PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1501-1509 (doi:10.1542/peds.2005-2890)
ARTICLE |
Ultrasound Examination of Extensive Limb Swelling Reactions After Diphtheria-Tetanus-Acellular Pertussis or Reduced-Antigen Content Diphtheria-Tetanus-Acellular Pertussis Immunization in Preschool-Aged Children
a Departments of Paediatrics
c Medical Imaging, Women's and Children's Hospital, Children, Youth, and Women’s Health Service, North Adelaide, Australia
b Discipline of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. The aim of this study was to determine the site, extent, and resolution of tissue involvement when extensive limb swelling occurred in the injected limb for children who received diphtheria-tetanus-acellular pertussis or reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine at 4 to 6 years of age.
METHODS. Children who had experienced an injection site reaction at 18 months of age were assigned randomly to receive an intramuscular injection of either reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine or diphtheria-tetanus-acellular pertussis vaccine between 4 and 6 years of age. Children who developed extensive limb swelling were recruited for assessment by clinical examination; ultrasound studies of the affected and opposite (control) arms were performed 24 to 48 hours after immunization and 48 to 96 hours later.
RESULTS. Twelve children with extensive limb swelling were enrolled in the study. Ultrasound examinations demonstrated swelling of both the subcutaneous and muscle layers of the vaccinated arm. Ultrasound assessment showed that the swelling exceeded the clinical measurements of skin redness and swelling. Subcutaneous and muscle tissues expanded to 281% and 111% of the tissue thicknesses of the control arm, respectively. Repeat ultrasound examinations after 48 to 96 hours showed considerable resolution of muscle swelling, compared with subcutaneous tissue swelling. There was no significant difference in the extent of swelling detected between children who received diphtheria-tetanus-acellular pertussis vaccine and those who received reduced-antigen content diphtheria-tetanus-acellular pertussis vaccine.
CONCLUSION. Extensive limb swelling reactions after diphtheria-tetanus-acellular pertussis or reduced-antigen content booster immunizations involved swelling of subcutaneous and muscle tissues with swelling and duration more marked in subcutaneous tissue.
Key Words: local reaction • adverse events • diphtheria • pertussis • tetanus • ultrasound
Abbreviations: DTaP—diphtheria-tetanus-acellular pertussis • Tdap—reduced-antigen content diphtheria-tetanus-acellular pertussis • DTwP—diphtheria-tetanus-whole-cell pertussis • ELS—extensive limb swelling • ISR—injection site reaction • CI—confidence interval
Immunization is a key primary prevention activity that has assisted significantly in the reduction of rates of childhood morbidity and premature death. Important components of a responsible immunization program are investigation and prevention of adverse vaccine reactions.1 In Australia, commencing in 1997, the National Health and Medical Research Council recommended a 5-dose course of diphtheria-tetanus-acellular pertussis (DTaP) vaccine as part of the childhood immunization schedule.2 This schedule included a primary 3-dose course of DTaP vaccine at 2, 4, and 6 months of age, a fourth dose at 18 months, and a fifth dose between 4 and 6 years of age.
Before 1997, diphtheria-tetanus-whole-cell pertussis (DTwP) vaccine was the recommended vaccine for all 5 doses. DTaP vaccine became the vaccine of choice because of an improved reactogenicity profile, compared with DTwP vaccine.2 Through passive surveillance of adverse events after immunization in South Australia, an increase in the rate of injection site reactions (ISRs) after the fourth dose of DTaP vaccine and an increased relative risk of an ISR after DTaP primary immunization were observed, in comparison with DTwP immunization.3 Similarly, in other countries, increases in the rates and severity of ISRs were observed with successive doses of DTaP vaccine.4–13 Previous studies indicated that the incidence ranged from 2% to 24% depending on the definition of extensive swelling reaction used.3–13 In contrast, rates of systemic reactions seemed to remain constant or even to decrease with later DTaP vaccine doses.14 The pathogenesis of ISRs is complex, probably multifactorial, and not fully understood.7,8,15
Of greater concern is the increased incidence of extensive limb swelling (ELS) reported after booster doses of DTaP vaccines.4,9,11–13 A variety of definitions of ELS reactions exist, including use of an arbitrarily defined cutoff measurement of superficial redness and/or swelling at the site of injection. In the Australian Immunisation Handbook, an ELS reaction is defined as swelling and/or redness over a substantial area, involving at least one half of the circumference of the limb and involving an adjacent joint above or below the injection site, commencing within 48 hours after immunization and resolving completely without sequelae.14 This type of reaction is not unique to DTaP vaccines and has been observed after administration of other vaccines, such as DTwP and hepatitis B vaccines.7–9
The reduced-antigen content diphtheria-tetanus-acellular pertussis (Tdap) vaccine was shown to result in less-extensive ISRs when used as booster immunizations for 4- to 6-year-old children who were primed with DTwP.16 A Tdap vaccine (Boostrix [GlaxoSmithKline Biologicals, Rixensart, Belgium], containing >2 IU of diphtheria toxoid, >20 IU of tetanus toxoid, 8 µg of pertussis toxoid, 8 µg of filamentous hemagglutinin, and 2.5 µg of pertactin) is licensed currently in many countries for use as a booster vaccine for adults and children from 10 years of age. It is not known whether there are likely to be fewer or less-severe reactions with a Tdap vaccine, compared with DTaP vaccine (Infanrix [GlaxoSmithKline Biologicals], containing 30 IU of diphtheria toxoid, 40 IU of tetanus toxoid, 25 µg of pertussis toxoid, 25 µg of filamentous hemagglutinin, and 8 µg of pertactin), when administered to 4- to 6-year-old children who were primed with DTaP vaccine and who experienced an ISR at 18 months of age.
The aim of this study was to use clinical and ultrasound examinations to determine the site, extent, and resolution of tissue involvement in the injected limb for children who developed an ELS response to DTaP or Tdap vaccination at 4 to 6 years of age. Ultrasonography was used previously to measure the thickness of subcutaneous and muscle layers, to determine appropriate needle length for intramuscular injections,17–19 but has not been used for formal assessment of ISRs after DTaP or Tdap immunization.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Subjects
As part of a larger, double-blind, prospective study conducted at the Women's and Children's Hospital with children who had experienced a previous ISR after DTaP vaccine administration at 18 months of age, 4- to 6-year-old children (n = 25) were assigned randomly to receive either DTaP vaccine (n = 13) or Tdap vaccine (n = 12). A previous ISR was defined as a history of swelling or redness centered at the site of injection, with the addition of one of the following: swelling to the nearest joint (with or without redness), swelling extending from joint to joint (with or without redness), swelling of >3-day duration (with or without redness), and/or requirement for hospitalization and/or medical attention including review by a medical practitioner. Children were enrolled from the Special Immunisation Service at the Women's and Children's Hospital and through the state scheme for surveillance of adverse events after immunization at the South Australian Immunisation Coordination Unit, Department of Health (Adelaide, South Australia). A letter was mailed to all families with a child who was reported as experiencing a large ISR after the 18-month DTaP vaccination. In South Australia, in addition to medical officer reporting, parental reporting of any adverse reaction to a vaccine is encouraged. Participation in the ultrasound study depended on the availability of the ultrasonographer at the time the ELS reaction was assessed clinically and provision of informed consent from the subject's parent/legal guardian.
Healthy children who had experienced an ISR at 18 months of age and who had received 4 doses of DTaP vaccine previously (at 2, 4, 6, and 18 months of age) were enrolled in the study. Subjects were excluded if they had received any vaccine or nonregistered drug within 30 days before study commencement, had an immunodeficiency condition, had evidence of previous or intercurrent diphtheria, tetanus, or pertussis disease or vaccination against any of these diseases since booster immunization in the second year of life, or had a history of an allergic disease that was likely to be exacerbated by any component of the study vaccine. Subjects were assigned randomly to receive either DTaP or Tdap vaccine, which was administered intramuscularly by the investigator team into the deltoid muscle of the left arm, with a 23-gauge, 25-mm-long needle, at an angle of 60°. The needle was inserted in the middle of the deltoid muscle, halfway between the acromion and the insertion of the deltoid muscle.
Reactogenicity
Solicited local and general symptoms were collected during a 15-day follow-up period (the day of immunization and 14 consecutive days). Solicited local signs of redness, swelling and increased mid-upper arm circumference, and pain localized to the injection site and solicited general symptoms of fever, irritability, drowsiness, and loss of appetite after immunization were recorded daily by parents on diary cards. The maximal swelling, redness, and induration of the affected upper arm were measured in millimeters by parents/caregivers, who were provided with a standardized, clear, flexible ruler. The circumference of the arm was measured by parents at a previously defined midhumeral point. The midhumeral point was defined as the midpoint between the acromion process and the lateral epicondyle of the humerus. This point was determined at the first appointment and was marked with a semipermanent tattoo. Parents were asked to complete a 4-point graded scale for pain (grade 0 = no pain, grade 1 = minor reaction to touch, grade 2 = protests on touch, and grade 3 = spontaneously painful) and for functional impairment (grade 0 = no impairment, grade 1 = easily tolerated, normal activity, grade 2 = discomfort, interferes with normal activity, and grade 3 = prevents normal activity) and to record the maximal grade daily.
Parents were instructed to inspect the injection site at the same time each day and to measure the size of any redness and/or swelling at the injection site. Parents were asked to notify study staff members if the child developed either redness or swelling of >50 mm (largest diameter) at the injection site, a >30-mm increase in injected limb circumference at the midhumeral point (compared with baseline), or any functional impairment of the arm. These screening criteria were used to ensure that all cases of suspected ELS were assessed by a medical officer. The child was examined by a study medical officer within 24 hours after notification by the parent/guardian. Ultrasound examinations were performed after clinical examination of the ELS reaction 24 to 48 hours after immunization and were repeated 48 to 96 hours after the first ultrasound assessment. The ultrasound assessments were blinded with respect to use of Tdap or DTaP vaccine.
Ultrasound Examinations
A linear-array transducer was used to assess the extent of swelling in the upper arm. The examination involved 6 transverse views at 2-cm intervals and 3 longitudinal views (in 9 segments). Aquasonic contact gel (Parker Laboratories, Fairfield, NJ) was applied to the skin, and a marker was used to define the areas for examination. Subcutaneous tissue thickness and muscle thickness were measured in both the affected arm and the nonaffected arm, and the absolute values were compared. Ultrasound examination of the joint was performed for children with clinically apparent swelling extending to a joint. A comparison between the clinically determined estimate of swelling extent and a measurement of the extent of edema of the tissues was undertaken during the ultrasound examination. A repeat ultrasound examination was performed 48 to 96 hours later, and a comparison between the initial and follow-up ultrasound examination findings was made to delineate changes to tissues during resolution of the local reaction.
Statistical Analyses
Fisher's exact test was used for comparisons of the incidence and severity of reactivity. The increase in thickness of muscle and subcutaneous tissue in the vaccinated arm, compared with the control arm, was reported as a proportional (percentage) increase in thickness, with the control arm being 100%. The differences in means for subcutaneous and muscle swelling in the 2 groups were compared by using an unpaired t test, assuming equal variance (Stata software, release 8.2; Stata Corp, College Station, TX). The appropriate t test was determined by using the Levene statistic to assess variance in the means between the 2 groups. The difference in thickness of muscle and subcutaneous tissue 48 to 96 hours after the initial ultrasound examination was also determined.
This study was conducted in the Department of Paediatrics and the Department of Medical Imaging at the Women's and Children's Hospital in Adelaide, South Australia. Both the primary study and the ultrasound study were approved by the Women's and Children's Hospital Research Ethics Committee, and informed consent was obtained before any study procedures were performed. The study was conducted according to the Declaration of Helsinki and good clinical practice.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Study Population
The study was conducted between March 2003 and June 2004. Twelve children (8 boys and 4 girls) who developed an ISR after either DTaP or Tdap vaccination were enrolled in the ultrasound study. All children enrolled in the study had redness and swelling of >50 mm at the site of injection and were considered to have an ELS reaction. Figures 1 and 2 show the clinical appearance of a typical ELS reaction. With unblinding, it was determined that 8 of the 12 subjects enrolled in the ultrasound study had received DTaP vaccine and 4 subjects had received Tdap vaccine. All children were of white origin, with a mean age of 4.4 years (Tdap: 4.7 years; DTaP: 4.3 years; range: 4–5.75 years).
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Parental Reporting of General Symptoms
All children reported grade 1 to 3 pain, with only 2 subjects, 1 from each group, reporting grade 3 pain. Only 1 subject (DTaP group) reported grade 3 functional impairment, with 5 subjects reporting grade 1 to 2 functional impairment in the DTaP group (n = 8) and 2 subjects reporting grade 1 functional impairment in the Tdap group (n = 4). With Fisher's exact test, there was no difference in the degree of functional impairment between the 2 vaccine groups (P = .999).
Three subjects in each group reported grade 1 fever. Equal proportions of children in each group reported irritability, drowsiness, and loss of appetite. Seven subjects required paracetamol (acetaminophen) to relieve symptoms associated with the immunization, ranging from 1 to 6 doses in total. Children who required >3 doses of paracetamol were male and had received DTaP vaccine. The child who reported grade 3 pain also reported grade 2 functional impairment and required 5 doses of paracetamol for adequate pain relief.
Parental Reporting of Local Symptoms
The extent of clinically measured redness and swelling in the injected limb for children who received DTaP and Tdap vaccines is recorded in Tables 1 and 2. Six of the 12 children developed redness at the immunization site within 24 hours after immunization. Five of these children were in the DTaP group. The onset of swelling occurred as early as 6 hours after immunization, with the total duration of swelling being 2 to 8 days. The onset of swelling occurred on the day of immunization for 3 subjects, on day 1 for 6 subjects, and on day 2 for 2 subjects. Four subjects developed their maximal swelling by day 1 and the remaining 8 subjects by day 2. All subjects developed redness and/or swelling of >50 mm within 48 hours after immunization. All recovered without sequelae. There were no serious adverse events reported for any children enrolled in the ultrasound study; specifically, no hospitalization was required for management of ELS reactions.
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Clinical Assessment of Swelling by Medical Officer
Nine subjects (DTaP, n = 7; Tdap, n = 2) had swelling of the deltoid region extending to the shoulder, 2 subjects (DTaP, n = 1; Tdap, n = 1) had swelling localized to the injection site, and 1 subject (Tdap group) had diffuse swelling of the upper arm. One of the 4 subjects in the Tdap group had swelling extending from beyond the shoulder joint to the cubital fossa but not encompassing the elbow joint.
Ultrasound Examinations 24 to 48 Hours After Immunization
Ultrasound examinations showed a diffuse, echogenic, "snowstorm" appearance, consistent with diffuse edema of the tissues (Figs 3 and 4). All children showed evidence of edema in both subcutaneous and muscle tissues, extending to the humeral cortex. Subcutaneous and muscle tissues expanded to a maximum of 281% and 111% of the tissue thickness of the control arm, respectively. No fluid was detected in the shoulder joint for children who clinically exhibited swelling that extended over the shoulder joint. The changes in subcutaneous and muscle tissue are detailed in Tables 1 and 3 and Fig 5. All children developed swelling of subcutaneous and muscle tissues. For subcutaneous tissue swelling, 42% of subjects had swelling of 
5 mm, 50% had swelling of 5.1 to 10 mm, and 8% had swelling of 10.1 to 15 mm. For muscle tissue swelling, 58% of subjects had swelling of 5 mm and 42% had swelling of 5.1 to 10 mm.
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The mean percentage increase in swelling of subcutaneous tissue for children who received DTaP vaccine (n = 8) was 136.0% (95% confidence interval [CI]: 73.1%–198.0%), compared with 124.3% (95% CI: 66.5%–182.0%) for children who received Tdap vaccine (n = 4). The unpaired Student's t test was used to test the hypothesis that the mean increases in subcutaneous and muscle thickness were equivalent in the 2 groups (subcutaneous swelling, P = .78; muscle swelling, P = .945). The variances in the means were equivalent in the 2 groups for subcutaneous (Levene statistic, P = .485) and muscle (Levene statistic, P = .434) swelling.
When clinical measurement of swelling by the medical officer, with the use of superficial landmarks, was compared with ultrasound assessment of the extent of deeper tissue swelling, the measurement obtained during the ultrasound examination exceeded the clinical assessment of swelling for 10 of the 12 subjects (Fig 6).
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Repeat Ultrasound Examinations 48 to 96 Hours After Initial Examinations
Eleven of the 12 subjects enrolled had a repeat ultrasound examination performed (1 subject failed to present for the second ultrasound assessment). Swelling in muscle tissue resolved more rapidly than the subcutaneous tissue swelling, as shown in Fig 5. Fifty percent (n = 6) of subjects had resolution of muscle swelling, compared with only 8.3% (n = 1) with resolution of subcutaneous swelling.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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An ELS reaction after booster doses of the acellular pertussis combination vaccines can seem alarming to parents and vaccine providers. If this reaction is not recognized, there may be an incorrect diagnosis of infective cellulitis, resulting in inappropriate treatment with antibiotics. This descriptive study demonstrated that the ELS reaction was attributable to marked edema in both the subcutaneous and muscle tissue spaces, with fluid accumulation being greater in the subcutaneous tissue space. It is interesting that there was significant subcutaneous edema, given that the vaccines were administered through the intramuscular route. The swelling of muscle tissue was generally not as extensive and seemed to resolve more rapidly than the swelling in subcutaneous tissue; this might be related to the better blood supply to muscle, compared with subcutaneous tissue. Despite the extensive swelling, there was no evidence of associated joint effusion.
The mechanism of ELS has not yet been defined clearly, with no apparent risk factors being evident, other than priming with previous DTaP vaccines. The characteristics of the swelling suggest angioedema rather than inflammatory cellulitis, given the absence of systemic fever and pain and the rapid resolution of swelling. Angioedema results from altered vascular permeability and can occur through a variety of mechanisms, including uninhibited activation of the complement pathway and mast cell degranulation, with release of vasoactive peptides. Additional research is required to determine the mechanism of ELS after vaccination. The pathogenesis of ELS is likely to be multifactorial. Several DTaP vaccine components (eg, aluminum, diphtheria toxoid, and pertussis toxoid) have already been shown to be associated with increased reactogenicity.7 High prevaccination antibody levels against 
1 antigen present in the vaccine, IgE antibody levels, and cell-mediated responses are other factors that may contribute to the increase in ELS reactions.8,15
Children who received primary doses of DTaP vaccine seemed to be at higher risk of experiencing an ELS reaction with booster doses of either diphtheria/tetanus/pertussis or DTaP vaccine.9,20,21 In this study, ELS reactions were seen with both DTaP and Tdap vaccine administration for the booster dose at 4 to 6 years of age.
Despite the size of ELS reactions, generally children experience only a mild degree of functional impairment or pain significant enough to require analgesia. This is supported by the outcomes of other studies that showed similar degrees of morbidity associated with large injection site reactions. In the study by Scheifele et al,22 19.3% of children who received diphtheria/tetanus/acellular pertussis/inactivated polio virus vaccine as a fifth dose developed redness or swelling of 50 mm that required an average of 5 days to resolve, with the largest reactions requiring up to 10 days. None of the children required medical attention. In a survey of 800 parents of children who received a fifth dose of acellular pertussis vaccine, the incidence of redness larger than an Oreo cookie was 25%.10 None of the children required hospitalization, and few children needed to interrupt educational activities after immunization.
All subjects who fulfilled the study criteria of a previous ISR at 18 months developed an ELS reaction after the 4-year booster dose of DTaP or Tdap vaccine. It should be noted that these criteria were likely to include children with less-severe reactions than might be included in other studies. If the definition provided in the Australian Immunisation Handbook is used, then 9 of the 12 subjects enrolled had swelling consistent with a diagnosis of ELS (including swelling at an adjacent joint). Because of the small sample size in this study, no inference can be made about the risk of recurrence of ISRs, apart from the statement that the risk seemed high in our study population. Although the selection process had the potential to lead to selection bias, when clinical estimates of ELS reactions were compared between subjects who participated in the ultrasound study and those who did not, there was no statistically significant difference between the 2 groups. Children who received an ultrasound examination were therefore representative of all children enrolled in the prospective study of ISRs at our study center (n = 25).
To our knowledge, ultrasonography has not been used previously to measure the extent of ELS reactions. Standardization of adverse event definitions is essential for accurate surveillance and reporting of vaccine-associated adverse events. The Brighton Collaboration is in the process of establishing definitions for vaccine-associated adverse events. Establishing a standardized definition for ELS reactions is required1 and will be important for both passive and active surveillance of adverse events after immunization, because a consistent definition will allow comparisons of different vaccine trials and surveillance systems.
Despite the increased local reactogenicity of booster doses, acellular pertussis combination vaccines remain the preferred vaccines for preventing pertussis, diphtheria, and tetanus for children because of the improved safety profile, compared with the more-serious systemic adverse events that occur more frequently with whole-cell pertussis vaccines. However, demonstration of an increase in ISRs after booster doses of DTaP vaccine was one of the factors that resulted in the 18-month booster dose being omitted from the Australian Standard Vaccination Schedule in 2003.3,4 The decision was also based on the prolonged immunity now known to result from a primary course of DTaP vaccine treatment.23 Provision of Tdap vaccine as an alternative may provide a safer alternative for children who developed an ELS reaction with previous booster doses. There are several formulations of Tdap vaccine available. Studies comparing adverse events after vaccination with a Tdap vaccine (5 flocculation units of tetanus toxoid, 2 flocculation units of diphtheria toxoid, 2.5 µg of pertussis toxoid, 5 µg of filamentous hemagglutinin, 3 µg of pertactin, and 5 µg of fimbriae types 2 and 3) or diphtheria/tetanus vaccine in 11- to 17-year-old subjects showed a lower incidence of ISRs (swelling of 50 mm) in the Tdap vaccine group, compared with the diphtheria/tetanus vaccine group (2.8% and 3.6%, respectively; Aventis Pasteur, unpublished data). We were unable to demonstrate any significant benefit from Tdap vaccine use in our study, but we acknowledge that the study was descriptive in design and was not powered to detect a difference between the 2 groups.
Surveillance, acknowledgment, and transparency in relation to vaccine-associated adverse events are essential to ensure public confidence in immunization programs. Additional research and education for providers and consumers about the nature and cause of adverse reactions such as those described in this study should be a priority.
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FOOTNOTES |
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Accepted May 25, 2006.
Address correspondence to Helen Siobhan Marshall, MBBS, MPH, DCH, University Department of Paediatrics, Women's and Children's Hospital, 72 King William Rd, North Adelaide 5006, South Australia, Australia. E-mail: helen.marshall{at}adelaide.edu.au
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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