National Academies Press: OpenBook

Adverse Effects of Pertussis and Rubella Vaccines (1991)

Chapter:6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions

« Previous: 5 Evidence Concerning Pertussis Vaccinces and Deaths Classified as Sudden Infant Death Syndrome (SIDS)
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 144

6
Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions

ANAPHYLAXIS

Clinical Description and Pathologic Aspects

The term anaphylaxis generally refers to a sudden, potentially life-threatening, systemic condition mediated by highly reactive molecules released from mast cells and basophils. Mediators include histamine, platelet-activating factor, and products of arachidonic acid metabolism (Fisher, 1987). Release of mediators depends typically upon the interaction of antigen with specific antibodies of the immunoglobulin E (IgE) class that are bound to the mast cells and basophils. Antibodies of other immunoglobulin classes are thought to mediate anaphylaxis on occasion. By definition, the antibodies are formed by prior exposure to the same or a closely related antigen. Anaphylaxis results from widespread release of mediators that enter the circulation, and thus, anaphylaxis is an expression of allergy that is systemic. At a cellular level, the reaction begins within seconds of exposure to the inciting antigen. However, depending upon the degree of sensitization (IgE antibody formation), and presumably upon the rate with which the antigen enters the circulation, localized or systemic symptoms may not be expressed for minutes or a few hours (Dolovich et al., 1973; Pearlman and Bierman, 1989). Symptoms are due to leaking of fluid from blood vessels, constriction of smooth muscle in certain viscera, and relaxation of vascular

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 145

smooth muscle. Classic symptoms include pallor and then diffuse erythema, urticaria and itching, subcutaneous edema, edema and spasm of the larynx, wheezing, tachycardia, hypotension, and hypovolemic shock (Kniker, 1988; Pearlman and Bierman, 1989). If death occurs, it is most commonly from airway obstruction caused by laryngeal edema or bronchospasm, or cardiovascular collapse from transudation of fluids from the intravascular space (Pearlman and Bierman, 1989). The tissues at autopsy show primarily widespread edema.

The clinical presentation of anaphylaxis can be produced by intravascular antigen-antibody reactions that activate the complement system. In this case, the antibodies may be of the IgG or IgM class. Peptides that are split from activated complement components act on mast cells and basophils to induce the release of the same mediators (Kniker, 1988). This reaction is recognized most clearly after intravenous administration of antigen; it has been hypothesized to occur rarely after intramuscular or subcutaneous injection through rapid entry (within 1 to 5 minutes) of large amounts of the antigen into the venous circulation. This reaction in an infant presumably could be mediated by IgG antibody received transplacentally from the mother; such antibody would be expected to persist for the first 6 months of life and possibly longer (Benacerraf and Kabat, 1950; Cohen and Scadron, 1946). Anaphylaxis also can occur without an obvious cause (Wiggins et al., 1989).

Shock caused by bacteremia with circulating bacterial endotoxin also appears to involve activation of the complement system (Fearon et al., 1975; Lachmann and Peters, 1982). Endotoxin shock has a clinical presentation different from that of anaphylaxis, however; it develops more slowly and is almost always associated with disseminated intravascular coagulation, with consumption of clotting factors and hemorrhage (Colman, 1989; Suffredini et al., 1989a,b). Endotoxin elicits the release of mediators of inflammation in addition to those from mast cells and basophils, including interleukin-1 and tumor necrosis factor (Michie et al., 1988; Morrison and Ryan, 1987). The Jarisch-Herxheimer reaction, described classically in patients with spirochetal disease within hours after beginning drug therapy, may be a form of endotoxemia or, at least, complement activation caused by circulating bacterial products (Bryceson, 1976).

The Arthus reaction is another immunologic response that can be associated with tissue damage. This reaction is mediated differently from anaphylaxis. The formation of antigen-antibody complexes with deposition in the walls of blood vessels is basic to this reaction. This is not an acute, immediately overwhelming condition. It generally develops over 12 to 24 hours if antibody levels are already high, or it can develop over several days (e.g., in serum sickness) as antibody levels increase and antigen persists. In this reaction, immune complexes in the walls of blood vessels

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 146

initiate an inflammatory reaction involving complement and white blood cells, particularly neutrophils. Tissue sections show acute inflammation, and profound tissue destruction can occur. The most common target organs in an Arthus-type reaction include kidney, skin, joints, lung, and brain (Henson, 1982).

History of Suspected Association with Pertussis Vaccines

Identical twins died 16 and 20 hours after their second DPT shot given at age 10 months (Werne and Garrow, 1946). Autopsy showed evidence of the vascular smooth muscle contraction and increased capillary permeability expected with anaphylaxis. Adverse reactions were not reported in other infants who received the same batch of vaccine. The injected material was sterile. The delayed response was noted to be atypical of the anaphylactic reactions reported to that time. The authors found no cases of anaphylactic reactions to DPT reported in the world's literature.

Evidence from Studies in Humans
Case Reports and Controlled Epidemiologic Studies

Anaphylaxis with shock is uncommon in infancy, but the exact frequency is unknown. Since the original reports in 1946, ''anaphylaxis" (sometimes used less strictly to apply to any type I or immediate hypersensitivity reaction) has been reported in additional infants after routine immunization with DPT. Osvath and colleagues (1979) reported 31 total complications that developed within 36 hours of injection of DPT vaccine into an estimated 300,000 children in Hungary. Five of the 31 reactions were urticaria, which is typically an IgE-mediated response; 7 other infants had severe shock with loss of consciousness (not necessarily allergic in origin) or laryngeal edema, a rate of 2.3 such reactions per 100,000 injections.  Eight of these 12 reactions occurred after the first injection, when specific IgE antibodies would not be expected to be present. (These are not passed from mother to infant across the placenta.) IgG antibodies to antigens in DPT might be present, however.  Serum total IgE levels were considered "moderately elevated" in 29 of the total 31 infants; the 2 babies with normal IgE levels were among those with allergic symptoms. Thus, serum IgE levels were not helpful in considering the possibility of allergy in these patients, and anaphylaxis was not proven.

Pollock and Morris (1983) analyzed data from the North West Thames region of England, where an intensified effort over the previous 7 years had

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 147

been undertaken to identify all severe adverse events following immunization. The authors identified events in two different ways: one derived from physicians' voluntary reports and the other from systematic review of hospital discharge diagnoses. Approximately 134,700 children completed courses of three doses of DPT vaccine (404,000 doses), and 135,500 children completed courses of DT vaccines. Eight children exhibited symptoms of anaphylaxis or collapse within 24 hours of receipt of DPT vaccine (some within minutes), for a rate of 6 cases per 100,000 children vaccinated (2 cases per 100,000 injections); an additional eight children exhibited similar symptoms after receiving primary or booster DT vaccine for an identical rate. The timing suggests that at least some of these cases may have been anaphylaxis. All children recovered without sequelae.

One hundred eighty-seven cases of anaphylaxis (ICD 9 code 995.0/999.4) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these 187 cases, 130 (70 percent) also received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physician's diagnosis was not required.

Two recent case reports (one an adult) describe a close temporal relationship between injection of DPT vaccine and an anaphylactic reaction (Leung, 1985; Ovens, 1986). Both patients survived without apparent long-term adverse effects.

Occurrence of a hypotonic, hyporesponsive state, or actual "collapse," has been reported after DPT administration (Cody et al., 1981; Galazka and Andrzejczak-Kardymowicz, 1972; Health Council of The Netherlands, 1987, 1988; Hopper, 1961). Its onset between 1 and 12 hours after immunization is compatible with an anaphylactic reaction, but other explanations are possible. Data regarding pathophysiology have not been given. (See the description of hypotonic, hyporesponsive episodes later in this chapter.)

Three of 13 children given three injections of DPT produced IgE antibody (in low levels) to the one pertussis antigen tested, pertussis toxin (PT) (Hedenskog et al., 1989), demonstrating that at least a weak IgE antibody response can occur after immunization.

Bordetella pertussis vaccine has been shown to increase the sensitivity of rodents to the effects of injected histamine (Arora et al., 1970; Munoz, 1985; Munoz and Bergman, 1968). Conceivably related is the finding that intradermal injection of histamine produced significantly larger wheals in infants after (compared to before) immunization with DPT vaccine (Sen et al., 1974). Results were maximal after 24 hours and increased markedly for 5 to 7 days. Reactions were equivalent after the first, second, or third

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 148

DPT shots. Injection of DT into children aged 2 to 5 years (a control group) did not increase the dermal response to histamine, but this population was not age-matched to that given DPT. It is not clear that these findings have any relationship to the occurrence of anaphylaxis after injection of DPT.

A 45-year-old male volunteer who was hyperimmunized with pertussis vaccine (eight shots of 2.4 NIH [National Institutes of Health] protective units each) to produce anti-pertussis immune globulin died of progressive renal failure secondary to a chronic diffuse vasculitis (Bishop et al., 1966). No etiology was proven for the vasculitis, but the case raises the possibility that an Arthus-type reaction was initiated by an antigen in the vaccine. The extraordinary hyperimmunization makes it impossible to extrapolate to possible responses to standard immunization practices.

Evidence from Studies in Animals

Pertussis vaccine is said to act as an adjuvant in the formation of skinsensitizing, IgE-like antibody in mice and rats (Clausen et al., 1970; Munoz and Bergman, 1977). At least two substances in the DPT vaccine, PT protein and endotoxin, are believed to have the potential for such an adjuvant effect (Munoz and Bergman, 1977; Tada et al., 1972).

Injection of B. pertussis vaccine has been shown to facilitate the induction of anaphylactic shock in the rat and mouse but not in the hamster, guinea pig, rabbit, or dog (Arora et al., 1970; Chang and Gottshall, 1974; Csaba and Muszbek, 1972; Munoz et al., 1987).

Injection of pertussis vaccine (0.1 ml/mouse, roughly 200 times the human dose) increased the susceptibility of mice to the lethal effects of various bacterial endotoxins injected subsequently (Kind, 1958). The increased endotoxin sensitivity was not present 1 or 3 days after administration of pertussis vaccine but was pronounced after 5 to 20 days.

Steinman and colleagues (1982) have developed a mouse model in which they can regularly induce a lethal shock-like syndrome by injection of 3 x 1010 heat-killed B. pertussis into mice sensitized by repeated injections of 1 mg of bovine serum albumin. Only mouse strains with certain histocompatibility (H-2) genotypes are susceptible, which is compatible with an immunologic basis for the reaction. PT is required for induction of this toxicity (Steinman et al., 1985), and immunization with PT antigens protects the mice against the reaction (Oksenberg et al., 1989). Pretreatment of the mice with histamine H1 receptor antagonists also protected the mice; this result is compatible with an allergic-immunologic basis for the reaction, but it does not prove such, since other actions of the antagonists are possible (Peroutka et al., 1987). Relatively large doses of pertussis vaccine and sensitizing antigen are used in this model compared with injections given to

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 149

humans; a particular immunizing schedule and certain mouse strains are required. Thus, the relevance of this reaction to that in infants is speculative. Munoz and colleagues (1987) and Wiedmeier and colleagues (1987) have described data suggesting that this reaction represents anaphylaxis and not encephalopathy, as some had hypothesized. The development of the reaction was unrelated to the capacity of PT to act as a toxin through its characteristic activity of ribosylation of key cellular proteins (Wiedmeier et al., 1987).

Endotoxin

Commercial DPT vaccines across the world have been reported to contain bacterial endotoxin, usually in concentrations of about l to 10 µg/ml (Geier et al., 1978; Ibsen et al., 1988). There was a direct correlation between endotoxin content and the percentage of DPT vaccine recipients who developed fever (Baraff et al., 1989), and it has been questioned whether the endotoxin in DPT vaccine might be responsible, at least in part, for immunologic reactions or encephalopathy. Animal studies have been cited in support of this hypothesis, for example, those showing that endotoxin or DPT vaccine can induce an increase in the permeability of cerebral blood vessels, which might predispose an individual to brain damage (Amiel, 1976; Bergman et al., 1978; Eckman et al., 1958). However, the use of animals to explore this hypothesis is complicated by the fact that different species respond differently to different endotoxins. Moreover, endotoxins from different bacteria cannot be compared on the basis of weight since weight does not accurately reflect biologic activity (Chaby et al., 1979). In short, data do not exist at present to indicate that the endotoxin present in DPT vaccines plays a role in the anaphylaxis associated with injection of DPT. Nor do data exist to support a role for endotoxin in the other immunologic reactions or in the encephalopathies that have been suspected sequelae of DPT immunization.

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and anaphylaxis includes a number of case reports, case series, studies in animals, and one controlled epidemiologic study. Anaphylaxis is rare in infants in the absence of an obvious exciting cause. Rates of anaphylaxis estimated from two reports (Osvath et al., 1979; Pollock and Morris, 1983) have been approximately 2 per 100,000 injections. The clinical presentation of cases with rapid onset after injection of vaccine and (in two cases) autopsy findings suggest that anaphylaxis can be caused by DPT injection. Laboratory studies to link an

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 150

immunologic reaction with the clinical event in such cases have not been reported, however. Specifically, no exciting antigen has been demonstrated, and whether or not specific antibody of the IgE (or another) class is required for such events to occur after DPT injection has not been shown. It has been postulated that endotoxin in the DPT vaccine might be involved in tissue damage distant from the site of injection or that an Arthus- or Jarisch-Herxheimer-type reaction might be initiated by constituents in the DPT vaccine; however, the clinical presentations and the pathologic findings, when available, of the adverse events discussed in this report do not clearly support these hypotheses. Furthermore, the animal models described to date employ antigen loads, dosage schedules, pathologic endpoints, add-on antigens, or other experimental conditions that deviate from the human situation that is the subject of concern. Consequently, although the data from animal experiments may be useful in formulating or modifying hypotheses, they do not implicate an immunologic or endotoxin-initiated basis for possible adverse events following DPT immunization.

The possibility of a causal relation with anaphylaxis is supported by biologic plausibility and clinical observation. Biologic plausibility derives largely from the knowledge that injection of foreign proteins into humans (and there are many foreign proteins in DPT vaccine) can be expected to elicit in some percentage of recipients IgE-mediated responses that present as anaphylaxis. The biochemical, immunologic, or immunohistologic techniques that could provide relevant evidence have not been applied. Nevertheless, the classic presentation and timing strongly suggest that DPT injection can cause anaphylaxis.

Reports of hives or angioneurotic edema following DPT administration have been obtained only through the CDC's MSAEFI system and are not well substantiated. Furthermore, in contrast to anaphylaxis, the occurrence of hives or angioneurotic edema in infancy without a known cause is not rare, so that the concurrence of DPT immunization and these conditions is, therefore, more likely to be observed coincidentally than anaphylaxis is. No biologically meaningful connection can be said, at present, to exist between DPT injection and hives, angioneurotic edema, an Arthus or Jarisch-Herxheimer reaction, or endotoxin-mediated tissue damage.

Conclusion

The evidence indicates a causal relation between DPT vaccine and anaphylaxis, although there is no reason to implicate the pertussis component more than the diphtheria or tetanus components of DPT vaccine. In the absence of formal studies of incidence, rates of anaphylaxis are estimated to be approximately 2 cases per 100,000 injections of DPT (6 per 100,000 children given three doses of DPT).

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 151

AUTISM

Clinical Description

Infantile autism represents one of the group of disorders now referred to as pervasive developmental disorders (Rutter, 1985; Volkmar and Cohen, 1986). The disorder, termed autism by Kanner in 1943, is characterized as having its onset before age 30 months, with disturbances in social relationships and language and stereotyped behaviors. Autistic children exhibit a failure to develop specific attachment relationships. For example, they do not follow their parents around the house or go to them to seek comfort, and they frequently fail to use eye contact as a social signal. Their language acquisition is not only markedly delayed but they fail to use social imitation. Most importantly, they fail to use speech for social communication. Little is known of the etiology or pathogenesis of autism. Two-thirds of autistic children remain severely disabled as adults, but a small percentage are able to work and interact with other individuals.

Descriptive Epidemiology

Prevalence rates of autism are estimated to be between 4 and 5 per 100,000 children under age 15 years (Wing et al., 1976). Rates are lower when administrative records, rather than interviews or case reviews, are used and when more restricted definitions of the syndrome are employed (DeMyer et al., 1981). Prevalence rates of autism must be viewed with caution given the heterogeneity of case definitions of pervasive developmental disorders and potential for biased case detection (Volkmar and Cohen, 1986). All studies report a higher incidence in males, with a male:female sex ratio on the order of 3:1 to 4:1 (Wing, 1981); however, girls as a group may be more severely affected (Volkmar and Cohen, 1986). An increased incidence of prenatal and perinatal complications has been noted in cases of pervasive developmental disorders (DeMyer et al., 1981). However, factors such as maternal age at birth, birth order, ordinal position, and season of birth have not been related to incidence rates (Volkmar and Cohen, 1986).

Evidence from Studies in Humans

The committee identified no case reports or other studies of autism following pertussis immunization. The sources examined include the CDC's MSAEFI system, which received no reports of autism (ICD 9 code 299.0) occurring within 28 days of DPT immunization from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 152

for Disease Control, personal communication, 1990). The lack of reports of cases within 28 days of DPT immunization is not surprising, however, given that a diagnosis of autism is difficult, if not impossible, before age 3 years.

Summary

No data were identified that address the question of a relation between vaccination with DPT or its pertussis component and autism. There are no experimental data bearing on a possible biologic mechanism.

Conclusion

There is no evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and autism.

ERYTHEMA MULTIFORME OR OTHER RASH

Clinical Description

Erythema multiforme is an acute, self-limited eruption characterized by symmetric erythematous, edematous, or bullous lesions of the skin or mucous membranes (or both) that pass through multiple morphologic stages (Hebra, 1866). A hypersensitivity reaction to a number of substances, including infectious agents, is a proposed mechanism, but the pathophysiology has not been defined.

Descriptive Epidemiology

Erythema multiforme, although rare, can occur in infancy and childhood. No population-based incidence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports

Erythema multiforme has been reported in association with several vaccines, including DPT (Leung, 1984; Leung and Szabo, 1987). These reports describe three cases, ranging in age from 2 months to 19 months, in which a maculopapular rash consisting of symmetrical lesions with central clearing ("iris" lesions) developed following DPT vaccination. A fourth case in a 5-year-old consisted of blisters on an erythematous base. The eruptions occurred from 2 hours to 3 days after receiving DPT vaccine and, at least in

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 153

two cases, cleared spontaneously within several days. The outcome in the other two cases was not reported.

Ten cases of erythema multiforme (ICD 9 code 695.1) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these 10 cases, 5 received oral poliovirus vaccine (OPV) at the time of DPT immunization, 1 case received OPV plus Haemophilus influenzae type b vaccine with DPT, and 3 cases received OPV plus measles-mumps-rubella vaccine (MMR) with DPT. No follow-up of the cases was made, and a physician's diagnosis was not required. If all 10 cases represent a reaction to DPT, which is unlikely in view of the long time frame and the administration of other vaccines, the frequency of erythema multiforme after DPT immunization would be approximately 1 per 8 million doses of DPT.

Rash as an adverse reaction to DPT vaccine appears to be rare; several reports of large series do not mention rashes (Cody et al., 1981). Isolated case reports describe a variety of self-limited rashes following DPT immunization, ranging from eczematous reactions (Hopper, 1961; Illingworth, 1987) and macular rashes involving the head and trunk (Hopper, 1961; Denning et al., 1987) to localized lesions at the injection site (Laude, 1981; Orlans and Verbov, 1982). None of these reports presents evidence specifically implicating the pertussis component of the vaccine.

Pertussis vaccine has been associated with increased skin reactions to injected histamine in mice (e.g., Parfentjev and Goodline, 1948). Various heat-killed gram-negative bacteria as well as their common endotoxin, lipopolysaccharide W, injected intradermally into a patient with erythema multiforme have reproduced its classic iris lesions (Shelley, 1980). Denning and colleagues (1987) raised the possibility that vaccine-associated rash may be due to the preservative thiomersal.

Aluminum Salts

The possibility has been raised that the aluminum salts regularly present in DPT vaccines might cause vaccination-associated rashes (see Appendix E for discussion). There are no data to indicate that aluminum salts play a role in DPT-associated rashes. 

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and erythema multiforme or other rash is limited to 4 cases reported in the literature and 10 unconfirmed cases

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 154

reported through the CDC's MSAEFI system. The unambiguous clinical presentation of erythema multiforme suggests that the vaccine exposure truly preceded the event. The relation is biologically plausible, since erythema multiforme is thought to be a dermal hypersensitivity reaction to a drug or other foreign antigen and pertussis vaccine could provide such a sensitizing antigen.

The temporal relation between DPT injection and the onset of rash suggests a possible causal relation. However, only four cases of such a relation have been documented, and none specifically implicates the pertussis component of the vaccine.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and erythema multiforme or other rash.

GUILLAIN-BARRÉ SYNDROME (POLYNEUROPATHY)

Clinical Description

The condition referred to as the Guillain-Barrè syndrome (GBS) was described by Chomel (1828), Graves (1843), Landry (1859), and Guillain, Barrè, and Strohl (1916) and is variously known as acute idiopathic, acute inflammatory, and postinfectious polyradiculopathy or polyneuropathy. The term Guillain-Barrè syndrome avoids the historical confusion and etiologic uncertainty of this disorder (Lancet, 1988). The severity and duration of the illness depends upon the degree to which spinal roots and peripheral nerves are affected by focal inflammation.

Infectious agents and other trigger factors have been thought to precipitate the illness. An epidemic of acute polyneuritis formed the basis for Chomel's original description. A more recent example is the association seen between influenza vaccination and GBS in 1976. Human immunodeficiency virus infection and Lyme disease are being increasingly identified as causes of acute painful polyradiculitis. Other infectious agents have been associated with the onset of GBS, including cytomegalovirus, Epstein-Barr virus, mycoplasma, and Campylobacter jejuni.  Tetanus vaccine has also been related to GBS (e.g., Newton and Janati, 1987; Pollard and Selby, 1978).

Diagnosis of GBS is sometimes difficult. The classic features of GBS are progression over days to a few weeks, relative symmetry, mild sensory signs or symptoms, cranial nerve involvement, onset of recovery 2 to 4 weeks after the halt of progression of symptoms, autonomic dysfunction,

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 155

initial absence of fever, elevated CSF protein after 1 week of symptoms, and abnormal results of electrodiagnostic studies with slowed conduction of F waves. The presence of radicular deficits, sensory disturbance, and areflexia and the absence of fever are all helpful in the diagnosis. Poliomyelitis, diphtheria, botulism, hysterical or tick paralysis, and acute toxic neuropathy (especially from organophosphorus compounds or hexacarbon abuse, as in glue sniffing) must be considered in the differential diagnosis.

Between 80 and 90 percent of patients with GBS have distinctive features on electrophysiologic studies that are characteristic of an acquired demyelinating neuropathy seen only with GBS, diphtheria, or exposure to organophosphorus compounds (McLeod, 1981; Miller, 1985).

Descriptive Epidemiology

GBS occurs at a rate of 1.7 per 100,000 persons in the United States. It is the most common cause of acute weakness in patients under age 40 years and is one of the most common neurologic causes of admission to intensive care units (Miller, 1985). The disorder is rare in children under age 2 years, although cases in infants and one case of neonatal GBS have been reported (Al-Qudah et al., 1988; Carroll et al., 1977; Eden, 1961; Evans, 1986; Gilmartin and Chien, 1977). No population-based incidence or prevalence rates of mono- or polyneuropathy were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports

Eleven cases of GBS (ICD 9 code 357.0) and no cases of polyneuropathy (ICD 9 code 356.9) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). All 11 cases received at least one other vaccine at the time of DPT immunization: 6 cases received OPV, 1 case received OPV plus mumps monovalent vaccine, 1 case received OPV plus hepatitis B conjugate vaccine, and 3 cases received OPV plus MMR. No follow-up of the cases was made, and a physician's diagnosis was not required.

Summary

Information concerning the possible relation between vaccination with DPT or its pertussis component and GBS is limited to 11 unconfirmed cases

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 156

reported through the CDC's MSAEFI system. GBS is a profound disorder whose diagnosis is reasonably reliable; thus, the vaccine exposure probably truly preceded the event in these cases. The specificity of an association, if present, would not be established, since all cases at the time of pertussis immunization also received tetanus antigen, which has been related to GBS. The fact that GBS is believed to be caused by or, at least, precipitated by a number of infectious agents also limits the specificity of association. There are no experimental data bearing on a possible biologic mechanism.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and GBS.

PERIPHERAL MONONEUROPATHY

Clinical Description

Peripheral mononeuropathy is a syndrome of sensory, motor, reflex, and vasomotor symptoms, singly or in any combination, produced by disease of a single peripheral nerve. Trauma is the most common cause of a localized injury to a single nerve. Mononeuropathy has also been observed following administration of monovalent tetanus vaccine (e.g., Blumstein and Kreithen, 1966; Quast et al., 1979; Reinstein et al., 1982; Tsairis et al., 1972).

Descriptive Epidemiology

Peripheral mononeuropathy is rare in infants and children. No population-based incidence or prevalence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports

Martin and Weintraub (1973) reported one case of brachial neuritis in a 5-month-old boy 2 days after receipt of a first dose of DPT in the left thigh. The neuritis was followed days later by an isolated seventh-nerve palsy. The brachial neuritis cleared within 48 hours, and the facial palsy resolved 2 weeks after onset. No antibodies against peripheral and central myelin were detected in the CSF.

Ehrengut (1977) reported a case of paresis of the sixth cranial nerve in a

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 157

child of unknown age 6 days after receiving a third dose of quadrivalent vaccine. The paresis was observed only ''briefly." No further information was given.

No cases of peripheral mononeuropathy (ICD 9 code 355.9) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccines were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). 

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and peripheral mononeuropathy is limited to two case reports, one of brachial neuritis and one of paresis of the sixth cranial nerve. The unambiguous clinical presentation of both cases occurred 2 to 6 days after the administration of DPT vaccine. Tetanus antigen, administered in conjunction with pertussis vaccine in DPT, has been related to peripheral mononeuropathy. There are no data bearing on a possible biologic mechanism.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and peripheral mononeuropathy.

HEMOLYTIC ANEMIA

Clinical Description

Hemolytic anemia results from the lysis of red blood cells, which leads to shortened in vivo survival of red blood cells and an inability of the bone marrow to compensate for their decreased life span. The hemolysis may be acute, chronic, or episodic in nature.

Infections and the use of biologic agents have both been associated with the development of hemolytic anemia (Zuelzer et al., 1970). Immune mechanisms could play an etiologic role in such associations. For example, antibodies to components of the vaccine could cross-react with red blood cell antigens, or vaccine antigens could bind to the red blood cell surface and react there with antibodies. Antibodies on the cell surface could fix complement and lyse the cell or expedite splenic clearance of the cells (Facktor et al., 1973).

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 158

Descriptive Epidemiology

Acute hemolytic anemia is not common at any age, but it can occur in early infancy. No population-based incidence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports

Evidence for a relation between hemolytic anemia and DPT vaccines is limited to rare case reports (Coulter and Fisher, 1985; Haneberg et al., 1978). Haneberg and colleagues (1978) described three cases of hemolytic anemia in infants following repeat doses of DPT vaccine. Case 1 was a 4month-old boy hospitalized with a diagnosis of hemolytic anemia 4 days after receiving his second dose of DPT vaccine. Case 2 was a 6-month-old girl hospitalized with anemia 3 weeks after receiving a second dose of DPT vaccine and a concomitant first dose of trivalent OPV. Her parents reported evidence of jaundice and reddish discoloration of the urine 2 weeks after receipt of the vaccines. Case 3 was a boy who was hospitalized at age 10 months and who had received his third dose of DPT vaccine at age 5.5 months and his first trivalent OPV at age 9 months. The date of symptom onset was not noted, although the authors reported that the infant was very pale "for weeks" prior to admission. Antibodies to diphtheria and tetanus and a trace of antibody to pertussis were eluted from the red blood cells of case 3, but not from the red blood cells of controls. Red blood cells from the other two patients had antibodies of undetermined specificity on their surfaces. These findings suggest an immunologic basis for the hemolysis.

Zupanska and colleagues (1976) reviewed a case series of 44 children, ages 3 months to 14 years, with autoimmune hemolytic anemia. The authors identified one case of acute disease following DPT immunization. The child recovered; no other details specific to the case were provided.

Coulter and Fisher (1985) reported on one case of hemolytic anemia in a 2.5-year-old boy, which first occurred following a fourth dose of DPT vaccine. Six days after vaccination, the boy became irritable and anorectic. Fever, vomiting, and apparent jaundice and anemia developed over the next 7 days, at which point the boy was hospitalized with a diagnosis of hemolytic anemia. The boy returned to a state of health until 6 days after his fifth DPT vaccination (age not specified), when he developed the same constellation of symptoms, plus loss of consciousness. The boy was rehospitalized with a diagnosis of hemolytic anemia. No laboratory tests were reported and, again, the boy recovered.

No cases of hemolytic anemia (ICD 9 code 282.9) occurring within 28 days

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 159

of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990).

Summary

Although the body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and hemolytic anemia is limited to rare case reports, the case described by Coulter and Fisher (1985) is suggestive of a causal relation because hemolytic anemia was detected 6 days after a DPT immunization on two separate occasions. Case 1 of Haneberg and colleagues (1978) had hemolysis within 4 days after DPT immunization. This could have been due to a chance concurrence, although antibodies to antigens found in each of the components of DPT vaccine were detected on the red blood cells of case 3 of Haneberg and colleagues, an observation that is compatible with a causal relation through the mechanism of an immunologic reaction. However, controls were not well described, and the antibodies detected were not shown to be specific to DPT vaccine. Evidence of a shared antigen in the DPT vaccine and on the human red blood cell would strongly increase the plausibility of a causal relation with the vaccine, but no such evidence has been reported. Pertussis antigens are not implicated any more strongly than the other constituents of the DPT vaccine are.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and hemolytic anemia.

JUVENILE DIABETES

Clinical Description

Juvenile diabetes, or, as it has been more recently classified, insulindependent diabetes mellitus (IDDM; also called type 1 diabetes), results from damage to pancreatic beta cells caused by an autoimmune reaction. Viral infection has been proposed as a trigger of the autoimmunity).

Descriptive Epidemiology

The annual incidence of IDDM in the United States is about 12 to 14 new cases per 100,000 children ages 0 to 16 years. By age 20, approximately 0.3 percent of persons will have developed the disease. Incidence

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 160

rates of IDDM are similar in males and females, but they are 1.5 times higher in whites than in blacks. The risk for siblings of IDDM cases is 7 to 18 times higher than the risk in the general population, suggesting that a genetic factor may be involved (LaPorte and Cruickshanks, 1985).

Evidence from Studies in Humans
Controlled Epidemiologic Study

Blumberg and colleagues (1988), in a surveillance study conducted in Los Angeles County in 1986, identified five children with hypotonic, hyporesponsive episodes (HHE) and six children who cried persistently for more than 3 hours following DPT immunization. A physical examination and medical history were conducted on and blood samples were collected from each child. Results were compared with those for 16 control children, ages 4 to 6 years, who had no reactions following DPT immunization. No abnormalities were noted in plasma insulin or serum glucose.

Case Report

A 16-month-old girl was reported to have developed IDDM about 3 weeks after injection of DPT (Champsaur et al., 1982). The authors proposed that the IDDM was caused by a coxsackievirus infection that began after the DPT shot. The child was genetically predisposed to IDDM in that she had the lymphocyte surface markers and the biochemical types of the complement proteins factor B and C4 that have been seen with increased frequency in individuals with IDDM. The possibility of whether DPT might have had an immunoboosting (adjuvant) effect was raised.

No cases of IDDM (ICD 9 code 250.1) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990).

Evidence from Studies in Animals

In animal studies, vaccines containing killed B. pertussis have been reported to induce hyperinsulinemia with variable hypoglycemia (reviewed in Furman et al., 1981). Islet-activating protein (pertussis toxin), which stimulates insulin release in animals, produced long-lasting amelioration of diabetes in spontaneously diabetic strains of rodents (Wardlaw and Parton, 1983). At a theoretical level, pertussis vaccines have been shown in animals and humans to have an adjuvant effect (Munoz and Bergman, 1977),

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 161

which might have the potential to enhance an autoimmune reaction. However, data are not available that support the possibility that injection of DPT might cause or facilitate the development of IDDM.

Summary

Information concerning the possible relation between vaccination with DPT or its pertussis component and IDDM consists of one controlled study of plasma insulin and serum glucose levels in 11 children with HHE or persistent crying following DPT immunization, one case report in which the authors suggested that a concomitant viral infection rather than the immunization was the causative factor, and animal studies of the effects of whole-cell pertussis vaccines or pertussis toxin on insulin and glucose metabolism. No biologic mechanism supporting a causal association has been proposed.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and IDDM.

LEARNING DISABILITIES AND HYPERACTIVITY

Clinical Description

The terms learning disability and hyperactivity (or, more currently, attention deficit disorder [ADD]) are frequently used in a general way to describe a heterogeneous group of problems. Recent studies, however, have focused on developing rigorous, operational definitions for both learning disability and ADD.

Learning Disability, Reading Disability, and Dyslexia

Learning disability is most commonly defined as "a severe discrepancy between achievement and intellectual ability" (Cone and Wilson, 1981; Reynolds, 1984; Rutter and Yule, 1975; Thorndike, 1963; United States Office of Education, 1977). The diagnosis of learning disability is established on the basis of performance on tests of ability (e.g., the Wechsler Intelligence Scales for Children) and achievement (e.g., the Woodcock-Johnson Psychoeducational Scales).

Most cases of learning disability represent difficulties in reading, and the terms learning disability and reading disability are frequently used interchangeably. To add further to this semantic confusion, reading disability is used interchangeably with the term dyslexia. The work of Liberman and

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 162

Vellutino and their colleagues (Liberman and Shankweiler, 1985; Mann et al., 1989; Vellutino, 1978, 1979; Vellutino and Scanlon, 1987) and others supports the belief that reading disability is the result of difficulties with language and words—their use, significance, meaning, pronunciation, and spelling.

Hyperactivity, Hyperkinesis, and Attention Deficit Disorder

ADD has, in the past, been referred to as brain damage, brain dysfunction, minimal brain dysfunction, hyperactivity, and hyperkinesis.  These terms reflect earlier concepts of the pathogenesis of what Still (1902) described as "morbid defects in moral control." In the first half of the twentieth century, behavioral disorders, including hyperactivity, were attributed to brain damage from trauma or infection, whether or not such an insult had been recognized (Bender 1942; Goldstein, 1936; Hohman, 1922; Meyer, 1904; Strauss and Lehtinen, 1947; Werner and Strauss, 1941).

By the 1950s, the concept of brain "dysfunction" rather than brain "damage" began to emerge in relation to hyperactivity. "Minimal brain dysfunction" was inferred from the presence of a cluster of symptoms, including specific learning deficits, hyperactivity, impulsivity, short attention span with or without mild neurologic signs, and changes in the EEG (Clements and Peters, 1962). Two subsequent decades of research have led to the recognition that minimal brain dysfunction is a meaningless concept. At present, the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (1987) uses the term ADD, a term developed because most investigators believed that an attentional rather than an activity problem was the cardinal symptom of the disorder (Cantwell, 1983).

Descriptive Epidemiology

Given the definition of learning disability, prevalence rates are especially sensitive to the cutoff score used to define the difference between ability and achievement. These cutoff scores are generally represented as standard deviations from the mean. For example, if the difference between the ability and achievement score is set at 1.5 standard deviations (approximately a 20-point difference between IQ and achievement), this will dictate a prevalence rate of 9 percent, assuming a normal distribution, and if a cutoff of 1.0 standard deviations is employed, the corresponding rate will be 16 percent.

Definitional issues certainly affect prevalence rates for ADD, and these issues have been discussed in detail previously (Shaywitz and Shaywitz, 1988). Not surprisingly, prevalence rates vary considerably, from less than

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 163

1 percent to above 20 percent (reviewed by Shaywitz and Shaywitz, 1988; Szatmari et al., 1990).

Evidence from Studies in Humans
Case Reports

No reports have been published in peer-reviewed scientific journals relating pertussis immunization to either learning disability or ADD. One anecdotal report (Coulter and Fisher, 1985) describes a child who was hyperactive and had delayed learning. His problems were attributed to a pertussis immunization that had caused fever and irritability as an infant. Although intelligent (his IQ score was reported as 126), his impulsive behavior was difficult for his parents and the school to tolerate. Few clinical details are provided, but what is available in the chapter suggests that the child would be diagnosed as having ADD. However, there is no basis by which ADD in this case can be attributed to pertussis immunization. No information is provided about the early school history of either parent. This might be relevant since familial influences are by far the most common cause of both learning disability and ADD among a large list of possibly related associations (Shaywitz and Shaywitz, 1989). Although no structural abnormalities have been described for ADD, evidence from several lines of investigation supports the belief that abnormalities in brain neurotransmitter systems, particularly brain catecholaminergic mechanisms, may be related to the emergence of ADD. A recent report suggests abnormalities in cerebral glucose utilization in young adults with a history of ADD as children (Zametkin et al., 1990).

Six cases of hyperactivity (ICD 9 code 314.01) and no cases of learning disability (ICD 9 code 215.2) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of the six cases of hyperactivity, four cases received OPV at the time of DPT immunization and two cases received OPV plus MMR. No follow-up of the cases was made, and a physician's diagnosis was not required. However, a diagnosis of either learning disability or ADD would not be expected to be made until the child was of school age.

Controlled Epidemiologic Studies

The relation between early immunization and later learning and attention was investigated by Butler and colleagues (1982), who examined a cohort of 13,135 children at age 5 years who had received routine DPT immuniza-

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 164

tions in infancy. The cohort was part of the National Childhood Development Study, which followed approximately 95 to 99 percent of all children born in Great Britain during a 1-week period in April 1970 (Chamberlain et al., 1975). Five years later, parents of 13,135 (approximately 80 percent) of the original group (excluding cases in Northern Ireland) were interviewed, and "several simple tests were administered" to the child by health visitors (Butler et al., 1982). Analysis gave no indication that the children who had been immunized against pertussis were developmentally disadvantaged. In fact, the children with no immunization against pertussis more frequently had poor scores on the various tests or were rated as intellectually abnormal. However, these results may have been biased because the sample children who were not immunized against pertussis were of lower socioeconomic class than those who were immunized. Many studies have indicated that school performance is directly associated with socioeducational variables such as the mother's level of education (Broman et al., 1985). In addition, it is not clear what measures were used to assess learning and attention. The authors reported a subsequent follow-up of a subset of 1,057 children at age 10 years in which the childrens' teachers rated each child's behavior and administered achievement tests of reading and arithmetic. No findings from the 10-year follow-up specific to pertussis immunization were reported.

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and learning disabilities or ADD is limited to one published case report, six cases reported through the CDC's MSAEFI system, and one follow-up report at age 5 of children enrolled in the National Childhood Development Study. The last study demonstrated improved intellectual outcome in children who had been immunized against pertussis compared with those who had not been immunized. However, this finding may reflect confounding owing to the fact that the sample children who were immunized against pertussis were of higher socioeconomic class than those who were not immunized, a factor associated with better school performance. The varied definitions, difficulty in diagnosis, and incomplete understanding of the causation of learning disabilities and ADD limit both the ability to ascertain that exposure to DPT vaccine truly preceded the event and the specificity of the putative association with pertussis vaccine. There are no data bearing on a possible biologic mechanism.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and the development of learning disabilities or ADD.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 165

PROTRACTED INCONSOLABLE CRYING AND SCREAMING

Clinical Description

Persistent crying has been commonly noted after DPT immunization and appears to be a reaction to vaccination. The usual course of events is as follows: the child receives the immunization and cries briefly in association with the vaccination. The crying following immunization is short-lived and the child returns to normal behavior. Then, sometime later, usually within 2 to 8 hours, the child starts to cry. The crying is persistent and frequently inconsolable. Occasionally, the cry is episodic in nature throughout a 24-hour period. Crying of this nature is common in infancy, and many causes are suspected.

A more unusual, high-pitched crying also has been reported after DPT immunization. This cry has been characterized as screaming or "a cerebral cry," and parents identify it by saying they "never heard their child cry like this before." There is no unanimity of what constitutes a scream or a cerebral cry (Cherry et al., 1988). Subjectivity in reporting high-pitched crying makes it difficult to develop reliable estimates of its frequency (Cody et al., 1981). In the following summary, the committee is necessarily relying on the verbal descriptions of the authors; these vary by study and include such different terms as crying; persistent or protracted crying; screaming; and prolonged, persistent, or high-pitched unusual screaming.

Descriptive Epidemiology

No population-based incidence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports and Case Series

Barkin and Pichichero (1979) surveyed parents of all children receiving DPT vaccine in one of four private practices in Denver, Colorado, between July 1977 and February 1988. Questionnaires were returned by 1,232 (85 percent) of the parents. Crying occurred after DPT immunization in 432 (35 percent) of the children; prolonged (duration not specified) screaming occurred in 159 (13 percent). There were marked differences by DPT series number in the number of children exhibiting crying and prolonged screaming, with the fewest reactions occurring after booster immunizations.

Coulter and Fisher (1985) reported one case of persistent crying and high-pitched screaming associated with subsequent mental and motor retardation. The child exhibited high fever, with crying and high-pitched screaming

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 166

of 3 days' duration following the first DPT shot at age 3.5 months. The second DPT shot 2 months later produced a similar clinical picture, but of shorter duration (duration not specified).  Mental and motor retardation were diagnosed at age 21 months and persisted.

Approximately 2,531 cases of "screaming" (ICD 9 code 799.8) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these, 1,864 (73.6 percent) cases received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physician's diagnosis was not required.

Controlled Epidemiologic Studies

A number of studies have examined rates of protracted crying and screaming in children following DPT immunization. In one of the larger controlled studies conducted to date, Cody and colleagues (1981) compared reactions occurring in children, ages 0 to 6 years, in the first 48 hours following 15,752 injections of DPT vaccine and 784 injections of DT vaccine. Crying was noted following 488 (3.1 percent) injections of DPT vaccine and 5 (0.7 percent) injections of DT vaccine. Not only was the event significantly (p = 0.0003) more frequent following DPT immunization, it was also of significantly longer duration (p value not given). No DT recipient cried for longer than 2 hours, whereas injections were associated with persistent crying for 3 to 21 hours following immunization. High-pitched, unusual crying (duration not specified) was reported following 17 (0.1 percent) DPT immunizations and following no DT immunizations; however, the difference was not statistically significant (p = 0.36) given the small number of cases observed.

Baraff and colleagues (1984) reported significant differences in the rates of persistent crying longer than 30 minutes by immunization site, by vaccine manufacturer, and by vaccine dose. With respect to immunization site, the percentage of recipients with persistent crying was 11, 8, and 7 percent for injections given in the buttock, upper lateral thigh, and midanterior thigh, respectively. Three percent of children receiving a full dose of DPT vaccine exhibited persistent crying; none of the children receiving a half-dose of vaccine did.

In a subsequent study comparing reaction rates following 9,920 DPT immunizations from 25 vaccine lots, Baraff and colleagues (1989) reported no differences in rates of screaming (duration not specified) by amount of endotoxin in the vaccine or by pertussis vaccine potency. There was a positive association of screaming with percent mouse weight gain (p = 0.001), a test of pertussis vaccine toxicity (see Appendix C for description);

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 167

the proportion of children exhibiting this symptom increased from 1.3 to 3.2 percent with increasing percent mouse weight gain. The finding of a positive association between screaming and percent mouse weight gain is surprising, given that percent mouse weight gain is inversely associated with toxicity. The finding was not explained.

Pollock and colleagues (1984) analyzed data from the North West Thames region of England, where an intensified effort had been undertaken to identify all severe adverse events of immunization occurring between 1975 and 1981. The authors studied a sample of individuals attending routine immunization clinics in Hertfordshire in which 6,004 children started primary immunization with DPT and 4,024 with DT. The DPT group was further divided into those receiving plain versus those receiving adsorbed vaccine. A total of 25,643 doses of vaccine were given: 1,125 of plain DPT, 13,917 of adsorbed DPT, and 10,601 of adsorbed DT. Crying occurred slightly more frequently (p value not given) in children receiving three doses of adsorbed DPT vaccine than in those receiving three doses of adsorbed DT vaccine (19.1 percent versus 14.4 percent, respectively). Similarly, a bout of screaming beginning within 12 hours of immunization and continuing for longer than an hour occurred slightly more frequently (p value not given) in children receiving three doses of adsorbed DPT vaccine than in those receiving three doses of adsorbed DT vaccine (1.9 percent versus 1.2 percent, respectively). Persistent crying for more than 5 hours and high-pitched screaming occurred with similar frequencies (0.9 percent after DPT versus 0.7 percent after DT) in the two groups.

Blumberg and colleagues (1988), in a surveillance study conducted in Los Angeles County in 1986, identified six children who cried persistently for more than 3 hours following DPT immunization. A physical examination and medical history were conducted on and blood samples were collected from each child. Results were compared with those for 16 control children, ages 4 to 6 years, who had no reactions following DPT immunization. Acute leukocytosis (average total white cell count, 9,400 cells/mm3) was observed in both cases and controls on the day following DPT immunization; no abnormalities were noted in plasma insulin or serum glucose. Five of the six children with persistent crying had severe local reactions, suggesting that localized inflammation may be a cause of persistent crying.

Long and colleagues (1990) assessed the rates of adverse events following pertussis vaccination in 538 children randomized to the standard four-dose immunization schedule or to a three-dose schedule with a saline injection substituted for DPT at age 6 months. In all, 1,553 doses of DPT vaccines were given. Prolonged crying (i.e., crying for more than 30 minutes) was reported following 6 percent of DPT immunizations and 0.5 percent of placebo vaccinations (p < 0.0001). Prolonged crying persisted for more than 3 hours following 0.9 percent of DPT immunizations. High-

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 168

pitched, unusual crying was reported after 3 percent of DPT immunizations; no cases occurred following the placebo vaccination (p < 0.0001). Of the 89 children who had prolonged crying or high-pitched, unusual crying, or both following DPT immunization, 77 had follow-up evaluations after age 2 years (mean age at evaluation, 3 years, 5 months). The nature of the follow-up, personnel, and tests used were not reported. No child was found to have a neurologic abnormality. One child had a delay in speech development of unknown etiology.

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and protracted inconsolable crying or screaming includes case reports, case series, and several controlled epidemiologic studies. Evidence of sufficient quality pertinent to this question can be summarized as follows. The evidence of controlled studies indicates a direct association, with rates of crying ranging from 3 to 19 percent in DPT recipients versus 1 to 14 percent in DT recipients; rates of persistent crying ranging from 1 to 6 percent in DPT recipients versus approximately 0 percent in DT recipients and 0.5 percent in placebo recipients; and rates of high-pitched, unusual crying ranging from 0.1 to 3 percent in DPT recipients versus approximately 0 percent in DT recipients. These results are generally consistent across studies, although comparison of study findings is complicated by the subjectivity in reporting certain of these events, particularly high-pitched crying, and by the variety of terms used to describe simple crying or screaming or high-pitched, unusual crying. Results from one study (Baraff et al., 1984) demonstrate a direct dose-response relation, with 3 percent of children receiving a full dose of DPT vaccine exhibiting persistent crying but with none of the children receiving a half-dose of the vaccine exhibiting crying. The obvious clinical presentation of crying, its timing, and the duration of persistent crying and high-pitched crying indicate that the exposure truly preceded the onset of the condition. It is reasonable to conclude that crying and screaming can occur in response to the pain, local reaction, and fever often observed after receipt of DPT vaccine.

The evidence concerning a possible relation between protracted, inconsolable crying or screaming and chronic residua such as mental or motor retardation is limited to a few case reports and one randomized controlled study (Long et al., 1990). The latter study reported no association between high-pitched or unusual crying following DPT immunization and a subsequent neurologic abnormality at age 3 years. However, it is not surprising that an event as infrequent as chronic neurologic damage was not detected given the study's small sample. There are no experimental data concerning

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 169

biologic mechanisms that support a causal association between DPT vaccine and chronic neurologic damage.

Conclusions

The evidence indicates a causal relation between the pertussis component of DPT vaccine and protracted, inconsolable, or high-pitched crying or screaming. Incidence rates are estimated to range from 0.1 to 6 percent of recipients of a DPT injection and vary with the type and dose of vaccine and with the immunization site.

Evidence is insufficient to indicate whether pertussis vaccine-associated protracted, inconsolable, or high-pitched crying or screaming does, or does not, lead to chronic neurologic damage.

REYE SYNDROME

Clinical Description

In 1963, Reye and coworkers described the clinical and pathologic features of a syndrome that occurred in 21 Australian children. The findings included prodromal illness, most commonly influenza, chickenpox (varicella), or gastroenteritis, followed by the onset of protracted vomiting. Initially, the patients were oriented, but irritable and lethargic. Subsequently, their level of consciousness varied from no loss of consciousness (Cincinnati Coma Grade I) to a deep comatose state with decerebrate and decorticate posturing, flaccid paralysis, loss of voluntary ventilatory control, and hyperpyrexia (Cincinnati Coma Grade V) (Heubi et al., 1987; Reye et al., 1963).

The case definition of Reye syndrome, according to the CDC, consists of (1) acute noninflammatory encephalopathy demonstrated by either the presence of less than 8 white blood cells per ml in the CSF or cerebral edema without perivascular or meningeal inflammation on histologic sections of the brain, associated with (2) fatty metamorphosis of the liver, diagnosed either by biopsy or autopsy, or (3) a serum glutamic-oxaloacetic transaminase level greater than three times normal and a high blood ammonia level, and (4) no more reasonable explanation for the cerebral or hepatic abnormalities. Major studies on Reye syndrome and medications (Hurwitz et al., 1985, 1987; Pinsky et al., 1988) have confirmed prior reports (Halpin et al., 1982; Starko et al., 1980; Waldman et al., 1982) of an association between ingestion of aspirin during antecedent viral illness and subsequent development of Reye syndrome.

The pathogenesis of Reye syndrome remains incompletely defined. The onset of emesis is considered to be the first sign of encephalopathy. Increasing metabolic derangements including elevated serum free fatty acids,

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 170

elevated serum ammonia, hypoglycemia, and decarboxylic acidemia are noted. Coincident with these changes, the intracranial pressure may become elevated, which precludes effective cerebral perfusion, leading to brain damage or death (Heubi et al., 1987). Morphologic and biochemical studies reveal the presence of an hepatic mitochondrial damage that is characteristic of the hepatic pathology of Reye syndrome.

Descriptive Epidemiology

A number of reports indicate that the incidence of Reye syndrome in the United States increased in the 1970s, with the incidence rate in Olmsted County, Minnesota, in persons under age 18 years, for example, rising from 1.1 per 100,000 person-years in 1970 to 1975 to 1.7 per 100,000 person-years in 1976 to 1981 (Nicolosi et al., 1985). The estimated incidence rate of Reye syndrome in Great Britain for the years 1976 to 1979 obtained in the NCES was 0.7 per 100,000 children age 2 to 36 months per year (Bellman et al., 1982). Since 1980, however, incidence rates have declined, with the annual number of Reye syndrome cases reported to the CDC's National Reye Syndrome Surveillance System falling from 555 (0.9 per 100,000 U.S. population under age 18 years) in 1980 to 20 in 1988 (Centers for Disease Control, 1989). The decline in Reye syndrome cases since late 1980 coincides with the decreased frequency and dose of aspirin-containing medication used in treating children with influenza-like illness (Barrett et al., 1986; Remington et al., 1986).

Evidence from Studies in Humans
Controlled Epidemiologic Study

In the NCES, a total of 37 cases of Reye syndrome were reported (a rate of 0.7 per 100,000 children per year). Only one of these cases occurred within 7 days of DPT immunization (Bellman et al., 1982). The case, a previously normal child, subsequently died; no cause of death was specified. Aspirin exposure in the child is unknown.

Case Reports and Case Series

Linnemann and colleagues (1974) reported on a cluster of 24 cases of Reye syndrome admitted to Children's Hospital Medical Center in Cincinnati in early 1974. The epidemic of Reye syndrome coincided with an epidemic of influenza in the immediate area. All recent immunizations were reviewed; only one child had been immunized (with OPV) within the previous month.

Corey and colleagues (1976) described 379 cases of confirmed Reye

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 171

syndrome reported to the CDC in late 1973 and early 1974. Five cases were reported to have received an immunization within the month prior to hospitalization; all five had an antecedent upper respiratory infection. Two of the five cases had received MMR in the week before hospitalization, one had received DPT 2 days before hospitalization, and two had received OPV in the month before hospitalization. No patient had a history of recent influenza vaccination.

Seven cases of Reye syndrome (ICD 9 code 331.8) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these, five cases received OPV at the time of DPT immunization and one case received OPV plus MMR. No follow-up of the cases was made, and a physician's diagnosis was not required.

Summary

Only 1 of the 37 cases of Reye syndrome identified in the NCES and none of the 24 cases in Linnemann and colleagues' series had received DPT vaccine within 7 days of onset. The lack of evidence of an association between DPT vaccine and Reye syndrome in these two defined populations, as well as the strong epidemiologic evidence linking aspirin intake with Reye syndrome, including the virtual disappearance of the disease in the United States coincident with the recommended proscription of aspirin in children, argues against a significant contribution of DPT vaccine to this disorder. There are no experimental data that bear on a biologic mechanism by which DPT vaccination might cause Reye syndrome.

Conclusion

The evidence does not indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and Reye syndrome.

SHOCK AND "UNUSUAL SHOCK-LIKE STATE" WITH HYPOTONICITY, HYPORESPONSIVENESS, AND SHORT-LIVED CONVULSIONS, USUALLY FEBRILE

Clinical Description

Shock or shock-like state, collapse, and hypotonic, hyporesponsive episodes (HHE) are terms that are used interchangeably in the literature to refer to an unusual reaction consisting of an acute diminution in sensory

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 172

awareness or loss of consciousness accompanied by pallor and muscle hypotonicity. As described, the syndrome has its onset between 1 and 12 hours after immunization. Most children are initially irritable and febrile. They then become pale, limp, and unresponsive or hyporesponsive. Respirations are shallow and cyanosis is frequently noted. The duration can be as short as a few minutes and as long as 36 hours (Cody et al., 1981; Siddiqui et al., 1989). The pathophysiology of this entity has not been well described.

At least some of the cases of HHE (as the syndrome is referred to in this report) may be due to anaphylaxis. Both HHE and anaphylaxis can occur within a few minutes to a few hours after injection of DPT. Both are accompanied by tachycardia, although most infants diagnosed with HHE have had fever, which increases the heart rate. Accompanying symptoms of urticaria or angioedema, especially of the larynx, would indicate anaphylaxis (by definition), not HHE. Shallow respirations and cyanosis might occur with either entity. It is possible that at least some cases of HHE represent atonic seizures, which consist of sudden loss of postural tone and consciousness, perhaps triggered by fever (Huttenlocher, 1987).

Descriptive Epidemiology

No population-based incidence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports and Case Series

Although Madsen in 1933 and Werne and Garrow in 1946 reported four deaths from apparent shock following pertussis vaccination, HHE was not systematically described until 1961, when Hopper surveyed 52 parents reporting illnesses in their children following vaccination. Six cases of "collapse" were described, with onset from 1 to several hours after vaccination. All cases recovered with no long-term sequelae noted.

Subsequent case reports of HHE following pertussis vaccination were published over the next 15 years (e.g., Aicardi and Chevrie, 1975; Forrester, 1965; Haire et al., 1967; Hannik and Cohen, 1979; Stewart, 1977; Strom, 1967).

Feery and colleagues (1985) compared the incidence and type of adverse events following administration of plain or adsorbed DPT vaccines in a masked prospective study of 2,041 vaccinations in 1,075 infants receiving routine childhood immunization. In all, 558 infants received a total of 1,031 doses of plain DPT vaccine and 517 infants received a total of 1,010

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 173

doses of adsorbed DPT vaccine. Three recipients of plain vaccine and one of adsorbed vaccine suffered HHE or collapse, giving HHE incidence rates of 291 and 99 cases per 100,000 injections of plain and adsorbed DPT vaccine, respectively.

Coulter and Fisher (1985) described several cases of shock or collapse following pertussis vaccination, some with subsequent death (p. 97) or disability, including learning disabilities (p. 118), hyperactivity (p. 125), and epilepsy (p. 125).

Baraff and colleagues (1989) prospectively studied 9,920 infants and children immunized with DPT from 25 different vaccine lots. HHE was rare (0 to 0.4 percent across lots; absolute numbers were not reported). There were insufficient cases for comparison of rates by vaccine potency, endotoxin content, or percent mouse weight gain. No information on longterm outcome of the HHE cases was provided.

Siddiqui and colleagues (1989) identified nine cases of HHE that occurred within 28 days of DPT vaccination in the state of Maryland in 1987. Approximately 259,000 doses of DPT vaccine were administered in Maryland during this time, representing an incidence rate of approximately 3.5 cases per 100,000 vaccinations. No information on long-term case outcome was provided.

Blumberg and colleagues (in press) examined physician and nurse reports from the Los Angeles area to identify severe adverse events following DPT vaccination. Cases were considered eligible for study if the onset of the adverse event was within 48 hours of immunization and if the study staff was able to evaluate the child within 24 hours of symptom onset. Eleven cases of HHE were identified, 10 following immunization with whole-cell vaccine and 1 following receipt of the Takeda acellular pertussis vaccine. Laboratory tests offered no evidence that altered insulin or glucose metabolism or biologically active pertussis toxin was related to HHE onset.

Eight hundred eighty-five cases of HHE (ICD 9 code 785.9) occurring within 28 days of DPT immunization were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Of these, 634 cases (71.6 percent) received at least one other vaccine at the time of DPT immunization. No follow-up of the cases was made, and a physician's diagnosis was not required.

Controlled Epidemiologic Studies

Cody and colleagues (1981) compared reactions occurring in children, ages 0 to 6 years, in the first 48 hours following 15,752 injections of DPT vaccine and 784 injections of DT vaccine (Table 6-1). Nine cases of HHE

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 174

TABLE 6-1 Controlled Studies of Shock and "Unusual Shock-Like State"a 

       

Children

Immunizations

HHE

 

Powerc

Reference

Years

Age

Vaccine

(No.)

(No.)

(No.)

RR (95% CI)b

50%

80%

Cody et al., 1981

1978-1979

0-6 years

DPT

15,752

15,752

9

1.0 (0.1-7.4)

7.8

18.9

     

DT

784

784

0

     

Pollock and Morris, 

1979

<2 years

DPT

134,700

404,100

8

4.0 (1.0-16.0)

4.1

7.5

1983d

   

DT

135,500

406,500

2

     
     

DPT

~17,000

~21,000

NRe

     
     

DT

~18.000

~24.000

NRe

     

Pollock et al., 1984     

1978-1980

3 months

DPT

6.004

13,917f

5

1.0 (0.3-3.3)

3.5

5.9

   

1 year

DT

4,024

10,601

4

     

Long et al., 1990

1984-1985

2-20 months

DPT

538

1,553

0

0.1 (0.0-2.3)

16.0

52.7

     

Placebog

218

218

0

     

a Shock and "unusual shock-like state" defined in report as hypotonic, hyporesponsive episodes (HHE).

b RR (95% CI), Estimated relative risk (95 percent confidence interval).

c "Power" denotes the probability that a statistical test based on a sample of the same size as the one in the study cited would find a statistically significant increased risk (with alpha = 0.05), given that the true RR in the population being studied is the number stated in the table. The numbers tabulated are the RRs such that the powers are 50 and 80 percent, respectively.

d First study based on voluntary reporting; second study based on systematic hospital activity analysis.

e NR, Not reported.

f Excludes 1,125 doses of plain DPT.

g Saline injection substituted for the fourth DPT dose at age 6 months.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 175

were reported following DPT vaccine for a rate of 57 per 100,000 injections. No cases of HHE were observed following DT vaccines. The difference in rates was not statistically significant (the RR was 1.0 and the 95 percent CI was 0.1 to 7.4), but the power of this study was very low. For instance, the RR would have to be 7.8 for the test to have 50 percent power. All cases occurred within 10 hours of immunization and usually within 4 hours, with episodes lasting from 10 minutes to 36 hours. Cases were associated with the primary immunization series only and occurred in infants aged 2 to 18 months. None of the affected infants had a past history of neurologic problems, convulsions, or developmental delay, and all returned to normal activities or were normal when evaluated by the investigators. The association of HHE with primary immunization has also been reported elsewhere (Health Council of The Netherlands, 1987, 1988).

A subsequent evaluation of the nine cases of HHE identified by Cody and colleagues (1981) was undertaken approximately 7 years later by Baraff and coworkers (1988). Eight of the nine children were contacted and six were given a complete neurologic and psychometric evaluation, the latter consisting of the Wechsler Intelligence Scale for Children—Revised. Two of the children exhibited low verbal IQ scores (i.e., less than 85 or more than 1 standard deviation below the mean). One of these demonstrated an articulatory deficit upon neurologic examination; the patient also had a history of familial speech problem. The authors concluded that there was no evidence that any of the nine cases of HHE suffered chronic neurologic damage as a result of their HHE.

Eight cases of anaphylaxis or collapse after DPT immunization were reported in the North West Thames study (Pollock and Morris, 1983; see section on Anaphylaxis for study description) in approximately 134,700 children receiving complete courses of three injections. Two similar cases were observed in 133,500 children receiving complete courses of three DT injections. Although the relative risk of HHE following DPT compared with that following DT vaccine is 4.0 (95 percent CI = 1.0 to 16.2), the authors note that the increased estimated relative risk could be an artifact of the voluntary reporting system. Symptoms of anaphylaxis or collapse varied in character and severity, and many occurred within a few minutes of the injection. In six cases, the predominant features were pallor, limpness, and apnea, which is consistent with the diagnosis of HHE.

A subsequent study by Pollock and colleagues (1984) compared rates of adverse events in 10,028 infants, of whom 6,004 started primary immunization with DPT vaccine and 4,024 with DT vaccine. The DPT group was further divided into those receiving plain versus those receiving adsorbed vaccine. The first vaccine dose for each child was scheduled at age 3 months, the second 6 to 8 weeks later, and the third, final dose 4 to 6 months following the second dose. A total of 25,643 doses of vaccine were given: 1,125 of plain DPT, 13,917 of adsorbed DPT, and 10,601 of adsorbed

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 176

DT. Rates of pallor and cyanosis, i.e., "hypotonia," were similar (40 per 100,000 doses) in both the adsorbed DPT (5 cases) and DT (4 cases) groups. The RR for HHE following DPT compared with that following DT vaccine is 1.0 with a 95 percent CI of 0.3 to 3.3. The power of this test, like those in the other controlled studies of HHE, was low: 50 percent for an RR of 3.5 and 80 percent for an RR of 5.9. Four cases occurred after plain DPT, but the major difference in the preparation of this vaccine makes comparisons difficult. All 13 children recovered quickly, and there were no sequelae.

Because each of these three studies had relatively low power, the committee combined the evidence from all three using the methods of meta-analysis described in Appendix D. The pooled RR was 1.6 with a 95 percent CI of 0.6 to 4.2 (under both the random- and fixed-effects models). Thus, the meta-analysis provides little evidence of a significantly increased risk of HHE following DPT compared with that following DT vaccine.

Blumberg and colleagues (1988), in a surveillance study conducted in Los Angeles County in 1986, identified five children who had HHE following DPT immunization. A physical examination and medical history were conducted on and blood samples were collected from each child. Results were compared with those for 16 control children, ages 4 to 6 years, who had no reactions following DPT immunization. Acute leukocytosis (average total white cell count, 9,400 cells/mm3) was observed in both cases and controls on the day following DPT immunization; no abnormalities were noted in plasma insulin or serum glucose. Follow-up at 1 month postimmunization revealed no persistent neurologic abnormalities in the five cases of HHE.

Long and colleagues (1990) prospectively assessed the rates of adverse events, including HHE, following pertussis vaccination in 538 children randomized to the standard four-dose immunization schedule or to a three-dose schedule with a saline injection substituted for DPT at age 6 months. In all, 1,553 doses of DPT vaccine were given. No cases of HHE were observed following DPT vaccination. However, it is not surprising that an event as infrequent as HHE was not detected given the study's relatively small sample size and, therefore, the study provides little information on the presence or absence of an association between DPT immunization and HHE.

Summary

The body of evidence concerning the possible relation between vaccination with DPT or its pertussis component and HHE includes case reports, case series, and several controlled epidemiologic studies. Incidence rates of HHE vary widely, from 3.5 to 291 per 100,000 injections. Epidemiologic evidence of sufficient quality pertinent to this question can be summarized as follows. Two of the three controlled studies comparing children immunized with DPT or DT (Cody et al., 1981; Pollock et al., 1984) found no association between HHE and DPT compared with that between HHE and

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 177

DT vaccine, and the other study (Pollock and Morris, 1983) found a significantly increased risk that the authors ascribed to the voluntary reporting system (Table 6-1). Dose-response relations cannot be evaluated from the available data. The easily visualized presentation of HHE suggests that exposure truly preceded the onset of the condition among the exposed cases.

The pathophysiologic basis of HHE is not understood. The clinical presentation of this adverse event includes a spectrum of signs, ranging from decreased responsiveness to shock, and in some reports, HHE is not differentiated from anaphylaxis. However, no clinical signs of allergy have been reported and no laboratory evidence for an immunologic reaction or any other mechanism has been presented. The clinical picture in some cases resembles a seizure, but there is no evidence for this possibility. Nevertheless, a clinical presentation that could be classified as HHE has been widely observed and reported. Thus, the evidence for causality rests here on the typical clinical presentation that occurs within a few hours after administration of the vaccine.

The evidence concerning a possible relation between HHE and chronic neurologic damage such as mental or motor retardation includes case reports, case series, and controlled epidemiologic studies. A few case reports have raised the possibility that HHE might be associated with permanent sequelae, but the three controlled studies that have examined this issue indicate no such relation. However, the relatively small number of HHE cases (27) followed up in these three studies would suggest that the likelihood that these studies would detect a rare sequela like chronic neurologic damage would be small. In addition, the difficulty in confirming a clear date of onset for certain types of chronic neurologic damage such as mental and motor retardation limits the ability to establish temporal priority of exposure among the few exposed cases reported.

Conclusion

The evidence is consistent with a causal relation between DPT vaccine and HHE. The available evidence does not implicate the pertussis component specifically.

Evidence is insufficient to indicate a causal relation between HHE following DPT immunization and the subsequent development of permanent neurologic damage.

THROMBOCYTOPENIA

Clinical Description

The term thrombocytopenia indicates decreased platelet numbers in the blood. Thrombocytopenia may stem from failure of platelet production,

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 178

splenic sequestration of platelets, increased platelet destruction, increased platelet utilization, or dilution of platelets. If thrombocytopenia is severe enough, petechiae and subcutaneous hemorrhages (purpura) may occur. The cause of idiopathic thrombocytopenic purpura, a common form of thrombocytopenia, is not understood. Immunologic mechanisms may be responsible for thrombocytopenia, as described earlier for hemolytic anemia.

Descriptive Epidemiology

Thrombocytopenia is associated with a variety of causes and is not uncommon in pediatric practice. No population-based incidence or prevalence rates were identified for the pediatric population.

Evidence from Studies in Humans
Case Reports and Case Series

Hennessen and Quast (1979) reported on 149 infants experiencing adverse events following pertussis vaccination. All cases were reported to vaccine manufacturers in Switzerland or Germany. Two cases of thrombocytopenia were reported on the same day by one physician 4 weeks after vaccination of two infants.

A 16-month-old girl was hospitalized with thrombocytopenic purpura days after receiving a booster injection of DPT and OPV (Champsaur et al., 1982). The authors concluded after virologic, immunologic, and animal studies that the purpura was caused by a concomitant coxsackievirus B 5 infection.

Thirteen cases of thrombocytopenia (ICD 9 codes 287.3 and 287.5) following DPT vaccination were reported through the CDC's MSAEFI system from 1978 to 1990, a period in which approximately 80.1 million doses of DPT vaccine were administered through public mechanisms in the United States (J. Mullen, Centers for Disease Control, personal communication, 1990). Both cases of thrombocytopenia also received OPV at the time of DPT vaccination, and of the 11 cases of thrombocytopenic purpura, 6 cases also received OPV, 1 received MMR, and 4 received OPV plus MMR. No follow-up of the cases was made, and a physician's diagnosis was not required.

Summary

Information concerning the possible relation between vaccination with DPT or its pertussis component and thrombocytopenia is limited to 3 published cases and 13 additional cases reported through the CDC's MSAEFI

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 179

system. The clinical presentation of thrombocytopenia limits the ability to establish whether exposure preceded the condition among these exposed cases. The specificity of association is also unestablished, given the multiple possible causes of thrombocytopenia. An immunologic basis might be proposed, but no experimental data exist to support an immunologic or other causal association.

Conclusion

There is insufficient evidence to indicate a causal relation between DPT vaccine or the pertussis component of DPT vaccine and thrombocytopenia.

REFERENCES

Aicardi J, Chevrie JJ. 1975. Accidents neurologiques consecutifs a la vaccination contre la coqueluche. [Neurological complications following immunization against pertussis.] Archives Francaises de Pediatrie 32:309-317.

Al-Qudah AA, Shahar E, Logan WJ, Murphy EG. 1988. Neonatal Guillain-Barrè syndrome. Pediatric Neurology 4:225-226.

American Psychiatric Association. 1987. Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM III-R). Washington, DC: American Psychiatric Association.

Amiel SA. 1976. The effects of Bordetella pertussis vaccine on cerebral vascular permeability. British Journal of Experimental Pathology 57:653-662.

Arora S, Sanyal RK, West GB. 1970. The sensitizing action of Bordetella pertussis vaccine. International Archives of Allergy and Applied Immunology 37:357-365.

Baraff LJ, Cody CL, Cherry JD. 1984. DTP-associated reactions: an analysis by injection site, manufacturer, prior reactions, and dose. Pediatrics 73:31-36.

Baraff LJ, Shields WD, Beckwith L, Strome G, Marcy SM, Cherry JD, Manclark CR. 1988. Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow up evaluation. Pediatrics 81:789-794.

Baraff LJ, Manclark CR, Cherry JD, Christenson P, Marcy SM. 1989. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain. Pediatric Infectious Disease Journal 8:502-507.

Barkin RM, Pichichero ME. 1979. Diphtheria-pertussis-tetanus vaccine: reactogenicity of commercial products. Pediatrics 63:256-260.

Barrett MJ, Hurwitz ES, Schonberger LB, Rogers MF. 1986. Changing epidemiology of Reye syndrome in the United States. Pediatrics 77:598-602.

Bellman MH, Ross EM, Miller DL. 1982. Reye's syndrome in children under three years old. Archives of Disease in Childhood 57:259-263.

Benacerraf B, Kabat EA. 1950. A quantitative study of the Arthus phenomenon induced passively in the guinea pig. Journal of Immunology 64:1-19.

Bender L. 1942. Post encephalitic behavior disorders in childhood. In: Bender L, ed. Encephalitis: A Clinical Study. New York: Grune & Stratton.

Bergman RK, Munoz JJ, Portis JL. 1978. Vascular permeability changes in the central nervous system of rats with hyperacute experimental allergic encephalomyelitis induced with the aid of a substance from Bordetella pertussis. Infection and Immunity 21:627-637.

Bishop WB, Carlton RF, Sanders LL. 1966. Diffuse vasculitis and death after hyperimmunization

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 180

with pertussis vaccine: report of a case. New England Journal of Medicine 274:616-619.

Blumberg DA, Morgan CA, Lewis K, Leach C, Holtzman A, Levin SR, Baraff LJ, Cherry JD. 1988. An ongoing surveillance study of persistent crying and hypotonic-hyporesponsive episodes following routine DTP immunization: a preliminary report. Tokai Journal of Experimental and Clinical Medicine 13(Suppl.):133-136.

Blumberg DA, Mink CM, Lewis K, Chatfield P, Leach C, Smith LP, Christenson PD, Guravita L, Steinfeld MBJ, March SM, Levin SR, Baraff LJ, Schonfeld N, Cherry JD. In press. Pathophysiology of reactions associated with pertussis vaccine. Developments in Biological Standardization.

Blumstein GI, Kreithen H. 1966. Peripheral neuropathy following tetanus toxoid administration. Journal of the American Medical Association 198:1030-1031.

Broman S, Bien E, Shaughnessy P. 1985. Low-Achieving Children: The First Seven Years. Hillsdale, NJ: Lawrence Erlbaum.

Bryceson ADM. 1976. Clinical pathology of the Jarisch-Herxheimer reaction. Journal of Infectious Diseases 133:696-704.

Butler NR, Golding J, Haslum N, Stewart-Brown S. 1982. Recent findings from the 1970 child health and education study. Journal of the Royal Society of Medicine 75:781-784.

Cantwell DP. 1983. Diagnostic validity of the hyperactive child (attention deficit disorder with hyperactivity) syndrome. Psychiatric Developments 3:277-300.

Carroll JE, Jedziniak M, Guggenheim MA. 1977. Guillain-Barrè syndrome: another cause of the "floppy infant." American Journal of Diseases of Children 131:699-700.

Centers for Disease Control. 1989. Reye syndrome surveillance—United States, 1987 and 1988. Morbidity and Mortality Weekly Report 38:325-327.

Chaby R, Ayme G, Caroff M, Donikian R, Haeffner-Cavaillon N, LeDur A, Moreau M, Mynard MC, Roumiantzeff M, Szabo L. 1979. Structural features and separation of some of the biological activities of the Bordetella pertussis endotoxin by chemical fractionation. In: Manclark CR, Hill JH, eds. International Symposium on Pertussis. DHEW Publication No. (NIH) 79-1830. Washington, DC: U.S. Government Printing Office.

Chamberlain R, Chamberlain G, Howlett B, Claireaux A. 1975. British Births, 1970, Vol. 1: The First Week of Life. London: Heinemann Medical.

Champsaur HF, Bottazo GF, Bertrams J, Assan R, Bach C. 1982. Virologic, immunologic, and genetic factors in insulin-dependent diabetes mellitus. Journal of Pediatrics 100:15-20.

Chang IC, Gottshall RY. 1974. Sensitization to ragweed pollen in Bordetella pertussis-infected or vaccine-injected mice. Journal of Allergy and Clinical Immunology 54:20-24.

Cherry JD, Brunell PA, Golden GS, Karzon DT. 1988. Report of the task force on pertussis and pertussis immunization—1988. Pediatrics 81(6, part 2):933-984.

Chomel AF. 1828. Journal Hebdomadaire de Medecine 1:333.

Clausen CR, Munoz J, Bergman RK. 1970. A reaginic type of antibody stimulated by extracts of Bordetella pertussis in inbred strains of mice. Journal of Immunology 104:312-319.

Clements SD, Peters JE. 1962. Minimal brain dysfunction in the school-aged child. Archives of General Psychiatry 6:185-187.

Cody CL, Baraff LJ, Cherry JD, Marcy SM, Manclark CR. 1981. Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650-660.

Cohen P, Scadron SJ. 1946. Effects of active immunization of mother upon offspring. Journal of Pediatrics 29:609-619.

Colman RW. 1989. The role of plasma proteases in septic shock. New England Journal of Medicine 320:1207-1209.

Cone TE, Wilson LR. 1981. Quantifying a severe discrepancy: a critical analysis. Learning Disability Quarterly 4:359-371.

Corey L, Rubin RJ, Hattwick MA, Noble GR, Cassidy E. 1976. A nationwide outbreak of

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 181

Reye's syndrome: its epidemiologic relationship to influenza B. American Journal of Medicine 61:615-625.

Coulter H, Fisher B. 1985. DPT: A Shot in the Dark. New York: Harcourt Brace Jovanovich.

Csaba B, Muszbek L. 1972. The effect of Bordetella pertussis vaccine on protease sensitivity and on the anaphylactic protease production in rats. Acta Allergologia 27:55-62.

DeMyer MK, Hingtgen JN, Jackson RK. 1981. Infantile autism reviewed: a decade of research. Schizophrenia Bulletin 7:388-451.

Denning D, Peet L, Poole J. 1987. Skin rash after triple vaccine. Archives of Disease in Childhood 62:510-511.

Dolovich J, Hargreave FE, Chalmeis R, Shier KJ, Cauldie J, Bienenstock J. 1973. Late cutaneous allergic responses in isolated-IgE-dependent reactions. Journal of Allergy and Clinical Immunology 52:38-46.

Eckman PL, King WM, Brunson JG. 1958. Studies on the blood brain barrier. I. Effects produced by a single injection of gram-negative endotoxin on the permeability of the cerebral vessels. American Journal of Pathology 34:631-643.

Eden AN. 1961. Guillain-Barrè syndrome in a 6-month-old infant. American Journal of Diseases of Children 102:224-227.

Ehrengut W. 1977. Neurale Komplikationen nach Pertussis-Schutzimpfung. [Neurological complications following whooping-cough vaccination.] Monatsschrift für Kinderheilkunde 125:908-911.

Evans OB. 1986. Guillain-Barré syndrome in children. Pediatrics in Review 8:69-74.

Facktor M, Bernstein RA, Fireman P. 1973. Hypersensitivity to tetanus toxoid. Journal of Allergy and Clinical Immunology 52:1-12.

Fearon DT, Ruddy S, Schur PH, McCabe WR. 1975. Activation of the properdin pathway of complement in patients with gram-negative bacteremia. New England Journal of Medicine 292:937-940.

Feery BJ, Finger WK, Kortus Z, Jones GA. 1985. The incidence and type of reactions to plain and adsorbed DTP vaccines. Australian Pediatric Journal 21:91-95.

Fisher M. 1987. Anaphylaxis. Diseases of Man 33:433-479.

Forrester RM. 1965. Immunization against whooping-cough. British Medical Journal 2:232.

Furman BL, Wardlaw AC, Stevenson LQ. 1981. Bordetella pertussis-induced hyperinsulinemia without marked hypoglycemia: a paradox explained. British Journal of Experimental Pathology 62:504-511.

Galazka A, Andrzejczak-Kardymowicz B. 1972. Complications and reactions after vaccination against pertussis. Epidemiological Review 26:411-424.

Geier MR, Stanbro H, Merril CR. 1978. Endotoxins in commercial vaccines. Applied and Environmental Microbiology 36:445-449.

Gilmartin RC, Chien LT. 1977. Guillain-Barré syndrome with hydrocephalus in early infancy. Archives of Neurology 34:567-569.

Goldstein K. 1936. Modification of behavior consequent to cerebral lesion. Psychiatric Quarterly 10:539-610.

Graves RJ. 1843. A System of Clinical Medicine, 1st edition. Dublin: Fannin.

Guillain G, Barré JA, Strohl A. 1916. Sur un syndrome de radiculonevrite avec hyperalbuminose due liquide cephalo-rachidien sans reaction cellulaire: remarques sur les caracteres cliniques et graphiques des reflexes tendineux. Bulletins et Memoires Societe Medicale des Hopitaux de Paris 40:1462-1470.

Haire M, Dane DS, Dick G. 1967. Reactions to combined vaccines containing killed Bordetella pertussis. The Medical Officer 117:55-58.

Halpin TJ, Holtzhauer FJ, Campbell RJ, Hall LJ, Correa-Villasenor A, Lanese R, Rich J, Hurwitz ES. 1982. Reye's syndrome and medication use. Journal of the American Medical Association 248:687-691.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 182

Haneberg B, Matre R, Winsnes R, Dalen A, Vogt H, Finne P. 1978. Acute hemolytic anemia related to diphtheria-pertussis-tetanus vaccination. Acta Paediatrica Scandinavica 67:345-350.

Hannik CA, Cohen C. 1979. Pertussis vaccine experience in the Netherlands. In: Manclark CR, Hill JC, eds. International Symposium on Pertussis. DHEW Publication No. (NIH) 79-1830. Washington, DC: U.S. Government Printing Office.

Health Council of The Netherlands. 1987. Adverse Reactions to Vaccines in the National Vaccination Programme in 1986. The Hague, The Netherlands: Gezondheidsraad.

Health Council of The Netherlands. 1988. Adverse Reactions to Vaccines in the National Vaccination Programme in 1987. The Hague, The Netherlands: Gezondheidsraad.

Hebra FV. 1866. On diseases of the skin including the exanthemata. New Syndeham Society 1:285-289.

Hedenskog S, Bjorksten B, Blennow M, Granstrom G, Granstrom M. 1989. Immunoglobulin E response to pertussis toxin in whooping cough and after immunization with a whole-cell and an acellular pertussis vaccine. International Archives of Allergy and Applied Immunology 89:156-161.

Hennessen W, Quast U. 1979. Adverse reactions after pertussis vaccination. International Symposium on Immunization: Benefit vs. Risk Factors, Brussels. Developments in Biological Standardization 43:95-100.

Henson PM. 1982. Antibody and immune-complex-mediated allergic and inflammatory reactions. In: Lachmann PJ, Peters DK, eds. Clinical Aspects of Immunology, 4th edition. Oxford: Blackwell.

Heubi JE, Partin JC, Partin JS, Schubert W.K. 1987. Reye's syndrome: current concepts. Hepatology 7:155-164.

Hohman LB. 1922. Post encephalitic behavior disorders in children. Johns Hopkins Hospital Bulletin 380:372-375.

Hopper JMH. 1961. Illness after whooping cough vaccination. The Medical Officer 106:241-244.

Hurwitz ES, Barrett MJ, Bregman D, Gunn WJ, Schonberger LB, Fairweather WR, Drage JS, LaMontagne JR, Kaslow RA, Burlington DB. 1985. Public Health Service study on Reye's syndrome and medications: report of the pilot phase. New England Journal of Medicine 313:849-857.

Hurwitz ES, Barrett MJ, Bregman D, Gunn WJ, Pinsky P, Schonberger LB, Drage LS, Kaslow RA, Burlington DB, Quinnan GV. 1987. Public Health Service study on Reye's syndrome and medications: report of the main study. Journal of the American Medical Association 257:1905-1911.

Huttenlocher PR. 1987. The child with a convulsive disorder. In: Behrman RE, Vaughan VC, eds. Nelson's Textbook of Pediatrics, 16th edition. Philadelphia: W.B. Saunders Co.

Ibsen P, Moller S, Heron I. 1988. Lipopolysaccharides in a traditional pertussis vaccine. Journal of Biological Standardization 16:299-309.

Illingworth R. 1987. Skin rashes after triple vaccine (letter). Archives of Disease in Childhood 62:979.

Kanner L. 1943. Autistic disturbances of affective contact. The Nervous Child 2:217-250.

Kind LS. 1958. Sensitivity of pertussis inoculated mice to endotoxin. Journal of Immunology 82:32-37.

Kniker WT. 1988. Anaphylaxis in children and adults. In: Bierman CW, Pearlman DS, eds. Allergic Diseases from Infancy to Adulthood. Philadelphia: W.B. Saunders Co.

Lachmann PJ, Peters DK. 1982. Complement. In: Lachmann PJ, Peters DK, eds. Clinical Aspects of Immunology, 4th edition. Oxford: Blackwell.

Lancet. 1988. Guillain-Barré syndrome (editorial). 2:659-661.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 183

Landry O. 1859. Note sur la paralysie ascendante aigue. Gazette Hebdomadaire Medical Chirurgical 6:472-474, 486, 488.

LaPorte RE, Cruickshanks KJ. 1985. Incidence and risk factors for insulin-dependent diabetes. In: Harris MI, Hamman RF, eds. Diabetes in America: Diabetes Data Compiled 1984. National Diabetes Data Group. NIH Publication No. 85-1468. National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Bethesda, MD: Public Health Service, U.S. Department of Health and Human Services.

Laude T. 1981. Herald patch in a DPT injection site. Journal of the American Academy of Dermatology 5:475-476.

Leung AKC. 1984. Erythema multiforme following DPT vaccination (letter). Journal of the Royal Society of Medicine 77:1066-1067.

Leung AKC. 1985. Anaphylaxis due to DPT vaccine (letter). Journal of the Royal Society of Medicine 78:175.

Leung AKC, Szabo T. 1987. Erythema multiforme following diphtheria-pertussis-tetanus vaccination. Kobe Journal of Medical Science 33:121-124.

Liberman IY, Shankweiler D. 1985. Phonology and the problems of learning to read and write. Remedial and Special Education 6:8-17.

Linnemann CC, Kauffman CA, Shea L, Schiff GM, Partin JC, Schubert WK. 1974. Association of Reye's syndrome with viral infection. Lancet 2:179-182.

Long SS, DeForest A, Smith DG, Lazaro C, Wassilak SGF. 1990. Longitudinal study of adverse reactions following diphtheria-tetanus-pertussis vaccine in infancy. Pediatrics 85:294-302.

Madsen T. 1933. Vaccination against whooping cough. Journal of the American Medical Association 101:187-188.

Mann VA, Cowin E, Schoeheimer J. 1989. Phonological processing, language comprehension, and reading ability. Journal of Learning Disabilities 22:76-89.

Martin GI, Weintraub MI. 1973. Brachial neuritis and 7th nerve palsy—a rare hazard of DPT vaccination. Clinical Pediatrics 12:506-507.

McLeod JG. 1981. Electrophysiological studies in the Guillain-Barré syndrome. Annals of Neurology 9(Suppl.):20-27.

Meyer A. 1904. The anatomical facts and clinical varieties of traumatic insanity. American Journal of Insanity 60:373-441.

Michie HR, Manogue KR, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello CA, Cerami A, Wolff SM, Wilmore DW. 1988. Detection of circulating tumor necrosis factor after endotoxin administration. New England Journal of Medicine 318:1481-1486.

Miller RG. 1985. Guillain-Barré syndrome: current methods of diagnosis and treatment. Postgraduate Medicine 77:57-64.

Morrison DC, Ryan JL. 1987. Endotoxins and disease mechanisms. Annual Review of Medicine 38:417-432.

Munoz JJ. 1985. Biological activities of pertussigen (pertussis toxin). In: Sekura RD, Moss J, Vaughan M, eds. Pertussis Toxin. New York: Academic Press.

Munoz JJ, Bergman RK. 1968. Histamine-sensitizing factors from microbial agents, with special reference to Bordetella pertussis. Bacteriology Reviews 32:103-126.

Munoz JJ, Bergman RK. 1977. Bordetella pertussis: Immunological and Other Biological Activities. New York: Marcel Dekker.

Munoz JJ, Peacock MG, Hadlow WJ. 1987. Anaphylaxis or so-called encephalopathy in mice sensitized to an antigen with the aid of pertussigen (pertussis toxin). Infection and Immunity 55:1004-1008.

Newton J, Janati A. 1987. Guillain-Barré syndrome after vaccination with purified tetanus toxoid. Southern Medical Journal 80:1053-1054.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 184

Nicolosi A, Hauser A, Kurland LT, Beghi E. 1985. Reye's syndrome: incidence and time trends in Olmsted County, MN, 1950-1981. Neurology 35:1338-1340.

Oksenberg JR, Ko C, Judd AK, Lim M, Kent A, Schoolnik GK, Steinman L. 1989. Multiple T and B cell epitopes in the SI subunit (''A"-monomer) of the pertussis toxin molecule. Journal of Immunology 143:4227-4231.

Orlans D, Verbov J. 1982. Skin reactions after triple vaccine. The Practitioner 226:1295-1296.

Osvath P, Csorba S, Endre L, Szabados B, Peter F. 1979. IgE levels of infants with complications after pertussis vaccination. Allergologia et Immunopathologia 7:111-114.

Ovens H. 1986. Anaphylaxis due to vaccination in the office. Canadian Medical Association Journal 134:369-370.

Parfentjev I, Goodline MA. 1948. Histamine shock in mice sensitized with hemophilus pertussis vaccine. Journal of Pharmacological and Experimental Therapeutics 92:411-413.

Pearlman DS, Bierman CW. 1989. Allergic disorders. In: Stiehm ER, ed. Immunologic Disorders in Infants and Children, 3rd edition. Philadelphia: W.B. Saunders Co.

Peroutka SJ, Kitamura K, Lim M, Steinman L. 1987. Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists. Neurology 37:1068-1072.

Pinsky PF, Hurwitz ES, Schonberger LB, Gunn WJ. 1988. Reye's syndrome and aspirin: evidence for a dose-response effect. Journal of the American Medical Association 260:657-661.

Pollard JD, Selby G. 1978. Relapsing neuropathy due to tetanus toxoid. Journal of Neurological Science 37:113-125.

Pollock TM, Morris J. 1983. A 7-year survey of disorders attributed to vaccination in North West Thames Region. Lancet 1:753-757.

Pollock TM, Miller E, Mortimer JY, Smith G. 1984. Symptoms after primary immunisation with DTP and with DT vaccine. Lancet 2:146-149.

Quast U, Hennessen W, Widmark RM. 1979. Mono- and poly-neuritis after tetanus vaccination. Developments in Biological Standardization 43:25-32.

Reinstein L, Pargament JM, Goodman JS. 1982. Peripheral neuropathy after multiple tetanus toxoid injections. Archives of Physical Medicine and Rehabilitation 63:332-334.

Remington PL, Rowley D, McGee H, Hall WN, Monto AS. 1986. Decreasing trends in Reye syndrome and aspirin use in Michigan, 1979 to 1984. Pediatrics 77:93-98.

Reye RDK, Morgan G, Baral J. 1963. Encephalopathy and fatty degeneration of the viscera: a disease entity in childhood. Lancet 2:749-752.

Reynolds CR. 1984. Critical measurement issues in learning disabilities. The Journal of Special Education 18:451-476.

Rutter M. 1985. Infantile autism and other pervasive developmental disorders. In: Rutter M, Hersov L, eds. Child and Adolescent Psychiatry: Modern Approaches, 2nd edition. Oxford: Blackwell.

Rutter M, Yule W. 1975. The concept of specific reading retardation. Journal of Child Psychology and Psychiatry 16:181-197.

Sen DK, Arora S, Gupta S, Sanyal RK. 1974. Studies of adrenergic mechanisms in relation to histamine sensitivity in children immunized with Bordetella pertussis vaccine. Journal of Allergy and Clinical Immunology 54:25-31.

Shaywitz BA, Shaywitz SE. 1989. Learning disabilities and attention disorders. In: Swaiman KF, ed. Pediatric Neurology, Vol. II. St. Louis: C.V. Mosby.

Shaywitz S, Shaywitz B. 1988. Attention deficit disorder: current perspectives. In: Kavanagh JF, Truss JFJ, eds. Learning Disabilities: Proceedings of the National Conference. Parkton, MD: York Press.

Shelley WB. 1980. Bacterial endotoxin (lipopolysaccharide) as a cause of erythema multiforme. Journal of the American Medical Association 243:58-60.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 185

Siddiqui MA, Lin FY, Trostel B, Israel E, Dwyer DM. 1989. Adverse events following DTP immunization in Maryland, 1987. Maryland Medical Journal 38:556-559.

Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. 1980. Reye's syndrome and salicylate use. Pediatrics 66:859-864.

Steinman L, Sriram S, Adelman NE, Zamvil S, McDevitt HO, Urich H. 1982. Murine model for pertussis vaccine encephalopathy: linkage to H-2. Nature 299:738-740.

Steinman L, Weiss A, Adelman N, Lim M, Zuniga R, Oehlert J, Hewlett E, Falkow S. 1985. Pertussis toxin is required for pertussis vaccine encephalopathy. Proceedings of the National Academy of Sciences 82:8733-8736.

Stewart GT. 1977. Vaccination against whooping-cough: efficacy versus risks. Lancet 1:234-237.

Still GF. 1902. The Coulstonian lectures on some abnormal physical conditions in children. Lancet 1:1008-1012, 1077-1082, 1163-1168.

Strauss AA, Lehtinen LE. 1947. Psychopathology and Education in the Brain-Injured Child. New York: Grune & Stratton.

Strom J. 1967. Further experience of reactions, especially of a cerebral nature, in conjunction with triple vaccination: a study based on vaccinations in Sweden, 1959-1965. British Medical Journal 4:320-323.

Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. 1989a. The cardiovascular response of normal humans to the administration of endotoxin. New England Journal of Medicine 321:280-287.

Suffredini AF, Harpel PC, Parrillo JE. 1989b. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. New England Journal of Medicine 320:1165-1172.

Szatmari P, Tuff L, Finlayson AJ, Bartolucci G. 1990. Aspergers syndrome and autismneurocognitive aspects. Journal of the American Academy of Child and Adolescent Psychiatry 29:130-136.

Tada T, Okumura K, Ochia T, Iwasa S. 1972. Effect of lymphocytosis-promoting factor of Bordetella pertussis on the immune response. II. Adjuvant effect of the production of reaginic antibody in the rat. International Archives of Allergy 43:207-216.

Thorndike RL. 1963. The concepts of over- and under-achievement. New York: Bureau of Publications, Teachers College, Columbia University.

Tsairis P, Dick PJ, Mulder DW. 1972. Natural history of brachial plexus neuropathy. Archives of Neurology 27:109-117.

United States Office of Education. 1977. Assistance to states for education for handicapped children: procedures for evaluating specific learning disabilities. Federal Register 42:62082-62085.

Vellutino FR. 1978. Toward an understanding of dyslexia: psychological factors in specific reading disability. In: Benton AL, Pearl D, eds. Dyslexia: An Appraisal of Current Knowledge. New York: Oxford University Press.

Vellutino FR. 1979. Dyslexia: Theory and Research. Cambridge, MA: MIT Press.

Vellutino FR, Scanlon DM. 1987. Phonological awareness and reading ability—evidence from a longitudinal and experimental study. Merrill-Palmer Quarterly Journal of Developmental Psychology 33:321-363.

Volkmar FR, Cohen DJ. 1986. Pervasive developmental disorders. In: Cavenar JO, ed. Psychiatry, Vol. 2. Philadelphia: J.B. Lippincott Co.

Waldman RJ, Hall WN, McGee H, Van Amburg G. 1982. Aspirin as a risk factor in Reye's syndrome. Journal of the American Medical Association 247:3089-3094.

Wardlaw AC, Parton R. 1983. Pertussis vaccine. In: Easmon CSF, Jeljaszewicz J, eds. Medical Microbiology, Vol. 2. New York: Academic Press.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×

Page 186

Werne J, Garrow I. 1946. Fatal anaphylactic shock occurrence in identical twins following second injection of diphtheria toxoid and pertussis antigen. Journal of the American Medical Association 131:730-735.

Werner H, Strauss AA. 1941. Pathology of the figure-background relation in the child. Journal of Abnormal Social Psychology 36:236-248.

Wiedmeier SE, Chung HT, Cho BH, Kim UH, Daynes RA. 1987. Murine responses to immunization with pertussis toxin and bovine serum albumin. I. Mortality observed after bovine albumin challenge is due to an anaphylactic reaction. Pediatric Research 22:262-267.

Wiggins CA, Dykewicz MS, Patterson R. 1989. Idiopathic anaphylaxis: a review. Annals of Allergy 62:1-4.

Wing L. 1981. Sex ratios in early childhood autism and related conditions. Psychiatry Research 5:129.

Wing L, Yeates SR, Brierley LM, Gould J. 1976. The prevalence of early childhood autism: comparison of administrative and epidemiological studies. Psychological Medicine 6:89-100.

Zametkin AJ, Nordahl TE, Gross M, King AC, Semple WE, Rumsey J, Hamburger S, Cohen RM. 1990. Cerebral glucose metabolism in adults with hyperactivity of childhood onset. New England Journal of Medicine 323:1361-1366.

Zuelzer WW, Mastrangelo R, Stulberg CS, Poulik MD, Page RH, Thompson RI. 1970. Autoimmune hemolytic anemia: natural history and viral-immunologic interactions in childhood. American Journal of Medicine 49:80-93.

Zupanska B, Lawkowicz W, Gorska B, Kozlowska J, Ochocka M, Rokicka-Milewska R, Derulska D, Ciepielewska D. 1976. Autoimmune haemolytic anaemia in children. British Journal of Haematology 34:511-520.

Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page144
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page145
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page146
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page147
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page148
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page149
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page150
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page151
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page152
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page153
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page154
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page155
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page156
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page157
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page158
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page159
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page160
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page161
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page162
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page163
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page164
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page165
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page166
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page167
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page168
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page169
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page170
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page171
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page172
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page173
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page174
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page175
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page176
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page177
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page178
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page179
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page180
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page181
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page182
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page183
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page184
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page185
Suggested Citation:"6 Evidence Concerning Pertussis Vaccines and Other Illnesses and Conditions." Institute of Medicine. 1991. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: The National Academies Press. doi: 10.17226/1815.
×
Page186
Next: 7 Evidence Concerning Rubella Vaccines and Arthritis, Radiculoneuritis, and Thrombocytopenic Purpura »
Adverse Effects of Pertussis and Rubella Vaccines Get This Book
×
Buy Paperback | $100.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Parents have come to depend on vaccines to protect their children from a variety of diseases. Some evidence suggests, however, that vaccination against pertussis (whooping cough) and rubella (German measles) is, in a small number of cases, associated with increased risk of serious illness.

This book examines the controversy over the evidence and offers a comprehensively documented assessment of the risk of illness following immunization with vaccines against pertussis and rubella. Based on extensive review of the evidence from epidemiologic studies, case histories, studies in animals, and other sources of information, the book examines:

  • The relation of pertussis vaccines to a number of serious adverse events, including encephalopathy and other central nervous system disorders, sudden infant death syndrome, autism, Guillain-Barre syndrome, learning disabilities, and Reye syndrome.
  • The relation of rubella vaccines to arthritis, various neuropathies, and thrombocytopenic purpura.

The volume, which includes a description of the committee's methods for evaluating evidence and directions for future research, will be important reading for public health officials, pediatricians, researchers, and concerned parents.

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    Switch between the Original Pages, where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

    « Back Next »
  6. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  7. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  8. ×

    View our suggested citation for this chapter.

    « Back Next »
  9. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!