Extensive Swelling After Booster Doses of Acellular Pertussis–Tetanus–Diphtheria Vaccines Margaret B. Rennels, MD*; Maria A. Deloria, BS‡; Michael E. Pichichero, MD§; Genevieve A. Losonsky, MD*; Janet A. Englund, MDi; Bruce D. Meade, PhD¶; Edwin L. Anderson, MD**; Mark C. Steinhoff, MD#; and Kathryn M. Edwards, MD‡‡ ABSTRACT. Background. Diphtheria and tetanus tox- antibody to diphtheria, tetanus, or pertussis toxin and oid combined with acellular pertussis (DTaP) vaccines rates of swelling of the whole thigh. are less reactogenic than diphtheria and tetanus toxoid Conclusions. Booster doses of DTaP vaccines can combined with whole cell pertussis (DTwP) vaccines. cause entire limb swelling, which is usually associated However, local reactions increase in rate and severity with redness and pain. Our data suggest that this exten- with each successive DTaP dose, and swelling of the entire sive swelling reaction may be more common with vac- injected limb has been reported after booster doses. cines containing high diphtheria toxoid content. Methods. We reviewed reports of swelling of the en- Pediatrics 2000;105(1). URL: http://www.pediatrics.org/ tire thigh or upper arm after the fourth and fifth dose, cgi/content/full/105/1/e12; pertussis, reactions, vaccine, respectively, of DTaP vaccines administered in the Na- diphtheria, toxoid. tional Institutes of Health multicenter comparative DTaP studies. Relationships were explored among reports of se- vere swelling, rates of other reactions, quantity of vaccine ABBREVIATIONS. DTaP, acellular pertussis combined with teta- contents, and prevaccination and postvaccination antibody nus and diphtheria toxoid vaccines; DTwP, whole cell pertussis levels to pertussis toxin, tetanus toxin, and diphtheria toxin. combined with tetanus and diphtheria toxoid vaccines; Ptxn, per- Results. Entire thigh swelling was an unsolicited re- tussis toxin; Dtxn, diphtheria toxin; Ttxn, tetanus toxin; Dtxd, diphtheria toxoid; Ttxd, tetanus toxoid; CBER, Center for Biologi- action reported in 20 (2%) of the 1015 children who re- cals Evaluation and Research. ceived 4 consecutive doses of the same DTaP vaccine. The reaction was associated with 9 of the 12 DTaP vac- cines evaluated. Although there were no reports of swell- cellular pertussis combined with tetanus and ing of the entire upper arm in 121 children given a fifth diphtheria toxoid vaccines (DTaP) have con- dose of the same DTaP, 4 (2.7%) of 146 recipients of 5 sistently been shown to be less reactogenic doses of a mixed schedule of DTaP vaccines experienced A than whole cell pertussis combined with tetanus and such swelling. Rates of other reactions were higher in 1–4 children with entire thigh swelling than in those with- diphtheria toxoid vaccines (DTwP). Some practi- out. Of the children with entire thigh swelling, 60% had tioners and parents therefore may have the impres- local pain, and 60% had erythema. All swelling subsided sion that DTaP injection is free of side effects. It is spontaneously without sequelae. There was a significant now well-established that rates of local reactions in- linear association between the rates of entire thigh swell- crease with each subsequent dose of DTaP vaccine.3–7 ing after dose 4 and diphtheria toxoid content in the Indeed, there have been 2 published reports of swell- DTaP products. Lesser degrees of swelling (>50 mm but ing of the entire injected thigh after a fourth consec- less than entire limb) correlated with pertussis toxoid utive dose of 2- and 3-component DTaP vaccines.8,9 content after dose 4 and aluminum content after dose 5. We studied the rate at which swelling of the entire No relationship was established between levels of serum injected muscle was spontaneously reported after booster doses of DTaP vaccines and ascertained whether it occurred with different DTaP products. From the *University of Maryland School of Medicine, Baltimore, Mary- Reaction forms filled out by parents of children par- land; ‡National Institute of Allergy and Infectious Diseases, National Insti- tute of Health, Bethesda, Maryland; §University of Rochester School of ticipating in the National Institutes of Health-sup- Medicine, Rochester, New York; iBaylor College of Medicine, Houston, ported multicenter trials of the safety and immuno- Texas; ¶Center for Biologicals Evaluation and Research, Food and Drug genicity of fourth and fifth consecutive doses of Administration, Bethesda, Maryland; #Johns Hopkins School of Public various DTaP vaccines were reviewed. Associated Health, Baltimore, Maryland; **St Louis University School of Medicine, St Louis, Missouri; ‡‡Vanderbilt University School of Medicine, Nashville, reactions were evaluated to examine whether swell- Tennessee. ing of the entire muscle was a benign reactive edema, This work was presented in part at the Academic Pediatric Societies’ An- as had been reported previously,9 or whether associ- nual Meeting; May 3, 1998; New Orleans, LA. ated symptoms were present. Additionally, to ex- The content of this presentation does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the plore whether there was a relationship between se- mention of trade names, commercial products, or organizations imply vere swelling and the quantity of a particular endorsement by the US Government. component in the involved vaccines, rates of entire Received for publication May 19, 1999; accepted Aug 12, 1999. limb swelling and swelling .50 mm (excluding Reprint requests to (M.B.R.) 22 S Greene St, Baltimore, MD 21201. E-mail: [email protected] those with whole limb swelling) were correlated PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad- with the content of selected different antigens con- emy of Pediatrics. tained in the vaccines. Finally, the pre- and post- http://www.pediatrics.org/cgi/content/full/105/1/Downloaded from www.aappublications.org/newse12 PEDIATRICS by guest on October Vol. 1, 1052021 No. 1 January 2000 1of6 fourth dose levels of antibodies to pertussis toxin $100.1°F. Temperatures were measured rectally after dose 4 and (Ptxn), diphtheria toxin (Dtxn), and tetanus toxin by mouth after dose 5. Reaction forms had separate spaces at the bottom for the parent to write in comments, other reactions, or any (Ttxn) were compared between children with, and physician visit. Study nurses, who were unaware of what vaccine without, entire limb swelling to explore whether an- the child had received, phoned the family on days 1 and 3 after tigen–antibody interaction might explain the exten- vaccination to obtain reaction data. Diary cards were collected sive swelling reaction. from the parents at the time of the postvaccination blood draw. Children were determined to have experienced entire thigh or METHODS deltoid swelling only if the parent wrote in the comments section that the entire thigh or upper arm was swollen, respectively. A Subjects subset of these children were seen by study personnel who con- The methods of these trials were published previously.3,4 firmed parental descriptions. Healthy 15- to 20-month-old children who had received a primary series of 1 of 13 DTaP vaccines or 1 of 2 DTwP vaccines at 2, 4, and Serology 6 months of age in a National Institutes of Health-supported Antibody measurements were performed on blood samples multicenter trial were invited to enroll into a fourth dose booster obtained immediately before and ;1 month after the fourth dose study in which children were given the same DTaP or DTwP, as of vaccine. For antibody to the pertussis antigens, results obtained administered in the primary series. A fifth dose of the Lederle previously3 were used in analyses. Serum diphtheria and tetanus DTwP vaccine or 1 of 6 of these DTaP vaccines was administered antitoxin levels were determined at the University of Maryland in to a subset of these children at 4 to 6 years of age. Children children who experienced entire thigh swelling after the fourth received a different vaccine at dose 4 or 5 if the vaccine given for dose of DTaP, and in 2 randomly selected control children per case the previous doses was not available. This study primarily ana- who received the same vaccine but had no thigh swelling. Neu- lyzed the children who received the same vaccine for all 4 or 5 tralizing antibody to Dtxn was measured in the Vero-cell assay doses. The trial was conducted through the 6 National Institutes of developed by Gupta et al10 and adapted by M. C. Anderson, Health supported Vaccine Evaluation Units: Baylor College of Center for Biologicals Evaluation and Research (CBER), Food and Medicine, Houston, TX; Johns Hopkins University School of Pub- Drug Administration. The assay was calibrated through use of lic Health, Baltimore, MD; St Louis University School of Medicine, reference antitoxin lot 451 with a unitage of 4 U/mL obtained St Louis, MO; University of Maryland School of Medicine, Balti- from CBER. This antitoxin was a freeze-dried preparation of the more, MD; University of Rochester School of Medicine, Rochester, US standard diphtheria antitoxin. Diphtheria toxin (lot 35 119 NY; and Vanderbilt University, Nashville, TN. The study was from CBER) was used at a concentration of .8 Lf/mL, allowing an approved by the institutional review boards of each participating assay sensitivity of .01 anti-toxin U/mL. Tetanus antitoxin levels center and written informed consent was obtained from a parent were measured by enzyme-linked immunosorbent assay by pre- or guardian before enrollment. viously