Case Report of Subcutaneous Nodules and Sterile Abscesses Due to Delayed Type Hypersensitivity to Aluminum-Containing Christine T. Lauren, MD,a, b Donald V. Belsito, MD,a Kimberly D. Morel, MD,a, b Philip LaRussa, MDb

Routine childhood have resulted in great reductions in abstract -preventable infectious diseases. Vaccine-related adverse events, albeit rare, can be of significant consequence. Although , or type I hypersensitivity, is recognized as a potential reaction after , delayed type hypersensitivity or type IV reactions are less so. We present a case of persistent subcutaneous nodules and sterile abscesses in the setting of delayed type hypersensitivity to aluminum, confirmed by patch testing Departments of aDermatology, and bPediatrics, Columbia and recurrence on re-exposure. We review sources of aluminum in common University Medical Center, New York, New York immunizations, principles for treatment, and strategies for management of Dr Lauren drafted the initial manuscript and future for this patient. critically reviewed the manuscript; Drs Morel, Belsito, and LaRussa critically reviewed the manuscript; and all authors approved the fi nal manuscript as submitted. Although anaphylaxis is recognized incident. At 4 months of age, he as a rare side effect of vaccination received second doses of Prevnar DOI: 10.1542/peds.2014-1690 with rates of 0.0001 to 0.002% or 13 and b Accepted for publication Jun 16, 2016 less, 1, 2 delayed type hypersensitivity vaccine (PedvaxHIB) in the right and Address correspondence to Christine T. Lauren, (DTH) reactions are less well known, left thighs, respectively. Within 3 to MD, Departments of Dermatology and Pediatrics, with reported frequencies of 0.35% 5 days, his mother reported a right Columbia University Medical Center, 161 Fort Washington Ave, 12th Floor New York, NY 10032. to 1.18%. 3 We present a case of thigh nodule and an erythematous E-mail: [email protected] persistent subcutaneous nodules left thigh nodule. At 5 months of PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, and sterile abscesses due to DTH to age, he received Pediarix in his left 1098-4275). aluminum to increase awareness of arm and 3 to 5 days later, developed Copyright © 2016 by the American Academy of this reaction and resources for vaccine erythema and swelling that persisted Pediatrics safety expert consultation. for 5 weeks. Culture-negative FINANCIAL DISCLOSURE: The authors have purulent material was drained after indicated they have no fi nancial relationships incision, suggesting a sterile abscess. relevant to this article to disclose. PATIENT PRESENTATION Violaceous subcutaneous nodules POTENTIAL CONFLICTS OF INTEREST: The authors were still present at all 3 sites when have indicated they have no potential confl icts of A 7-month-old healthy boy the child was seen at 7 months of age interest to disclose. presented with a 3-month history (Fig 1). He had no history of hives, FUNDING: This work was supported in part by the of subcutaneous nodules at sites of respiratory distress, mucosal swelling, Clinical Safety Assessment Network previous immunizations. Vaccinations or fever. Ultrasound examination of through a subcontract with America’s Health at 2 months of age (Prevnar 13 these nodules demonstrated teardrop- Insurance Plans under contract 200-2002-00732 and in part by contract U50 CU220700 from the Centers [pneumococcal 13-valent conjugate shaped echogenic areas extending vaccine], ActHib [Haemophilus b from the skin to the subcutis, the ]), and Pediarix largest measuring 1.1 cm in diameter To cite: Lauren CT, Belsito DV, Morel KD, et al. (--acellular (Fig 2). Case Report of Subcutaneous Nodules and Sterile pertussis [DTaP]- [hep Abscesses Due to Delayed Type Hypersensitivity to B]-inactivated vaccine [IPV]) Aluminum was the only component Aluminum-Containing Vaccines. Pediatrics. 2016; 138(4):e20141690 at 3 months of age occurred without common to the vaccinations that

PEDIATRICS Volume 138 , number 4 , October 2016 :e 20141690 CASE REPORT TABLE 1 Ingredients in Vaccinations, Only Common Component in Vaccinations Received at Sites of Nodules was Aluminum4 Pediarix (DTaP, Hep B, IPV) PedvaxHIB Prevnar 13 (Pneumococcal) (Haemophilus infl uenzae b) Aluminum X X X X — — Latex X X — Neomycin X — — FIGURE 1 Polymyxin B X — — Representative nodule when the patient was 7 Polysorbate X — X months of age at time of initial evaluation. Soy — — X Yeast protein X — — X, present; —, not present.

recommendation was that future vaccinations. Topical steroids under vaccinations be aluminum-free when occlusion resulted in subsequent available (eg, H. influenzae b: ActHib, improvement. Six weeks later, the inactivated trivalent polio: IPol, nodule spontaneously drained and trivalent influenza: Fluzone). purulent material, followed by Although aluminum-free alternatives resolution. At the time of manuscript were not available for subsequent preparation, measles-mumps-rubella, DTaP, conjugate pneumococcal, Varicella, IPV, and influenza vaccines, and Hep B immunizations, the all of which are aluminum-free, were FIGURE 2 benefits of vaccination were felt to received without incident. Ultrasound examination of subcutaneous nodule outweigh the potential of an adverse at time of initial examination when the patient reaction. It was recommended was 7 months of age. that pneumococcus and DTaP DISCUSSION resulted in nodule formation ( Table vaccinations were first priorities, Aluminum hypersensitivity, a DTH 1).4 Patch testing was performed with the stipulation that topical reaction, is a rare, underrecognized 8,9 by using empty Finn chambers steroid preparations could be entity. Local erythema and (SmartPractice, Phoenix, AZ) on used to mitigate the severity of induration are more common after Scanpor tape (Actavis Norway) the expected reactions. Live viral aluminum-containing vaccines applied to the back for 48 hours. vaccines (measles-mumps-rubella, compared with aluminum-free 10 Readings at 48 and 96 hours Varicella) do not contain aluminum vaccines. Although mild vaccination demonstrated 1+ and 2+ reactions, and should be given according to the site reactions are most commonly 11 respectively ( Fig 2). recommended schedule. Hepatitis reported, persistence of erythema, A vaccine (aluminum-containing) sterile abscess,12 or subcutaneous The history and clinical findings was deferred until higher priority nodules weeks to months after supported our impression of DTH to vaccinations were completed. vaccination can also occur. 10, 13 – 27 aluminum. Subsequent vaccination Lesions and severe pruritus may with IPOL (aluminum-free IPV) Subsequent vaccinations included develop within days to months after was well-tolerated. The patient’s a third Prevnar 13 (aluminum- vaccination, may last for years, and case was reviewed by the Centers containing) in the right deltoid and may be recalcitrant to treatment. for Disease Control and Prevention influenza (aluminum-free) in the Cutaneous changes include dermatitis, (CDC)-funded Clinical Immunization left deltoid at 12 months of age, hyperpigmentation, lichenification, Safety Assessment (CISA) Network, followed by a second aluminum-free and hypertrichosis. It is not clear which provides expert consultation in his left deltoid. how many cases of sterile abscesses on the evaluation, management, and He then inadvertently received an are secondary to DTH, but the assessment of causality of adverse aluminum-containing PedvaxHIB association with this reaction pattern events after licensed vaccines. 5 – 7 The vaccine in his right deltoid at 13 and aluminum has been reported. 21 review concurred with the diagnosis months. Two weeks later, redness Nonencapsulated granulomatous of aluminum hypersensitivity and was noted on the skin of the right infiltrates in subcutaneous nodules 22 assisted with the development arm with a palpable 2.5 × 1.8 cm and sterile abscesses21 have been of a vaccination plan to minimize subcutaneous nodule ( Fig 4) at the described with evidence of aluminum subsequent aluminum exposure. The site of his Prevnar 13 and PedvaxHIB within macrophages.23, 28

e2 LAUREN et al ingredients may change. A list of are placed on the skin and left excipients can be found at http:// undisturbed for 48 hours or longer. www. cdc. gov/ vaccines/ pubs/ Skin eruptions present at 72 to 96 pinkbook/ downloads/ appendices/ hours after application are graded B/ excipient- table- 2. pdf 29 on a severity scale of 1+ to 3+ and signify a DTH to the suspected There are various aluminum allergen. formulations, including: -hydroxyphosphate sulfate, Empty Finn chambers, which are -hydroxide, -phosphate, generally considered inert and or -potassium sulfate. Aluminum- nonreactive, 31 contain aluminum. FIGURE 3 hydroxide has become more widely Testing with the Finn chamber Patch testing to empty aluminum Finn Chambers used and has been implicated in alone induced a DTH reaction revealed a 2+ papulovesicular reaction with accentuation at the margin along the point of the increased incidence of DTH in our patient. A negative result maximal contact with the chamber rim. Finn reactions. 14 – 16, 24 Our patient received to a Finn chamber test does not chamber, inset. immunizations containing the exclude aluminum hypersensitivity. hydroxide and phosphate forms. Aluminum chloride hexahydrate (2%) in petrolatum is a standard Improper placement of vaccine in preparation for patch testing. the dermis or subcutis, as opposed to Previous studies14 – 16, 24 suggested intramuscularly, has been proposed that the higher concentration of as a trigger for development of aluminum in this preparation 17,26, 27 aluminum hypersensitivity. results in more positive test Epidermal Langerhans cells have results. Other studies used diluted been implicated in the pathogenesis aluminum chloride. 12 Given our 14 of this reaction. In some reports, patient’s positive reaction to the the rate of hypersensitivity empty Finn chamber, we did not reaction decreased by adjusting proceed to testing with the standard FIGURE 4 the route of administration to preparation, however many reports 26 Site of re-exposure to aluminum containing . In our test both chamber and reagent vaccine when the patient was 13 months of case, ultrasonography showed a tract age. Pen markings outline the border of the simultaneously to limit the number of palpable subepidermal nodule. from the skin surface, suggesting potential office visits. deposition of vaccine along the path Intramuscular injection of of the injection to the subcutaneous As with other DTH reactions, aluminum, a common adjuvant space, which may have allowed recurrence can be anticipated with 14,24 in inactivated vaccines and in priming of presenting cells. repeat exposure. Patch testing 14–16 allergen immunotherapy leaves and intercurrent illness Treatment of symptomatic nodules a “depot” of antigen, prolonging have been reported to result in may be ineffective. Topical steroids exposure to antigen presenting cells progression or recurrence of may be unsuccessful given the depth and improving host immunologic previous subcutaneous nodules. of the reaction pattern. Occlusion response. Common vaccinations Symptoms include increasing may increase the potency of the given within the first year of life, pruritus, enlargement of existing topical steroid and limit scratching; including DTaP, Pediarix, hepatitis nodules or development of new hydrocolloid dressings alone have A, Hep B, pneumococcal conjugate nodules. In our patient, reexposure also been reported with variable (Prevnar), and some H. influenzae to aluminum-containing vaccines effect.15, 16 Intralesional steroids and b vaccines contain aluminum. Live resulted in a similar reaction at the topical capsaicin have been used with virus vaccines are aluminum-free, injection site, but without flare of varying success 18; side effects include as are some inactivated vaccines, previous nodules in the remaining atrophy and absorption. The effect including meningococcal, seasonal extremities. of these treatments on the immune influenza, IPV, and certain H. Delayed reaction to aluminum has response is not clear. influenzae b vaccines. Other been previously classified as an excipients and preservatives used Patch testing to evaluate allergen- irritant reaction rather than the more in the immunization manufacturing induced eruptions has been fitting immunologically mediated process have also been reported to described.30 Plastic or aluminum DTH reaction. 2 DTH may manifest cause DTH reactions. The package wells (Finn chambers) containing days to weeks after the inciting agent. insert4 should be reviewed because small amounts of suspected allergens Sensitization after initial exposure is

PEDIATRICS Volume 138 , number 4 , October 2016 e3 necessary for development of a DTH. basis is important, because the ACKNOWLEDGMENTS Our patient’s initial vaccinations risk of reaction should be weighed The CISA Hypersensitivity at age 2 and 3 months likely against the risk of exposure Working Group members were: sensitized him to aluminum with a and potential consequences of Jane Gidudu, MD, (CDC), , resultant hypersensitivity reaction vaccine-preventable disease(s). MD, and Robert Wood, MD (Johns on reexposure at age 4, 5, 12, and Consultation with a pediatric Hopkins University), Cornelia 13 months. Aluminum has been allergist-immunologist or infectious Dekker, MD, (Stanford University), reported to be responsible for 77% to disease specialist with vaccine Nicola Klein, MD, PhD, and Roger 3,15 85% of all DTH to vaccinations. expertise is suggested. The CDC- Baxter, MD, (Kaiser Permanente 7 Other reported ingredients include funded CISA network was able to of Northern California), Kathryn 32 33,34 polysorbate, thimerosal, provide the necessary vaccine safety Edwards, MD (Vanderbilt University), 35 36 phenoxyethanol, formaldehyde, expertise in this case. US healthcare Renata Engler, MD, (Walter Read 37 and polymyxin B . Although providers with a vaccine safety Army Medical Center), Melvin neomycin and others are known question about a specific patient Berger, MD, PhD (Case Western causes of DTH, there have been no residing in the United States can Reserve University) and Steven reports of vaccine DTH to date. contact CISA at [email protected] Dreskin, MD, PhD (University to request a case evaluation; this of Colorado Denver). Although severe vaccine- service is free of charge, but not all associated allergic reactions are a cases are accepted. Any unexpected contraindication to reexposure,38 or clinically significant suspected ABBREVIATIONS there are no reports of life immunization reaction should be CDC: Centers for Disease Control threatening reactions to aluminum- reported to the Vaccine Adverse and Prevention containing vaccines in a sensitized Event Reporting System (http:// CISA: Clinical Immunization patient. Alternative preparations vaers.hhs. gov/ index 39 ) to allow Safety Assessment that do not contain, or contain less for proper signal detection of this DTaP: diphtheria-tetanus-acellu- of, the suspected allergen should reaction within the US population. lar pertussis always be selected when available. Additional information regarding DTH: delayed type hypersensi- For immunizations without an vaccines and vaccine safety may tivity aluminum-free alternative, a risk/ be found at http://www. cdc. gov/ IPV: inactivated benefit discussion on a case-by-case vaccinesafety/index. html. 40 for Disease Control and Prevention. The fi ndings and conclusions in this article are those of the authors and do not necessarily represent the offi cial position of the Centers for Disease Control and Prevention.

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