immunoglobulins (RIGs) are special hypersensitivity reaction. Disadvantages of HRIG
neutralizing antibodies that immediately neutralize include cost, chances of transmission of potential
virus on contact. RIGs give a coating to the virus plasma borne infections, erratic supply,
so that it can not enter the nerve endings resulting development of some rare side effects like angio
in reduction or total obliteration of inoculated virus. edema, nephrotic syndrome and anaphylactic
Replication of virus is also prevented by RIG. shock etc. Patients sensitive to other human
Administration of RIGs as part of routine post immunoglobulins products may be sensitive to
exposure prophylaxis is intended to provide a HRIG also. The dose of HRIG is 20 units/kg body
passive source of antibodies before endogenous weight to a maximum of 2000 units.
development of antibodies by the vaccine.
Equine rabies immunoglobulin (ERIG).10,13: It is
Pregnancy and lactation are not contraindication.
produced by immunizing horses with low dose of
The need for RIG appears to be on the rise,
rabies vaccines. The modern automated
because of the ubiquity of human exposure to
ultrafiltration technology saves the time and makes
rabies virus from uncontrolled canine sources in
it safer. Easy availability and low cost are its
developing countries.10,12,13
advantages. Due to presence of foreign protein,
Indications for use of RIGs13 there are chances of immediate hypersensitivity
reaction. It is the main disadvantage of this
All category III bites as per WHO product. It is given in dose of 40 units/kg body
classification. weight with maximum of 4000 units.

38
Administration of RIGs : As much as equine antitoxin (ATS). The half life of TIG is
anatomically feasible the RIG should be infiltrated 4 weeks and significant blood levels are maintained
through, into and around the wound. The upto 14 weeks. As a prophylactic, TIG is given in
remaining portion of the calculated amount of dose of 250 to 500 IU by IM route. It does not
RIG, if any, is to be injected in the deltoid region cause serum sickness like reactions. If TIG is not
in older children and adults or anterolateral aspect available, the use of IVIG may be considered.
of thigh in newborns, infants and young children.
ATS is another preparation used for this
It should be given at a site different from the one
purpose. The standard dose is 1500 IU, injected
where the vaccine is administered. For injecting
subcutaneously after negative skin sensitivity test.
RIG and vaccine separate syringes should be used.
It gives protection for about 7 to 10 days. Being a
If the administration of RIG is delayed, it can be
foreign protein, ATS is rapidly excreted from the
administered up to the seventh day after the first
body and there may be very little antibody at the
dose of vaccine. Caution is needed while injecting
end of two weeks. It may not cover tetanus
RIG in certain tissues like finger pulp as excess of
incubation period in all cases. Therefore, it is less
fluid can result in increased compartment pressure
reliable and not favored for routine use.
leading to necrosis. For small children calculated
dosage of RIG may be insufficient to infiltrate all The infants born to the mothers who have
the wounds. In this situation, RIG should be diluted not previously received 2 doses of tetanus toxoid
with sterile normal saline 2 to 3 fold to permit are exposed to the risk of neonatal tetanus. They
thorough effective infiltration of all the wounds. can be protected by 250 IU of TIG or 750 IU of
In case of ERIG skin sensitivity testing is essential, ATS, if given within 6 hours of birth.
but not required for HRIG.12,13 RSVIVIG: Administration of respiratory syncytial
Tetanus: Tetanus prevention consists of viral IV immunoglobulin (RS-IVIG) is
postexposure administration of vaccine and recommended in dose of 750 mg/kg for protecting
antitoxin following a tetanus-prone injury. Need high risk children against serious complications
is determined by type of injury and history of from RSV disease. Immunoprophylaxis reduces
immunization. Although wounds with major tissue the frequency and total days of hospitalization for
injury are most tetanus prone, any type of wound, RSV infection in high risk infants. These agents
if contaminated, can lead to tetanus. Tetanus are administered monthly from beginning
toxoid vaccine is given immediately if history of (October-December) to end (March-May) of RSV
tetanus immunization is not available, is unsure, season. Another IM preparation is also available
or 60 months have elapsed since previous booster and given in dose of 15 mg/kg. Candidates for
dose. Simultaneous passive immunoprophylaxis immunoprophylaxis include children with lung
is also indicated in these circumstances.10,14 diseases like bronchopulmonary dysplasia and
premature babies to be discharged from hospital
Two types of preparations are available for during RSV season.15,16
this purpose, Tetanus Human Immunoglobulin
Points to remember
(TIG) and Tetanus Antitoxin (Anti tetanus serum
ATS). TIG is a freeze-dried preparation containing Passive immunoprophylaxis has vital role
immunoglobulin mainly IgG obtained from plasma in prevention of certain infections in
or serum from immunized human donors. It is susceptible individuals, used mainly as post
more efficacious, longer acting and safer than exposure prophylaxis.

39
th
Animal derived products are known for (Eds), Nelson textbook of Pediatrics, 16 Edn.
serious reactions. Human derived New Delhi, Harcourt (India) Private Limited,
preparations are safer and are commonly 2000;pp768-776.
used now-a-days. 8. Mahoney FJ, Hepatitis B Virus. In: Long SS,
Pickering LK, Prober CG, Eds, Principles and
Various immunoglobulins are used as Practice of Pediatric Infectious Diseases,
passive prophylaxis for susceptible st
1 Edn, New York, Churchill Livingstone.
individuals against measles, rubella, 1997; pp1193-1202.
hepatitis-A, hepatitis-B, varicella, tetanus, 9. Parthas Immunization digest. Parthasarathy A,
st
rabies, RSV, etc. Certain preparations are Lokeshwar MR, Shah NK, 1 Edn, New Delhi,
recently introduced for clinical use and Jaypee Brothers, 2005; pp41-42.
some are expected in the near future. 10. Dubey AP, Singh S (Eds) IAP Guide Book on
rd
References Immunization (3 Edn) 2005;pp20-21.
11. Arvin AM: Varicella-Zoster Virus In: Long SS,
1. Fischer GW. Prevention of infectious Pickering LK, Prober CG, Eds, Principles and
diseases. In: Long SS, Pickering LK, Prober st
Practice of Infectious Diseases, 1 Edn, New
CG (Eds), Principles and Practice of Pediatric York, Churchill Livingstone 1997; pp1144-
st
Infectious Diseases, 1 Edn. New York, 1154.
Churchill Livingstone 1997; pp44-49.
12. Centres for Diseases Control and Prevention:
2. Immunoglobulins. In: Parks Textbook of Varicella Zoster Immunoglobulin for the
th
Preventive and Social Medicine, 18 Edn. (Ed) prevention of Chicken Pox: recommendations
Park K. Jabalpur. M/s. Banarasidas Bhanot of the immunization practices advisory
2005; pp97-98. committee. Ann Intern Med 1984; 100: 859-
3. Cohn JE, Strong LE, Hughes Jr. Wl, Mulford 865.
DJ, et al. Introduction and research objectives, 13. Ghosh TK. Prevention of Rabies by vaccination
Bull WHO. 1982;60(1):43-47. and immunoglobulin therapy: Some
4. Subbarao EK, Andrews-Mann L, Amin S, et al. controversies and solutions In: Ghosh TK,
Postexposure prophylaxis for measles in a Kalra A, (Eds), Infectious diseases In Children
neonatal intensive care unit. J Pediatr 1990; and newer vaccines. Part-II Agra, 2003: pp171-
117: 782-785. 176.
5. Maldonado YA. Rubeola virus (Measles and 14. Prajapati BS. Prajapati RB. Rabies
subacute sclerosing panencephalitis). In: Long Immunoglobulins in Practice. Bulletin of
SS, Pickering LK, Prober CG (Eds) Principles Infectious Diseases Chapter of IAP.
st
and Practice of Infectious Diseases, 1 Edn, 15. Rathore MH: Clostridium Tetani. In: Long SS,
New York, Churchill Livingstone, 1997; Pickering LK, Prober CG, Eds, Principles and
pp1251-1262. Practice of Pediatric Infectious Diseases,
st
6. Maldonado Y. Ruibella. In: Behrman RE, 1 Edn, New York, Churchill Livingstone 1997;
Kleigman RM, Jenson HB, Eds, Nelson pp1081-1084.
th
Textbook of Pediatrics, 16 Edn, New Delhi, 16. McIntosh K: Respiratory syncytial virus In:
Harcourt (India) Private Limited, 2000; pp951- Behrman RE, Kleigman RM, Jenson HB (Eds),
954. th
Nelson Textbook of Pediatrics, 16 Edn, New
7. Snyder JD, Pickering LK. Viral Hepatitis In: Delhi, Harcourt (India) Pvt. Ltd. 2000; pp991-
Behrman RE, Kliegman RM, Jenson HB. 993.

40
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 BCG is safe and must be given to all newborns.
asymptomatic children is not recommended. However BCG immunization is not recommended
Asymptomatic children should be immunized in in developed countries with a low risk of
accordance with recommended childhood contracting tuberculosis. The most commonly
immunization schedule. Children with used live vaccine is oral polio vaccine. Rider and
asymptomatic or symptomatic HIV infection colleagues reported from Zaire that no serious side
should receive all the killed and conjugate vaccines effects were reported in infants with HIV infection
and toxoids such as DPT, Hep B and Hib according who were given trivalent Sabin vaccine. However,
to the recommended schedule. Patients with HIV use of inactivated poliovirus vaccine (IPV) is
infection have a high risk of infections with generally recommended as this does not carry the
Hemophilus influenzae type b (Hib) and risk for development of paralytic disease.
pneumococcus. So HIV infected patients should
receive Hib and conjugate pneumococcal vaccines. Table 1 summarizes the recommendations
Most evidence supports the idea that immunization for immunizing HIV infected children. In general
with these vaccines should be given early in the children with symptomatic HIV infection have
course of HIV infection. Annual immunization poor immunologic response to vaccine. Hence
with influenza vaccine is also recommended in when these children are exposed to vaccine
HIV infected children. The use of this vaccine preventable disease, they should be considered
has been questioned in patients with more susceptible regardless of the history of
advanced HIV infection because of the risk of immunization and should receive if indicated,
severe disease and likelihood of a poor response passive immuno-prophylaxis or chemoprophylaxis.
to immunization with influenza vaccine in patients. 2. Patients with malignancy
Most experts prefer to give influenza vaccine
thinking that benefits do exceed the risk. The Leukemia is the most common form of
safety of immunization with live attenuated vaccine childhood malignancy. Most of these cases occur
is a matter of concern as discussed earlier; hence before the age of 10 years. Other tumors like
it is necessary to weigh the risk and benefits before Hodgkins and Non Hodgkins lymphoma occur
deciding to administer the live vaccine to the child. more frequently in the age group over 10 years.
Measles vaccine should be given to asymptomatic Hib and pneumococci are important causes of
HIV infected children3 and symptomatic but not infection in patients with hematological
severely immuno-compromised HIV infected malignancies.4 Patients with Hodgkins disease are
children. Severely immuno-compromised HIV frequently splenectomized as part of their diagnosis
Patients with CD4 lymphocyte count less than and therapy making these patients particularly
15% should not receive measles vaccine. Currently vulnerable to disseminated pneumococcal
varicella vaccine is recommended for HIV infected infection. Also these patients are at increased risk
children who have CD4 T lymphocyte count more of invasive Hib disease.4 Antibody response is
than 25% percent (those with no evidence of likely to be best when these patients are
immuno-suppression). WHO currently immunized at least 2 weeks before splenectomy
recommends BCG immunization for all children or before initiation of chemotherapy. During
in developing countries at high risk for tubercular chemotherapy, antibody responses to vaccination
infection including HIV infected children. BCG is are impaired. Immunization is effective if carried
given at birth and no HIV infected child is out 3 months after cessation of chemotherapy or
symptomatic or immuno-deficient at birth. Hence radiation therapy. The immune response to killed

42
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 contraindicated owing to severe side effects in
children undergoing maintenance chemotherapy cancer patients undergoing chemotherapy.
is similar to those of healthy children.5 Oral polio However it can be given 3 months after cessation
vaccine can induce paralytic polio and should be of chemotherapy or before initiating
avoided in children undergoing chemotherapy for chemotherapy.
cancer. Primary varicella zoster virus (VZV) 3. Patients on steriod therapy
infection causes high mortality in children with
malignancy. The available vaccine for protection The degree of immuno-suppression in a child
is live attenuated VZ vaccine. The vaccine has receiving corticosteroids is influenced not only by
been shown to be effective and safe in children the duration, route and dose of steroids but also
with leukemia who are in remission. The by the underlying disease and other concurrent
frequency of side effects from the vaccine is low therapy the patient is receiving. The vaccines other
and the breakthrough disease can be treated with than live viral vaccines may safely be given, and
acyclovir. The sero-conversion rates are 88% after the following guidelines 6 are useful for
one dose and 98% after two doses. The immunity administration of live vaccines in recipients of
is stable for more than 5 years. The risk for herpes steroids.
zoster after vaccination was lower than in patients a) Topical therapy or local injection of
who had natural varicella. Cancer patients who corticosteroids: Usually does not result in immuno-
are infected with measles have a high mortality suppression that would contraindicate
rate. Immunization with measles vaccine is administration of live viral vaccines.
43
b) Physiological maintenance dose of Live viral vaccine may have demonstrated
corticosteroids: Such children can receive live reduced immunogenicity when given shortly
vaccine. before or during few months after receipt of IG.
This has shown to inhibit the response to measles
c) Low or moderate dose of systemic vaccine.7,8 Measles vaccine should be deferred
corticosteroids or an alternate day therapy: for 3 months after Tetanus IG, HRIG, HBIG, IG
Children receiving less than 2 mg/kg per day of administration; for 6-7 months after blood / plasma
prednisolone can receive the live viral vaccine administration and 10-11 months after IVIG
during corticosteroid therapy. administration in the dose of 2gm / kg as in
d) High dose of systemic corticosteroids given Kawasaki disease or ITP.6
daily for less than 14 days: Children receiving less Immunoglobulin preparation also contains
than 2 mg/kg per day of prednisolone for duration rubella, mumps and varicella antibodies. High dose
of less than 14 days can receive live viral vaccine of passively acquired antibodies can inhibit the
immediately after discontinuation of therapy. If response to live rubella vaccination for as long as
there is no urgency it is preferable to delay 3 months.9,10 Administration of rubella vaccine
immunization until 2 weeks after corticosteroids should be postponed for at least 3 months. The
have been discontinued. effect of IG preparation on the response to live
e) High dose of systemic corticosteroids given daily mumps and live varicella vaccine is not studied;
or an alternate day for 14 days or more: Children postponement of mumps and varicella vaccines
receiving more than 2 mg/kg per day of for 3 months and 5 months respectively is
prednisolone should not receive live virus vaccine recommended because of possible interference by
until corticosteroids have been discontinued for administration of IG.
at least 1 month. Immunoglobulin administration should be
Children with a disease that by itself is considered delayed for 2 weeks after MMR and 3 weeks
to suppress immune response and who are after varicella vaccine for adequate antibody
receiving corticosteroids: These children should response to occur.
not be given live vaccines. 5. Immunization of adolescents
4. Immunization of children who recently Adolescence should be considered an
received immunoglobulin appropriate age for top up immunization as well
Administration of immunoglobulin (IG) as administration of certain vaccines which may
preparation has not been demonstrated to cause not have been given earlier. Table 2 shows
significant inhibition of the immune responses to vaccination schedule for adolescents
inactivated vaccines and toxoids. Concurrent 6. Vaccination during outbreak
administration of recommended dose of hepatitisB
immunoglobulin (HBIG), tetanus immunoglobulin Measles outbreak: During outbreak, monovalent
(TIG) or human rabies immune globulin (HRIG) measles vaccine may be given to infants as young
and the corresponding inactivated vaccine or as 6 months of age. Seroconversion rates are
toxoid for post exposure prophylaxis does not significantly lower in children immunized before
impair the efficacy of vaccine and provides the age of 9 months. These infants should receive
immediate and long term immunity. another dose of measles vaccine or preferably

44
Table 2. Vaccination schedule for its safety, high cost, non-availability in large
adolescents 11 quantity and efficacy. The SA 14-14-2 vaccine
produced by China is a live attenuated, cheap and
Vaccine Age
effective vaccine. The vaccine is likely to be used
Tetanus toxoid and Booster at 10 and 16 yrs
in India in endemic areas to prevent outbreaks of
diphtheria (dT)
Japanese B encephalitis in recent future.
MMR 1 dose if not given earlier
Hepatitis B 3 doses (0, 1, 6 months) 7. Immunization for travellers 11
if not given earlier
The risk of travellers contracting infectious
Typhoid vaccine Vi vaccine given every
disease depends on the region/country to be
3 years (other typhoid
visited, duration of trip and nature and conditions
vaccines not available)
of travel. Uniform recommendations are not
Varicella vaccine* 1 dose up to 13 years
possible because the epidemiology of disease differ
2 doses after 13 years
in various geographical areas. The physician should
(if not given earlier)
try to update routine immunization and provide
Hepatitis A vaccine* 2 doses, 6 months apart
destination specific immunizations. For instance,
(if not given earlier)
vaccines commonly recommended for Indian
*If the child has suffered from chicken pox and travellers include yellow fever vaccine for those
Hepatitis A (serological evidence) in the past the intending to go to destinations in South America
respective vaccine need not be given. and sub-Saharan Africa (except for infants less
than 9 months and pregnant women) and
MMR after the age of 1 year. During outbreak, meningococcal vaccine for those intending to go
susceptible children above the age of 1 year should on a Haj pilgrimage. Similarly, visitors coming to
be given a dose of MMR. If MMR vaccine is not India from Western Europe/North America are
affordable or not available, then monovalent usually advised vaccination against typhoid and
measles vaccine may be given. Hepatitis A, especially if the stay is likely to be
prolonged.
Meningococcal outbreak: Because secondary
Points to remember
cases can occur several weeks or more after the
onset of disease in index case, meningococcal All killed vaccines can be given in HIV
vaccine may be offered as a possible adjunct to infected children, irrespective of the clinical
chemoprophylaxis when an outbreak is caused by status. While giving live attenuated
a sero-group contained in the vaccine.6 vaccines, it is necessary to weigh the risks
and benefits.
Japanese B encephalitis outbreak: Vaccination
is the method of choice for prevention of JE. This Patients with malignancies should receive
should ideally be used to prevent the outbreak. vaccines like pneumococcal, influenzae and
Contrary to common belief, this vaccine is not hepatitis B vaccines before starting therapy,
meant to be used as an outbreak vaccine. In India including splenectomy.
after introduction of vaccine in high-risk areas of Patients on prednisolone in a dose of
Andhra Pradesh, cases of JE decreased from 300 2 mg/kg for a period of more than 2 weeks
cases in 2002 to 25 in 2003. The inactivated should be given live vaccines one month
mouse brain vaccine is troubled by issues regarding after discontinuation of the steriods.

45
Vaccines recommended for adolescents in children with acute lymphocytic leukemia
should be administered. after cessation of chemotherapy. Pediatrics
1981;67:222-229.
Immunization for travellers and during out
breaks need the knowledge of local 6. American Academy of Pediatrics 2003 Red
Book: Report of the committee on infectious
epidemiology of the VPDs. th
disease 26 Edn, Elk Grove Village IL,
References American Academy of Pediatrics.
1. OBrien W, Grovit-Ferbas K, Namazi A, et al. 7. Dengler T, Strnad N, Zimmermann R, et al.
Human immunodeficiency virus-type 1 Pneumococcal vaccination after heart and liver
replication can be increased in peripheral blood transplantation. Immune response in
of seropositive patients after influenza immunosuppressed patients and in healthy
vaccination. Blood 1995;86:1082-1089. controls. Dtsch Med Wochenschr 1996;121:
2. Staprans S, Hamilton B, Follansbee S, et al. 1519-1525.
Activation of virus replication after vaccination 8. American Academy of Pediatrics. Measles. In
of HIV-1 infected individuals. J Exp Med Peter G (ed.) 1997 Red Book: Report of the
th
1995;182:1727-1737. Committee on Infectious Disease, 24 Edn, Elk
3. Mclaughlin M, Thomas P, Onorato I et al. Live Grove Village IL, American Academy of
virus vaccines in human immunodeficiency Pediatrics, 1997; pp 344-357.
virus infected children: A retrospective survey. 9. Mauch T, Crouch N, Freese D, et al. Antibody
Pediatrics 1988;82:229-233. response of pediatric solid organ transplant
4. Feldman S, Gigliotti F, Shenep J, et al. Risk of recipients to immunization against influenza
Haemophilus influenza type b disease in virus. J Pediatr 1995;127:957-960.
children with cancer and response of 10. American Academy of Pediatrics. Rubella. In:
immunocompromised leukemia children to a Peter G (ed.) 1997 Red Book: Report of the
th
conjugate vaccine. J Infect Dis 1990;161:926- Committee on Infectious Disease, 24 Ed, Elk
931. Grove Village, IL, American Academy of
5. Van der Does-van den Berg A, Hermans J, Pediatrics, 1997; pp 456-462.
Nagel J and van Steeins G. Immunity to 11. IAP Guide Book on immunization IAP
diphtheria, pertussis, tetanus, and poliomyelitis committee on Immunization 2003-2004.

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
RADIOLOGIST TALKS TO YOU

THE CENTRAL NERVOUS SYSTEM- plexuses in the ventricles. The triangular,


ANATOMICAL BASIS OF symmetrical dark grey structures seen on either
RADIOLOGY side of the midline are the lateral ventricles
(Fig 1). The choroid plexus is easy to note in the
* Vijayalakshmi G
adult and older child as it shows calcification
** Elavarasu E
which appears as a white spot in the posterior
** Porkodi
part of the body of the lateral ventricle. From the
** Malathy K
lateral ventricle the CSF flows down through the
*** Venkatesan MD
foramen of Munro into the third ventricle. This is
In this issue we will start the study of the the small round midline fluid space (Fig 2). It then
central nervous system. Ultrasound, CT and MRI passes through the aqueduct of Sylvius which is
are useful. Let us study the appearances in the very thin and not discernible in CT axial images.
various sections obtained by these imaging CSF in the fourth ventricle is seen as a midline
modalities. For this, we will combine the study of round fluid space. The CSF filled central ventricles
anatomy, physiology and embryology. This kind are easily identifiable and any change or distortion
of approach will help us understand the various in these help in diagnosis.
pathologies of CNS seen in children. If you recall embryology, the cranial part of
the neural tube which forms the brain develops
Water forms the major part of the body and
dilatations that are the future ventricles. The
also determines the appearances of body structure
cerebral cortex and the corpus striatum form
in all types of imaging. The brain is suspended
from the telencephalon and therefore are related
within a waterbath of CSF. The distribution of
to the telencephalic vesicles or the lateral
this extracellular fluid varies in the different
ventricles. So look for these structures on either
anatomical spaces that are enclosed in the cranium,
side of the lateral ventricles. The corpus striatum
varying from a thin film in the normal subdural
or basal ganglia consist of the medial caudate
space to larger collections in the ventricles and
nucleus abutting the lateral wall of the lateral
basal cisterns.
ventricle. The lateral part of the basal ganglia which
As we trace the formation and flow of CSF is the lenticular nucleus is separated from the
we will note the anatomical landmarks that we caudate nucleus by the internal capsule (Fig 1).
see in cranial CT. CSF is formed in the choroid On either side of the third ventricle are the
thalami or the diencephalic structures. Caudal to
* Addl.Professor these is the midbrain. The CSF cavity here is the
** Asst. Professor aqueduct which is not discernible. Therefore look
*** Professor for the colliculi (Fig.3) on the dorsal aspect that
, Department of Radiology, will help you identify this part. This is shaped like
Chenglepet Medical College Hospital, Chenglepet a double U.

47
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 If the flow of CSF down this conduit is
and the medulla oblongata which are the stopped at any point, the proximal part of the
rhombencephalic structures (Fig.4). The folding system dilates. Look at the normal size of the
of the neural tube brings the pons to lie anterior ventricles (in Fig. 1 to 4) See the concave lateral
to the fourth ventricle while the medulla is placed border in the case of the lateral ventricles. When
posteriorly. This is an important relation which the lateral ventricle dilates the outer edge bulges.
will help you to know the site of lesions and The normal third ventricle which is thin and slit
therefore the pathology. like assumes a round shape (Fig.5) when there is
distal obstruction, as in aqueduct stenosis. When
From the fourth ventricle the CSF flows the fourth ventricle also becomes dilated and
through the foramina of Magendie and Luschka more spherical, we can call it tetraventricular
into the subarachnoid space . From the hydrocephalus (Fig.6). This happens when thick
subarachnoid space the fluid is absorbed through basal exudates block the outlets of the fourth
the arachnoid villi into the dural venous sinuses. ventricle or disturb the flow through the arachnoid
The villi consist of projections of fused arachnoid villi.
membrane and endothelium of the sinuses which The central, fluid filled ventricles are readily
act as valves allowing the CSF to flow into the identified and aid in knowing the level of the section
venous sinuses. 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 non tender, firm, hyperpigmented tumorous


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

51
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 2. Shermak MA, Perlman EJ, Carson BS,
have been reported6. Giant Melanocytic Naevus Dufresne CR.Giant congenital nevocellular
with progressive sclerodermoid reaction in a nevus overlying an encephalocele.J Craniofac
newborn has also been described.7 In our case it Surg 1996;7(5):376-383.
was a cutis verticis gyrata like appearance. 3. Cabrere H, Gomez ML, Garcia S. Lipomatous
melanocytic nevomatosis.J Eur Acad Dermatol
Whether the evolution of this unique Venerol 2002;16(4):377-379.
appearance of the lesion in our patient mimicking 4. Martinez-Granero MA, Pascual-Castroviejo I,
the contours of the brain is related to the Roche Herrere MC, Urgelles Fajardo E.
embryological origin of the neuroectoderm is not Neurocutaneous melanosis and congenital
known . It is well known that in some dermal melanocytic nevi.Neurolgia 1997;12(7): 287-
naevi there are neuroid changes in the deeper 292.
parts.The differentiation of these neuroid naevi 5. Schaffer JV, MC Niff JM, Bolognia JL.
from solitary neurofibroma may be difficult in Cerebral mass due to neurocutaneous
Melanosis:eight years later.Pediatr Dermatol
routinely stained sections but distinction may be
2001;18(5):367-377.
possible by immunohistochemistry employing
6. Maldonada R, Orozco L. Desmoplastic
myelin basic protein which is positive only in
hairless hypopigmented nevus:a variant of
neurofibroma.8 These findings support the belief
congenital melanocytic nevi. Br J Dermatol
that dermal melanocytic nevi are hamartomas of 2003;148(6) 1253-1255.
both melanocytic and neural cells. In the etiology
7. Pattee SF, Hansen RC, Bangert JL, Joganic EF.
of melanocytic naevi it is proposed that during Giant congenital nevus with progressive
embryogenesis a morphogenic error in the sclerodermoid reaction. Pediatr Dermatol
neuroectoderm results in the dysregulated growth 2001;18(4):320-324.
and distribution of melanoblasts from the neural 8. Elder D, Elenitsas R. Benign pigmented lesions
crest to the leptomeninges and the integument.9 and malignant melanoma. In: Levers
th
Histopathology of skin 8 Edn. Lippincott-
References Raven, Philadelphia 1997; p 636.
1. Mathur NB, Maria A, Khandpur S, Bala S. Giant 9. Marghoob AA. Congenital melanocytic nevi-
congenital melanocytic nevus with cutis vertis evaluation and management. Dermatol Clin N
gyrate.Indian Pediatr 2001;38:553-556 Am 2002;20:607-616.

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
CASE STUDY

CAVERNOUS SINUS THROMBOSIS conjunctiva and bilateral lateral rectus palsy


A CASE REPORT (Fig.1). The pupils and rest of the CNS
examination were normal except for meningeal
* Arunkumar J signs.
** Lakshmi S
** Kumarasamy K Based on these, a diagnosis of cavernous
** Ravisekar CV sinus thrombosis was made and the child was
** Venkataraman P investigated. Routine investigations revealed
*** Vasanthamallika TK polymorphonuclear leucocytosis. CSF was
normal and blood, pus and CSF culture were
Introduction negative. CT scan showed dilated superior
Intracranial septic venous thrombosis is very ophthalmic vein on the right side. Contrast MRI
rare in the post antibiotic era. It may complicate confirmed the thrombus in the cavernous sinus
meningitis, epidural or subdural abscess or spread (Fig.2).
from extracranial veins. A review of literature
The child showed remarkable improvement
between 1940 and 1988 has identified only 88
with antibiotics (vancomycin and ceftriaxone for
cases. The treatment is controversial and the
three weeks and metronidazole for two weeks)
outcome is fatal in approximately 30% and nearly
and steroids (dexamethasone 0.2mg/kg/dose iv
half have chronic neurological sequelae including
every 8 hours for seven days) and was discharged
oculomotor weakness, blindness, ptosis, proptosis,
with bilateral resolving lateral rectus palsy and
hemiparesis and hypopituitarism.1
partial ptosis on the right side.
Case report
Anticoagulants were not initiated as its role
A four year old boy presented with history is controversial and for the fear of spread of
of furuncle over the bridge of the nose. He also infection as the child had septic foci in the face2.
had swelling in the right periorbital region and low
grade fever. Subsequently, the child became toxic Discussion
with increase of swelling, pain and limitation of Septic facial lesion remain the most frequent
movements of both eye balls. He then developed predisposing infection for intracranial venous
right sided ptosis, mild proptosis, chemosis of thrombosis, the others being infection of sinuses
* Postgraduate and jaw. Staphylococcus aureus is the most
** Asst. Professor common pathogen isolated in nearly two thirds
*** Addl. Professor followed by pneumococci, H. influenzae and
Institute of Child Health and Hospital for Children, anaerobes. Gram negative rods and fungi may be
Chennai - 8. isolated in chronic forms.3

54
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.

Fig. 1. Clinical picture with bilateral squint Corticosteroids are universally used in
and residual ptosis right eye patients treated non surgically.3,5 This does not
prove that steroids influence the morbidity or
The principal symptoms are fever and mortality of cavernous sinus thrombosis but their
periorbital edema initially affecting one eye. use as an adjunctive therapy might partially prevent
Within 24-48 hours the other eye becomes cranial nerve dysfunction caused by
involved through spread from intercavernous inflammation.3,6
sinuses. The classical physical features include There are insufficient data regarding the
ptosis, proptosis, chemosis, oculomotor palsies and indication of anticoagulant therapy2 because the
painful limitation of movements of eyeball. condition is rare. Anticoagulation should be
Depending on the involvement of sixth, third considered only when there is no evidence of
or fifth cranial nerve and sympathetic plexus there cortical venous infarction either clinically or on
may be focal deficits. Contralateral hemiparesis imaging. Early addition of heparin to the primary
results if internal carotid artery is thrombosed. treatment with antibiotics (within seven days of
hospitalization) may reduce the morbidity and
The differential diagnosis includes other mortality in this disease.1 However there is a
causes of periorbital edema: orbital cellulitis, potential danger of hemorrhagic cerebral infarction
carotico-cavernous fistula, idiopathic and enhance spread of infection.
granulomatous inflammation of the superior orbital
fissure and cavernous sinus (Tolosa Hunt Cavernous sinus surgical exposure and
Syndrome), periarteritis nodosa associated with drainage is not recommended because of the high
cerebral venous sinus thrombosis (Cogans risk of damage to vital nerves.
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.
Fig. 2. MRI showing thrombus in the right
The mainstay of therapy is early intravenous cavernous sinus
55
Recent advances in interventional neuro anticoagulants indicated? J Laryngol Otol
radiology and endovascular techniques enable the 2002; 116 (9) : 667 676.
local delivery of thrombolytic agents to selective 3. Migirov L, Eyal A, Kroneberg J. Treatment of
venous channels where thrombosis occur and these cavernous sinus thrombosis. I Med Assn J
newer techniques will undoubtedly be used with 2002; 4: 468469.
increasing frequency in the future for the treatment 4. Verma A, Solbring MV. Infection of the nervous
of cortical venous thrombosis. system. In: Bradley WG, Daroff RB, Fenichel
GM, Jankovic J (Eds). Neurology in clinical
th
References practice, 4 Edn, Vol II, Elsevier, USA. 2004;
pp 1488 1489.
1. Southwick FS, Swastz MN. Inflamatory
thrombosis of major dural venous sinuses and 5. Johanson DL, Markle BM, Wiedermann BL,
cortical veins. In: Wilkins RH, Rengachary SS Hanahan L. Treatment of intracranial
(EDs) Neurosurgery, 2nd Edn,Vol III, McGraw- abscesses associated with sinusitis in children
Hill, USA 1996;PP3307-3308. and adolescents. J Pediatr 1988; 113: 15 23.
2. Bhatia K. Jones NS. Septic cavernous sinus 6. Southwick FS, Richardson EP, Swartz MN.
thrombosis secondary to sinusitis: are 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 nose, fingers and toes leading to multiple scar


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

58
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 nerve growth factor receptor (TrkA) related
disturbances. In: Clinical Pediatric Neurology disorder. Neuropediatrics. 2000;31:39-41.
th
4 Edn. W.B. Saunders Company, Philadelphia 5. Levi-Montalcini R. the nerve grwoth factor.
2001;pp 216-218. Thirty-five years later. EMBO J 1987; 6:1145-
2. Indo Y. Molecular basis of congenital 1154.
insensitivity to pain with anhidrosis (CIPA): 6. Asaumi K, Nakanishi T, Asahara H, Inoue H,
mutations and polymorphisms in TRDA Takigawa M. Espression of neurotrophins and
(NTRK) gene encoding the receptor tyrosine their receptors (Trk) during fracture healing.
kinase for nerve growth factor. Hum Mutat Bone 2000; 26:625-633.
2001;18:462-471. 7. Dyck PJ, Chance P, Lebo R, Camey JA.
3. Swanson AG. Congenital insensitivity to pain Hereditary motor and sensory neuropathies. In:
with anhidrosis. Arch neurol 1963; 8:299-306. Dyck PJ, Thomas PK, Griffin JW, Low PA,
4. Toscano E, Delta Casa R, Mardy S, et al. Poduslo JF (Eds). Peripheral Neuropathy
Multisystem involvement in congenital Vol 2 WB Saunders, 1993;pp1094-1123.
59
8. Greco A, Filla R, Tubine B, Romano L, Penso family with CIPA and pyruvate kinase
D, Piertotti MA. A novel NTRK1 Mutation deficiency. Hum Mutat 2001;18:308-318.
associated to insensitivity to pain with 10. Shatzky S, Moses S, Levy J, et al . Congenital
anhidrosis. IS J Hum Genet 1999; 64:1207- insensitivity to pain with anhidrosis (CIPA) in
1210. Israli-Bedouins. Genetic heterogeneity, novel
9. Indo Y, Mardy S, Miura Y, et al. Congenital mutations in the TRKA/NFG receptor gene
insensitivity to pain with anhidrosis (CIPA): clinical findings and results of nerve
novel mutations of the TRKA (NTRK1) gene, conduction studies. Am J Med Genet
a putative uniparental disomy, and a linkage 2000;92:353-360.
of the mutant TRKA and PKLR genesis in a

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 serology are rather unsatisfactory as will be
advancing illness.6 Overall sensitivity is around discussed later. Blood cultures may actually turn
50 % but drops considerably with prior antibiotic out to be cheaper and very cost effective in the
therapy.5 Failure to isolate the organism may be long run, as positive cultures unequivocally
caused by several factors which includes establish the diagnosis of enteric fever and all other
inadequate laboratory media, the volume of blood investigations for PUO can be safely deferred.
taken for culture, the presence of antibiotics and
the time of collection. For blood culture it is Bone Marrow Culture :
essential to inoculate media at the time of drawing Salmonella typhi is an intracellular pathogen
blood. in the reticuloendothelial cells of the body including
Salmonella can be easily cultured in most the bone marrow.5 Studies have revealed that the
microbiologic laboratories with use of routine median bacteremia in the bone marrow is 9 CFU/
culture media (Hartleys media, Blood agar and ml (IQR, 1 to 85; range, 0.1 to 1,5805) compared
MacConkey agar). Automated blood culture to 0.3 CFU/ml (IQR, 0.1 to 10; range, 0.1 to
systems such as BACTEC certainly enhance the 399) in blood. This bone marrow: peripheral blood
recovery rate. Sufficient amount of blood should ratio which is around 4.8 (IQR, 1 to 27.5) in the
be collected for culture as the median bacterial first week of the illness increases to 158 (IQR, 60
count in the peripheral blood is only 0.3 CFU/ml to 397) during the third week owing to
(inter quartile range 0.1 to 10; range, 0.1 to 399).7 disappearance of bacteria from the peripheral
At least 10 ml of blood in adults and 5ml in blood.7 The overall sensitivity of bone marrow
children should be collected. Dilution should be cultures ranges from 80 95 % and is good even
appropriate in order to adequately neutralize the in late disease and despite prior antibiotic
bactericidal effect of serum and a ratio of 1:5 to therapy.5,11-13
1:10 of blood to broth is recommended. Clot
The invasive nature of bone marrow
cultures, wherein the inhibitory effect of serum is
aspiration deters from its use as a first line
obviated have not been found to be of superior
investigation for diagnosis of typhoid fever. It is
sensitivity as compared to blood cultures in several
however a very useful and valid investigation in
clinical studies.8-10 In the laboratory, blood culture
evaluation of PUO wherein the marrow should
bottles should be incubated at 370 C and checked
be inoculated in the culture bottle at the bedside.
for turbidity, gas formation and other evidence of
growth after 1, 2, 3 and 7 days. For days 1,2 and Stool, Urine and Other Cultures :
3 only bottles showing signs of positive growth
Stool specimen should be collected in a sterile
are cultured on agar plates. On day 7 all bottles
wide mouthed container. Specimens should
should be sub-cultured before being discarded as
preferably be processed within 2 hours after
negative.
collection. If there is a delay the specimen should
There are considerable advantages of routine be stored in a refrigerator at 40 C or in a cool box
blood cultures in investigation of suspected enteric with freezer packs. The sensitivity of stool culture
fever. Not only are they 100% specific, but they depends on the amount of feces cultured, and the
also provide information on the antimicrobial positivity rate increases with the duration of the
sensitivity of the isolate. This is vital in todays illness. Rectal swabs should be avoided as these
scenario of multidrug resistance. Moreover are less successful. Stool cultures are positive in
alternative methods for diagnosis particularly 30% of patients with acute enteric fever.5 For the

62
detection of carriers, several samples should be by Salmonella paratyphi A, paratyphi B, other
examined because of irregular shedding of Salmonella species and other members of the
salmonella. Urine cultures are not recommended Enterobacteriaceae family.20 Antibodies against the
for diagnosis in view of poor sensitivity.5,14 Other O antigen are predominantly IgM, rise early in
methods such as duodenal string and skin snip the illness and disappear early.20 The H antigens
culture of rose spots have been reported to be are flagellar antigens of Salmonella typhi,
more efficacious than blood cultures but are paratyphi A and paratyphi B. Antibodies to H
mainly of academic importance.14-16 antigens are both IgM and IgG, rise late in the
illness and persist for a longer time.19,20 Usually,
Antimicrobial Sensitivity Testing
O antibodies appear on day 6-8 and H antibodies
The crucial issue here pertains to on days 10-12 after the onset of disease. The test
fluoroquinolone susceptibility testing. is usually performed on an acute serum (at first
Fluoroquinolones were introduced in 1989 and contact with the patient). A convalescent serum
during the past decade there has been a progressive should preferably also be collected so that paired
increase in the MICs of ciprofloxacin in titrations can be performed.
Salmonella typhi and paratyphi.5 Since the current
Conventionally, a positive WIDAL test result
MICs are still below the National Committee for
implies demonstration of rising titers in paired
Clinical Laboratory Standards (NCCLS) suscepti-
blood samples 10-14 days apart.19 Unfortunately
bility breakpoint, laboratory reports will continue
this criterion is purely of academic interest.
to report Salmonella typhi/paratyphi as
Decisions about antibiotic therapy cannot wait for
ciprofloxacin/ofloxacin sensitive.17 However use
results from two samples. Moreover antibiotics
of fluoroquinolones in this scenario is associated
may dampen the immune response and prevent a
with a high incidence of clinical failure.5,17 It has
rise in titers even in truly infected individuals.
also been demonstrated that resistance to nalidixic
Therapeutic decisions have to be generally based
acid is a surrogate marker for high ciprofloxacin
on results of a single acute sample. In endemic
MICs, predicts fluoroquinolone failure and can
areas, baseline anti O and anti H antibodies are
hence be used to guide antibiotic therapy (i.e, if
present in the population owing to repeated
culture results show resistance to nalidixic acid
subclinical infections with Salmonella typhi/
irrespective of the results of ciprofloxacin/
paratyphi, infections with other Enterobacteria-
ofloxacin sensitivity, quinolones should not be used
ceae and other tropical diseases such as dengue
or if used high doses should be given).18 Since
and malaria.19-21 These antibody titers vary with
MIC testing is not within the scope of most
age, socio economic strata, urban or rural areas
laboratories, nalidixic acid susceptibility testing is
and prior immunization with the TAB vaccine.
mandatory to help guide choice of antibiotics.
Establishing appropriate cut offs for distinguishing
Serologic Tests acute from past infections is thus important for
the population where the test is applied. In one
WIDAL test : study from Central India, anti O and anti H titer
This test first described by F Widal in 1896, of more than 1: 80 was seen in 14% and 8%
detects agglutinating antibodies against the O and respectively of a study sample of 1200 healthy
H antigens of Salmonella typhi and H antigens of blood donors. 22
paratyphi A and B.6,19 The O antigen is the While interpreting the results of the WIDAL
somatic antigen of Salmonella typhi and is shared test, both H and O antibodies have to be taken

63
into account. There is controversy about the positive typhoid fever, however 14% results would
predictive value of O and H antibodies for be false positive and 10% false negative.21 Hence,
diagnosis of enteric fever. Certain authorities claim it is important to realize the limitations of the
that O antibodies have superior specificity and WIDAL test and interpret the results carefully in
positive predictive value (PPV) because these light of endemic titers so that both over diagnosis
antibodies decline early after an acute infection.23 and under diagnosis of typhoid fever and the
Other studies report a poorer positive predictive resulting consequences are avoided.24
value of O antibodies probably due to rise of these
antibodies in other salmonella species, gram- Other Serologic Tests
negative infections, in unrelated infection and In view of the limitations of the WIDAL test
following TAB vaccination 21. For practical and need for a cheap and rapid diagnostic method,
purpose and for optimal result this test should be several attempts to develop alternative serologic
done after 5-7 days of fever by tube method and tests have been made. These include rapid dipstick
level of both H and O antibodies of 1 in 160 assays, dot enzyme immunoassays and
dialution (four fold rise) should be taken as cut agglutination inhibition tests.25-27
off value for diagnosis. H anitbodies once positive
can remain positive for a long time. Enzyme Immunoassay (EIA) test or
Typhidot? test A dot enzyme immunoassay that
The WIDAL test as a diagnostic modality
detects IgG and IgM antibodies against a 50 KD
has suboptimal sensitivity and specificity.19-21 It
Outer Membrane Protein distinct from the somatic
can be negative in up to 30% of culture proven
(O), flagellar (H) or capsular (Vi) antigen of
cases of typhoid fever. Sub optimal sensitivity
Salmonella typhi is commercially available as
results from negativity in early infection, prior
Typhidot.27 The sensitivity and specificity of this
antibiotic therapy and failure to mount an immune
test has been reported to vary from 70%-100%
response by certain individuals.19 Poor specificity,
and 43% - 90% respectively.28-33 This dot EIA
an even greater problem and is a consequence of
test offers simplicity, speed, early diagnosis and
preexisting baseline antibodies in endemic areas,
high negative and positive predictive values. The
cross reactivity with other Gram-negative
detection of IgM reveals acute typhoid in the early
infections and non-typhoidal salmonella,
phase of infection, while the detection of both
anamnestic reactions in unrelated infections and
IgG and IgM suggests acute typhoid in the middle
prior TAB or oral typhoid vaccination. The purity
phase of infection. In areas of high endemicity
and standardization of antigens used for the
where the rate of typhoid transmission is high the
WIDAL test is a major problem and often results
detection of specific IgG increase. Since IgG can
in poor specificity and poor reproducibility of test
persist for more than 2 years after typhoid
results.19 The slide WIDAL test should also be
infection34 the detection of specific IgG can not
discouraged owing to high rate of false positives.20
differentiate between acute and convalescent
Nowithstanding these problems, the WIDAL cases. Further more, false positive results
test may be the only test available in certain attributable to previous infection may occur. On
resource poor set ups for diagnosis of enteric. In the other hand IgG positivity may also occur in
Vietnam, using a cutoff of >1/200 for the O the event of current reinfection. In cases of
agglutinin or >1/100 for H agglutinin test reinfection there is a secondary immune response
performed on acute-phase serum the WIDAL test with a significant boosting of IgG over IgM, such
could correctly diagnose 74% of blood culture that the later can not be detected and its effect

64
masked. A possible strategy for solving this Vi antigen has been found to be superior to
problem is to enable the detection of IgM by somatic and flagellar antigen and has been
ensuring that it is unmasked 35. The original reported as ranging from 50% to 100% in different
Typhidot test was modified by inactivating the studies.37-40 Similarly specificity estimates have
total IgG in the serum samples. Studies with been reported to vary from 25% to 90%.37-40 The
modified test, Typhidot M, have shown that suboptimal and variable sensitivity and specificity
inactivation of IgG removes competitive binding estimates, inability to detect Salmonella paratyphi
and allows the access of the antigen to the specific infection and Vi antigen negative strains of S typhi
IgM when it is present. are serious limitations of the Vi antigen detection
tests.
The Typhidot M that detects only IgM
antibodies of Salmonella typhi has been reported Molecular Methods
to be slightly more specific in a couple of
studies.26,33 The limitations of cultures and serologic tests
advocate for development of alternative diagnostic
IDL Tubex test The Tubex test is easy to strategies. PCR as a diagnostic modality for
perform and takes approximately 2 minutes typhoid fever was first evaluated in 1993 when
time36. The test is based on detecting antibodies Song et al successfully amplified the flagellin gene
to a single antigen in S. typhi only. The 09 antigen of S typhi in all cases of culture proven typhoid
used in this test is very specific found in only sero fever and from none of the healthy controls.41
group D salmonellae. A positive result always Moreover some patients with culture negative
suggest a salmonellae infection but not which typhoid fever were PCR positive suggesting that
group D salmonella is responsible. Infection by PCR diagnosis of typhoid may have superior
other serotypes like S. paratyphi A give negative sensitivity than cultures. Over the next 10 years a
result. This test detects IgM antibodies but not handful of studies have reported PCR methods
IgG which is further helpful in the diagnosis of targeting the flagellin gene, somatic gene, Vi
current infections. antigen gene, 5S-23S spacer region of the
IgM dipstick test26 The test is based on the ribosomal RNA gene, invA gene and hilA gene
binding of S. typhi specific IgM antibodies to S. of Salmonella typhi for diagnosis of typhoid
typhi lipopolysaccharide (LPS) antigen and the fever.42-50 These studies have reported excellent
staining of the bound antibodies by an antihuman sensitivity and specificity when compared to
IgM antibody conjugated to colloidal dye particles. positive (blood culture proven) and healthy
This test will be useful in places where culture controls. The turnaround time for diagnosis has
facilities are not available as it can be performed been less than 24 hours.
without formal training and in the absence of
These reports should be viewed within the
specialized equipments. One should keep in mind
context of certain limitations. Clinical utility of PCR
that specific antibodies appear a week after the
tests has been inadequately evaluated.
onset of symptoms so the sensitivity of this test
Performance of the test in individuals with febrile
increases with time.
illnesses other than typhoid, in those with past
Antigen detection tests Enzyme history of typhoid, carriers of S typhi, and those
immunoassays, counterimmune electro-phoresis vaccinated with typhoid vaccine is not known.
and co-agglutination tests to detect serum or Patients with a clinical diagnosis of typhoid fever
urinary somatic/flagellar/Vi antigens of Salmonella who are culture negative but PCR positive may
typhi have been evaluated.37-40 Sensitivity of in fact be false positives. Comparison of PCR to
65
bone marrow cultures as a gold standard may be 2. Deshmukh CT, Nadkarni UB, Karande SC. An
a superior way of evaluating the sensitivity and analysis of children with typhoid fever admitted
specificity of these tests, but has not been done. in 1991. J Postgrad Med 1994; 40: 204-207.
The tests claim to detect as few as 10 organisms, 3. Pandey KK, Srinivasan S, Mahadevan S, Nalini
but it should be remembered that in typhoid the P, Rao RS. Typhoid fever below five years.
median bacteremia is 0.3 CFU/ml of blood.7 Using Indian Pediatr 1990; 27: 153-156.
small volumes of blood for DNA extraction may 4. Chiu CH, Tsai JR, Ou JT, Lin TY. Typhoid fever
significantly lower the sensitivity of these tests. in children: a fourteen-year experience. Acta
The cost and requirement for sophisticated Pediatr Taiwan 2000; 41: 28-32.
instruments is also a potential drawback of 5. Parry CM, Hien TT, Dougan G, White NJ, Farrar
molecular methods. JJ. Typhoid Fever. N Engl J Med 2002; 347:
1770-1782.
Conclusion
6. Ananthanarayan R, Panikar CKJ. Textbook of
The complete blood count is the logical first Microbiology. Chennai: Orient Longman
investigation. Presence of a normal or low 1999; 244249.
leukocyte count with eosinopenia points to possible
7. Wain J, Pham VB, Ha V, et al Quantitation of
enteric. It also helps in evaluation of alternative
bacteria in bone marrow from patients with
diagnoses such as malaria, dengue and other typhoid fever: relationship between counts and
bacteremias. Blood cultures remain the most clinical features. J Clin Microbiol 2001; 39:
effective investigations for diagnosis of enteric till 1571-1576.
date. They should be sent early in the course of
8. Hoffman SL, Edman DC, Punjabi NH, Lesmana
the illness and prior to starting antibiotic therapy. M, Cholid A, Sundah S, Harahap J. Bone
Susceptibility testing for nalidixic acid should be marrow aspirate culture superior to
routinely done for all isolates to aid choice of streptokinase clot culture and 8 ml 1:10 blood-
antibiotics. Bone marrow culture is a highly to-broth ratio blood culture for diagnosis of
sensitive diagnostic test even in late stages of the typhoid fever. Am J Trop Med Hyg 1986; 35:
illness and with prior antibiotic therapy. It should 836-839.
be performed in all patients with prolonged pyrexia 9. Simanjuntak CH, Hoffman SL, Darmowigoto
if routine investigations have failed to establish a R, Lesmana M, Soeprawoto, Edman DC.
diagnosis. The WIDAL test has several limitations Streptokinase clot culture compared with
and should be requested for in the second week whole blood culture for isolation of Salmonella
of the illness and its results interpreted with caution. typhi and S. paratyphi A from patients with
Data on baseline titers in the local population enteric fever. Trans R Soc Trop Med Hyg 1988;
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in determining appropriate cut offs for the WIDAL. 10. Escamilla J, Florez-Ugarte H, Kilpatrick ME.
The modified WIDAL test, Typhidot, Tubex and Evaluation of blood clot cultures for isolation
Vi antigen tests need to be evaluated further before of Salmonella typhi, Salmonella paratyphi-A
their routine use can be recommended. Molecular and Brucella melitensis. J Clin Microbiol
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11. Farooqui BJ, Khurshid M, Ashfaq MK, Khan
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Microbiol Infect 1998; 4: 64-69.
19. Olopoenia LA, King AL. Widal agglutination
30. Handojo I, Dewi R. The diagnostic value of the
test - 100 years later: still plagued by
ELISA-Ty test for the detection of typhoid
controversy. Postgrad Med J 2000; 76: 80-
fever in children. Southeast Asian J Trop Med
84.
Pub Hlth 2000; 31: 702-707.
20. Rodrigues C. The Widal test more than 100
31. Bhutta ZA, Mansurali N. Rapid serologic
years old: abused but still used. J Assoc
diagnosis of pediatric typhoid fever in an
Physicians India 2003; 51:7-8.
endemic area: a prospective comparative
21. Parry CM, Hoa NT, Diep TS, Wain J, Chinh evaluation of two dot-enzyme immunoassays
NT, Vinh H, Hien TT, White NJ, Farrar JJ. Value and the Widal test. Am J Trop Med Hyg 1999;
of a single-tube Widal test in diagnosis of 61(4): 654-657.
typhoid fever in Vietnam. J Clin Microbiol 32. Jackson AA, Ismail A, Ibrahim TA, Kader ZS,
1999; 37: 2882-2886. Nawi NM. Retrospective review of dot enzyme
22. Shukla S, Patel B, Chitnis DS. 100 years of immunoassay test for typhoid fever in an
WIDAL test and its reappraisal in an endemic endemic area. Southeast Asian J Trop Med Pub
area. Indian J Med Res 1997; 105: 53-57. Hlth 1995; 26: 625-630.
67
33. Choo KE, Davis TM, Ismail A, Tuan Ibrahim hilA gene in clinical samples from Colombian
TA, Ghazali WN. Rapid and reliable serological patients. J Med Microbiol 2004; 53: 875-878.
diagnosis of enteric fever: comparative
43. Cocolin L, Manzano M, Astori G, Botta GA,
sensitivity and specificity of Typhidot and
Cantoni C, Comi G. A highly sensitive and fast
Typhidot-M tests in febrile Malaysian
non-radioactive method for the detection of
children. Acta Tropica 1999; 72: 175-183.
polymerase chain reaction products from
34. Saha SK, Talukdar SY, Islam M, Saha S. A highly Salmonella serovars, such as Salmonella typhi,
ceftriaxone resistant Salmonella typhi in in blood specimens. FEMS Immunol Med
Bangladesh. The Ped Infect Dis J 1999; 18 : Microbiol 1998; 22: 233-239.
297-303. 44. Chaudhry R, Laxmi BV, Nisar N, Ray K, Kumar
35. Bhutta ZA. Impact of age and drug resistance D. Standardisation of polymerase chain
on mortality in typhoid fever. Arch Dis Child reaction for the detection of Salmonella typhi
1996; 75 : 214-217. in typhoid fever. J Clin Pathol 1997; 50: 437-
439.
36. Lim PL, Tam FC, Cheong YM, Jegathesan M.
One-step 2-minute test to detect typhoid- 45. Zhu Q, Lim CK, Chan YN. Detection of
specific antibodies based on particle separation Salmonella typhi by polymerase chain reaction.
in tubes. J Clin Microbiol 1998; 36: 2271- J Appl Bacteriol 1996; 80: 244-251.
2278. 46. Hashimoto Y, Itho Y, Fujinaga Y, Khan AQ,
37. Rao PS, Prasad SV, Arunkumar G, Shivananda Sultana F, Miyake M, Hirose K, Yamamoto H,
PG. Salmonella typhi Vi antigen co- Ezaki T. Development of nested PCR based on
agglutination test for the rapid diagnosis of the ViaB sequence to detect Salmonella typhi.
typhoid fever. Indian J Med Sci 1999; 53:7-9. J Clin Microbiol 1995; 33: 775-777.

38. Sharma M, Datta U, Roy P, Verma S, Sehgal S. 47. Hirose K, Itoh K, Nakajima H, Kurazono T,
Low sensitivity of counter-current immuno- Yamaguchi M, Moriya K, Ezaki T, Kawamura
electrophoresis for serodiagnosis of typhoid Y, Tamura K, Watanabe H. Selective
fever. J Med Microbiol 1997; 46: 1039-1042. amplification of tyv (rfbE), prt (rfbS), viaB, and
fliC genes by multiplex PCR for identification
39. Pandya M, Pillai P, Deb M. Rapid diagnosis of of Salmonella enterica serovars typhi and
typhoid fever by detection of Barber protein Paratyphi A. J Clin Microbiol 2002; 40: 633-
and Vi antigen of Salmonella serotype typhi. J 636.
Med Microbiol 1995; 43:185-188.
48. Haque A, Ahmed N, Peerzada A, Raza A, Bashir
40. Chaicumpa W, Ruangkunaporn Y, Burr D, S, Abbas G. Utility of PCR in diagnosis of
Chongsa-Nguan M, Echeverria P. Diagnosis of problematic cases of typhoid. Jpn J Infect Dis
typhoid fever by detection of Salmonella typhi 2001; 54: 237-239.
antigen in urine. J Clin Microbiol. 1992; 30 :
49. Massi MN, Shirakawa T, Gotoh A, Bishnu A,
2513-2515.
Hatta M, Kawabata M. Quantitative detection
41. Song JH, Cho H, Park MY, Na DS, Moon HB, of Salmonella enterica serovar typhi from
Pai CH. Detection of Salmonella typhi in the blood of suspected typhoid fever patients by
blood of patients with typhoid fever by real-time PCR. Int J Med Microbiol 2005;
polymerase chain reaction. J Clin Microbiol 295:117-120.
1993; 31:1439-1443.
50. Prakash P, Mishra OP, Singh AK, Gulati AK,
42. Sanchez-Jimenez MM, Cardona-Castro N. Nath G. Evaluation of nested PCR in diagnosis
Validation of a PCR for diagnosis of typhoid of typhoid fever. J Clin Microbiol 2005; 43:
fever and salmonellosis by amplification of the 431-432.

68
Diagnosis of Enteric Fever in light of endemic titers so that both overdiagnosis
and underdiagnosis of enteric and the resulting
1. Contrary to the popular belief leukopenia
consequences are avoided.
perceived as an important diagnostic feature of
typhoid fever is reported only in limited cases. 9. Typhoid test detects IgG and IgM against
outer membrane protein of Salmonella typhi. As
2. Blood culture is the gold standard for
IgG can persist over a long time it is difficult to
diagnosis of typhoid fever. Blood culture can turn
distinguish between acute infection and
out to be cheaper and cost effective in the long
convalescent cases.
run as positive culture unequivocally establishes
the diagnosis and also gives the sensitivity pattern, 10.This test has been improved in modified
thereby helping in the choice of antibiotics. typhidot M test which detects only IgM antibodies.
3. Since MIC is not within the scope of most 11. Other serological tests IDL tubex and
laboratories nalidixic acid sensitivity is a surrogate IgM dipstick test detects only IgM antibodies to
marker of fluoroquinolone sensitivity and nalidixic different S typhi antigens.
acid susceptibility testing is mandatory to help to
12.Molecular methods like PCR are still in
guide the choice of antibiotics.
experimental stage not used in day to day practice.
4. Sensitivity of marrow culture is 80 95
13.The modified Widal test, Typhidot,
% even in late disease and prior to antibiotic
Tubex and Vi antigen tests need to be evaluated
therapy. Marrow should be inoculated in the
further before their routine use can be
culture bottle at bed side.
recommended.
5. Widal is the most widely used test in the
Treatment of Enteric Fever
diagnosis of typhoid fever in our country. It has
poor sensitivity due to its negativity in early The timely appropriate management of typhoid
infection, prior antibiotic therapy may influence it fever, can considerably reduce both morbidity and
and certain individual fail to mount an immune mortality. General supportive measures like use
response to the disease. It should be done after 5- of antipyretics, maintenance of hydration,
7 days of fever by tube method and level of 1 in appropriate nutrition and prompt recognition and
160 for both H and O antibodies are usually taken treatment of complications are extremely important
as diagnostic. for a favorable outcome. The child should
6. Widal test also has poor specificity due continue to have normal diet and no food should
to preexisting base line antibodies in endemic areas. be restricted.
Cross reactivity with other Gram negative In areas of endemic disease 90% or more of
infection and nontyphoidal salmonella, prior typhoid cases can be managed at home with
typhoid vaccination and anamnestic reaction in proper oral antibiotics and good nursing care1.
unrelated infection. Data on base line titers of O Close medical follow up is necessary to look for
and H antibodies should be generated in development of complications or failure to respond
determining the appropriate cut of for Widal test. to therapy.
7. Slide Widal test should be discouraged
Patients with persistent vomiting, inability to
due to high rate of false positivity.
take oral feed, severe diarrhea and abdominal
8. It is important to realize the limitations of distension usually require parenteral antibiotic
the Widal test and interpret the results carefully therapy preferably in a hospital.
69
Antimicrobial Therapy Ciprofloxacin, ofloxacin, perfloxacin and
fleroxacin are common fluoroquinolones proved
Since 1990s Salmonella typhi has developed
to be affective and used in adults. In children the
resistance simultaneously to all the drugs used in
first two are only used in our country and there is
first line treatment (chloramphenicol,
no evidence of superiority of any particular
cotrimoxazole and ampicillin) and are known as
fluroquinolones. Norfloxacin and nalidixic acid
Multi Drug Resistant typhoid fever (MDRTF).
do not achieve adequate blood concentration after
There are some reports of re-emergence of fully
oral administration and should not be used.
susceptible strain to first line drugs2. But these
Fluoroquinolones have the advantage of lower
reports are few and unless antibiotic sensitivity
rates of stool carriage than the first line drugs8.
testing shows the organisms to be fully susceptible
However, fluoroquinolones are not approved by
to first line drugs they are not advocated for
Drug Controller General of India to be used under
empirical therapy in typhoid.
18 years of age unless the child is resistant to all
Fluoroquinolones are widely regarded as the other recommended antibiotics and is suffering
most effective drug for the treatment of typhoid from life threatening infection.
fever3. But unfortunately some strains of S. typhi
have shown reduced susceptibility to Of the third generation cephalosporins oral
fluoroquinolones 4,5. On routine disc testing with cefixime has been widely used in children9,10,11.
the recommended break points, organisms Amongst the third generation cepha-losporins in
showing suspectibility to fluoroquino-lones shows injectable form ceftriaxone, cefotaxime and
poor clinical response to actual treatment. These cefoperazone are used of which ceftriaxone is most
organisms when tested by disc testing with convenient.
nalidixic acid shows resistance to it. So in other Fluoroquinolones like ofloxacin or
words resistance to nalidixic acid is a surrogate ciprofloxacin are used in a dose of 15mg per kg
marker which predicts fluoroquinolones failure and of body weight per day to a maximum of 20mg/
can be used to guide antibiotic therapy. The kg/day.
resistance to fluoroquino-lones may be total or
partial. The nalidixic acid resistant S typhi Of the oral third generation cephalosporins,
(NARST) is a marker of reduced susceptibility to oral cefixime is used in a dose of 15-20 mg per kg
fluoroquinolones. per day in two divided doses. Parenteral third
With the development of fluoroquinolones generation cephalosprins include ceftriaxone 50-
resistance third generation cephalosporins were 75mg per kg per day in one or two doses;
used in treatment but sporadic reports of resistance cefotaxime40 80 mg per kg per day in two or
to these antibiotics also followed 6. three doses and cefoperazone 50-100 mg per kg
per day in two doses.
Recently azithromycin are being used as an
alternative agent for treatment of uncomplicated Azithromycin is used in a dose of 10mg per
typhoid fever 7. kg given once daily for 14 days.
Aztreonam and imipenem are also potential Fluoroquinolones are the most effective drug
third line drugs which are used recently3. for treatment of typhoid fever. For nalidixic acid
There is now considerable amount of sensitive S. typhi (NASST) 7 days course are
evidence from the long term use of fluroquinolones highly effective. Though shorter courses are
in children that neither they cause bone or joint advocated but they should be reserved for
toxicity nor impairment of growth. containment of epidemics. For nalidixic acid
70
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 Bibliography

Multidrug resistamt typhoid cases, resistant 1. Punjabi NH. Typhoid fever. In:Rakel RE, editor
to 1st line drugs, namely chloramohenicol, Conns Current therapy. Fifty second edition.
co-trimoxazole and ampicillin are reported Philadelphia : WB Saunders; 2000:161-165.
since 1990. They need to be treated with 2nd 2. Sood S, Kapil A, Das B, Jain Y, Kabra SK. Re-
line drugs like 3rd generation cephalospotins. emergence of chloramphenicol sensitive
Salmonella typhi. Lancet 1999; 353:1241-
Most of the typhoid cases can be managed 1242.
at home with oral antibiotics and good nursing 3. Parry CM, Hien TT, Dougan G, White NJ, Farrar
care. JJ. Typhoid fever. N Engl J Med 2002;
347:1770-1782.
For severe cases with persistent vomiting, 4. Gupta A, Swarnkar NK, Choudhary SP.
inability to take oral feeds, severe diarrhea, Changing antibiotic Sensitivity in enteric fever.
abdominal distensions parenteral antibiotic, J Trop Ped 2001; 47:369-371.
will be needed preferably in a hospital. 5. Dutta P, Mitra U, Dutta S, De A, Chatterjee M
K, Bhattacharya S K. Ceftriaxone therapy is
Though some strain have shown reemergence ciprofloxacin treatment failure typhoid fever
of sensitivity to first line drugs still it is too in children. In J Med Res 2001; 113:210-213.
early for their recommendation in emperic 6. Saha SK, Talukder SY, Islam M. Saha S. A
therapy. highly Ceftriaxone resistant Salmonella typhi
in Bangladesh. Pediatr Infect Dis J 1999;
The nalidixic acid resistant S. typhi (NARST) 18(3):297-303.
is a marker of reduced susceptibility to 7. Background document : The diagnosis,
fluoroquinolones. treatment and prevention of Typhoid fever.
Communicable Disease Surveillance and
Third generation cephalosporin, both oral and Response, Vaccines and Biologicals. World
injectables are recommended first line Health Organisation. May 2003. WHO/V &
treatment. Of the oral 3rd generation B/03.07.
cephalosporins, cefixime and cefpodoxime 8. Gotuzzo E, Carrillo C. Quinolones in typhoid
fever. Infect D is Clin Pract 1994; 3:345-351.
proxelil are used commonly and of parenteral
9. Bhutta ZA, Khanl, Molla AM. Therapy of
preparation ceflriaxone, cefotaxime, and
multidrug resistant typhoidal salmonellosis in
cefoperazone are used, of which ceftriaxone childhood : a randomized controlled
is most convenient. Oral 3rd generation comparism of therapy with oral cefixime
cephalosporin is to be used in higher dose in versus IV ceftriaxone. Pediatr Infect Dis J
typhoid fever. 1994:13:990-994.
10. Girgis N1, Tribble DR, Sultan Y, Farid Z. Short
Azithromycin is used as an alternative agent course chemotherapy with cefixime in children
in treatment of uncomplicated typhoid fever. with multidrug resistant Salmonella typhi
septicalmia. J Trop Ped 1995; 41:364-365.
Aztreonam and Imepenem are potential
11. Girgis NI, Sultan Y, Hammad O, Farid Z.
second line drugs Comparison of the efficacy, safety and cost of
cefixime, ceftriaxone and aztreonam in the
For life threatening infection resistant to all
treatment of multidrug resistant Salmonella
other recommended antiobiotics typhi septicalmia in children. Ped Infect Dis
fluoquinolones may be used. J 1995; 14:603-605.
72
AUTHOR INDEX

Ajit Saxena (250) Krishna Kumar(61) Rana K S (181)


Alka Sophia Rao (262) Kulandai Kasthuri R (139) Randeep Singh (99)
Anjul (252) Kumarasamy K (322) Rashmi Kapoor (27)
Anuradha D (87) Kush Jhunjhunwala (281) Raveendranath V (319)
Arunkumar J (322) Lakshmi (322) Ravisekar CV (322)
Arun Kumar Manglik (146) Lalitha AV (16) Renu P Kurup (61)
Arun MK (35) Lalitha Janakiraman (92,265) Sandeep Aggarwal (309)
Ashish Bavdekar (232) Mahadevan S (134)
Santosh T Soans (35)
Ashok Pareek (99) Mahesh Babu (110)
Saradambal N (319)
Balachandran A (160) Mahesh Baldwa (155)
Sathyaprakash.M (92)
Balaji V (252) Malathi Sathiyasekaran (79)
Shalini Jain (325)
Baldev S Prajapati (301) Malathy K (246, 316)
Behera M K (181) Meena Jayashankar (87) Sheila Bhave (232)
Bharat Prajapati (190) Meharban Singh (167) Shivbalan So (79,160)
Bhaskar Raju B (79) Mukesh kumar singh (292) Shrishu R Kamath (51,252)
Bhavneet Bharti (6) Muralinath S (262) Shyam Kukreja (309)
Chandralekha K (87) Nammalwar BR (262) Siraj N Huda (250)
Chhangani NP (99) Natarajan B. (85,176) Sood A (181)
Deenadayalan .M (92, 265) Naveen Thacker (221) Sridharan S (256)
Deepali Mankad (74) Nilesh Jain (325) Sri Venkateswaran K (319)
Deshmukh LS (178) Niranjan shendurnikar (292) Subba Rao SD (16)
Dinesh Kumar J (87) Nitin K Shah (197) Subramanyam L (160)
Dutta AK (281) Pangrikar AG (178) Suchitra Ranjit (51,252)
Editorial Board IJPP (95) Parthasarathy A (272) Sujatha L (319)
Elavarasu E (246, 316) Porkodi (246, 316)
Susheela Rajendran (319)
Faisal Haque (250) Pradip Vincent (256)
Sunit Singhi (6)
Farzana.Beg (250) Pramod Sharma (99)
Tapan Kumar Ghosh (239)
Fazal Nabi (74) Purushothaman (319)
Vasanthamallika TK (322)
Ganesh R. (79,92,265) Radha Rajagopalan (252)
Venkatesan MD (246, 316)
Gautam Ghosh (146) Raghupathy P. (123)
Gowrishankar NC (160) Rajal Prajapati (301) Venkataraman P (322)
Gurinder Arora (116) Rajeshwari (252) Vijayakumar M (262)
Imteyaz Ahmad Khan (250) Raju C Shah (190) Vijayalakshmi G (85,176,246, 315)
Indra Shekhar Rao M (208) Ramakrishnan TV (43) Vijayasekaran D. (160)
Janani Sankar (262) Ramalingam A (85,176) Vipin M. Vashishtha (220)
Krishan Chugh (116) Ramesh S (256) Vyas BR (325)

73
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
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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 : ..........................................................................................................