A SIDE EFFECT OF VACCINATION

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					 CONTINUING EDUCATION SERIES
 ONCOLOGY/IMMUNOLOGY




                          This CE is published through an unrestricted educational grant from
                                                 Bristol-Myers Squibb.




          Side Effects of Vaccination:
    A Consumer’s Guide to Cause and Effect
                                                    John D. Grabenstein, RPh, PhD, FASHP




I
      got vaccinated four weeks ago. I                Credit — This lesson is good for 0.2 CE units, with a passing grade of
      got sick two weeks ago. Are the                 70%.
      two events related? The two
      events are related in time, cer-                Objectives
tainly. But do the vaccination and the                1. To describe historical examples of adverse events truly and spurious-
illness have a cause-and-effect relation-                ly associated with vaccination.
ship? Investigating relationships                     2. To describe a rational basis for deciding whether adverse events are
between vaccines and adverse events                      causally or coincidentally linked to a medication.
is important, to keep people healthy.If               3. To demonstrate how to apply this rational basis to a variety of
a vaccine does cause an adverse reac-                    exposure—outcome associations.
tion, we need to find out as soon as
possible and respond appropriately.                   Key Words — adverse events, causality, immunization, side effects,
     But jumping to the conclusion                    vaccines
that two events are causally related is
scientifically improper. Jumping to a
conclusion can also delay finding the
true cause of an illness. For example,              complicated, intricate social endeav-     evidence, and consider conflicting
assuming that egg allergy was linked                ors that require vast amounts of ener-    lines of argument. What caused the
to anaphylaxis after measles–                       gy (eg, time, labor, money) to set in     adverse effect? Did the vaccine pre-
mumps–rubella (MMR) vaccination                     motion and sustain.                       cipitate the event, or was it an inno-
may have delayed recognition of the                      Making an ill-founded claim          cent bystander? To render a verdict,
role of gelatin allergy.1–2                         about vaccine safety is like pulling      what evidence does the court of sci-
     Vaccination programs provide                   the stop cord on a moving train. It is    ence need?
great public benefit, both to individu-             certainly possible to bring a vaccina-         A good example of the objective,
als and to communities. By several                  tion train to a complete halt, if need-   analytical approach is the prompt
measures, vaccines provide more                     ed. But such a drastic measure should     assessment in 1999 of rotavirus vac-
benefits than any other medical inter-              follow objective analysis, not unsub-     cine as a cause of intussusception.5–6
vention.3–4 Vaccination programs are                stantiated criticism. The energy          Clinical trials detected intussuscep-
                                                    required to get the train rolling again   tion in both the vaccine and placebo
                                                    leads us to want solid evidence,          groups, enough to warrant mention
*Directorate of Health Care Operations, U.S.        rather than false alarms.                 in the package insert, but not a risk
Army Medical Command, 5111 Leesburg Pike,                                                     sufficient to withhold licensing. The
Falls Church, VA 22041.                             SIDE-EFFECT DETECTIVES                    sentinel surveillance program within
    The opinions or assertions contained here-          As we investigate the relation-       the Vaccine Adverse Event Reporting
in are the private views of the author and are
not to be construed as official or reflecting the
                                                    ship between a vaccine and an             System (VAERS) identified more cases
views of the US Department of the Army or the       adverse event, we collect clues, sift     of intussusception than expected,
Department of Defense.



1308        Volume 35, December 2000
Oncology/Immunology CE Series




                                      TABLE 1                                                  I know several people who
                                                                                          reached erroneous conclusions
             Steps in Assessing Cause-and-Effect Relationships                            about their health after being told
                                                                                          their blood work yielded a positive
  Step 0. Gather Information.                                                             antinuclear antibody (ANA) test. An
  If considering an individual case, gather objective information about the person
  and the condition of interest, to use in later steps. Confirm the diagnosis. Con-
                                                                                          ANA value can be used to assess sys-
  firm exposure to the medication of interest.                                            temic lupus erythematosus (SLE), an
  Step 1. Already Acknowledged?
                                                                                          autoimmune disease. These people
  Find out whether recognized experts already concede that the vaccine (medica-           assumed that they had an autoim-
  tion) causes the effect (see also Table 2).                                             mune disease solely on the basis of
  Step 2. Novel Event?                                                                    one ANA test. It takes less time to
  Is the condition novel, unique, never reported before? New syndromes are rare.          reach that conclusion than to learn
  Step 3. Determine Baseline.                                                             the intricacies of the ANA test,
  If not novel, determine how often the symptom or condition or disease affects           including its propensity for false-neg-
  the general population (preferably a corresponding population of the same age).         ative and false-positive results.
  Step 4. Compare Vaccinated to Unvaccinated.                                             Indeed, the main use of ANA tests
  Leveling the playing field as much as possible, compare the occurrence of the           may be to exclude SLE as a diagnosis.
  symptom or condition among vaccinated people to its occurrence among unvac-             With the disease, the test is positive
  cinated people.
                                                                                          95% of the time.Without the disease,
  Step 5. Full Analysis.                                                                  the test is positive 50% of the time.
  If the baseline rate of occurrence is not known, then use criteria for cause-and-
  effect relationship proposed by Robert Koch and further refined by Sir Austin
                                                                                          In other words, a negative test has
  Bradford Hill and others38 (see also Table 3).                                          more meaning than a positive test.7
                                                                                               Similarly, one should confirm
                                                                                          exposure to the vaccine by checking
                                                                                          dates of vaccination and lot numbers,
enough to warrant a public warning           cerns about adverse events? This arti-       for example. I have talked with sever-
and to commission controlled stud-           cle suggests a five-step method              al military personnel and their fami-
ies. Those controlled studies revealed       applicable to vaccines and other             lies concerned about the adverse
an attributable risk of one case of          medications (Table 1).                       effects of anthrax vaccine they
intussusception per 5,000 to 12,000                                                       received during military basic train-
vaccine recipients.                          STEP 0: GATHER INFORMATION                   ing. The irony here is that anthrax
      An objective approach is not the            Begin with Step 0 if you are            vaccine is not administered during
only one available. Holding rigidly to       investigating the health of a particu-       basic training, so any adverse events
a “vaccines can do no harm” philoso-         lar person. If not, and you are consid-      in that setting certainly would be mis-
phy is one approach, but an inappro-         ering adverse events in a broader per-       attributed if blamed on anthrax vac-
priate one. Similarly, assuming that a       spective, proceed directly to Step 1.        cine.
vaccine causes harm before the facts         Ultimately, that broader perspective              After individual exposure and
support this conclusion is also inap-        relies on the validity and veracity of       clinical data are collected and consid-
propriate. Examples of recent, well-         the individual clinical cases that pop-      ered, proceed to Step 1.
publicized, unsubstantiated claims           ulate it. So, the reliability of the indi-
appear below.                                vidual cases is key.                         STEP 1: ALREADY
      This article focuses specifically           For Step 0, gather objective infor-     ACKNOWLEDGED?
on vaccines, but this approach to rea-       mation about this individual who                 Step 1 applies information that
soning applies to all medications and        interests you. Confirm the diagnosis.        science has already accumulated, and
many environmental exposures. Does           Distinguish objective signs or values        for which there is consensus. Do rec-
fluoxetine lead to suicide? Does silde-      from subjective symptoms. Ask about          ognized experts already concede that
nafil cause heart attacks? Do cellular       pre-existing conditions. Collect             the vaccine causes the adverse effect
telephones cause brain cancer? Do            appropriate laboratory data. See if          in question?
power lines cause leukemia? These            signs or symptoms appeared before                Vaccines have been administered
and analogous questions of this sort         vaccination. Ask what specialists or         since Edward Jenner gave smallpox
can be addressed in a similar manner.        subspecialists had been consulted,           vaccination in 1796. With over 200
      So, how should we evaluate con-        and so on.                                   years of experience, medicine has


                                                                                                    Hospital Pharmacy     1309
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                                                                    TABLE 2

                                          Summarized Version of the Vaccine Injury Table

 Vaccine contents                     Illness, disability, injury,                           Time period for first symptom
                                      or condition covered                                   or manifestation of onset or of
                                      (acute complications refer to                          significant aggravation after
                                      complications of conditions listed                     vaccine administration
                                      in this column)
                                                                                             Limit for                    Limit for
                                                                                             Compensationa                Reportingb
 Tetanus toxoid (eg,                  Anaphylaxis and anaphylactic shock                     4 hours                      7 days
 DTaP, DTP, DT; Td, TT)               Brachial neuritis                                      2–28 days                    28 days
                                      Any acute complication (including death)               Within period specified
 Whole-cell pertussis                 Anaphylaxis and anaphylactic shock                     4 hours                      7 days
 bacteria or specific                 Encephalopathy (or encephalitis)                       72 hours                     7 days
 pertussis antigen(s)                 Any acute complication (including death)               Within period specified
 (eg, DTaP, DTP, P, DTP-Hib)
 Measles, mumps, or                   Anaphylaxis and anaphylactic shock.                    4 hours                      7 days
 rubella viruses (eg, MMR,            Encephalopathy (or encephalitis)                       5 to 15 days                 7 days
 MR, M, R)                            Any acute complication (including death)               Within period specified
 Measles virus (eg, MMR, MR, M) Thrombocytopenic purpura                                     7–30 days                    30 days
                                Vaccine-strain measles viral infection                       6 months                     6 months
                                in an immunodeficient recipient
                                Any acute complication (including death)                     Within period specified
 Rubella virus (eg, MMR, MR, R)       Chronic Arthritis                                      7-42 days                    42 days
                                      Any acute complication (including death)               Within period specified
 Live poliovirus (OPV)                Paralytic Polio
                                      —in a non-immunodeficient recipient                    30 days                      30 days
                                      —in an immunodeficient recipient                       6 months                     6 months
                                      —in a vaccine-associated community case                No limit                     No limit
                                      Vaccine-strain polio viral infection
                                      —in a non-immunodeficient recipient                    30 days                      6 months
                                      —in an immunodeficient recipient                       6 months                     No limit
                                      —in a vaccine-associated community case                No limit                     No limit
                                      Any acute complication (including death)               Within period specified
 Inactivated poliovirus (eg, IPV)     Anaphylaxis and anaphylactic shock                     4 hours                      7 days
                                      Any acute complication (including death)               Within period specified
 Hepatitis B vaccines                 Anaphylaxis and anaphylactic shock                     4 hours                      7 days
                                      Any acute complication (including death)               Within period specified
 Haemophilus influenzae               Early-onset Hib disease                                7 days                       7 days
 type b polysaccharides               Any acute complication (including death)               Within period specified
 (unconjugated, PRP vaccines)
 Haemophilus influenzae               No condition specified                                 Not applicable
 type b polysaccharide
 conjugates
 Varicella virus                      No condition specified                                 Not applicable
 Rotavirus                            No condition specified                                 Not applicable
 a
  Claims may also be filed for a condition with onset outside the time intervals or a condition not included in this table. Information on fil-
 ing a claim may be obtained by calling 800-338-2382 or at www.hrsa.gov/bhpr/vicp.
 b
   From the Reportable Events Table, 42 USC 300aa-25, which lists conditions reportable by law. Events described in the manufacturers’
 package insert as contraindications to additional doses of a vaccine must also be reported. Individuals are encouraged to report any clini-
 cally significant or unexpected events (even if not certain the vaccine caused the event) for any vaccine, whether or not listed here. To
 report call 800-822-7967 or go to www.fda.gov/cber/vaers/report.htm.

 Source: Vaccine Injury Compensation Program, version of October 1998, www.hrsa.dhhs.gov/bhpr/vicp/table.htm




1310      Volume 35, December 2000
                                                                                   Oncology/Immunology CE Series




                                          TABLE 3                                         observed in dogs given repeated
                                                                                          injections of a toxin derived from the
      Intricate Criteria for Assessing Cause-and-Effect Relationships                     sea anemone.9 The death of an Egypt-
                                                                                          ian pharaoh from a wasp sting,
  1. How strong is the association between the exposure and the outcome?                  recorded in hieroglyphics around
  2. What is the quality of the evidence for an association?                              2640 BC, is the oldest known report
  3. Is there a dose-response relationship?                                               of anaphylaxis. Anaphylaxis, also
  4. Is there consistency among several studies?                                          called “serum shock,” was increasing-
  5. Is there a specific cause for the effect observed?
                                                                                          ly recognized in the early 1900s as
                                                                                          equine antitoxins and sera became
  6. Did the cause exist before the effect occurred?
                                                                                          common modes of treating infec-
  7. Is the outcome plausible, given what we know about biology?                          tious diseases.14
  Source: Adapted from Rothman & Greenland38                                                  “Serum sickness” (Serumkran-
                                                                                          kheit) was a novel diagnosis when it
                                                                                          was associated with injections of ani-
                                                                                          mal sera in 1905 by von Pirquet and
assembled considerable understand-             listed on the Vaccine Injury Table        Schick.14 The symptoms that com-
ing of adverse events to consider              appear in Table 2.                        prise serum sickness (eg, edema,
after vaccination.                                  In some cases, patient advocacy      fever, urticaria, maculopapular rash,
     We understand quite well that             groups may make a point of disavow-       myalgia) had certainly been recog-
injection of any vaccine can result in         ing a purported link between vacci-       nized in the 1890s with repeated
swelling, redness, and soreness at the         nation and an adverse event. For          injections, but the convergence of
injection site.8 We should acknowl-            example, the National Multiple Scle-      these individual symptoms into a
edge that people also report                   rosis Society and the World Health        consistent syndrome, even with the
swelling, redness, and soreness after          Organization agree that there is no       first injection, became widely
injection of isotonic sodium chloride.         reliable evidence for a link between      acknowledged in the early 1900s.2,14
This suggests that at least some injec-        hepatitis B vaccination and multiple           Scientists recognized in the
tion-site symptoms are related to the          sclerosis.11–13                           1960s that 20% to 30% of the women
mechanical process of depositing a                  An adverse-event controversy         who took the sedative thalidomide
volume of fluid within a muscle or             rarely involves a case where vaccine      during pregnancy delivered children
subcutaneous space.                            advocates acknowledge causality.          with limb and organ deformities.
     More rarely, vaccine recipients           Accepted warnings form the basis          Aside from the increased rate of birth
can have a severe allergic reaction to         for the indications and contraindica-     defects, it was the pattern of birth
vaccination, such as anaphylaxis or            tions of vaccine product inserts. To      defects of the limbs (phocomely) that
anaphylactic shock.9 Anaphylaxis can           consider the matter further, pro-         was unusual, almost unprecedent-
also be caused by peanuts, penicillin,         ceed to Step 2.                           ed.15
and other agents, of course. But exist-                                                       When veterans of the Persian
ing data, plus the rapid time course           STEP 2: NOVEL EVENT?                      Gulf War returned home, some
between exposure and reaction,                     Is the adverse event in question      reported symptoms and illnesses that
leave little doubt that anaphylaxis            novel? Has it ever been reported          raised questions about the health
shortly after vaccination is associated        before? Step 3 asks if the symptom or     consequences of their service. After
in a causal way. When anaphylaxis              disease is unique, one-of-a-kind.         considerable inquiry, illnesses among
happens within minutes of a vaccina-               New adverse events are rare.          Gulf War veterans are generally
tion there are few alternate explana-          None of the recent allegations of         acknowledged by scientists as not
tions.                                         harm after vaccination is a novel         being qualitatively unique. No unique
     Some other adverse events are             event. The allegations regard the link-   syndrome or set of syndromes has
presumed to be caused by a vaccine             age between the adverse event and         been found. In other words, these vet-
after a vaccination. The more serious          the vaccination, not the novelty of       erans develop the same symptoms
of these events are included in the            the adverse event itself.                 and diseases as people who did not
Vaccine Injury Table, the list used in             Anaphylaxis was “new” in 1902         deploy to the Persian Gulf. It also
the Vaccine Injury Compensation                when Portier and Richet coined the        does not appear that these veterans
Program.10 Adverse events currently            term to describe a syndrome they          die or develop disease more often


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than people who did not serve in the        might wonder whether the vaccine           STEP 4: COMPARE
Persian Gulf,16–19 but that is a question   offered some protection against GBS.       VACCINATED TO
more properly considered by the             Conversely, if the GBS rate among          UNVACCINATED
methods described at Step 3 and Step        vaccinated people was much more                 For Step 4, leveling the playing
4.                                          common than once per 62,000, we            field as much as possible, compare
     If the condition or disease was        should wonder whether vaccination          the rates of adverse events among
unrecognized before people started          increases the risk of contracting GBS.     vaccinated people and unvaccinated
being immunized with a particular                The same logic applies to other       people. For example, we would find
vaccine, then the likelihood of a           adverse events. Between 6% to 10%          evidence for an association between
cause-and-effect relationship rises.        of unvaccinated pregnant women             vaccination and Guillain-Barré syn-
This situation is very rare. In such a      will spontaneously miscarry their          drome only if the rate among vacci-
rare case, we would consider other          fetuses.21 With this rate as a starting    nated people was substantially high-
criteria, as discussed in Step 5.           point, we then expect that 6% to 10%       er than once per 62,000 people per
     The more common situation,             of vaccinated pregnant women               year.
however, is that unvaccinated people        would miscarry. Similarly, we need to           A slightly elevated rate of GBS
get a given illness too.Which leads us      know how often heart attacks,              has been associated with influenza
to Step 3.                                  leukemia, thyroid disease, diabetes, or    vaccine in some years (eg, 1976,
                                            any other event happens among              1992, 1993), but not in most years.
STEP 3: DETERMINE BASELINE                  unvaccinated people.                       The risk of GBS was 2 to 8 cases per
     The more common situation will              The ideal situation is to know        million influenza vaccine recipients
be that the adverse event in question       how often the adverse event hap-           higher in those three years than the
is not novel, not unique. In that case,     pens among people who share every          background incidence rate. In other
Step 3 asks how often the symptom           other risk factor except vaccination.      years, the GBS rate was essentially the
or the disease affects people unex-         In other words, the comparison             same among people vaccinated or
posed to the medication of interest.        group should have the same age dis-        unvaccinated against influenza. GBS
For vaccines, Step 3 asks how often         tribution, gender mix, health status,      does occur in people recently immu-
unvaccinated people contract or             and other personal characteristics as      nized with other vaccines. In isolated
develop the symptom or disease.             people who get the vaccine. Return-        individuals, GBS recurred with revac-
     To illustrate, we will consider        ing to the GBS example, it might help      cination.22 But other vaccines have
Guillain-Barré syndrome (GBS). GBS          to know the specific incidence rates       not been found to induce a rate of
is a demyelinating disease that dam-        of GBS among adolescents, 20- to 45-       GBS higher than baseline.
ages nerves,causing temporary weak-         year-old adults, or people 65 and               Step 4 is the critical step where
ness. From 80% to 85% recover fully         older, depending on the specific com-      many purported links between
from GBS.About two-thirds of all GBS        parison being made. This helps com-        adverse event and vaccine fail to
cases are provoked by an acute infec-       pare apples to apples.                     meet objective, scientific standards.
tion, at a rate of about once per                If reliable data do not exist, then   For example, brain damage (ie, chron-
62,000 people per year. GBS clearly         scientists and health officials have a     ic encephalopathy) after whole-cell
occurs in the absence of vaccination.       responsibility to determine the base-      pertussis vaccination does not sub-
Indeed, the Centers for Disease Con-        line. Only from the baseline can ele-      stantially differ among vaccinated
trol and Prevention (CDC) reports           vations above baseline be recog-           and unvaccinated children.22–25 This
that more than 99% of people who            nized.                                     alleged side effect, which launched
contract GBS were not vaccinated                 Whenever the symptom or con-          much of the current antivaccine
during the weeks before vaccina-            dition happens in people who have          movement, has no substantiated basis
tion.20                                     not been vaccinated, then the burden       in scientific fact.
     If the background rate of GBS is       of proof in our “court”is to show that          Similarly, sudden infant death
one among 62,000 unvaccinated peo-          the condition happens more often in        syndrome (SIDS) occurs no more
ple per year, then we begin by              vaccinated people than unvaccinated        often in the interval shortly after
expecting GBS to occur once per             people. Step 3 establishes the essen-      infant vaccination than in compara-
62,000 vaccinated people per year           tial baseline that permits the critical    ble intervals before or after vaccina-
also. If the rate was much less com-        comparison step, Step 4.                   tion. Indeed, the rate of SIDS fell in
mon than once per 62,000, then we                                                      the US as infant vaccination rates




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increased, but without a cause-and-        confounding effects that imperil sim-        being fully isolated from the body
effect relationship. The fall in SIDS      ple comparisons.Workshops at Johns           and repeatedly grown in pure cul-
cases is more properly attributed to       Hopkins University and the National          ture, it can induce the disease anew.37
the recommendations to put infants         Institute for Allergy and Infectious              Henle and Koch did not consider
“back to sleep,” rather than on their      Diseases found no basis for a cause-         the world beyond microbiology, so
stomachs.2,24                              and-effect link between diabetes and         their list was short. Their postulates
      On the other hand, people            vaccination.29–30 In addition, the inves-    have been augmented and refined
exposed to oral poliovirus vaccine         tigators of a study upon which the           over the years, perhaps most notably
(OPV) are certainly subject to a high-     assertions are based recently pub-           by Sir Austin Bradford Hill, leader of
er risk of paralytic poliomyelitis than    lished results showing there is no           the team that advanced our under-
people not exposed to OPV.The asso-        association between vaccination and          standing of the link between tobacco
ciation is very rare, about once per       diabetes.31 Similarly, other researchers     and lung cancer and cardiovascular
2.4 million doses, but it is a true        have not found an increased risk of          disease.Hill suggested nine aspects of
cause-and-effect relationship.22,26        diabetes associated with vac-                an exposure-outcome association to
      Leveling the playing field to        cination.32–36                               help distinguish causal from non-
assess side effects is easier said than         If there is no increased rate of ill-   causal associations: (1) strength of
done. A proper comparison involves         ness among vaccinated people, rela-          association, (2) consistency of stud-
two groups of similar age, gender          tive to a proper comparison with             ies, (3) specificity of effect, (4) tem-
mix,state of health,employment,like-       unvaccinated people, there is no evi-        porality, (5) biologic gradient, (6)
liness to report symptoms, and many        dence of a cause-and-effect relation-        plausibility, (7) coherence, (8) experi-
other factors. Information about self-     ship. It cannot and should not be            mental evidence, and (9) analogy.The
selected groups of people is substan-      ruled out entirely, however. The stud-       modern variants of these criteria are
tially less reliable and generalizable     ies may not have been large enough           described by Rothman and Green-
than information derived from a ran-       to rule out rare effects or effects of       land (Table 3).38
dom sample of a large population.          small magnitude. Scientists must                  The CDC publication,Epidemiol-
Epidemiologists invest whole careers       keep an open mind, of course, striv-         ogy and Prevention of Vaccine-Pre-
in the pursuit of valid comparisons.       ing to avoid the words “never” or            ventable Disease discusses the most
An apples-to-apples comparison             “always.”                                    reliable and conclusive ways to estab-
requires rigorous planning and often            And what if an increased rate of        lish causal relationships for vaccine
relies on hard-to-find or expensive-to-    illness in a proper comparison is            adverse events,39 and they are rela-
assemble data sets.                        found? Is the vaccine doomed or              tively few. Causal links between a vac-
      Some people used a set of inap-      damned? Not necessarily. The steps           cine and an adverse event may be
propriate comparisons to conclude          above are the first steps in epidemio-       established if they produce a unique
that childhood vaccination increases       logic analysis, but there is much more       laboratory result, a unique clinical
the risk of diabetes. The issue starts     to consider. Thus, we next apply Step        syndrome, or an epidemiologic study
with some ecological comparisons,          5.                                           shows vaccinated persons are more
analyses that look at broad popula-                                                     likely than unvaccinated persons to
tions in which multiple factors can        STEP 5: FULL ANALYSIS                        experience the adverse event.
exert effects simultaneously. Epidemi-          Step 5 involves a broader set of             Beyond the narrow confines of
ologists interpret ecological data         criteria than those considered above.        medicine, other scientists propose
with caution,because this design pro-      Criteria for cause-and-effect relation-      ways of distinguishing true science
vides only weak evidence upon              ships started with the infectious-dis-       from pseudoscience. James Lett sug-
which to gain cause-and-effect under-      ease work of Jacob Henle in 1840 and         gests six rules for evidential reason-
standing.                                  Robert Koch in 1882.37                       ing: falsifiability, logic, comprehen-
      These diabetes claims are based           Henle’s and Koch’s postulates           siveness, honesty, replicability, and
on analyzing nations with different        consist of three criteria for causation:     sufficiency (Table 4).40
rates of diabetes and different poli-      (1) the parasite occurs in every case
cies for timing of childhood vaccina-      of the disease and under circum-             USING THE STEPS
tions.27–28 No adjustments were made       stances that account for pathologic               Wakefield and colleagues raised
for varying degrees of scrutiny in         changes and clinical course; (2) it          concerns about MMR vaccine leading
diagnosing diabetes, varying case def-     occurs in no other disease as non-           to inflammatory bowel disease (IBD,
initions of diabetes, or other biases or   pathogenic parasite; and (3) after           eg, ulcerative colitis, Crohn’s dis-


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                                      TABLE 4                                           vated (and to a lesser extent oral)
                                                                                        poliovirus vaccines. In 1961, the gov-
                         Lett’s Rules for Evidential Reasoning                          ernment required all polio vaccine to
                                                                                        be free of SV40, but more than a mil-
  Falsifiability: It must be possible to conceive of evidence that would prove the      lion people had already received vac-
  claim false.                                                                          cines containing this virus.61 SV40
  Logic: Any argument offered as evidence in support of a claim must be sound.          can cause some cancers in rodents.
  Comprehensiveness: All of the available evidence must be considered.                  Recently, researchers found SV40 in
  Honesty: Evidence must be evaluated without self-deception.                           people with rare cancers (eg,
  Replicability: Evidence from experimental results or evidence that might be           ependymomas,            osteosarcomas,
  coincidental must be repeated.                                                        mesotheliomas), but many of these
  Sufficiency: Evidence must be adequate to establish the truth, where                  people were too young to have
   (a) the burden of proof rests on the claimant,                                       received poliovirus vaccine contain-
   (b) extraordinary claims demand extraordinary evidence, and                          ing SV40. So if unvaccinated people
   (c) evidence based upon authority or testimony is always inadequate for a bio-       have SV40 virus in their tumors, Step
   logically implausible claim.                                                         4 calls on us to ask if vaccinated peo-
  Source: Adapted from Lett40                                                           ple with these rare cancers are more
                                                                                        likely to involve SV40 than unvacci-
                                                                                        nated people. The evidence shows
ease).41 Wakefield’s theory is based        to decreased absorption of nutrients,      that the risk is the same, not elevated.
on 12 people referred to a specialty        permitting developmental disorders         There is no indication that any
service, even though no vaccine             like autism.41 This case against MMR       increased risk due to SV40 exists.62
viruses were isolated from these            is based on speculation and events               Space does not allow an exhaus-
patients. Other laboratories using          coinciding in time, no more.51,55–56       tive consideration of every side effect
more sensitive and specific tests           Again, this alleged association fails on   ever blamed on a vaccine. But the dis-
failed to detect any findings to sup-       the basis of Steps 0 and 4. Moreover,      cussion above provides a uniform
port an association.42–45 Epidemiolog-      scientifically valid evidence runs con-    framework within which to address
ic studies failed to confirm an associ-     trary to the speculation.57–59             the role of any vaccine (indeed, any
ation between measles virus and                  Multiple sclerosis (MS) is typical-   medication) on the incidence of aller-
IBD.46–51 A purported association           ly diagnosed in the third and fourth       gic diseases, arthritis, thyroid disease,
between MMR vaccine and IBD fails           decade of life, coincidentally a time      or any other medical condition.
at Steps 0 and Step 4: The individual       when health care providers are vac-
clinical information is unpersuasive        cinated against hepatitis B. Isolated      IMPLICATIONS FOR
and there is no evidence for an             case reports of MS in adults vaccinat-     PHARMACISTS
increased risk, compared with unvac-        ed against hepatitis B received wide-           After the diagnosis of a serious
cinated people.52–54                        spread attention in France.At least six    disease, it is rational to search for the
     Several alleged associations share     controlled studies are currently           disease’s precipitating cause.Vaccina-
the common feature that the diseases        underway, which will objectively           tions, however, are memorable,
are diagnosed at the typical age of         address Step 4. But the hundreds of        painful, well-documented events that
vaccination. Two current naïve exam-        millions of people around the world        have become convenient foci for
ples of this confusion are MMR vac-         vaccinated against hepatitis B who         blame.11,55,63–65
cine with autism and hepatitis B vac-       did not contract MS already suggest             Vaccinations are intentional stim-
cine with multiple sclerosis. Each will     that an association is at worst very       uli of the immune system. But the
be discussed in turn.                       rare.11–12 Other evidence shows that       human immune system gets uninten-
     Autism is typically diagnosed          influenza vaccination of people who        tional stimuli all the time. Every trip
after the first birthday, as a child’s      already have MS does not affect            to a church, school, shopping center,
vocal skills begin to manifest. This is     attack rate or disease progression.60      or other place where humans con-
the time when MMR vaccine is                     Can vaccination cause cancer?         gregate leads to viral and bacterial
administered. The other “evidence”          Soon after simian virus 40 (SV40) was      exchange. We ingest microbes daily
offered for an association between          discovered in 1960, SV40 was found         in our food and water. Breaches of
MMR and autism is Wakefield’s infer-        to be a contaminant of monkey kid-         the skin or mucosa introduce more
ence that bowel problems could lead         ney cells used to manufacture inacti-      microbes. Families with children in


1314       Volume 35, December 2000
                                                                                         Oncology/Immunology CE Series




daycare know well that they get               1998–1999. MMWR. 1999;48:577–81.                  24. Institute of Medicine. Vaccine Safety
                                                                                                Forum: Summaries of Two Workshops.
more infections than other people,            6. Advisory Committee on Immunization             Washington, DC: National Academy Press;
because their kids bring other kids’          Practices. Withdrawal of rotavirus vaccine        1997.
                                              recommendation. MMWR. 1999;48:1007.
germs home with them.                                                                           25. Gangarosa EJ, Galazka AM, Wolfe CR, et
      Despite humanity’s daily encoun-        7. Wallach J. Interpretation of Diagnostic        al. Impact of anti-vaccine movements on
                                              Tests. 6th ed. Boston: Little, Brown & Co.;       pertussis control: The untold story. Lancet.
ters with microbial antigens, vaccines        1996.                                             1998;351:356–61.
still seem unnatural and frightening          8. Grabenstein JD. ImmunoFacts:Vaccines
to some people. We can expect addi-                                                             26. Advisory Committee on Immunization
                                              and Immunologic Drugs. St. Louis, MO:             Practices. Poliomyelitis prevention in the
tional alarms over vaccine side               Facts and Comparisons, Inc.; November             United States: Updated recommendations.
                                              2000.
effects in coming years. How will we                                                            MMWR. 2000;49(RR-5):1–22.
know if it is a true alarm (like intus-       9. Grabenstein JD. Anaphylaxis: Epineph-          27. Classen JB. The timing of immunization
                                              rine and emergency responses. Hosp                affects the development of diabetes in
susception) or a false alarm (like dia-       Pharm. 1997;32:1377–8,1382–9.                     rodents. Autoimmunity. 1996;24:137–45.
betes, IBD, autism, multiple sclerosis)?
                                              10. Grabenstein JD. Compensation for vac-         28. Classen DC, Classen JB. The timing of
Good science — with intellectually            cine injury: Balancing society’s need and         pediatric immunization and the risk of
honest inquiry — is the answer.               personal risk. Hosp Pharm. 1995;30:831–6.         insulin-dependent diabetes mellitus. Infect
      An oft-quoted book on adverse           11. World Health Organization. Lack of evi-       Dis Clin Pract. 1997;6:449–54.
events after vaccination is Sir Graham        dence that hepatitis B vaccine causes mul-        29. Institute for Vaccine Safety Workshop
                                              tiple sclerosis. Weekly Epidemiol Rec.
Wilson’s The Hazards of Immuniza-             1997;72:149–52.
                                                                                                Panel. Childhood immunizations and type 1
tion.66 Wilson concludes his book by                                                            diabetes: Summary of an Institute for Vac-
                                              12. Dorozynski A. Suspension of hepatitis B       cine Safety Workshop. Pediatr Infect Dis J.
saying: “Vaccines, of one sort or             vaccination condemned. BMJ. 1998;317:             1999;18:217–22.
another, have conferred immense               1034.                                             30. Vaccination and its adverse events: Real
benefit on mankind but, like aero-            13. National Multiple Sclerosis Society. No       or perceived. BMJ. 1999;317:159–60.
planes and motor-cars, they have              foundation for hepatitis B alarm. Inside MS.      31. Karvonen M, Cepaitis Z, Tuomilehto J.
their dangers. . . .” It is for us, and for   1999;17(1):3.                                     Association between type 1 diabetes and
those who come after us, to see that          14. Parish HJ. A History of Immunization.         Haemophilus influenzae type b vaccina-
                                              Edinburgh: E & S Livingstone, Ltd; 1965.          tion: Birth cohort study. BMJ. 1999;
the sword which vaccines and antis-                                                             318:1169–72.
era have put into our hands is never          15. Sherman M, Strauss S. Thalidomide: A
                                              twenty-five year perspective. Food Drug           32. Blom L, Nystrom L, Dahlquist G. The
allowed to tarnish through over-con-          Cosmetic Law J. 1986;41:458–66.                   Swedish childhood diabetes study: Vaccina-
fidence, negligence, carelessness, or                                                           tions and infections as risk determinants for
                                              16. Sartin JS. Gulf war illnesses: Causes and     diabetes in childhood. Diabetologia.
want of foresight on our part.”               controversies. Mayo Clin Proc. 2000;              1991;34:176–81.
      Reliable information about vac-         75:811–9.
                                                                                                33. Dahlquist G, Gothefors L. The cumula-
cine safety is available from a variety       17. Riddle JR, Hyams KC, Murphy FM, et al.        tive incidence of childhood diabetes melli-
of sources, including the CDC at              In the borderland between health and dis-         tus in Sweden unaffected by BCG-vaccina-
                                              ease following the Gulf War. Mayo Clin            tion. Diabetologia. 1995;38:87374.
www.cdc.gov/nip/vacsafe/con-                  Proc. 2000;75:777–9.
cerns/default.htm.                                                                              34. Heijbel H, Chen RT, Dahlquist G. Cumu-
                                              18. Ismail K, Everitt B, Blatchley N, et al. Is   lative incidence of childhood-onset IDDM
                                              there a Gulf War syndrome? Lancet.                is unaffected by pertussis immunization.
REFERENCES                                    1999;353:179–82.                                  Diabetes Care. 1997;20:173–5.
1. Khakoo GA, Lack G. Recommendations         19. Straus SE. Bridging the gulf in war syn-      35. Hyoty H, Hiltunen M, Reunanen A, et al.
for using MMR vaccine in children allergic    dromes. Lancet. 1999;353:162–3.                   Decline of mumps antibodies in Type 1
to eggs. BMJ. 2000;320:929–32.                                                                  (insulin-dependent) diabetic children and a
                                              20. Centers for Disease Control and Preven-
2. Pickering LK,ed.2000 Red Book: Report      tion. Guillain-Barré syndrome and influenza       plateau in the rising incidence of type 1 dia-
of the Committee on Infectious Diseases,      vaccine. www.cdc.gov/nip/vacsafe/con-             betes after introduction of the mumps-
25th ed. Elk Grove Village, IL: American      cerns/GBS/default.htm. Accessed Septem-           measles-rubella vaccine in Finland. Dia-
Academy of Pediatrics; 2000.                  ber 9, 2000.                                      betologia. 1993;36:1303–8.
3. Centers for Disease Control and Preven-    21. Grabenstein JD.Vaccines and antibodies        36. Parent M, Fritschi L, Siemiatycki J, et al.
tion. Achievements in public health,          in relation to pregnancy and lactation. Hosp      Bacille Calmette-Guérin vaccination and
1900–1999: Impact of vaccines universally     Pharm. 1999;34:949–56,959–60.                     incidence of IDDM in Montreal, Canada.
recommended for children—United States,                                                         Diabetes Care. 1997;20:767–72.
1990–1998. MMWR. 1999;48:243–8.               22. Fenichel GM. Assessment: Neurologic
                                              risk of immunization. Neurology. 1999;            37. Kelsey JL, Thompson WD, Evans AS.
4. Grabenstein JD. Immunization from the      52:1546–52.                                       Methods in Observational Epidemiology.
perspective of a millennium. Hosp Pharm.                                                        New York: Oxford University Press; 1986.
2000;35:619–30.                               23. Advisory Committee on Immunization
                                              Practices. Pertussis vaccination: Use of acel-    38. Rothman KJ, Greenland S. Modern Epi-
5. Centers for Disease Control and Preven-    lular pertussis vaccines among infants and        demiology. 2nd ed. Philadelphia: Lippincott-
tion. Intussusception among recipients of     young children. MMWR. 1997;46(RR-                 Raven; 1998.
rotavirus      vaccine—United       States,   7):1–25.                                          39. Atkinson W, Wolfe C, Humiston S, et al.,


                                                                                                             Hospital Pharmacy         1315
Oncology/Immunology CE Series




ed. Epidemiology and Prevention of Vac-         48. Jones P, Fine P, Piracha S. Crohn's disease      vaccine: No epidemiological evidence for a
cine-Preventable Diseases. 6th ed. Atlanta:     and measles. Lancet. 1997;349:473.                   causal    association.  Lancet.     1999;
Centers for Disease Control and Preven-                                                              353:2026–9.
tion; 2000.                                     49. Feeney M, Clegg A, Winwood P, et al. A
                                                case-control study of measles vaccination            58. Gillberg C, Heijbel H. MMR and autism.
40. Lett J. Field guide to critical thinking.   and inflammatory bowel disease. Lancet.              Autism. 1998;2:423–4.
Skeptical Inquirer. 1990;(Winter):1–7.          1997;350:764–6.
                                                                                                     59. Miller D, Wadsworth J, Diamond J, Ross
41. Wakefield AJ, Murch SH, Anthony A, et       50. Miller E, Waight P. Measles, measles vac-        E. Measles vaccination and neurological
al. Ileal-lymphoid-nodular hyperplasia, non-    cination, and Crohn’s disease: Second                events. Lancet. 1997;349:730–1.
specific colitis, and pervasive developmen-     immunisation has not affected incidence in
tal disorder in children. Lancet.               England [letter]. BMJ. 1998;316:1745.                60. Miller AE, Morgante LA, Buchwald LY, et
1998;351:637–41.                                                                                     al. A multicenter, randomized, double-blind,
                                                51. Peltola H, Patja A, Leinikki P, et al. No evi-   placebo-controlled trial of influenza immu-
42. Liu Y, Van Kruiningen HJ, West AB, et al.   dence for measles, mumps, and rubella vac-           nization in multiple sclerosis. Neurology.
Immunocytochemical evidence of Listeria,        cine-associated inflammatory bowel dis-              1997;48:312–4.
Escherichia coli and Streptococcus anti-        ease or autism in a 14-year prospective
gens in Crohn's disease. Gastroenterology.      study. Lancet. 1998;351:1327–8.                      61. Brown F, Lewis AM, eds. Simian virus 40
1995;108:1396–404.                                                                                   (SV40): A possible human polyomavirus;
                                                52. Van Damme W, Lynen L, Kegels G, et al.           symposium proceedings. Dev Biol Stand.
43. Iizuka M, Nakagomi O, Chiba M, et al.       Measles vaccination and inflammatory                 1998;94:1–406.
Absence of measles virus in Crohn’s dis-        bowel disease. Lancet. 1997;350:1174–5.
ease. Lancet. 1995;345:199.                                                                          62. Strickler HD, Rosenberg PS, Devesa SS,
                                                53. Miller E, Goldblatt D, Cutts F. Measles          et al. Contamination of poliovirus vaccines
44. Haga Y, Funakoshi O, Kuroe K, et al.        vaccination and inflammatory bowel dis-              with simian virus 40 (1955-1963) and sub-
Absence of measles viral genomic sequence       ease. Lancet. 1998;351:755–6.                        sequent cancer rates. JAMA. 1998;279:
in intestinal tissues from Crohn’s disease by                                                        292–5.
nested polymerase chain reaction. Gut.          54. Metcalf J. Is measles infection associated
1996;38:211–5.                                  with Crohn's disease? The current evidence           63. Grabenstein JD. Vaccine side effects:
                                                does not prove a causal link [editorial].            Separating mirage from reality. J Am Pharm
45. Afzal MA, Minor PD, Begley J, et al.        BMJ. 1998;316:166.                                   Assoc. 1999;39:417–9.
Absence of measles virus genome in inflam-
matory bowel disease. Lancet. 1998;             55. Nicoll A, Elliman D, Ross E. MMR vacci-          64. Grabenstein JD. The natural history of a
351:646–7.                                      nation and autism 1998: Déjà vu-pertussis            vaccine and its disease. Hosp Pharm.
                                                and brain damage 1974 [editorial]? BMJ.              1996;31:559,563–8,571–2.
46. Nielson LLW, Nielsen NM, Melbye M, et       1998;316:715–6.
al. Exposure to measles in utero and                                                                 65. Grabenstein JD, Wilson JP. Are vaccines
Crohn's disease: Danish register study. BMJ.    56. Chen RT, DeStefano F. Vaccine adverse            safe? Risk communication applied to vac-
1998;316:196–7.                                 events: Causal or coincidental? Lancet.              cines. Hosp Pharm. 1999;34:713–8,721–9.
                                                1998;351:611–3.
47. Hermon-Taylor J, Ford J, Sumar N, et al.                                                         66. Wilson GS. The Hazards of Immuniza-
Lancet. 1995;345:922–3.                         57. Taylor B, Miller E, Farrington CP, et al.        tion. London: Athlone Press; 1967.
                                                Autism and measles, mumps, and rubella




1316       Volume 35, December 2000
 CONTINUING EDUCATION SERIES
 ONCOLOGY/IMMUNOLOGY                                This CE is published through an unrestricted
                                                    educational grant from Bristol-Myers Squibb.



                            Continuing Education Quiz
                     To take this CE quiz online, go to www.drugfacts.com

1. Which of the following is an               actually occurred                    A. from 6% to 10%
   example of a vaccine-adverse            C. both A and B                         B. 50%
   event association later found           D. neither A nor B                      C. Two-thirds
   to be unrelated to vaccina-                                                     M. More than 99%
   tion?                                6. Which of the following is an
   A. anthrax vaccine and injection-       adverse event acknowledged           11. If 6% to 10% of unvaccinated
      site symptoms                        to be caused by vaccination?             women who are pregnant
   B. diphtheria-tetanus-pertussis         A. Systemic lupus erythematosus          spontaneously miscarry their
      vaccine and sudden infant               after diphtheria vaccination          fetuses, what proportion of
      death syndrome                       B. Heart attacks after hepatitis A       vaccinated    women      are
   C. influenza vaccine and egg               vaccination                           expected to do so?
      allergy                              C. Serum sickness after yellow-          A. 3% to 5%
   D. tetanus toxoid and anaphylax-           fever vaccination                     B. 6% to 10%
      is                                   D. Anaphylaxis after any vaccina-        C. 12% to 20%
                                              tion                                  D. 24% to 40%
2. An example of an adverse
   event that led to the cessation      7. Name a relatively novel med-         12. In some years, but not others,
   of a national vaccination pro-          ication-adverse event combi-             people vaccinated against
   gram was:                               nation:                                  influenza have a substantially
   A. rotavirus vaccine and intussus-      A. diphtheria antitoxin and ana-         higher rate of Guillain-Barré
      ception                                 phylaxis in 1902                      syndrome than unvaccinated
   B. influenza vaccine and brachial       B. influenza vaccine and Guil-           people.
      neuritis                                lain-Barré syndrome in 1976           A. True
   C. tetanus toxoid and Guillain-         C. varicella      vaccine    and         B. False
      Barré syndrome                          headache in 1995
   D. measles vaccine and chronic          D. hepatitis B vaccine and multi-    13. Infants vaccinated against
      arthritis                               ple sclerosis in 1998                 diphtheria, tetanus, and per-
                                                                                    tussis have a substantially
3. An objective rationale for           8. If an adverse event after vac-           higher rate of chronic
   assessing     causal    links           cination is not novel, it means          encephalopathy than unvac-
   between vaccines and adverse            that the event also occurs               cinated infants.
   events can also be applied to           among unvaccinated people.               A. True
   other medications, as well as           A. True                                  B. False
   environmental exposures.                B. False
   A. True                                                                      14. Which of the following fac-
   B. False                             9. If an adverse event occurs               tors weakens the hypothesis
                                           among unvaccinated people,               that vaccination leads to dia-
4. The first signal of an associa-         the key question in Step 3 is:           betes?
   tion between rotavirus vac-             A. Does it really occur among            A. reliance on ecological com-
   cine and intussusception                   vaccinated people?                       parisons
   came from:                              B. Does it really occur among            B. failure to adjust for diagnostic
   A. the VICP program                        unvaccinated people?                     scrutiny
   B. a toll-free hotline                  C. How often does it occur               C. Failure to use common case
   C. the VAERS program                       among vaccinated people?                 definitions
   D. clinical trials                      D. How often does it occur               D. all of the above
                                              among unvaccinated people?
5. Step 0 in the scheme pro-                                                    15. Which of the following alter-
   posed in this article involves:      10. Roughly what fraction of                native explanations could
   A. verifying an individual’s expo-       cases of Guillain-Barré syn-            explain a temporal relation-
      sure to the vaccine                   drome occur in the absence              ship between hepatitis B vac-
   B. verifying that an adverse event       of vaccination?                         cine and multiple sclerosis?


                                                                                          Hospital Pharmacy      1317
Oncology/Immunology CE Series




   A. hepatitis A vaccine is known             C. brachial neuritis                      assessing     cause-and-effect
      to cause multiple sclerosis              D. intussusception                        relationships?
   B. multiple sclerosis is known to                                                     A. Any biological hypothesis is
      follow hepatitis B viral infec-      17. The Vaccine Injury Table                     sufficient
      tion                                     includes which of the follow-             B. Effect must occur before
   C. adults vaccinated against                ing events after rubella vacci-              cause
      hepatitis B virus because of             nation?                                   C. Strength     of     association
      occupational risks are often of          A. chronic arthritis                         between exposure and out-
      the same age as people newly             B. acute arthritis                           come
      diagnosed with multiple scle-            C. thrombocytopenic purpura               D. Any one of several studies
      rosis                                    D. paralytic poliomyelitis                   shows a statistically significant
   D. not enough reports of multi-                                                          finding
      ple sclerosis in hepatitis B vac-    18. Reports to the Vaccine
      cine recipient have been                 Adverse Event Reporting Sys-          20. Reports to the Vaccine
      mailed in                                tem (VAERS) are required for              Adverse Event Reporting Sys-
                                               adverse events listed in the              tem (VAERS) are required for
16. The Vaccine Injury Table                   Vaccine Injury Table.                     adverse events listed as con-
    includes which of the follow-              A. True                                   traindications to additional
    ing events after tetanus tox-              B. False                                  doses of a vaccine.
    oid administration?                                                                  A. True
    A. inflammatory bowel disease          19. Which of the following is one             B. False
    B. Guillain-Barré syndrome                 of the intricate criteria for


Oncology/Immunology CE Series                                   Note: Your answer sheet will be graded confidentially and
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1318     Volume 35, December 2000