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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



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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

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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

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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

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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

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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

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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

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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).

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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

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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

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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

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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,

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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

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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,

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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

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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

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