Vaccine consensus statement (for healthy, but comments on ID)

[Guest guest]

With the recent talk about vaccines, I thought I'd pass this along as a

good reference. Obviously, it's not comprehensive (indeed, may even

have come out *before* the rotovirus vaccine problems, b/c I think it's

from 1996. But it's a helpful resource.... as always, though, I'm

*just* sending this as a resource, not advice -- your docs are the best

ones to discuss this with, because second to you as parents, they

probably know your children better than everyone else in the world!

Recommendations of the Advisory Committee on Immunization Practices - Vaccines

http://www.medscape.com/govmt/CDC/MMWR/1996/sep/rr4512/rr4512.html

Update: Vaccine Side Effects, Adverse Reactions, Contraindications, and

Precautions

Recommendations of the Advisory Committee on Immunization

Practices (ACIP)

Authors: Tuttle, M.D., T. Chen, M.D., M.A., C.

Hadler, M.D., C. ,

M.D., M.P.H., J. Terracciano, D.O., M.P.H., Epidemiology and

Surveillance Division, National

Immunization Program, in collaboration with the Advisory Committee on

Immunization Practices (ACIP).

Summary: This report provides updated information concerning the

potential adverse events associated with

vaccination for hepatitis B, poliomyelitis, measles, mumps, diphtheria,

tetanus, and pertussis. This information

incorporates findings from a series of recent literature reviews,

conducted by an expert committee at the Institute

of Medicine (IOM), of all evidence regarding the possible adverse

consequences of vaccines administered to

children. This report contains modifications to the previously published

recommendations of the Advisory

Committee on Immunization Practices (ACIP) and is based on an ACIP

review of the IOM findings and new

research on vaccine safety. In addition, this report incorporates

information contained in the " Recommendations

of the Advisory Committee on Immunization Practices: Use of Vaccines and

Immune Globulins in Persons with

Altered Immunocompetence " (MMWR 1993;42[No. RR-4]) and the " General

Recommendations on Immunization:

Recommendations of the Advisory Committee on Immunization Practices

(ACIP) " (MMWR 1994;43[No. RR-1]).

Major changes to the previous recommendations are highlighted within the

text, and specific information

concerning the following vaccines and the possible adverse events

associated with their administration are

included: hepatitis B vaccine and anaphylaxis; measles vaccine and a)

thrombocytopenia and possible risk for

death resulting from anaphylaxis or disseminated disease in

immunocompromised persons; diphtheria and

tetanus toxoids and pertussis vaccine (DTP) and chronic encephalopathy;

and tetanus-toxoid-containing vaccines

and a) Guillain-Barré syndrome, brachial neuritis, and c) possible

risk for death resulting from anaphylaxis.

These modifications will be incorporated into more comprehensive ACIP

recommendations for each vaccine when

such statements are revised. Also included in this report are interim

recommendations concerning the use of

measles and mumps vaccines in a) persons who are infected with human

immunodeficiency virus and persons

who are allergic to eggs; ACIP is still evaluating these

recommendations. [MMWR 45(No. RR-12):inclusive page

numbers, 1996]

Contents

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Online Resources

Related articles and abstracts

Summary

Introduction

Hepatitis B Vaccine

Vaccine Side Effects and Adverse Reactions

Poliomyelitis Prevention

Precautions and Contraindications

Adverse Reactions

Measles Prevention

Side Effects and Adverse Reactions

Precautions and Contraindications

Management of Patients with Contraindications to Measles

Vaccine

Simultaneous Administration of Vaccines

Mumps Prevention

Adverse Effects of Vaccine Use

Contraindications to Vaccine Use

DTP

Side Effects and Adverse Reactions Following DTP

Vaccination

Precautions and Contraindications

Tables

Footnotes

References

Introduction

Immunization has enabled the global eradication of smallpox [1], the

elimination of poliomyelitis from the

Western hemisphere [2], and major reductions in the incidence of other

vaccine-preventable diseases in the

United States (Table 1). However, although immunization has successfully

reduced the incidence of

vaccine-preventable diseases, vaccination can cause both minor and,

rarely, serious side effects. Public

awareness of and controversy about vaccine safety has increased,

primarily because increases in vaccine

coverage resulted in an increased number of adverse events that occurred

after vaccination. Such adverse events

include both true reactions to vaccine and events coincidental to, but

not caused by, vaccination. Despite

concerns about vaccine safety, vaccination is safer than accepting the

risks for the diseases these vaccines

prevent. Unless a disease has been eradicated (e.g., smallpox), failure

to vaccinate increases the risks to both the

individual and society.

In response to concerns about vaccine safety, the National Childhood

Vaccine Injury Act of 1986 established a

no-fault compensation process for persons possibly injured by selected

vaccines [3]. The Act also mandated that

the Institute of Medicine* (IOM) review scientific and other evidence

regarding the possible adverse

consequences of vaccines administered to children.

IOM constituted an expert committee to review all available information

on these vaccine adverse events; such

information included epidemiologic studies, case series, individual case

reports, and testimonials. To derive their

conclusions, the IOM committee members created five categories of

causality to describe the relationships

between the vaccines and specific adverse events. The first IOM review

examined certain events occurring after

administration of pertussis and rubella vaccines (Table 2) [4]. The

second IOM review examined events occurring

after administration of all other vaccines usually administered during

childhood (i.e., diphtheria and tetanus

toxoids and measles, mumps, hepatitis B, Haemophilus influenzae type b

[Hib], and polio virus vaccines) (Table

3) [5]. Two other IOM committees have met since the findings of the

second review were published. These two

committees have published their findings concerning both the diphtheria

and tetanus toxoids and pertussis

vaccine (DTP) and chronic nervous system dysfunction (Figure 1) [6] and

research strategies for

vaccine-associated adverse events [7].

Figure 1. (click here to zoom image) Scenarios in which acute neurologic

illnesses that occur after vaccination

with diphtheria and tetanus toxoids and pertussis vaccine (DTP) might be

associated with subsequent chronic

nervous system dysfunction -- Institute of Medicine, 1994.

The Advisory Committee on Immunization Practices (ACIP) recently

reviewed the findings of the IOM committees

and modified the previously published ACIP recommendations to ensure

consistency with IOM conclusions.

These recommendations, which are included in this report, update all

previously published ACIP

recommendations pertaining to the precautions, contraindications, side

effects, and adverse re-actions**

associated with specific vaccines. ACIP accepted the IOM conclusions for

almost all vaccine adverse events; the

few exceptions generally occurred because new information that was

available to ACIP had not been available

when the IOM committees published their recommendations. These

exceptions included a) oral polio virus

vaccine (OPV) and Guillain-Barré syndrome (GBS), tetanus-toxoid-

containing vaccines and GBS, and c) DTP

and chronic nervous system dysfunction.

In addition, this report incorporates information contained in the

" Recommendations of the Advisory Committee

on Immunization Practices: Use of Vaccines and Immune Globulins in

Persons with Altered Immunocompetence "

(MMWR 1993; 42[No. RR-4]) and the " General Recommendations on

Immunization: Recommendations of the

Advisory Committee on Immunization Practices (ACIP) " (MMWR 1994;43[No.

RR-1]). To facilitate recognition of

the new recommendations in this re-port, all major changes that are

being made to the previously published

ACIP statements are highlighted within the text. These changes include

information on the following vaccines

and the possible adverse events associated with their administration:

Hepatitis B vaccine and anaphylaxis;

Measles vaccine and a) thrombocytopenia and possible risk for

death resulting from anaphylaxis or

disseminated disease in immunocompromised persons;

DTP and chronic encephalopathy; and

Tetanus-toxoid-containing vaccines and a) GBS, brachial

neuritis, and c) possible risk for death resulting

from anaphylaxis.

The modifications contained in this report, and possibly other changes

as new information becomes available,

will be incorporated into more comprehensive ACIP recommendations for

each vaccine when such statements are

revised.

Hepatitis B Vaccine

The following recommendations concerning adverse events associated

with hepatitis B vaccination update

those applicable sections in " Hepatitis B Virus: A Comprehensive

Strategy for Eliminating Transmission in the

United States Through Universal Childhood Vaccination--Recommendations

of the Immunization Practices

Advisory Committee (ACIP) " (MMWR 1991;40[No. RR-13]).

Vaccine Side Effects and Adverse Reactions

Hepatitis B vaccines are safe to administer to adults and children. More

than an estimated 10 million adults and

2 million infants and children have been vaccinated in the United

States, and at least 12 million children have

been vaccinated worldwide.

Vaccine-Associated Side Effects

Pain at the injection site (3%-29%) and a temperature greater than 37.7

C (1%-6%) have been among the most

frequently reported side effects among adults and children receiving

vaccine [8-12]. In placebo-controlled studies,

these side effects were reported no more frequently among vaccinees than

among persons receiving a placebo

[11,12]. Among children receiving both hepatitis B vaccine and DTP,

these mild side effects have been observed

no more frequently than among children receiving only DTP.

The recommendation to begin hepatitis B vaccination soon after birth has

raised the concern that a substantial

number of infants will require an extensive medical evaluation for

elevated temperatures secondary to hepatitis

B vaccination. Several population-based studies to evaluate this

possibility are in progress.

Adverse Events

In the United States, surveillance of adverse reactions indicated a

possible association between GBS and receipt

of the first dose of plasma-derived hepatitis B vaccine (CDC,

unpublished data) [13]. However, an estimated 2.5

million adults received one or more doses of recombinant hepatitis B

vaccine during 1986-1990, and available

data concerning these vaccinees do not indicate an association between

receipt of recombinant vaccine and GBS

(CDC, unpublished data).

Based on reports to the Vaccine Adverse Events Reporting System

(VAERS), the estimated incidence rate of

anaphylaxis among vaccine recipients is low (i.e., approximately one

event per 600,000 vaccine doses

distributed). Two of these adverse events occurred in children (CDC,

unpublished data). In addition, only one

case of anaphylaxis occurred among 100,763 children ages 10-11 years

who had been vaccinated with

recombinant vaccine in British Columbia (D. Scheifele, unpublished

data), and no adverse events were

reported among 166,757 children who had been vaccinated with

plasma-derived vaccine in New Zealand [5].

Although none of the persons who developed anaphylaxis died, this

adverse event can be fatal; in addition,

hepatitis B vaccine can--in rare instances--cause a life-threatening

hypersensitivity reaction in some persons

[5]. Therefore, subsequent vaccination with hepatitis B vaccine is

contraindicated for persons who have

previously had an anaphylactic response to a dose of this vaccine.

Large-scale hepatitis B immunization programs for infants in Alaska, New

Zealand, and Taiwan have not

established an association between vaccination and the occurrence of

other severe adverse events, including

seizures and GBS (B. McMahon and A. Milne, unpublished data) [14].

However, systematic surveillance for

adverse reactions in these populations has been limited, and only a

minimal number of children have received

recombinant vaccine. Any presumed risk for adverse events that might be

causally associated with hepatitis B

vaccination must be balanced with the expected risk for hepatitis B

virus (HBV)-related liver disease. Currently,

an estimated 2,000-5,000 persons in each U.S. birth cohort will die as a

result of HBV-related liver disease

because of the 5% lifetime risk for HBV infection.

As hepatitis B vaccine is introduced for routine vaccination of infants,

surveillance for vaccine-associated adverse

events will continue to be an important part of the program despite the

current record of safety. Any adverse

event suspected to be associated with hepatitis B vaccination should be

reported to VAERS. VAERS forms can be

obtained by calling .

Poliomyelitis Prevention

The following recommendations concerning adverse events associated

with poliomyelitis vaccination update

those applicable sections in " Poliomyelitis Prevention: Recommendation

of the Immunization Practices

Advisory Committee (ACIP) " (MMWR 1982;31:22-6,31-4) and " Poliomyelitis

Prevention: Enhanced-Potency

Inactivated Poliomyelitis Vaccine--Supplementary Statement " (MMWR

1987;36:795-8).

Precautions and Contraindications

Pregnancy

Although no conclusive evidence documents the adverse effects of OPV or

inactivated polio virus vaccine (IPV) in

pregnant women and their developing fetuses, vaccination of pregnant

women should be avoided. However, if

immediate protection against poliomyelitis is necessary, OPV or IPV can

be given.

Immunodeficiency

Persons who have congenitally acquired immune-deficiency diseases (e.g.,

combined immunodeficiency,

hypogammaglobulinemia, and agammaglobulinemia) should not be given OPV

because of their substantially

increased risk for vaccine-associated disease. Furthermore, persons who

have altered immune status resulting

from acquired conditions (e.g., human immunodeficiency virus [HIV]

infection, leukemia, lymphoma, or

generalized malignancy) or who have immune systems compromised by

therapy (e.g., treatment with

corticosteroids, alkylating drugs, antimetabolites, or radiation) should

not receive OPV because of the theoretical

risk for paralytic disease.

IPV--and not OPV--should be used to vaccinate immunodeficient persons

and their household contacts. Many

immunosuppressed persons are already immune to polio viruses because of

previous vaccination or exposure to

wild-type virus when they were immunocompetent. Although such persons

should not receive OPV, their risk for

paralytic disease may be less than that of persons who have congenitally

acquired immunodeficiency. Although

a protective immune response to IPV in the immunodeficient patient

cannot be ensured, the vaccine is safe and

some protection may result from its administration. If a household

contact of an immunodeficient person is

vaccinated inadvertently with OPV, the OPV recipient should avoid close

physical contact with the

immunodeficient person for approximately 4-6 weeks after vaccination

(i.e., during the period of maximum

excretion of vaccine virus). If such contact cannot be avoided, rigorous

hygiene and hand washing after

contact with feces (e.g., after diaper changing) and avoidance of

contact with saliva (e.g., by not

sharing eating utensils or food) should be practiced. These practices

are an accept-able, but probably

less effective, alternative than refraining from contact. Because

immunodeficiency is possible in other

children born to a family in which one child is immunodeficient, OPV

should not be administered to a member of

such a house-hold until the immune status of the recipient and other

children in the family is documented.

Adverse Reactions

OPV

In rare instances, administration of OPV has been associated with

paralytic poliomyelitis in healthy

recipients and their contacts. Very rarely, OPV has caused fatal

paralytic poliomyelitis in

immunocompromised persons [5]. Other than efforts for identifying

persons with immune-deficiency

conditions, no procedures are currently available to identify persons

likely to experience such adverse reactions.

Although the risk of vaccine-associated paralysis is extremely small for

vaccinees and their susceptible, close,

personal contacts, they should be informed of this risk.

Available data do not indicate a measurable increased risk for GBS

after receipt of OPV. Initial reports (at the

time of IOM review) of two studies conducted in Finland suggested that

OPV might cause GBS. These studies

identified an apparent increased incidence of GBS that was temporally

associated with mass OPV vaccination

of children and adults who had previously received IPV [15,16]. Since

the IOM review, a reanalysis of the data

derived from the studies conducted in Finland and an analysis of an

observational study conducted in the

United States have not demonstrated a casual relationship between OPV

and GBS in infants [17].

Because OPV contains trace amounts of streptomycin, bacitracin, and

neomycin, its use is contraindicated in

persons who have previously had an anaphylactic reaction to OPV or to

these antibiotics.

IPV

No serious side effects of currently available IPV have been documented.

Since IPV contains trace amounts of

streptomycin and neomycin, there is a possibility of hypersensitivity

reactions in individuals sensitive to these

antibiotics.

Measles Prevention

The following recommendations concerning adverse events associated

with measles vaccination update those

applicable sections in " Measles Prevention: Recommendations of the

Immunization Practices Advisory

Committee " (MMWR 1989; 38[No. S-9]), and they apply regardless of

whether the vaccine is administered as a

single antigen or as a component of measles-rubella (MR) or

measles-mumps-rubella (MMR) vaccine.

Information concerning adverse events associated with the mumps

component of MMR vaccine is reviewed

later in this document (see Mumps Prevention), and information

concerning the rubella component is located

in the previously published ACIP statement for rubella [18].

Side Effects and Adverse Reactions

More than 240 million doses of measles vaccine were distributed in the

United States from 1963 through 1993.

The vaccine has an excellent record of safety. From 5% to 15% of

vaccinees may develop a temperature of >=103

F (>=39.4 C) beginning 5-12 days after vaccination and usually lasting

several days [19]. Most persons with fever

are otherwise asymptomatic. Transient rashes have been reported for

approximately 5% of vaccinees. Central

nervous system (CNS) conditions, including encephalitis and

encephalopathy, have been reported with a

frequency of less than one per million doses administered. The incidence

of encephalitis or encephalopathy after

measles vaccination of healthy children is lower than the observed

incidence of encephalitis of unknown

etiology. This finding suggests that the reported severe neurologic

disorders temporally associated with measles

vaccination were not caused by the vaccine. These adverse events should

be anticipated only in susceptible

vaccinees and do not appear to be age-related. After revaccination, most

reactions should be expected to occur

only among the small proportion of persons who failed to respond to the

first dose.

Personal and Family History of Convulsions

As with the administration of any agent that can produce fever, some

children may have a febrile seizure.

Although children with a personal or family history of seizures are at

increased risk for developing idiopathic

epilepsy, febrile seizures following vaccinations do not in themselves

increase the probability of subsequent

epilepsy or other neurologic disorders. Most convulsions following

measles vaccination are simple febrile

seizures, and they affect children without known risk factors.

An increased risk of these convulsions may occur among children with a

prior history of convulsions or those

with a history of convulsions in first-degree family members (i.e.,

siblings or parents) [20]. Although the precise

risk cannot be deter-mined, it appears to be low.

In developing vaccination recommendations for these children, ACIP

considered a number of factors, including

risks from measles disease, the large proportion (5%-7%) of children

with a personal or family history of

convulsions, and the fact that convulsions following measles vaccine are

uncommon. Studies conducted to

date have not established an association between MMR vaccination and the

development of a residual

seizure disorder [5]. ACIP concluded that the benefits of vaccinating

these children greatly outweigh the risks.

They should be vaccinated just as children without such histories.

Because the period for developing vaccine-induced fever occurs

approximately 5-12 days after vaccination,

prevention of febrile seizures is difficult. Prophylaxis with

antipyretics has been suggested as one alternative,

but these agents may not be effective if given after the onset of fever.

To be effective, such agents would have to

be initiated before the expected onset of fever and continued for 5-7

days. However, parents should be alert to

the occurrence of fever after vaccination and should treat their

children appropriately.

Children who are being treated with anticonvulsants should continue to

take them after measles vaccination.

Because protective levels of most currently available anticonvulsant

drugs (e.g., phenobarbital) are not achieved

for some time after therapy is initiated, prophylactic use of these

drugs does not seem feasible.

The parents of children who have either a personal or family history of

seizures should be advised of the small

increased risk of seizures following measles vaccination. In particular,

they should be told in advance what to do

in the unlikely event that a seizure occurs. The permanent medical

record should document that the small risk of

post immunization seizures and the benefits of vaccination have been discussed.

Subacute Sclerosing Panencephalitis (SSPE)

Measles vaccine significantly reduces the likelihood of developing

SSPE, as evidenced by the near elimination

of SSPE cases after widespread measles vaccination began. SSPE has

been reported rarely in children who do

not have a history of natural measles infection but who have received

measles vaccine. The available evidence

suggests that at least some of these children may have had an

unidentified measles infection before

vaccination and that the SSPE probably resulted from the natural

measles infection. The administration of live

measles vaccine does not increase the risk for SSPE, regardless of

whether the vaccinee has had measles

infection or has previously received live measles vaccine [5,21].

Thrombocytopenia

Surveillance of adverse reactions in the United States and other

countries indicates that MMR vaccine can, in

rare circumstances, cause clinically apparent thrombocytopenia within

the 2 months after vaccination. In

prospective studies, the reported incidence of clinically apparent

thrombocytopenia after MMR vaccination

ranged from one case per 30,000 vaccinated children in Finland [22]

and Great Britain [23] to one case per

40,000 in Sweden, with a temporal clustering of cases occurring 2-3

weeks after vaccination [24]. With passive

surveillance, the reported incidence was approximately one case per

100,000 vaccine doses distributed in

Canada and France [25], and approximately one case per 1 million doses

distributed in the United States [26].

The clinical course of these cases was usually transient and benign,

although hemorrhage occurred rarely [26].

Furthermore, the risk for thrombocytopenia during rubella or measles

infection is much greater than the risk

after vaccination. Of 30,000 school-children in one Pennsylvania

county who had been infected with rubella

during the 1963-64 measles epidemic, 10 children developed

thrombocytopenic purpura (incidence: one case

per 3,000 children) [27]. Based on case reports, the risk for

thrombocytopenia may be higher for persons who

previously have had idiopathic thrombocytopenic purpura, particularly

for those who had thrombocytopenic

purpura after an earlier dose of MMR vaccine [5,28,29].

Revaccination Risks

There is no evidence of an increased risk for adverse reactions after

administration of live measles vaccine to

persons who are already immune to measles as a result of either previous

vaccination or natural disease.

Precautions and Contraindications

Pregnancy

Live measles vaccine, when given as a component of MR or MMR, should not

be given to women known to be

pregnant or who are considering becoming pregnant within the next 3

months. Women who are given

monovalent measles vaccine should not become pregnant for at least 30

days after vaccination. This precaution

is based on the theoretical risk of fetal infection, although no

evidence substantiates this theoretical risk.

Considering the importance of protecting adolescents and young adults

against measles, asking women if they

are pregnant, excluding those who are, and explaining the theoretical

risks to the others before vaccination are

sufficient precautions.

Febrile Illness

The decision to administer or delay vaccination because of a current or

recent febrile illness depends largely on

the cause of the illness and the severity of symptoms. Minor illnesses,

such as a mild upper-respiratory infection

with or without low-grade fever, are not contraindications for

vaccination. For persons whose compliance with

medical care cannot be assured, every opportunity should be taken to

provide appropriate vaccinations.

Children with moderate or severe febrile illnesses can be vaccinated as

soon as they have recovered from the

acute phase of the illness. This wait avoids superimposing adverse

effects of vaccination on the underlying

illness or mistakenly attributing a manifestation of the underlying

illness to the vaccine. Performing routine

physical examinations or measuring temperatures are not prerequisites

for vaccinating infants and children who

appear to be in good health. Asking the parent or guardian if the child

is ill, postponing vaccination for children

with moderate or severe febrile illnesses, and vaccinating those without

contraindications are appropriate

procedures in childhood immunization programs.

Allergic Reactions

Hypersensitivity reactions rarely occur after the administration of

MMR or any of its component vaccines. Most

of these reactions are minor and consist of a wheal and flare or

urticaria at the injection site. Immediate,

anaphylactic reactions to MMR or its component vaccines are extremely

rare. Although >70 million doses of

MMR vaccine have been distributed in the United States since VAERS was

implemented in 1990, only 33 cases

of anaphylactic reactions that occurred after MMR vaccination have

been reported. Furthermore, only 11 of

these cases a) occurred immediately after vaccination and occurred

in persons who had symptoms

consistent with anaphylaxis (CDC, unpublished data). In the past,

persons who had a history of anaphylactic

reactions (i.e., hives, swelling of the mouth or throat, difficulty

breathing, hypotension, and shock) following

egg ingestion were considered to be at increased risk for serious

reactions after receipt of measles-containing

vaccines, which are produced in chick embryo fibroblasts. Protocols

requiring caution were developed for skin

testing and vaccinating persons who had had anaphylactic reactions

after egg ingestion [30-34]. However, the

predictive value of such skin testing and the need for special

protocols when vaccinating egg-allergic persons

with measles-containing vaccines is uncertain. The results of re-cent

studies suggest that anaphylactic

reactions to measles-containing vaccines are not associated with

hypersensitivity to egg antigens but with

some other component of the vaccines. The risk for serious allergic

reaction to these vaccines in egg-allergic

patients is extremely low, and skin testing is not necessarily

predictive of vaccine hypersensitivity [35-37].

Therefore, ACIP is re-evaluating whether skin testing and the use of

special protocols are routinely necessary

when administering MMR or other measles-containing vaccines to persons

who have a history of

anaphylactic-like reactions after egg ingestion. MMR and its component

vaccines contain hydrolyzed gelatin as

a stabilizer. The literature contains a single case report of a person

with an anaphylactic sensitivity to gelatin

who had an anaphylactic reaction after receipt of the MMR vaccine

licensed in the United States [38]. Similar

cases have occurred in Japan [39]. Therefore, ACIP is currently

considering recommendations for vaccination

of persons who have had ananaphylactic reaction to gelatin or

gelatin-containing products. In the meantime,

such persons should be vaccinated with MMR and its component vaccines

with extreme caution.

MMR vaccine and its component vaccines contain trace amounts of

neomycin. Al-though the amount present is

less than that usually used for a skin test to determine

hypersensitivity, persons who have experienced

anaphylactic reactions to neomycin should not be given these vaccines.

Most often, neomycin allergy is

manifested by contact dermatitis rather than anaphylaxis. A history of

contact dermatitis to neomycin is not a

contraindication to receiving measles vaccine. Live measles virus

vaccine does not contain penicillin.

Thrombocytopenia

Children who have a history of thrombocytopenic purpura or

thrombocytopenia may be at increased risk for

developing clinically significant thrombocytopenia after MMR

vaccination. The decision to vaccinate should

depend on the benefits of immunity to measles, mumps, and rubella and

the risks for recurrence or

exacerbation of thrombocytopenia after vaccination or during natural

infections with measles or rubella. The

benefits of immunization are usually greater than the potential risks,

and administration of MMR vaccine is

justified--particularly with regard to the even greater risk for

thrombocytopenia after measles or rubella

disease. However, avoiding a subsequent dose might be prudent if the

previous episode of thrombocytopenia

occurred in close temporal proximity to (i.e., within 6 weeks after)

the previous vaccination. Serologic evidence

of measles immunity in such persons may be sought in lieu of MMR vaccination.

Recent Administration of Immune Globulins

Previous recommendations, based on data from persons who received low

doses of immune globulin

preparations, stated that MMR and its individual component vaccines

could be administered as early as 6

weeks to 3 months after administration of immune globulins [40,41].

However, recent evidence suggests that

high doses of immune globulins can inhibit the immune response to

measles vaccine for more than 3 months

[42,43]. Administration of immune globulins also can inhibit the

response to rubella vaccine [42]. The effect of

immune globulin preparations on the response to mumps vaccine is

unknown, but commercial immune

globulin preparations contain antibodies to these viruses.

Blood (e.g., whole blood, packed red blood cells, and plasma) and

other antibody-containing blood products

(e.g., immune globulin; specific immune globulins; and immune

globulin, intravenous [iGIV]) can diminish the

immune response to MMR or its individual component vaccines.

Therefore, after an immune globulin

preparation is received, these vaccines should not be administered

before the recommended interval (Table 4

and Table 5). However, the postpartum vaccination of

rubella-susceptible women with the rubella or MMR

vaccine should not be delayed because anti-Rho(D) IG (human) or any

other blood product was received

during the last trimester of pregnancy or at delivery. These women

should be vaccinated immediately after

delivery and, if possible, tested at least 3 months later to ensure

immunity to rubella and, if necessary, to

measles.

If administration of an immune globulin preparation becomes necessary

because of imminent exposure to

disease, MMR or its component vaccines can be administered

simultaneously with the immune globulin

preparation, although vaccine-induced immunity might be compromised.

The vaccine should be administered

at a site remote from that chosen for the immune globulin inoculation.

Unless serologic testing indicates that

specific antibodies have been produced, vaccination should be repeated

after the recommended interval (Table

4 and Table 5).

If administration of an immune globulin preparation becomes necessary

after MMR or its individual

component vaccines have been administered, interference can occur.

Usually, vaccine virus replication and

stimulation of immunity will occur 1-2 weeks after vaccination. Thus,

if the interval between administration of

any of these vaccines and subsequent administration of an immune

globulin preparation is <14 days,

vaccination should be repeated after the recommended interval (Table 4

and Table 5), unless serologic testing

indicates that antibodies were produced.

Altered Immunocompetence

Non-HIV-Infected Persons. Replication of vaccine viruses can be

enhanced in per-sons with

immune-deficiency diseases and in persons with immunosuppression, as

occurs with leukemia, lymphoma,

generalized malignancy, or therapy with alkylating agents,

antimetabolites, radiation, or large doses of

corticosteroids. Evidence based on case reports has linked measles

vaccine and measles infection to

subsequent death in some severely immunocompromised children. Of the

>200 million doses of measles

vaccine administered in the United States, fewer than five such deaths

have been reported [5]. Patients who

have such conditions or are undergoing such therapies (excluding most

HIV-infected patients) should not be

given live measles virus vaccine.

Patients with leukemia in remission who have not received chemotherapy

for at least 3 months may receive

live-virus vaccines. The exact amount of systemically absorbed

corticosteroids and the duration of

administration needed to suppress the immune system of an otherwise

healthy child are not well defined.

Most experts agree that steroid therapy usually does not

contraindicate administration of live virus vaccine

when it is short term (i.e., <2 weeks); low to moderate dose;

long-term, alternate-day treatment with

short-acting preparations; maintenance physiologic doses (replacement

therapy); or administered topically

(skin or eyes), by aerosol, or by intra-articular, bursal, or tendon

injection [44]. Although of recent theoretical

concern, no evidence of increased severe reactions to live vaccines

has been reported among per-sons

receiving steroid therapy by aerosol, and such therapy is not in

itself a reason to delay vaccination. The

immunosuppressive effects of steroid treatment vary, but many

clinicians consider a dose equivalent to either

2 mg/kg of body weight or a total of 20 mg per day of prednisone as

sufficiently immunosuppressive to raise

concern about the safety of vaccination with live virus vaccines [44].

Corticosteroids used in greater than

physiologic doses also can reduce the immune response to vaccines.

Physicians should wait at least 3 months

after discontinuation of therapy before ad-ministering a live-virus

vaccine to patients who have received high

systemically absorbed doses of corticosteroids for >=2 weeks.

HIV-Infected Persons. Because of the increased risk for severe

complications associated with measles

infection and the absence of serious adverse events after measles

vaccination among HIV-infected persons

[41,45], ACIP has recommended that MMR vaccine be administered to all

asymptomatic HIV-infected persons

and that MMR vaccine be considered for administration to all

symptomatic HIV-infected persons who would

otherwise be eligible for measles vaccine--even though the immune

response may be attenuated in such

persons [41,44,45]. There is a theoretical risk for an in-crease

(probably transient) in HIV viral load following

MMR vaccination because such effects have been observed with other

vaccines [46,47].

Because of the recently reported case of pneumonitis in a measles

vaccinee who had an advanced case of

acquired immunodeficiency syndrome (AIDS) [48] and because of other

evidence indicating a diminished

antibody response to measles vaccination among severely

immunocompromised persons [49], ACIP is

re-evaluating the recommendations for vaccination of severely

immunocompromised HIV-infected persons. In

the interim, it may be prudent to withhold MMR or other

measles-containing vaccines from HIV-infected

persons with evidence of severe immunosuppression, defined as either

a) CD4+ T-lymphocyte counts <750 for

children ages <12 months, <500 for children ages 1-5 years, or <200

for persons ages >=6 years; orb) CD4+

T-lymphocytes constituting <15% of total lymphocytes for children ages

<13 years or <14% for persons ages

>=13 years [50,51].

ACIP continues to recommend MMR for HIV-infected persons without

evidence of measles immunity [47] who

are not severely immunocompromised [50,51]. Severely immunocompromised

and other symptomatic

HIV-infected patients who are exposed to measles should receive immune

globulin (IG), regardless of prior

vaccination status [44]. In addition, health-care providers should

weigh the risks and benefits of measles

vaccination or IG prophylaxis for severely immunocompromised

HIV-infected patients who are at risk for

measles exposure because of outbreaks or international travel.

Because the immunologic response to both live and killed antigen

vaccines may decrease as HIV disease

progresses [44,52], vaccination early in the course of HIV infection

may be more likely to induce an immune

response. Therefore, HIV-infected infants without severe

immunosuppression should routinely receive MMR as

soon as possible upon reaching their first birthday. Evaluation and

testing of asymptomatic persons to

identify HIV infection are not necessary before deciding to administer

MMR or other measles-containing

vaccine [44].

Management of Patients with Contraindications to Measles Vaccine

If immediate protection against measles is required for persons with

contraindications to measles vaccination,

passive immunization with IG, 0.25 mL/kg (0.11 mL/lb) of body weight

(maximum dose=15 mL), should be given

as soon as possible after known exposure. Exposed symptomatic

HIV-infected and other immunocompromised

persons should receive IG regardless of their previous vaccination

status; however, IG in usual doses may not be

effective in such patients. For immunocompromised per-sons, the

recommended dose is 0.5 mL/kg of body weight

if IG is administered intramuscularly (maximum dose=15 mL). This

corresponds to a dose of protein of

approximately 82.5 mg/kg (maximum dose=2,475 mg). Intramuscular IG may

not be needed if a patient with HIV

infection is receiving 100-400 mg/kg IGIV at regular intervals and the

last dose was given within 3 weeks of

exposure to measles. Because the amounts of protein administered are

similar, high-dose IGIV may be as effective

as IG given intramuscularly. However, no data are available concerning

the effectiveness of IGIV in preventing

measles.

Simultaneous Administration of Vaccines

In general, simultaneous administration of the most widely used live and

inactivated vaccines does not impair

antibody responses or increase rates of adverse reactions [53]. The

administration of MMR vaccine yields results

similar to the administration of individual measles, mumps, and rubella

vaccines at different sites or at different

times.

Vaccines recommended for administration at 12-15 months of age can be

administered at either one or two

visits. There are equivalent antibody responses and no clinically

significant increases in the frequency of

adverse events when DTP, MMR, and OPV (or IPV) vaccines and H.

influenzae type b conjugate vaccine (HbCV)

are ad-ministered either simultaneously at different sites or at

separate times. If a child might not be brought

back for future vaccinations, all vaccines (including DTP [or DTaP],

OPV[or IPV], MMR, varicella, HbCV, and

hepatitis B vaccines) may be administered simultaneously, as appropriate

to the child's age and previous

vaccination status.

Mumps Prevention

The following recommendations concerning adverse events associated

with mumps vaccination update those

applicable sections in " Mumps Prevention " (MMWR

1989;38:388-92,397-400), and they apply regardless of

whether the vaccine is administered as a single antigen or as a

component of MR or MMR vaccine. Information

concerning adverse events associated with the measles component of MMR

vaccine is reviewed earlier in this

document (see Measles Prevention), and information concerning the

rubella component is located in the

previously published ACIP statement for rubella [18].

Adverse Effects of Vaccine Use

In field trials before licensure, illnesses did not occur more often in

vaccinees than in unvaccinated controls [54].

Reports of illnesses following mumps vaccination have mainly been

episodes of parotitis and low-grade fever.

Allergic reactions including rash, pruritus, and purpura have been

temporally associated with mumps

vaccination but are uncommon and usually mild and of brief duration. The

reported occurrence of encephalitis

within 30 days of receipt of a mumps-containing vaccine (0.4 per million

doses) is not greater than the observed

background incidence rate of CNS dysfunction in the normal population.

Aseptic meningitis has been

epidemiologically associated with receipt of the vaccine containing the

Urabe strain of mumps virus,

but not with the vaccine containing the Jeryl Lynn strain, the latter of

which is used in vaccine

distributed in the United States [5]. During 1988-1992, 15 sentinel

surveillance laboratories in the

United Kingdom identified 13 aseptic meningitis cases that had occurred

within 15-35 days after

vaccination with the Urabe strain (i.e., 91 cases per 1 million doses

distributed) [55]. No

vaccine-associated aseptic meningitis cases have been re-ported since

1992, when only the Jeryl Lynn

strain has been used [23]. Febrile seizures also have been infrequently

reported. However, no

evidence suggests that mumps vaccine causes residual seizure disorder

[5]. Although sensorineural

deafness following mumps vaccination has been reported rarely, the data

are inadequate to

distinguish vaccine from nonvaccine causation. No association has been

established between mumps

vaccination and pancreatic damage or subsequent development of diabetes

mellitus [5].

Contraindications to Vaccine Use

Pregnancy

Although mumps vaccine virus has been shown to infect the placenta and

fetus [56] , there is no evidence that it

causes congenital malformations in humans. How-ever, because of the

theoretical risk of fetal damage, it is

prudent to avoid giving live virus vaccine to pregnant women. Live mumps

vaccine, when combined with rubella

vaccine, should not be administered to women known to be pregnant or who

are considering becoming pregnant

within the next 3 months. Women vaccinated with monovalent mumps vaccine

should avoid becoming pregnant

for 30 days after the vaccination. Routine precautions for vaccinating

postpubertal women include asking if they

are or may be pregnant, excluding those who say they are, and explaining

the theoretical risk to those who plan

to receive the vaccine. Vaccination during pregnancy should not be

considered an indication for termination of

pregnancy. However, the final decision about interruption of pregnancy

must rest with the individual patient

and her physician.

Severe Febrile Illness

Vaccine administration should not be postponed because of minor or

intercurrent febrile illnesses, such as mild

upper respiratory infections. However, vaccination of persons with

severe febrile illnesses should generally be

deferred until they have re-covered from the acute phase of the illness.

Allergic Reactions

Hypersensitivity reactions rarely occur after the administration of

MMR or any of its component vaccines. Most

of these reactions are minor and consist of a wheal and flare or

urticaria at the injection site. Immediate,

anaphylactic reactions to MMR or its component vaccines are extremely

rare. Although >70 million doses of

MMR vaccine have been distributed in the United States since VAERS was

implemented in 1990, only 33 cases

of anaphylactic reactions that occurred after MMR vaccination have

been reported. Furthermore, only 11 of

these cases a) occurred immediately after vaccination and occurred

in persons who had symptoms

consistent with anaphylaxis (CDC, unpublished data).

In the past, persons who had a history of anaphylactic reactions

(i.e., hives, swelling of the mouth or throat,

difficulty breathing, hypotension, and shock) following egg ingestion

were considered to be at increased risk

for serious reactions after receipt of mumps-containing vaccines,

which are produced in chick embryo

fibroblasts. Protocols requiring caution were developed for skin

testing and vaccinating persons who had had

anaphylactic reactions after egg ingestion [30-34]. However, the

predictive value of such skin testing and the

need for special protocols when vaccinating egg-allergic persons with

mumps-containing vaccines is uncertain.

The results of re-cent studies suggest that anaphylactic reactions to

mumps-containing vaccines are not

associated with hypersensitivity to egg antigens but with some other

component of the vaccines. The risk for

serious allergic reaction to these vaccines in egg-allergic patients

is extremely low, and skin testing is not

necessarily predictive of vaccine hypersensitivity [35-37]. Therefore,

ACIP is re-evaluating whether skin testing

and the use of special protocols are routinely necessary when

administering mumps-containing vaccines to

persons who have a history of anaphylactic-like reactions after egg ingestion.

MMR and its component vaccines contain hydrolyzed gelatin as a

stabilizer. The literature contains a single

case report of a person with an anaphylactic sensitivity to gelatin

who had an anaphylactic reaction after

receipt of the MMR vaccine licensed in the United States [38]. Similar

cases have occurred in Japan [39].

Therefore, ACIP is currently considering recommendations for

vaccination of persons who have had

ananaphylactic reaction to gelatin or gelatin-containing products. In

the meantime, such persons should be

vaccinated with MMR or other mumps vaccines with extreme caution.

Since mumps vaccine contains trace amounts of neomycin (25 mg), persons

who have experienced anaphylactic

reactions to topically or systemically administered neomycin should not

receive mumps vaccine. Most often,

neomycin allergy is manifested as a contact dermatitis, which is a

delayed-type (cell-mediated) immune response,

rather than anaphylaxis. In such persons, the adverse reaction, if any,

to 25 mg of neomycin in the vaccine

would be an erythematous, pruritic nodule or papule at the site of

injection after 48-96 hours. A history of

contact dermatitis to neomycin is not a contraindication to receiving

mumps vaccine. Live mumps virus vaccine

does not contain penicillin.

Recent Injection of Immune Globulin

The effect of immune globulin preparations on the response to mumps

vaccine is unknown, but commercial

immune globulin preparations contain mumps antibodies. Therefore,

monovalent mumps or rubella-mumps

vaccine should be given at least 2 weeks before the administration of

an immune globulin preparation or

deferred until approximately 3 months after the administration of an

immune globulin preparation. For

suggested time intervals between administration of immune globulin

preparations and vaccines containing

live measles virus, refer to Table 5.

Altered Immunocompetence

In theory, replication of the mumps vaccine virus may be potentiated

in patients with immune deficiency

diseases and by the suppressed immune responses that occur with

leukemia, lymphoma, or generalized

malignancy or with therapy with corticosteroids, alkylating drugs,

antimetabolites, or radiation. In general,

patients with such conditions should not be given live mumps virus

vaccine. Because vaccinated persons do

not transmit mumps vaccine virus, the risk of mumps exposure for those

patients may be reduced by

vaccinating their close susceptible contacts.

An exception to these general recommendations is in persons infected

with HIV; asymptomatic HIV-infected

children should receive MMR as soon as possible upon reaching their

first birthday [44], and MMR vaccine

should be considered for all symptomatic HIV-infected children who do

not have evidence of severe

immunosuppression (see Measles Prevention, Altered Immunocompetence).

Patients with leukemia in remission whose chemotherapy has been

terminated for at least 3 months may also

receive live mumps virus vaccine. Most experts agree that steroid

therapy usually does not contraindicate

administration of live virus vaccine when it is short term (i.e., <2

weeks); low to moderate dose; long-term,

alternate-day treatment with short-acting preparations; maintenance

physiologic doses (replacement therapy);

or administered topically (skin or eyes), by aerosol, or by

intra-articular, bursal, or tendon injection [44].

However, mumps vaccine should be avoided if systemic immunosuppressive

levels are reached by prolonged,

extensive, topical application.

DTP

The following recommendations concerning adverse events associated

with DTP vaccination update those

applicable sections in " Diphtheria, Tetanus, and Pertussis:

Recommendations for Vaccine Use and Other

Preventive Measures-- Recommendations of the Immunization Practices

Advisory Committee (ACIP) " (MMWR

1991;40[No. RR-10]).

Side Effects and Adverse Reactions Following DTP Vaccination

Local reactions (generally erythema and induration with or without

tenderness) are common after the

administration of vaccines containing diphtheria, tetanus, or pertussis

antigens. Occasionally, a nodule may be

palpable at the injection site of adsorbed products for several weeks.

Sterile abscesses at the injection site have

been reported rarely (6-10 events per million doses of DTP). Mild

systemic reactions such as fever, drowsiness,

fretfulness, and anorexia occur frequently. These reactions are

substantially more common following the

administration of DTP than of DT, but they are self-limited and can be

safely managed with symptomatic

treatment.

Acetaminophen is frequently given by physicians to lessen fever and

irritability associated with DTP vaccination,

and it may be useful in preventing seizures among

febrile-convulsion-prone children. However, fever that does

not begin until >=24 hours after vaccination or persists for more than

24 hours after vaccination should not be

assumed to be due to DTP vaccination. These new or persistent fevers

should be evaluated for other causes so

that treatment is not delayed for serious conditions such as otitis

media or meningitis. Moderate-to-severe

systemic events include high fever (i.e., temperature of >=40.5 C [

>=105 F]); persistent, inconsolable crying

lasting >=3 hours; collapse (hypotonic-hyporesponsive episode); or

short-lived convulsions (usually febrile).

These events occur infrequently. These events appear to be without

sequelae [57-59]. Other more severe

neurologic events, such as a prolonged convulsion orencephalopathy,

although rare, have been reported in

temporal association with DTP administration.

Approximate rates for the occurrence of adverse events following receipt

of DTP (regardless of dose number in

the series or age of the child) are shown in Table 6 [60,61]. The

frequencies of local reactions and fever are

substantially higher with in-creasing numbers of doses of DTP, while

other mild-to-moderate systemic reactions

(e.g., fretfulness, vomiting) are substantially less frequent [59-61].

Concern about the possible role of pertussis vaccine in causing

neurologic reactions has been present since the

earliest days of vaccine use. Rare but serious acute neurologic

illnesses, including encephalitis/encephalopathy

and prolonged convulsions, have been anecdotally reported following

receipt of whole-cell pertussis vaccine

given as DTP [62,63]. Whether pertussis vaccine causes or is only

coincidentally related to such illnesses or

reveals an inevitable event has been difficult to determine conclusively

for the following reasons: a) serious

acute neurologic illnesses often occur or become manifest among children

during the first year of life irrespective

of vaccination; there is no specific clinical sign, pathologic

finding, or laboratory test which can determine

whether the illness is caused by the DTP; c) it may be difficult to

determine with certainty whether infants <6

months of age are neurologically normal, which complicates assessment of

whether vaccinees were already

neurologically impaired before receiving DTP; and d) because these

events are exceedingly rare, appropriately

designed large studies are needed to address the question.

Despite these methodologic difficulties, the National Childhood

Encephalopathy Study (NCES) and other

controlled epidemiologic studies have provided evidence that DTP can

cause acute encephalopathy [64-68].

This adverse event occurs rarely, with an estimated risk of zero to

10.5 episodes per million DTP vaccinations

[68]. A detailed follow-up of the NCES indicated that children who had

had a serious acute neurologic illness

after DTP administration were significantly more likely than children

in the control group to have chronic

nervous system dysfunction 10 years later. These children with chronic

nervous system dysfunction were

more likely than children in the control group to have received DTP

within 7 days of onset of the original

serious acute neurologic illness (i.e., 12 [3.3%] of 367 children vs.

six [0.8%] of 723 children) [69].

After reviewing the follow-up data, IOM concluded that the NCES

provided evidence of an association between

DTP and chronic nervous system dysfunction in children who had had a

serious acute neurologic illness after

vaccination with DTP. The committee proposed three possible

explanations for this association. First, the acute

neurologic illness and subsequent chronic nervous system dysfunction

might have been caused by DTP.

Second, DTP might trigger an acute neurologic illness and subsequent

chronic nervous system dysfunction in

children who have underlying brain or metabolic abnormalities. Such

children might experience similar

chronic dysfunction in the absence of DTP vaccination if other stimuli

(e.g., fever or infection) are present.

Third, DTP might cause an acute neurologic illness in children who

have underlying brain or metabolic

abnormalities that would inevitably have led to chronic nervous system

dysfunction even if the acute

neurologic illness had not developed [6]. IOM concluded that the NCES

data do not support one explanation

over another.

According to IOM, the balance of evidence was consistent with a causal

relation-ship between DTP and some

forms of chronic nervous system disorders in children who had

developed an acute neurologic disorder after

receiving DTP. However, IOM also concluded that the results were

insufficient to determine whether DTP

increases the overall risk for chronic nervous system dysfunction in children.

A subcommittee of the National Vaccine Advisory Committee (NVAC) also

re-viewed the study and concluded

that the results were insufficient to determine whether DTP

administration before the acute neurologic event

influenced the potential for neurologic dysfunction 10 years later (Ad

hoc Subcommittee of the NVAC,

unpublished data, 1994). ACIP concurs with this evaluation.

Although the NCES examined and reported risk for the 7 days after DTP

vaccination, the increased risk for

serious acute neurologic illness occurred primarily during the first 3

days after DTP administration [64]. Thus,

if an association between DTP and chronic encephalopathy exists, the

risk is primarily in the first 3 days after

DTP vaccination.

Among a subset of children who were participating in the NCES and who

had infantile spasms, both DTP and

DT vaccination appeared either to precipitate early manifestations of

the condition or to lead to its

identification by parents [70]. IOM reviewed this and other studies

and concluded that neither vaccine causes

the illness [71,72].

Sudden infant death syndrome (SIDS) is listed on death certificates as

the cause of death for 5,000-6,000 infants

(ages 0-364 days) each year in the United States. Be-cause the peak

incidence of SIDS for infants occurs at 2-4

months of age, many instances of a close temporal relation between SIDS

and receipt of DTP are to be expected

by simple chance. Only one methodologically rigorous study has suggested

that DTP vaccination might cause

SIDS [73]. A total of four deaths were reported within 3 days of DTP

vaccination, compared with 1.36 expected

deaths. However, these deaths were unusual in that three of the four

occurred within a 13-month interval during

the 12-year study. These four children also tended to be vaccinated at

older ages than their controls, suggesting

that they might have had other unrecognized risk factors for SIDS

independent of vaccination. In contrast, DTP

vaccination was not associated with SIDS in several larger studies

performed in the past decade [62,74-76]. In

addition, none of three studies that examined unexpected deaths among

infants not classified as SIDS found an

association with DTP vaccination [73,75,76]. IOM re-viewed these studies

and concluded that the available

information does not establish a causal relationship between DTP and

SIDS [4].

IOM concluded recently that no available evidence indicates that DTP

might cause transverse myelitis,

other more subtle neurologic disorders (e.g., hyperactivity, learning

disorders, and infantile autism),

and progressive degenerative conditions of the CNS [4]. Furthermore, one

study indicated that children

who received pertussis vaccine exhibited fewer school problems than

those who did not, even after adjustment

for socioeconomic status [77].

Recent data suggest that infants and young children who have ever had

convulsions (febrile or afebrile) or who

have immediate family members with such histories are more likely to

have seizures following DTP vaccination

than those without such histories [78,79]. For those with a family

history of seizures, the increased risks of

seizures occurring within 3 days of receipt of DTP or 4-28 days

following receipt of DTP are identical, suggesting

that these histories are nonspecific risk factors and are unrelated to

DTP vaccination [79].

Rarely, immediate anaphylactic reactions (i.e., swelling of the mouth,

breathing difficulty, hypotension, or shock)

have been reported after receipt of preparations containing diphtheria,

tetanus, and/or pertussis antigens.

However, no deaths caused by anaphylaxis following DTP vaccination have

been reported to CDC since the

inception of vaccine-adverse-events reporting in 1978, a period during

which more than 80 million doses of

publicly purchased DTP vaccine were administered. While substantial

under reporting exists in this passive

surveillance system, the severity of anaphylaxis and its immediacy

following vaccination suggest that such

events are likely to be reported. Although no causal relation to any

specific component of DTP has been

established, the occurrence of true anaphylaxis usually contraindicates

further doses of any one of these

components. Rashes that are macular, papular, petechial, or urticarial

and appear hours or days after a dose of

DTP are frequently antigen-antibody reactions of little consequence or

are due to other causes, such as viral

illnesses, and are unlikely to recur following subsequent injections

[80,81]. In addition, there is no evidence for a

causal relation between DTP vaccination and hemolytic anemia or

thrombocytopenic purpura.

Precautions and Contraindications

General Considerations

The decision to administer or delay DTP vaccination because of a current

or recent febrile illness depends largely

on the severity of the symptoms and their etiology. Although a moderate

or severe febrile illness is sufficient

reason to postpone vaccination, minor illnesses such as mild

upper-respiratory infections with or without

low-grade fever are not contraindications. If ongoing medical care

cannot be assured, taking every opportunity

to provide appropriate vaccinations is particularly important.

Children with moderate or severe illnesses with or without fever can

receive DTP as soon as they have recovered.

Waiting a short period before administering DTP avoids superimposing the

adverse effects of the vaccination on

the underlying illness or mistakenly attributing a manifestation of the

underlying illness to vaccination.

Routine physical examinations or temperature measurements are not

prerequisites for vaccinating infants and

children who appear to be in good health. Appropriate immunization

practice includes asking the parent or

guardian if the child is ill, postponing DTP vaccination for those with

moderate or severe acute illnesses, and

vaccinating those without contraindications or precautionary circumstances.

When an infant or child returns for the next dose of DTP, the parent

should always be questioned about any

adverse events that might have occurred following the previous dose.

A history of prematurity generally is not a reason to defer vaccination

[82-84]. Pre-term infants should be

vaccinated according to their chronological age from birth.

Immunosuppressive therapies--including irradiation, antimetabolites,

alkylating agents, cytotoxic drugs, and

corticosteroids (used in greater than physiologic doses)--may reduce the

immune response to vaccines.

Short-term (<2-week) corticosteroid therapy or intra-articular, bursal,

or tendon injections with corticosteroids

should not be immunosuppressive. Although no specific studies with

pertussis vaccine are avail-able, if

immunosuppressive therapy will be discontinued shortly, it is reasonable

to defer vaccination until the patient

has been off therapy for 1 month; otherwise, the patient should be

vaccinated while still on therapy [85].

Special Considerations for Preparations Containing Pertussis Vaccine

Precautions and contraindications guidelines that were previously

published regarding the use of pertussis

vaccine were based on three assumptions about the risks for adverse

events associated with pertussis

vaccination: a) that the vaccine on rare occasions caused acute

encephalopathy resulting in permanent brain

damage; that pertussis vaccine aggravated preexisting CNS disease;

and c) that certain non-encephalitic

reactions are predictive of more severe reactions with subsequent doses

[86]. In addition, children from whom

pertussis vaccine was withheld were thought to be well protected by herd

immunity, a belief that is no longer

valid. The current revised ACIP recommendations reflect better

understanding of the risks associated not only

with pertussis vaccine but also with pertussis disease.

Contraindications

If any of the following events occur in temporal relationship to the

administration of DTP, further vaccination

with DTP is contraindicated (Table 7):

1.An immediate anaphylactic reaction. The rarity of such reactions to

DTP is such that they have not been

adequately studied. Because of uncertainty as to which component

of the vaccine might be responsible, no

further vaccination with any of the three antigens in DTP should

be carried out. Alternatively, because of

the importance of tetanus vaccination, such individuals may be

referred for evaluation by an allergist and

desensitized to tetanus toxoid if a specific allergy can be

demonstrated [87,88].

2.Encephalopathy (not due to another identifiable cause). This is

defined as an acute, severe CNS

disorder occurring within 7 days following vaccination and

generally consisting of major alterations in

consciousness, unresponsiveness, generalized or focal seizures

that persist more than a few hours, with

failure to recover within 24 hours. Even though causation by DTP

cannot be established, no subsequent

doses of pertussis vaccine should be given. It may be desirable

to delay for months before administering the

balance of the doses of DT necessary to complete the primary

schedule. Such a delay allows time for

clarification of the child's neurologic status.

Precautions

If any of the following events occur in temporal relation to receipt of

DTP, the decision to give subsequent doses

of vaccine containing the pertussis component should be carefully

considered (Table 7). Although these events

were considered absolute contraindications in previous ACIP

recommendations, there may be circumstances,

such as a high incidence of pertussis, in which the potential benefits

outweigh possible risks, particularly

because these events are not associated with permanent sequelae [86].

The following events were previously

considered contraindications and are now considered precautions:

1.Temperature of >=40.5 C (>=105 F) within 48 hours not due to another

identifiable cause. Such a

temperature is considered a precaution because of the likelihood

that fever following a subsequent dose of

DTP also will be high. Because such febrile reactions are usually

attributed to the pertussis component,

vaccination with DT should not be discontinued.

2.Collapse or shock-like state (hypotonic-hyporesponsive episode)

within 48 hours. Although these

uncommon events have not been recognized to cause death nor to

induce permanent neurological sequelae,

it is prudent to continue vaccination with DT, omitting the

pertussis component [58,89].

3.Persistent, inconsolable crying lasting >=3 hours, occurring within

48 hours. Follow-up of infants

who have cried inconsolably following DTP vaccination has

indicated that this reaction, though unpleasant,

is without long-term sequelae and not associated with other

reactions of greater significance [59].

Inconsolable crying occurs most frequently following the first

dose and is less frequently reported following

subsequent doses of DTP [60]. However, crying for >30 minutes

following DTP vaccination can be a predictor

of increased likelihood of recurrence of persistent crying

following subsequent doses [59] . Children with

persistent crying have had a higher rate of substantial local

reactions than children who had other

DTP-associated reactions (including high fever, seizures, and

hypotonic-hyporesponsive episodes),

suggesting that prolonged crying was really a pain reaction [89].

4.Convulsions with or without fever occurring within 3 days.

Short-lived convulsions, with or without

fever, have not been shown to cause permanent sequelae [57,90].

Furthermore, the occurrence of prolonged

febrile seizures (i.e., status epilepticus***), irrespective of

their cause, involving an otherwise normal child

does not substantially increase the risk for subsequent febrile

(brief or prolonged) or afebrile seizures. The

risk is significantly increased (p=0.018) only among those

children who are neurologically abnormal before

their episode of status epilepticus [91]. Accordingly, although a

convulsion following DTP vaccination has

previously been considered a contraindication to further doses,

under certain circumstances subsequent

doses may be indicated, particularly if the risk of pertussis in

the community is high. If a child has a seizure

following the first or second dose of DTP, it is desirable to

delay subsequent doses until the child's

neurologic status is better defined. By the end of the first year

of life, the presence of an underlying

neurologic disorder has usually been determined and appropriate

treatment instituted. DT vaccine should

not be administered before a decision has been made about whether

to restart the DTP series. Regardless of

which vaccine is given, it is prudent also to administer

acetaminophen, 15 mg/kg of body weight, at the time

of vaccination and every 4 hours subsequently for 24 hours

[92,93].

Vaccination of Infants and Young Children Who Have Underlying Neurologic

Disorders

Infants and children with recognized, possible, or potential underlying

neurologic conditions present a unique

problem. They seem to be at increased risk for the appearance of

manifestations of the underlying neurologic

disorder within 2-3 days after vaccination. However, more prolonged

manifestations or increased progression of

the disorder or exacerbation of the disorder as a result of DTP

vaccination have not been recognized [94]. In

addition, most neurologic conditions in infancy and young childhood are

associated with evolving, changing

neurological findings. Functional abnormalities are often unmasked by

progressive neurologic development.

Thus, confusion over the interpretation of progressive neurologic signs

may arise when DTP vaccination or any

other therapeutic or preventive measure is carried out.

Protection against diphtheria, tetanus, and pertussis is as important

for children with neurologic disabilities as

for other children. Such protection may be even more important for

neurologically disabled children. They often

receive custodial care or attend special schools where the risk of

pertussis is greater because DTP vaccination is

avoided for fear of adverse reactions. Also, if pertussis affects a

neurologically disabled child who has difficulty

in handling secretions and in cooperating with symptomatic care, it may

aggravate preexisting neurologic

problems because of anoxia, intracerebral hemorrhages, and other

manifestations of the disease. Whether and

when to administer DTP to children with proven or suspected underlying

neurologic disorders must be decided

on an individual basis. Important considerations include the current

local incidence of pertussis, the near

absence of diphtheria in the United States, and the low risk of

infection with Clostridium tetani. On the basis of

these considerations and the nature of the child's disorder, the

following approaches are recommended:

1.Infants and children with previous convulsions. Infants and young

children who have had prior

seizures, whether febrile or afebrile, appear to be at in-creased

risk for seizures following DTP vaccination

than children and infants without these histories [79]. A

convulsion within 3 days of DTP vaccination in a

child with a history of convulsions may be initiated by fever

caused by the vaccine in a child prone to febrile

seizures, may be induced by the pertussis component, or may be

unrelated to the vaccination. As noted

earlier, current evidence indicates that seizures following DTP

vaccination do not cause permanent brain

damage. Among infants and children with a history of previous

seizures, it is prudent to delay DTP

vaccination until the child's status has been fully assessed, a

treatment regimen established, and the

condition stabilized. It should be noted, however, that delaying

DTP vaccination until the second 6 months

of life will increase the risk of febrile seizures among persons

who are predisposed. When DTP or DT is

given, acetaminophen, 15 mg/kg, should also be given at the time

of the vaccination and every 4 hours for

the ensuing 24 hours [92,93].

2.Infants as yet unvaccinated who are suspected of having underlying

neurologic disease. It is

prudent to delay initiation of vaccination with DTP or DT (but

not other vaccines) until further observation

and study have clarified the child's neurologic status and the

effect of treatment. The decision as to whether

to begin vaccination with DTP or DT should be made no later than

the child's first birthday.

3.Children who have not received a complete series of vaccine and who

have a neurologic event

occurring between doses. Infants and children who have received

one or more doses of DTP and who

experience a neurologic disorder (e.g., a seizure) not temporally

associated with vaccination, but before the

next scheduled dose, present a special management challenge. If

the seizure or other disorder occurs before

the first birthday and before completion of the first three doses

of the primary series of DTP, further doses

of DTP or DT (but not other vaccines) should be deferred until

the infant's status has been clarified. The

decision whether to use DTP or DT to complete the series should

be made no later than the child's first

birthday and should take into consideration the nature of the

child's problem and the benefits and possible

risks of the vaccine. If the seizure or other disorder occurs

after the first birthday, the child's neurologic

status should be evaluated to ensure that the disorder is stable

before a subsequent dose of DTP is given.

4.Infants and children with stable neurologic conditions. Infants and

children with stable neurologic

conditions, including well-controlled seizures, may be

vaccinated. The occurrence of single seizures

(temporally unassociated with DTP) do not contraindicate DTP

vaccination, particularly if the seizures can

be satisfactorily explained. Parents of infants and children with

histories of convulsions should be informed

of the increased risk of postvaccination seizures. Acetaminophen,

15 mg/kg, every 4 hours for 24 hours,

should be given to children with such histories to reduce the

possibility of postvaccination fever [92,93].

5.Children with resolved or corrected neurologic disorders. DTP

vaccination is recommended for infants

with certain neurologic problems, such as neonatal hypocalcemic

tetany or hydrocephalus (following

placement of a shunt and without seizures), that have been

corrected or have clearly subsided without

residua.

Vaccination of Infants and Young Children Who Have a Family History of

Convulsion or Other CNS

Disorder

A family history of convulsions or other CNS disorder is not a

contraindication to pertussis vaccination [95].

Acetaminophen should be given at the time of DTP vaccination and every 4

hours for 24 hours to reduce the

possibility of postvaccination fever [92,93].

Preparations Containing Diphtheria Toxoid and Tetanus Toxoid

The only contraindication to tetanus and diphtheria toxoids is a history

of a neurologic or severe

hypersensitivity reaction following a previous dose. Vaccination with

tetanus and diphtheria toxoids is not

known to be associated with an increased risk of convulsions. Local side

effects alone do not preclude continued

use. If an anaphylactic reaction to a previous dose of tetanus toxoid is

suspected, intradermal skin testing with

appropriately diluted tetanus toxoid may be useful before a decision is

made to discontinue tetanus toxoid

vaccination [86]. In one study, 94 of 95 persons with histories of

anaphylactic symptoms following a previous

dose of tetanus toxoid were nonreactive following intradermal testing

and tolerated further tetanus toxoid

challenge without incident [86]. One person had erythema and induration

immediately following skin testing, but

tolerated a full IM dose without adverse effects. Mild, nonspecific

skin-test reactivity to tetanus toxoid,

particularly if used undiluted, appears to be fairly common. Most

vaccinees develop inconsequential cutaneous

delayed hypersensitivity to the toxoid. Although very rare, severe

hypersensitivity re-actions may occur

after receipt of tetanus-toxoid-containing vaccines; these reactions can

be life-threatening [5].

Persons who experienced Arthus-type hypersensitivity reactions or a

temperature of >103 F (>39.4 C) following

a prior dose of tetanus toxoid usually have high serum tetanus antitoxin

levels and should not be given even

emergency doses of Td more frequently than every 10 years, even if they

have a wound that is neither clean nor

minor.

If a contraindication to using tetanus-toxoid-containing preparations

exists for a person who has not completed a

primary series of tetanus toxoid immunization and that person has a

wound that is neither clean nor minor,

only passive immunization should be given using tetanus IG (TIG).

On the basis of a) a report of a 42-year-old man who had GBS on three

separate occasions after receipt of

tetanus toxoid and evidence that a vaccine-induced immunologic

response can cause GBS, IOM concluded

that tetanus-toxoid-containingvaccines can trigger the onset of GBS in

adults. GBS can be a life-threatening

disease. Persons who have a history of GBS associated with a

particular vaccine may be at increased risk for

recurrent GBS after subsequent doses of that vaccine [5]. However, in

a study in which an estimated 1.2 million

doses of tetanus-containing toxoid were administered to persons >18

years of age, two cases of GBS were

expected by chance alone during the 6 weeks after vaccination, and

only one case was reported (CDC,

unpublished data). This finding suggests that the risk for GBS after

administration of tetanus toxoid is

extremely low.

No increased risk for GBS has been observed with the use of DTP in

children. In a study of 0.7 million children

of preschool-ages who were vaccinated with DTP during a 7-year period,

three cases of GBS were expected by

chance alone during the 6 weeks after vaccination, and only two cases

were reported [17].

Because tetanus vaccination has been associated rarely with recurrence

of GBS, the decision to administer

additional doses of tetanus-toxoid-containing vaccine to persons who

have had GBS within 6 weeks after

receiving tetanus toxoid should be based on the benefits of subsequent

vaccination and the risk for recurrence

of GBS. For example, vaccination is usually justified for children

whose primary immunization schedules are

incomplete (i.e., fewer than three doses have been received); but

routine booster vaccination probably is not

indicated for adults who have received three or more doses.

Vaccination with tetanus-toxoid-containing vaccines has been

associated with brachial neuritis in adult

vaccinees, with a relative risk of 5-10 in comparison with the

population-based background incidence and a

1-month attributable incidence of approximately one-half to one case

per 100,000 recipients of tetanus toxoid

[5].

Although no evidence exists that tetanus and diphtheria toxoids are

teratogenic, waiting until the second

trimester of pregnancy to administer Td is a reasonable pre-caution for

minimizing any concern about the

theoretical possibility of such reactions.

Misconceptions Concerning Contraindications to DTP

Some health-care providers inappropriately consider certain conditions

or circumstances as contraindications to

DTP vaccination. These include the following:

1.Soreness, redness, or swelling at the DTP vaccination site or

temperature of <40.5 C (<105 F).

2.Mild, acute illness with low-grade fever or mild diarrheal illness

affecting an otherwise healthy child.

3.Current antimicrobial therapy or the convalescent phase of an acute

illness.

4.Recent exposure to an infectious disease.

5.Prematurity. The appropriate age for initiating vaccination among

the prematurely born infant is the usual

chronological age from birth [82-84]. Full doses (0.5 mL) of

vaccine should be used.

6.History of allergies or relatives with allergies.

7.Family history of convulsions.

8.Family history of SIDS.

9.Family history of an adverse event following DTP vaccination.

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Footnotes

* An independent research organization chartered by the National Academy

of Sciences.

** In this publication, the terms " side effects " and " adverse reactions "

are used interchangeably to denote the

undesirable secondary effects resulting from vaccination.

*** Any seizure lasting >30 minutes or recurrent seizures lasting a

total of 30 minutes without the child

regaining full consciousness.

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