Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers, and persistent crying.

OBJECTIVE: The pathophysiology of severe reactions to diphtheria-tetanus-pertussis (DTP)vaccine is not well understood. Active pertussis toxin in DTP vaccine has been proposed to cause severe DTP vaccine reactions. Large doses of pertussis toxin cause hyperinsulinemia and hypoglycemia as well as leukocytosis with a predominant lymphocytosis in animal models. To learn more about the causes of and risk factors for severe DTP vaccine reactions, children experiencing severe DTP vaccine reactions were studied. DESIGN: Prospective, referral-based surveillance. SETTING: Los Angeles, CA. SUBJECTS: Children experiencing severe reactions within 48 hours of DTP immunization and evaluated within 24 hours of the reaction. Severe reactions included encephalopathy, persistent crying > or = 3 hours, hypotonic-hyporesponsive episodes (collapse episodes), fever > or = 40.5 degrees C, or seizures. Some comparisons were made between children with DTP vaccine-associated seizures and a comparison group of children experiencing febrile seizures unrelated to immunization. OUTCOME MEASURES: A history and physical examination were performed. Follow-up examinations were performed 1 month later. Blood was collected for complete blood cell count with leukocyte differential count, serum chemistry measurements, and insulin and glucose values. Serum was assayed for active pertussis toxin, both in free and immune-complex masked states. RESULTS: Sixty children experienced severe reactions within 48 hours of DTP immunization: 32 children had seizures only, 14 subjects had hypotonic-hyporesponsive episodes, 2 subjects had fever > or = 40.5 degrees C only, 4 subjects had persistent crying > or = 3 hours, 6 children had seizures and fever > or = 40.5 degrees C, and 2 children had persistent crying and seizures. The children with seizures had a high rate of personal and family histories of seizures, and 90% had documented fevers (> or = 38 degrees C). Persistent crying was associated with painful local reactions. Effects that may have been due to vaccine pertussis toxin were not found. Lymphocytosis did not occur, nor did hypoglycemia. Some relatively elevated insulin values were noted; however, this finding was also noted in the comparison group of children experiencing febrile seizures unrelated to immunization. No biologically active pertussis toxin was found in the acute sera of children experiencing severe DTP vaccine reactions. CONCLUSIONS: Seizures associated with DTP vaccine have similar clinical characteristics as febrile seizures, and persistent crying is initiated by painful local reactions. Vaccine endotoxin is a cause of febrile DTP vaccine reactions. We found no evidence that DTP vaccine pertussis toxin plays a role in severe DTP vaccine reactions.

An overview of the status of acellular pertussis vaccines in practice.

Infection with Bordetella pertussis continues to result in widespread morbidity and mortality. Although whole cell pertussis vaccines are effective in controlling pertussis, concerns relating to adverse effects following vaccination have led to the development of a new generation of pertussis vaccines. Acellular pertussis vaccines have decreased endotoxin content and are less reactogenic than whole cell vaccines. The composition of acellular pertussis vaccines varies, resulting in differing immunogenicity. Recent studies have demonstrated that these vaccines, in general, have an efficacy similar to that of whole cell vaccines. The development of acellular pertussis vaccines is an advance that should result in less discomfort from vaccination and the potential for increased vaccine usage, resulting in the possible elimination of this disease.

Agrobacterium radiobacter and CDC group Ve-2 bacteremia.

Agrobacterium radiobacter and CDC Group Ve-2 are rare human pathogens. The simultaneous infection with both of these bacteria in an immunocompromised host is reported. Review of the UCLA microbiology laboratory records revealed one additional case of A. radiobacter bacteremia and two additional cases of CDC Group Ve-2 bacteremia over a 3-year period. The clinical experience with these organisms is reviewed. Both organisms are opportunistic pathogens with a predilection for patients with foreign bodies in place. Although CDC Group Ve-2 bacteremia may respond to antibiotic therapy alone, the cure of A. radiobacter infections often requires foreign body removal.

Pneumocystis carinii isolated from lung lavage fluid in an infant with cystic fibrosis.

Pneumocystis carinii (P. carinii) cysts were identified in bronchoalveolar lavage fluid from a 15-week-old child newly diagnosed with cystic fibrosis who presented with bronchitis, pneumonia, and weight loss. The child was not infected with human immunodeficiency virus (HIV), and there was no evidence of impaired immunity or exposure to individuals with known or suspected P. carinii disease. Culture of the lavage fluid also revealed pathogens typical of lung disease associated with cystic fibrosis. It is suspected that the presence of P. carinii in this patient represented a new acquisition, as has been described in immunocompetent infants and children. Whether P. carinii infection complicated cystic fibrosis-associated lung disease in this patient is unknown.

Infectious disease considerations in pediatric organ transplantation.

Infections are a major cause of morbidity and mortality after organ transplantation in children. Immunosuppression, surgery, and invasive devices all predispose to infection. A comprehensive pretransplantation evaluation can minimize risks and help anticipate special problems. Appropriate anti-microbial coverage during the perioperative period decreases the risk of infection. Bacteria and fungi are the major causes of infections occurring in the first month after transplantation. The site of infection during this period varies by organ transplanted: liver recipients often have intraabdominal infections, kidney recipients are predisposed to urinary tract infections and perinephric abscesses, and heart recipients often have respiratory tract or sternal wound infections. Viruses play a major role in infections occurring more than 1 month after transplantation, with cytomegalovirus the most significant agent. Other viruses of concern include herpes simplex virus, varicella-zoster virus, several common respiratory viruses, and Epstein-Barr virus with associated lymphoproliferative disorders. Tuberculosis, toxoplasmosis, and Pneumocystis pneumonia also occur later. Appropriate immunization and antimicrobial prophylaxis can help prevent infectious complications after transplantation.

An ongoing surveillance study of persistent crying and hypotonic-hyporesponsive episodes following routine DTP immunization: a preliminary report.

Hypotonic-hyporesponsive episodes and persistent crying are specific complications of pertussis immunization. Hyperinsulinemia, hypoglycemia, and leukocytosis have been noted after pertussis vaccine administration in a murine model. Five children with hypotonic-hyporesponsive episodes and 6 children with persistent crying following DTP immunization were studied. The children were found to have leukocytosis acutely, similar to findings reported in children following routine DTP immunization. No abnormalities were noted in plasma insulin or serum glucose. Five of 6 children with persistent crying had severe local reactions, suggesting that localized inflammation may be a cause of persistent crying.

The agglutinin response to whole-cell and acellular pertussis vaccines is Bordetella pertussis--strain dependent.

OBJECTIVE: To determine the significance of the Bordetella pertussis strain used as the antigen in the agglutinin assay for the evaluation of pertussis vaccines. DESIGN: Randomized, double-blind study. SETTING: Health maintenance organization clinics, primary care clinic at a referral hospital, and private practices in Los Angeles County, California. PARTICIPANTS: Forty healthy infants. SELECTION PROCEDURES: Convenience sample. INTERVENTIONS: Twenty infants received whole-cell pertussis-component diphtheria-tetanus-pertussis vaccine (DTP), and 70 infants received acellular pertussis-component diphtheria-tetanus-pertussis vaccine (APDT) at ages 2, 4, and 6 months. MEASUREMENTS: The agglutinin assay was performed using three separate B pertussis strain preparations: (1) strains 130 and 138 in equal quantities, the constituents of the DTP vaccine, (2) strain 460, and (3) strain Tohama, the constituent of the APDT vaccine. RESULTS: The agglutinin titers were highly strain dependent; in both groups of vaccinees at both ages the Tohama values were highest, followed by strain 460 and then strains 130/138. The vaccine groups had comparable titers at age 2 months regardless of the assay antigen used. However, at age 7 months, after three immunizations, the DTP group geometric mean titer was more than 10 times greater than that of the ADPT group using strains 130/138, but only 2.6 times higher using strain 460 and almost equivalent using Tohama strain. CONCLUSION: Vaccine group agglutinin value comparisons strongly depend on assay antigens used.

Detection of antibodies inhibiting the ADP-ribosyltransferase activity of pertussis toxin in human serum.

Bordetella pertussis produces a protein virulence factor termed pertussis toxin. Many candidate pertussis vaccines are based on the rationale that an immune response that neutralizes the virulence activities of this toxin, which are thought to arise from its catalytic ADP-ribosyltransferase activity, would be beneficial. The report describes two methods that quantify the inhibition of this activity by human serum. One, termed a direct assay, involves an initial incubation of toxin with serum, a second incubation that activates the toxin, and a third incubation that measures the ADP-ribosyltransferase activity of the mixture. The other assay, termed a plate assay, involves immobilization of the toxin, exposure of the immobilized toxin to serum and washing of the plate, and then activation and assay of the toxin's ADP-ribosyltransferase activity. The plate assay may be more selective than the direct assay in terms of identifying antibodies that neutralize the toxin in vivo. Sera from controls, selected patients presenting with cough, and vaccinated infants were first analyzed by the direct assay. In contrast to sera from controls, sera from several of the patients and vaccinated infants strongly inhibited activity. Dose-response curves of inhibition were determined for samples from three vaccinated infants by both the direct and plate assays. One of the samples had a dose-response curve of a different shape and thus differed not only in titer but also in functional characteristics. A comparison of inhibition of ADP-ribosyltransferase activity and neutralization in a CHO cell assay indicated that there was incomplete agreement between the two assays. Taken together, these results indicate that measurement of inhibition of ADP-ribosyltransferase activity by human serum is practical and may be useful in the evaluation of responses to pertussis vaccines.

A search for Bordetella pertussis infection in university students.

University students with persistent cough of greater than or equal to 6 days' duration were evaluated for evidence of infection with Bordetella pertussis. Of 130 students studied during a 30-month period, 34 (26%) were found to have evidence of recent infections with B. pertussis. Infection was identified by direct fluorescent antibody assay of a nasopharyngeal specimen in one student and serologically in 33 additional subjects. B. pertussis was not recovered on culture of nasopharyngeal specimens from any subjects. Students with B. pertussis infection were identified in seven of the eight 3-month periods in which students were enrolled during the 30-month investigation, suggesting an endemic rather than epidemic pattern of infection in this university population. Illnesses of students with pertussis were similar to the illnesses of students without pertussis. The findings in this study suggest that adult populations in which endemic illness occurs at a relatively constant rate may be the reservoirs for pertussis outbreaks in susceptible children. Immunization programs in the future will need to employ booster doses for adults if complete control of B. pertussis infection is our goal.

Effect of foscarnet cream on experimental UV radiation-induced herpes labialis.

A topical 3% foscarnet cream formulation was evaluated for its ability to treat experimental UV radiation (UVR)-induced herpes labialis in a double-blind study. Healthy adult volunteers with a history of sunlight-induced herpes labialis were randomly assigned at four centers to receive either foscarnet cream (n = 152) or a vehicle control (n = 150). Following measurement of the minimal erythematous dose (MED), the subjects' lips were exposed to 4 MEDs of UV light. Subjects applied the cream on the UVR-exposed area approximately eight times daily beginning immediately after UVR exposure and continuing for 7 days, or until all lesions had a minimum of 4 days of treatment. There were no significant differences between groups in the percentages of subjects that developed any lesion, aborted lesions (did not progress beyond a papule), immediate lesions (developed within 48 h of UVR), or delayed classic lesions (developed 48 h to 7 days after UVR). Treatment with foscarnet significantly reduced the mean lesion area (49 versus 81 mm2; P = 0.01), the maximum lesion area (80 versus 141 mm2; P = 0.01), and the time to healing (P = 0.03) of the delayed classic lesions (n = 78). There was also a trend for a decrease in the mean duration of these lesions (156 versus 191 h; P = 0.08) and the duration of pain (3.9 versus 4.3 days; P = 0.06) in foscarnet-treated subjects. There were no clinically significant adverse reactions. These data suggest that topical foscarnet can be efficacious and deserves further evaluation for the treatment of herpes labialis.

A randomized clinical trial of acellular pertussis vaccines in healthy adults: dose-response comparisons of 5 vaccines and implications for booster immunization.

The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were compared in a multicenter, randomized, double-blind trial. A total of 481 healthy adults were given a single intramuscular booster dose of ACV or placebo. Three different dose levels were tested for 4 ACVs: full strength (the dose level proposed for infant immunization), one-third strength, and one-tenth strength. For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor injection site reactions were common and similar in frequency among vaccinated groups. Late-onset injection site reactions were seen in all ACV groups. Dose-related increases in mean antibody titers against vaccine antigens were seen after immunization with all ACVs. Antibody responses against antigens not known to be present in the vaccines were detected after immunization with 4/5 ACVs. Antibody levels fell significantly during the year after immunization. These data support evaluation of ACVs for broader use among adolescents and adults.

Household contact study of Bordetella pertussis infections.

Household contacts of primary pertussis cases were evaluated. Infection was determined by culture, direct fluorescent antibody assay, and serological criteria. Agglutinin titers and values of ELISA IgG and IgA antibodies to lymphocytosis-promoting factor, filamentous hemagglutinin, and pertactin were determined. In 39 households 255 subjects were exposed; 114 remained well (group 1), 53 had mild illness (group 2), and 88 had pertussis (group 3). The infection rates were 46% (group 1), 43% (group 2), and 80% (group 3). In a subgroup of subjects seen within 14-28 days of exposure, it was found that none with clinical pertussis had a value of IgG antibody to pertactin in acute-phase sera of > or = 50 ELISA units (EU) per mL or an agglutinin titer of > 256. Of the primary cases, 53% were > or = 13 years of age. These data point out the importance of Bordetella pertussis infections in adolescents and adults as a source of infection in young children. Our subgroup data suggest that high values of antibody to pertactin and high agglutinin titers may be predictive of protection against clinical pertussis.

Comparison of an acellular pertussis-component diphtheria-tetanus-pertussis (DTP) vaccine with a whole-cell pertussis-component DTP vaccine in 17- to 24-month-old children, with measurement of 69-kilodalton outer membrane protein antibody.

Healthy 17- to 24-month-old children, previously immunized with three doses of whole-cell diphtheria-tetanus-pertussis (DTP) vaccine, were enrolled in a multi-center double-blind, randomized study comparing a DTP vaccine with an acellular pertussis-component (APDT) and a conventional whole-cell pertussis-component DTP vaccine. Thirty-eight children received APDT vaccine, and 37 children received DTP vaccine. APDT vaccine recipients had significantly less local pain and warmth than DTP vaccine recipients. Antibody responses to lymphocytosis-promoting factor were similar in the two groups. The APDT vaccine recipients had a higher IgG antibody response to filamentous hemagglutinin than the DTP vaccinees had. Equivalent agglutinin responses were seen in the two groups. The APDT vaccine recipients had a significantly better antibody re-enzyme-linked immunosorbent assay, than DTP vaccinees had 1 month and 1 year after immunization. This APDT vaccine was immunogenic and caused fewer local reactions than conventional DTP vaccine when administered as a fourth dose to 17- to 24-month-old children.

Metabolic and hematologic effects and immune complex formation related to pertussis immunization.

Selected metabolic, hematologic, and immunologic functions were evaluated in 3- to 6-mo-old Finnish infants who received whole-cell pertussis-component diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) vaccine, and in 4- to 6-y-old Los Angeles children who received either a licensed DTP vaccine or an acellular pertussis component DTP vaccine. One d after immunization, there was an increase in total leukocytes and neutrophils and a decrease in lymphocytes in all vaccinees. In 4- to 6-y-old children the leukocytosis and neutrophilia were greater in recipients who received the standard DTP vaccine than in vaccinees who received an acellular pertussis component DTP vaccine. In infants there was an increase in the mean plasma insulin concentration but no change in the glucose concentration 24 h after immunization; no increase in the mean plasma insulin was noted in the 4- to 6-y-old children. Three 4- to 6-y-old vaccinees had higher circulating immune complex concentrations after immunization and two of these children had high clinical reaction scores. The etiology of adverse reactions after DTP immunization is multifactorial. In contrast with findings in animals, our findings do not demonstrate a clinically significant effect due to lymphocytosis-promoting factor on glucose metabolism in vaccinated children. Neutrophilia in vaccinees is probably due to endotoxin, and some reactions may be due to circulating immune complexes.

Reactogenicity and immunogenicity of a double-strength acellular pertussis vaccine.

The reactogenicity and immunogenicity of a double-strength acellular pertussis vaccine were evaluated after administration to 16 4-6-year-old children. The vaccine contained toxoided lymphocytosis-promoting factor (6.0 micrograms/dose), filamentous haemagglutinin (70 micrograms/dose), agglutinogens (1.4 micrograms/dose) and the 69 kDa protein (approximately 8.0 micrograms/dose). The vaccine was extremely well tolerated with few minor side effects following immunization. Significant increases in antibodies to all pertussis vaccine components were noted. In summary, this double-strength acellular pertussis vaccine, containing a very high dose of filamentous haemagglutinin, had minimal reactogenicity and was immunogenic. These findings, as well as other studies with this vaccine, indicate that filamentous haemagglutinin is not a major determinant of vaccine reactogenicity.

Comparison of acellular and whole-cell pertussis-component DTP vaccines. A multicenter double-blind study in 4- to 6-year-old children.

An acellular pertussis-component combined diphtheria and tetanus toxoids, and pertussis (APDT) vaccine adsorbed was compared with a licensed whole-cell pertussis-component combined diphtheria and tetanus toxoids, and pertussis (DTP) vaccine adsorbed for reactogenicity and immunogenicity when given as the fifth DTP immunization to eighty-two 4- to 6-year-old children. The reaction rates with both vaccines were low; APDT vaccine recipients had significantly less pain and warmth at the injection site than did DTP vaccine recipients. Antibody responses to pertussis antigens (lymphocytosis-promoting factor, filamentous hemagglutinin, and agglutinogens) and to diphtheria and tetanus toxoids were all brisk. The APDT vaccine recipients had a more marked response in antibodies to filamentous hemagglutinin and a less marked response in agglutinins than whole-cell vaccine recipients. On the day after immunization, both APDT and DTP vaccine recipients had an increase in mean leukocyte and neutrophil counts. This APDT vaccine is immunogenic and less reactogenic than a DTP vaccine with a whole-cell pertussis component when administered as a booster to 4- to 6-year-old children.

Pathophysiology of reactions associated with pertussis vaccine.

Many adverse clinical events occur after pertussis immunization in children, but the pathophysiology is not well understood. It has been suggested that some of these adverse events may be due to biologically-active LPF and endotoxin present in DTP vaccines. Fifty-six children were studied who experienced severe reactions (fever greater than or equal to 40.5 degrees C, seizures, persistent crying greater than or equal to 3 hours or hypotonic-hyporesponsive episodes) within 48 hr of DTP immunization. Leukocytosis with neutrophilia was noted acutely (after vaccination) compared to follow-up (approximately one month later). No changes in insulin or glucose values were noted. Utilizing the CHO cell assay, no biologically-active LPF was found in the acute sera of children who had DTP-associated seizures. We found no evidence that biologically-active LPF or altered insulin/glucose metabolism were related to severe DTP-associated reactions.

Comparison of acellular and whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants. The APDT Vaccine Study Group.

In a multicenter, double-blind, randomized, longitudinal study, 252 children received licensed Lederle diphtheria-tetanus toxoids and pertussis vaccine adsorbed (DTP) at 2, 4, and 6 months of age, and 245 children received a DTP vaccine with the Lederle/Takeda acellular pertussis component (APDT) at the same ages. Both groups of children received APDT vaccine at 18 months of age. After each of the first three immunizations, APDT vaccine recipients had fewer local and systemic reactions than did DTP vaccinees. Reactions after the 18-month APDT vaccination were minimal in severity regardless of the vaccine previously received. Antibody responses to lymphocytosis-promoting factor and agglutinogens were more pronounced in DTP recipients; however, APDT recipients had a better serologic response to filamentous hemagglutinin, and responses to the 69K protein were equivalent. This APDT vaccine produces fewer reactions than the standard whole-cell DTP vaccine. The protective significance of the serologic responses to the APDT vaccine is unknown, but the greater response to filamentous hemagglutinin and equivalent response to the 69K protein compared with those to DTP vaccine seem promising.

Report of a US public health service workshop on hypotonic-hyporesponsive episode (HHE) after pertussis immunization.

Hypotonic-hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae. Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping. This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition. Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae. The workshop participants felt that a detailed descriptive study of approximately 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypoth