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Indian Pediatr 2015;52:
933-938 |
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Study of Common Illnesses Before and After
Vaccination: A Risk-interval Approach
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Rajeev Z Kompithra, *Rajiv Sarkar, Leni G Mathew, *Jayaprakash
Muliyil and *Gagandeep Kang
From the Departments of Child Health and
*Gastrointestinal Sciences, Christian Medical College,
Vellore, Tamil Nadu, India.
Correspondence to: Dr Rajeev Z Kompithra, Department
of Child Health, Christian Medical
College and Hospital, Vellore, Tamil Nadu, India.
Email:
[email protected]
Received: May 09, 2015;
Initial review: June 04, 2015;
Accepted: August 21, 2015.
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Objective: To compare the proportion of children who developed a
specified illness in the 7 day post-vaccination window, with the
background rate of the same event in the 7 day pre-vaccination
window.
Study design: Risk interval approach
(Self-controlled case-series).
Setting: Well Baby Clinic of Christian Medical
College, Vellore.
Participants: 1602 healthy infants and under-six
children presenting for routine vaccination.
Outcome measures: Episode of any illness.
Methods: The interviewer enquired about any
adverse event or illness experienced by the child for each day of the
week preceding the administration of age-appropriate vaccines. A second
interview (telephonic) was conducted by the same interviewer one week
following vaccine administration to enquire about adverse event(s)
experienced by the child for each day of the subsequent week using a
similar protocol.
Results: With multiple vaccines delivered at
appropriate ages, common childhood illnesses that could be reported as
adverse events following immunization, except fever (RR=5.7, 95%
CI=4.50-7.35), occurred at higher rates pre-vaccination. Risk Ratios of
fever following whole cell (RR=9.3, 95% CI=6.43-13.52) and acellular
(RR=8.5, 95% CI=3.82-18.91) vaccines were similar, with both showing a
decreasing trend with increasing age. The gastrointestinal adverse event
profile [diarrhea (RR=0.6, 95% CI=0.14-2.51) and vomiting (RR=1.0, 95%
CI=0.14-7.10)] for rotavirus vaccine was similar pre- and
post-immunization.
Conclusions: Since most adverse events to vaccines are also
common childhood illnesses, estimating the background rates of common
illnesses is important to accurately ascertain a causal relationship.
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E nsuring safety of vaccines through close
monitoring of adverse events helps build community trust, which in turn
is the key to the success and long-term sustenance of immunization
programs worldwide [1,2]. In particular, acute self-limiting adverse
events following vaccination, some of which are also common illnesses in
children, are the most frequent illnesses ascribed to vaccines [3].
However, other than data from clinical trials, most published evidence
provides limited information about the profile of adverse events,
especially in settings where multiple and combination vaccines are
administered simultaneously according to a routine immunization program.
The objective of this study was to compare the
proportion of children who developed a specified illness in the 7 day
post-vaccination window with the background rate of the same
event in the 7 day pre-vaccination window using a risk-interval
approach, which has the advantage of involving only immunized subjects
[4].
Methods
The study was conducted in the Well Baby Clinic of
Christian Medical College (CMC), Vellore from February 2013 to July
2014. As this is a private tertiary care center, where the caretakers
have to pay out of pocket for vaccines and services, the clientele for
vaccination comprises mostly of the lower and upper middle income groups
living in Vellore and its adjoining districts and states [5].
Study design: The risk-interval (also known as
vaccinated cohort) approach is a special case of the self-controlled
case series (SCCS) design and is a relatively new statistical
methodology to analyze occurrence of acute common self-limiting or rare
events resulting from the administration of a vaccine [4]. This design
differs from traditional methods (cohort, case-control) in that the
classification of exposed and unexposed time intervals occur within the
same individual [4,6]. This allows one to measure the temporal variation
in baseline incidence (pre- and post-immunization) of an illness, while
controlling for all fixed (time invariant) confounders [7]. Moreover,
since cases serve as their own controls, the likelihood of selection
bias between exposed and unexposed subjects is effectively eliminated
[8]. Although this approach has frequently been applied to a single
outcome variable at a time, joint outcomes involving co-administration
of multiple vaccines can also be studied [6]. The statistical power of
this method closely approximates that of a cohort study when the periods
of risk following immunization are short [4,6].
Enrolment: All healthy infants and under-six
children presenting to the Well Baby Clinic for routine vaccination were
eligible to participate. Infants and children were not eligible if they
did not meet the criteria for routine Universal Immunization Program
(UIP) / IAP Schedules for Immunization. Infants on intramuscular, oral
or intravenous corticosteroid therapy, known/suspected case of impaired
immune function, and those with malignancy, chronic diarrhea, growth
faltering, hypersensitivity to any component of a routinely administered
vaccine, fever (axillary temperature > 99ºF [37.2ºC] / oral temperature
>100ºF [37.8ºC] by digital thermometer) on the day of immunization,
progressive/undiagnosed neurological illness or encephalopathy due to
prior vaccine administration were excluded from the study. Before
vaccination, children whose caretakers were unable or unwilling to
recall the adverse events for each of the seven days prior to
vaccination were not included in the study. Other reasons for exclusion
following screening were children who presented with lapsed immunization
that was more than one month overdue, inability to participate due to
upcoming travel, lack of time to complete the interview process and
respond to the phone calls, and lack of access to either a landline or a
mobile phone.
The study protocol was reviewed and approved by the
CMC Institutional Review Board. Written informed consent was obtained
from parents/guardians of the participating children, prior to
enrolment. The protocol required all routine vaccines to be administered
as per the IAP Schedule at recommended ages [9-11].
Recording of illness: Information was
collected on a wide range of commonly reported adverse events following
administration of vaccines using a structured questionnaire.
Following enrolment, the parent/caretaker was asked
whether the infant had experienced any of the specified illnesses in the
seven days prior to the day of immunization. The interviewer enquired
about any adverse event or illness experienced by the child for each day
of the week preceding the administration of the vaccine. A second
interview (telephonic) was conducted by the same interviewer one week
following the vaccine administration to enquire about adverse event(s)
experienced by the child for each day of the subsequent week. A set of
pre-specified questions were asked during both interviews and no probing
questions were asked. Both interviews covered the same set of questions
in the same order. This information was recorded in a confidential
register which also included study serial number, hospital number,
child’s name, mother’s name, telephone number, address and vaccine(s)
given to the child.
All interviews were conducted by nurses working at
the Well Baby Clinic, using standard operational definitions [12-14].
Personnel conducting the interviews were trained at the start of the
study, and periodically thereafter, to ensure uniformity of data
collection. Random check of the interview process was conducted by a
pediatrician working in the Well Baby Clinic to cross-validate the data
collected.
Sample size: Approximately twenty different
relatively common illnesses reported as adverse events were included.
These occur at rates between 1-25% of immunized children depending on
the vaccine and dose. However, the incidence of these events in the
immediate pre-immunization period is unknown. Therefore, a conservative
sample size estimate of 1584 infants was calculated, which had adequate
power to detect an expected 1% prevalence of pre-immunization adverse
events in infants, with a 95% confidence interval (CI) of ±0.5%. Based
on this sample size, it was planned to enroll 1600 children for the
study.
Statistical analysis: Data were analyzed
using STATA for Windows version 10.1 (StataCorp, College Station, TX,
USA). The frequency of adverse events in children pre- and post-
immunization was compared using the chi-square test
or the Fisher’s exact test. For the risk-interval
analysis, the 7 day post-immunization period was considered as the
"exposed" period for each child, whereas the 7 day pre-immunization
period was considered as the "unexposed" period contributing to the
baseline risk. The association between vaccination and the observed
adverse event was investigated using a matched-pair cohort analysis
[15], and risk ratios (RR) with 95% CI calculated. Analysis was
performed for all children at first, followed by stratified analysis
based on the age and the type of vaccine(s) administered.
Results
A total of 2394 children were screened, of whom 1602
children (826 males and 776 females) were included in this study.
Reasons for exclusion included upcoming travel (n=75), lack of
time to complete the interview and respond to phone calls (n=57),
not having access to landline or mobile phone (n=162),
lapsed/overdue immunization (n= 493) and fever (n = 5).
The number of infants and children who were vaccinated at different ages
and included in the study are presented in Table I. Of the
1602 children included in the study, all caretakers could be contacted
within a fortnight post-immunization with 1537, 1586 and 1602 contacted
by the 9 th, 12th,
and 15th day
post-immunization, respectively.
TABLE I Children Vaccinated at Different Ages and Included in the Study (N=1602)
Completed age |
No. |
Vaccine |
6 Weeks |
(114) |
DTwP1, OPV1, IPV1, Hib1, HepB2 |
|
(105) |
DTaP1, OPV1, IPV1, Hib1, HepB2, |
10 Weeks |
(108) |
DTwP2, OPV2, IPV2, Hib2 |
|
(50) |
DTwP2, IPV2, Hib2, Rotavirus vaccine 1 |
|
(99) |
DTaP2, OPV2, IPV2, Hib2 |
14 Weeks |
(110) |
DTwP3, OPV3, IPV3, Hib3, HepB3 |
|
(50) |
DTwP3, IPV3, Hib3, HepB3, Rotavirus vaccine 2 |
|
(107) |
DTaP3, OPV3, IPV3, Hib3, HepB3 |
6 months |
(84) |
Flu vaccine |
9 months |
(110) |
Measles |
1 year |
(110) |
Hepatitis A vaccine |
15 months |
(112) |
MMR and Varicella vaccines |
18 months |
(112) |
DTwP B1, OPV4, Hib B1, IPV B |
2 years |
(111) |
Typhoid vaccine and Hepatitis A |
5 years |
(110) |
DTwP B2 / OPV5 |
|
(110) |
MMR2 and Typhoid 2 |
The number of children who did not report any illness
either pre- or post-immunization were 725 (45.3%) whereas 877 (54.7%)
reported one or more illnesses within 7 days before of after
immunization. Of those who reported having illness around the time of
immunization, 333 (38%) children reported illness during the
pre-immunization period only, whereas 352 (40.1%) reported having
illness during the post-immunization period only; 192 (21.9%) children
reported having illness both during the pre- and the post-immunization
period. The most frequently reported illnesses were upper respiratory
illnesses such as rhinitis (347, 21.7%) and cough (134, 8.4%), fever
(69, 4.3%), and gastrointestinal illnesses (Table II).
None of the children reported hypotonic-hyporesponsive episode (HHE),
seizure, pruritus, difficulty in breathing or breath holding, either
during the pre- or the post vaccination period.
TABLE II Different Illnesses Reported Pre-vaccination and Post- Vaccination, No. (%)
Illness* |
All children (n=1602) |
Infants (n=1047) |
Older children (n=555) |
|
Before |
After |
Before |
After |
Before |
After |
|
vaccination |
vaccination |
vaccination |
vaccination |
vaccination |
vaccination |
Crying |
11 (0.7) |
4 (0.3) |
7 (0.7) |
4 (0.4) |
4 (0.8) |
0 (0) |
Persistent inconsolable screaming |
0 (0) |
2 (0.1) |
0 (0) |
2 (0.2) |
0 (0) |
0 (0) |
Diarrhea |
60 (3.8) |
38 (2.4) |
44 (4.2) |
28 (2.7) |
16 (2.9) |
10 (1.8) |
Vomiting |
50 (3.1) |
24 (1.5) |
40 (3.8) |
16 (1.5) |
10 (1.8) |
8 (1.4) |
Constipation |
26 (1.6) |
2 (0.1) |
20 (1.9) |
1 (0.1) |
6 (1.1) |
1 (0.2) |
Abdominal colic |
3 (0.2) |
3 (0.2) |
3 (0.3) |
3 (0.3) |
0 (0) |
0 (0) |
Drowsiness |
2 (0.1) |
0 (0) |
1 (0.1) |
0 (0) |
1 (0.2) |
0 (0) |
Cough |
134 (8.4) |
57 (3.6) |
94 (9.0) |
42 (4.0) |
40 (7.2) |
15 (2.7) |
Wheezing |
2 (0.1) |
1 (0.1) |
2 (0.2) |
1 (0.1) |
0 (0) |
0 (0) |
Hoarseness |
4 (0.3) |
1 (0.1) |
3 (0.3) |
1 (0.1) |
1 (0.2) |
0 (0) |
Stridor |
0 (0) |
2 (0.1) |
0 (0) |
2 (0.2) |
0 (0) |
0 (0) |
Rapid breathing |
1 (0.1) |
0 (0) |
1 (0.1) |
0 (0) |
0 (0) |
0 (0) |
Rhinitis |
347 (21.7) |
137 (8.6) |
250 (23.9) |
88 (8.4) |
97 (17.5) |
49 (8.8) |
Irritability/Restlessness |
7 (0.4) |
1 (0.1) |
4 (0.4) |
1 (0.1) |
3 (0.5) |
0 (0) |
Rash |
9 (0.6) |
3 (0.2) |
6 (0.6) |
2 (0.2) |
3 (0.5) |
1 (0.2) |
Ear pain |
9 (0.6) |
3 (0.2) |
7 (0.7) |
2 (0.2) |
2 (0.4) |
1 (0.2) |
Fever |
69 (4.3) |
397 (24.8) |
40 (3.8) |
231 (22.1) |
29 (5.2) |
166 (29.9) |
Watery eyes |
1 (0.1) |
0 (0) |
0 (0) |
0 (0) |
1 (0.2) |
0 (0) |
*The following illnesses were not reported, either pre- or
post-immunization: HHE (hypotonic hyporesponsive episode),
difficult breathing, breath holding, seizure, pruritus. |
TABLE III Matched-Pair Analysis of the Risk of Selected Adverse Events Post-vaccination, Relative Risk (95% CI)
|
All children (N=1602) |
Infants (n=1047) |
Older children (n=555) |
Respiratory illnesses# |
0.41 (0.35 - 0.48) |
0.38 (0.32 - 0.49) |
0.46 (0.34 - 0.62) |
Gastrointestinal illnesses$ |
0.52 (0.39 - 0.68) |
0.47 (0.34 - 0.65) |
0.66 (0.38 - 1.13) |
Neurological illnesses‡ |
0.38 (0.11 - 1.24) |
0.75 (0.21 - 2.66) |
- |
Dermatological illnesses^ |
0.33 (0.09 - 1.23) |
0.33 (0.07 - 1.65) |
0.33 (0.03 - 3.20) |
Fever |
5.75 (4.50 - 7.35) |
5.78 (4.18 - 7.98) |
5.72 (3.93 - 8.33) |
Other illnesses** |
0.33 (0.15 - 0.76) |
0.43 (0.17 - 1.06) |
0.14 (0.02 - 1.16) |
#Cough, wheezing, stridor, rhinitis, hoarseness,
rapid breathing; $Diarrhea, vomiting, constipation,
abdominal colic; ‡Persistent inconsolable screaming,
irritability/restlessness, drowsiness; ^ Rash; **
Crying, ear pain, watery eyes. |
When the entire sample size of 1602 vaccinated
infants and children comprising all age groups were analyzed for adverse
events 7 days before and after immunization, the only illness with
significantly higher reporting during the post-immunization period was
fever (RR=5.75, 95% CI=4.50-7.35). On the other hand, gastrointestinal
(RR=0.52, 95% CI=0.39-0.68) and respiratory (RR=0.41, 95% CI=0.35-0.48)
illnesses were significantly lower during the post immunization period (Table
III).
The risk of fever was higher for pertussis containing
vaccines post immunization (RR=9.18, 95% CI=6.55-12.86), the risk being
similar in children given whole cell (RR=9.32, 95% CI=6.43-13.52) and
acellular (RR=8.50, 95% CI=3.82-18.91) vaccines, respectively. When
analyzed age-wise, the frequency of fever was significantly higher
during the post-immunization period at 6 (RR=16.00, 95% CI=6.10-41.98),
10 (RR=12.20, 95% CI=5.11-29.10), 14 (RR=7.09, 95% CI=3.85-13.05) weeks,
at 18 months (RR=6.33, 95% CI=3.24-12.38) and at 5 years (RR=10.40, 95%
CI=4.44-24.35) with the administration of pertussis containing vaccines,
although the risk of fever following immunization showed a decreasing
trend with increasing age.
When analyzed by age separately for whole-cell and
acellular pertussis vaccines, children administered whole-cell pertussis
vaccine tended to have a higher risk of fever than those administered
acellular pertussis vaccine at 6 (RR=20, 95% CI=5-79.97 for whole-cell
and 12, 3.18-45.23 for acellular vaccine) and 14 weeks (RR=8, 95%
CI=3.96-16.17 for whole-cell and 4.67, 1.34-16.24 for acellular
vaccine). At 10 weeks; however, children reported similar risk of fever
with both vaccines (RR=12, 95% CI=4.50-31.97 for whole-cell and 13,
1.98-85.46 for acellular vaccine).
Significantly more children reported having fever
following simultaneous administration of MMR and varicella vaccines at
15 months of age (RR=2.5, 95% CI=1.02-6.15), typhoid and hepatitis A
vaccines at 2 years of age (RR=4.83, 95% CI=2.06-11.35) as well as
typhoid and MMR combination (RR=4.33, 95% CI=1.23-15.21) at 5 years of
age. However, fever was not significantly reported when measles vaccine
(RR=1.86, 95% CI=0.74-4.65) or hepatitis A vaccine (RR=2.00, 95%
CI=0.79-5.04) was given alone at 9 months and 1 year of age,
respectively.
Among infants given rotavirus vaccine at 10 and 14
weeks, the frequency of GI illnesses such as diarrhea (RR=0.60, 95%
CI=0.14-2.51) and vomiting (RR=1.00, 95% CI=0.14-7.10) were comparable
pre- and post- immunization.
Discussion
This study has documented that common childhood
illnesses reported as adverse events following immunization actually
occur at similar or higher rates pre-vaccination, with the exception of
fever.
Expectedly, pertussis-containing vaccine clusters
produced significant fever post-vaccination, although the decrease in
relative risk with increasing age is contrary to what has earlier been
reported [16,17]. When whole and acellular DPT vaccine combinations were
analyzed separately by age, the risk of fever was not found to be as
markedly different as previously reported [17-20]. On the other hand,
the typhoid Vi-polysaccharide vaccine when administered in combination
with hepatitis A was observed to be more pyrogenic, than when
administered alone, as observed earlier in Indian children [21].
All the study subjects were vaccinated on the day of
appointment, despite their recent history of minor illness. Yet, the
significant decline in all adverse events except fever, in the post
immunization period suggests the possibility of a "healthy-vaccinee
effect" (postponement of immunization due to illness of infant or child
in the recent past) [8,22,23]. It has been hypothesized that this
healthy-vaccinee effect may occasionally result in lower background
rates of adverse events and illnesses in the immediate post-vaccination
period [8, 24]. Nevertheless, the study shows that none of these events,
except fever, have been precipitated or aggravated by vaccination.
This study has several limitations. It was conducted
in a clinic setting where mostly children of affordable caretakers avail
of vaccines and services. Also, only caregivers who were able to recall
their child’s adverse event during the pre-immunization period were
interviewed. These may have resulted in this cohort not being
representative of all children in the community. However, this lack of
representativeness is unlikely to affect the overall study findings,
given the study design. Additionally, restricting study participation to
such respondents significantly enhanced compliance to protocol, with no
dropout. This study was powered to detect illnesses with a 1% or higher
prevalence, but some of the illnesses were reported at a much lower
frequency than expected, for which the sample size was inadequate. Since
the study was designed to ascertain the adverse events profile of a
cluster of vaccines as administered in a routine immunization schedule,
the contribution of individual vaccines could not always be delineated,
although this has been attempted to, where possible. Also, caregivers’
decision to not opt for certain vaccines such as the pneumococcal
conjugate vaccine (PCV) due to their high cost made it difficult to
profile their adverse events. Further, telephonic interview of the
caregivers, post-vaccination, could potentially have introduced a
reporting bias. Previous studies have; however, shown that telephone
encounters can substantially contribute to the detection of possible
local and systemic vaccination reactions [25-27]. Moreover, the same
nurse who recorded the pre-immunization illness history also conducted
the telephonic interview.
A large proportion of events ascribed to and reported
as adverse events due to vaccine administration are actually common
illnesses in children, coinciding with vaccination. This study
highlights the importance of estimating the background rates of common
illnesses to accurately ascertain a causal relationship. Large scale
studies using similar methodology need to be conducted among infants and
children in diverse settings in India for a more accurate estimation of
vaccine attributable risk.
Acknowledgements: Staff of Well Baby Clinic and
Wellcome Trust Research Laboratory, Christian Medical College, Vellore.
Contributors: RZK: patient enrolment, data
acquisition, data analysis and drafting of the manuscript; RS: data
analysis and drafting of the manuscript; LGM, JM and GK:
conceptualization, data analysis, interpretation and critical review of
the manuscript. All the authors were involved in preparation of the
manuscript.
Funding: Internal fluid research grant, Christian
Medical College, Vellore.
Competing interests: None stated.
What is Already Known?
• The adverse event rates of a single or one
combination vaccine, with background rates not factored in.
What this Study Adds?
• Common childhood illnesses reported as
adverse events following immunization were documented at similar
or higher rates pre-vaccination, with the exception of fever.
|
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