Association between aluminum and iron exposure in maternal blood and umbilical cord blood and congenital heart defects in children.

Background: Congenital heart disease (CHDs) is the major cause of mortality from birth defects, affecting up to 1% of live births worldwide. However, the relationship between aluminum (Al) and iron (Fe) levels and the risk of CHDs has yielded inconsistent results. Methods: We conducted a pair-matched case-control study that included 97 CHDs and 194 non-CHDs to investigate the association and interaction between Al/Fe exposure and the risk of CHDs in a birth cohort study in Lanzhou, China. Results: Higher concentrations of cord blood Al were associated with a greater risk of total CHDs (aOR = 2.826, 95% CI [1.009-7.266]) and isolated CHDs (aOR = 10.713, 95% CI [1.017-112.851]) compared to the lowest Al level. Both in maternal blood and cord blood, a significant dose-effect was observed between Al level and total CHDs (Ptrend < 0.05), but a similar pattern was not observed for Fe. High Al in addition to high Fe appeared to elicit a stronger association with CHDs than both lowest tertile of Al and Fe level in umbilical cord blood, particularly for multiple CHDs, septal defects and patent ductus arteriosus. Conclusions: Our study suggests that exposure to Al during pregnancy (≥2,408 µg/L) is significantly associated with an increased risk of CHDs in offspring, especially septal defects, and that high levels of Al and Fe are strongly correlated with fetal heart development. Further research is needed to understand the underlying mechanisms.

New bithiophene derivative attenuated Alzheimer's disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission.

BACKGROUND: One of the hypotheses that leads to an increased incidence of Alzheimer's disease (AD) is the accumulation of aluminum in the brain's frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. METHODOLOGY: Adult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3-6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. MAIN FINDINGS: Al disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-ß plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. CONCLUSION: Taking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-ß plaques and phosphorylation of tau.

Long-term prognosis of vaccine-induced contact allergy to aluminium: Third patch-test with additional test preparations.

BACKGROUND: A high incidence of local itching subcutaneous nodules and aluminium allergy was observed in clinical trials of a new aluminium adsorbed pertussis vaccine in Gothenburg, Sweden, in the 1990s. A total of 495 children with itching nodules were patch tested with aluminium chloride hexahydrate 2% and an empty Finn Chamber®, 377 (76%) with positive reactions. When 241 of them were re-tested some years later 186 (3 out of 4) had unexpectedly lost their patch test reactivity. AIM: To investigate the long-term prognosis of vaccine-induced contact allergy to aluminium by a third patch test about 20 years after Patch test I. METHODS: Twenty individuals with positive and 11 with negative results in Patch test II were tested a third time with the same sensitisers as in in the first two tests. Three additional aluminium preparations were also tested. RESULTS: A total 15 out of 20 persons with positive results in the second test had lost their patch test reactivity. Two of 11 with negative tests had turned positive again. The addition of the preparations gave no conclusive results. CONCLUSION: Contact allergy to aluminium caused by vaccination with aluminium-adsorbed vaccines in childhood seems to fade away with time as measured by loss of patch test reactivity.

Correlation between daily life aluminium exposure and breast cancer risk: A systematic review.

BACKGROUND: Epidemiological data indicate that the role of environmental factors on breast cancer (BC) incidence remains undetermined. Our daily life exposure to aluminium (Al) is suspected to influence BC development. This review proposes a state of the art on the association between Al and BC risk combined with a critical point of view on the subject. METHODS: We searched the PubMed database using terms related to Al and BC up to November 18, 2022. Reports were eligible if they were cohort or case-control studies or meta-analyses. FINDINGS: Six studies focused on the relationship between deodorant and antiperspirant use and BC incidence and didn't produce consistent results. Among 13 studies relating Al content in mammary tissues and BC risk, results are not unanimous to validate higher Al content in tumor tissues compared to healthy ones. We detail parameters that could explain this conclusion: the absence of statistical adjustments on BC risk factors in studies, the confusion between deodorant and antiperspirant terms, the non-assessment of global Al exposure, and the focus on Al in mammary tissues whereas a profile of several metals seems more appropriate. The clinical studies are retrospective. They were carried out on small cohorts and without a long follow-up. On the other hand, studies on cell lines have shown the carcinogenic potential of aluminum. Moreover, studies considered BC as a unique group whereas BC is a heterogeneous disease with multiple tumor subtypes determining the tumor aggressiveness. CONCLUSION: In light of the precautionary principle and based on the data obtained, it is better to avoid antiperspirants that contain Al. Deodorants without aluminum are not implicated in breast cancer, either clinically or fundamentally.

Effects of aluminium chloride added to common patch test substances.

BACKGROUND: A modulating effect of aluminium regarding type IV reactions might exist but has not been further investigated. OBJECTIVES: The aim of this study was to investigate the effect on patch test reactions when adding aluminium chloride hexahydrate (Al-Cl) to common test preparations. MATERIALS AND METHODS: Al-Cl in different concentrations was added to nickel sulphate 15.0% aqua (Ni), methylisothiazolinone 0.2% aqua (MI) and fragrance mix I 10.0% aqua/ethanol (FM I). The Ni preparations were tested in 120 consecutive patients. MI and FM I were tested in participants known to have contact allergy to the respective allergen. McNemar's test was used to decide which Ni preparation had the highest sensitivity. Wilcoxon signed-rank test was used to calculate pairwise comparison in summarized test score for the preparations with MI and FM I. RESULTS: Adding Al-Cl 20.0%/30.0% to Ni identified twice as many patients with contact allergy to nickel compared to Ni without Al-Cl. Adding Al-Cl 20.0%/10.0% to MI, decreased the patch test reactivity compared to MI without Al-Cl. No differences in patch reactivity were noticed when adding Al-Cl to FM I. CONCLUSION: Al-Cl 20.0% or 30.0% seems to enhance the patch test reactivity to Ni 15.0% aqua.

Critical evaluation on roles of macrophagic myofasciitis and aluminum adjuvants in HPV vaccine-induced adverse events.

Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes an immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies," particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. As Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."

Workers in Australian prebake aluminium smelters: update on risk of mortality and cancer incidence in the Healthwise cohort.

OBJECTIVES: To investigate mortality and the rates of incident cancer among a cohort of aluminium industry workers. METHODS: Among 4507 male employees who worked in either of two Australian prebake smelters for at least 3 months, data linkage was undertaken with the Australian National Death Index and Australian Cancer Database. Standardised Mortality Ratios (SMRs) and Standardised Incidence Rates (SIRs) were estimated for the whole cohort and for: production; maintenance and office workers. SMRs and SIRs were calculated by time since first employment. RESULTS: Among production workers, there was an excess risk of mortality from mesothelioma (SMR 2.8, 95% CI 1.3 to 5.2), lung (SMR 1.4, 95% CI 1.0 to 1.8), prostate (SMR 1.9, 95% CI 1.3 to 2.7) and liver cancer (SMR 2.0, 95% CI 1.1 to 3.4) and the SIR was also increased for overall respiratory cancers, specifically lung cancers. An excess risk of death from stomach cancer (SMR 2.9, 95% CI 1.2 to 6.1) and Alzheimer's disease (SMR 3.4, 95% CI 1.1 to 7.9) was seen among maintenance workers. The overall risk of death was similar to that of the Australian general population, as was mortality from cancers overall and non-malignant respiratory disease. CONCLUSIONS: No excess risk of death from bladder cancer or non-malignant respiratory disease was found. Excess lung cancer mortality and incidence may be explained by smoking and excess mortality from mesothelioma may be explained by asbestos exposure. An excess risk of mortality from liver and prostate cancer has been shown in production workers and requires further investigation.

Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months.

OBJECTIVE: To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months. METHODS: A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization. RESULTS: The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25). CONCLUSION: In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.

Adverse reactions after oral provocation with aluminium in children with vaccination granulomas and aluminium contact allergy.

BACKGROUND: According to their parents, some children with aluminium contact allergy and vaccination granulomas may react to aluminium-containing foods by developing dermatitis, granuloma itch and subjective symptoms. OBJECTIVES: The objective of this study is to determine whether oral intake of aluminium-containing pancakes can cause adverse events and/or systemic contact dermatitis (SCD) in children with vaccination granulomas and aluminium contact allergy. PATIENTS/METHODS: A total of 15 children aged 3-9 years (mean age, 5 years) with vaccination granulomas and positive patch-test results to aluminium chloride hexahydrate 2%/10% pet. completed a 3-week blinded randomized controlled crossover oral aluminium/placebo provocation study with pancakes. Granuloma itch and other subjective symptoms were evaluated daily on a visual analogue scale (VAS). Dermatitis was evaluated by the primary investigator, and sleep patterns were tracked with an electronic device. Aluminium bioavailability was assessed by measuring aluminium excretion in the urine. The children served as their own controls with the placebo provocations. RESULTS: All 15 children completed the study. The mean VAS scores were slightly higher during aluminium provocations compared with placebo for granuloma itch (mean VAS, 1.5 vs. 1.4, p = 0.6) but identical for other subjective symptoms (0.6 vs. 0.6, p = 1). There were no differences in sleep patterns and no significant correlation between urinary aluminium excretion and symptom severity. Three children developed a symmetrical rash on the face or buttocks on day 4 of the aluminium provocations, but not during placebo provocations. CONCLUSIONS: No difference was found between oral aluminium intake and the occurrence of subjective symptoms and granuloma itch, but on a case-basis oral aluminium may be associated with the development of systemic contact dermatitis.

p-Coumaric acid ameliorates cognitive and non-cognitive disturbances in a rat model of Alzheimer's disease: The role of oxidative stress and inflammation.

BACKGROUND: Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease resulting in cognitive and non-cognitive deficits. Aluminum is recognized as a risk factor for the etiology, pathogenesis, and progression of AD. The present study was designed to determine the effects of p-coumaric acid (p-CA), a phenolic compound, on spatial cognitive ability and non-cognitive functions and to identify the role of oxidative stress and inflammation in an AD rat model induced by aluminum chloride (AlCl3). METHODS: Both AlCl3 (100 mg/kg/day; P.O.) and p-CA (100 mg/kg/day; P.O.) treatments were given for six consecutive weeks. During the fifth and sixth weeks of the treatment period, the cognitive and non-cognitive functions of the rats were assessed using standard behavioral tests. Additionally, oxidative-antioxidative status, inflammatory markers, and histological changes were evaluated in the cerebral cortex and hippocampal regions of the rats. RESULTS: The results of this study showed that AlCl3 exposure enhanced anxiety-/depression-like behaviors, reduced locomotor/exploratory activities, and impaired spatial learning and memory. These cognitive and non-cognitive disturbances were accompanied by increasing oxidative stress, enhancing inflammatory response, and neuronal loss in the studied brain regions. Interestingly, treatment with p-CA alleviated all the above-mentioned neuropathological changes in the AlCl3-induced AD rat model. CONCLUSION: The findings suggest that both anti-oxidative and anti-inflammatory properties of p-CA may be the underlying mechanisms behind its beneficial effect in preventing neuronal loss and improving cognitive and non-cognitive deficits associated with AD.

Aluminum overload in the reverse osmosis dialysis era: does it exist?

BACKGROUND: Aluminum accumulation is a well-described complication in dialysis patients. Improvements in hemodialysis technology have possibly eliminated the occurrence of aluminum overload. Limited evidence suggests that aluminum overload may decline in the era of aluminum removal from dialysis fluids, even with the use of aluminum binders. METHODS: We examined the data from January 2014 to June 1, 2020, identified through our electronic records, to evaluate the desferrioxamine (DFO) test results for aluminum overload. The presentation and treatment of aluminum overload were recorded. RESULTS: Ninety-nine dialysis patients were enrolled for the DFO test. Forty-seven patients (47.5%) were identified as DFO test positive for aluminum overload, of which 14 (14/47) patients had symptoms, including one patient with an unexplained fracture, eight patients with unexplained anemia despite high-dose erythropoiesis-stimulating agents, and five patients with hypercalcemia (serum calcium >11 mg dL-1). None of the patients with aluminum overload developed encephalopathy. Only four of the 47 patients had microcytic anemia. Patients requiring longer treatments (>10 months versus <10 months) had similar basal serum aluminum (p = 0.219) but had an increase in serum aluminum after DFO (p = 0.041). Furthermore, the treatments decreased erythropoietin doses in the aluminum overload group, with serum total alkaline phosphatase levels <60 U L-1 (p = 0.028). CONCLUSION: We concluded that aluminum overload existed in the reverse osmosis dialysis era. In light of non-obvious symptoms, such as anemia and bone turnover change, serum aluminum in dialysis patients should be monitored in countries using aluminum-based phosphate binders, despite reverse osmosis dialysis.

Aluminum: The 2022 American Contact Dermatitis Society Allergen of the Year.

Aluminum recently was selected as the 2022 Allergen of the Year by the American Contact Dermatitis Society. Aluminum contact allergy, which most often is related to its use as an adjuvant in select vaccines and allergen-specific immunotherapies, tends to present with pruritic subcutaneous nodules at the injection site. Allergy to aluminum-containing antiperspirants manifests as axillary vault dermatitis. In this article, we highlight the growing recognition of aluminum contact allergy, particularly in the pediatric population, focusing on distinct presentations of aluminum allergic contact dermatitis (ACD), unique sources of exposure, and nuances of patch testing to this metal.

Risk factors for granulomas in children following immunization with aluminium-adsorbed vaccines: A Danish population-based cohort study.

BACKGROUND: Aluminium-adsorbed vaccines may in some children cause severely itching nodules at the injection site, known as vaccination granulomas. OBJECTIVE: To investigate vaccine-, child- and maternal-level risk factors for the development of vaccination granulomas following immunization with aluminium-adsorbed vaccines. METHODS: A Danish population-based cohort study with 553 932 children born in Denmark from 1 January 2009 to 31 December 2018, vaccinated with an aluminium-adsorbed vaccine during the first year of life, followed until 31 December 2020. Poisson regression was used to estimate granuloma rate ratios according to the type of adjuvant, accumulated dose of aluminium, timing of vaccination appointments, sex, gestational age, having siblings with granulomas, maternal age and maternal ethnicity. RESULTS: We identified 1901 vaccination granuloma cases (absolute risk, 0.34%). Among vaccine level factors, revaccination (third vs. first vaccination appointment, adjusted rate ratio [RR] 1.26, 95% confidence interval [CI] 1.03-1.55), the specific adjuvant used (aluminium phosphate vs. hydroxide, RR 0.58, 95% CI 0.48-0.70) and dosage (≥1.0 mg vs. <1.0 mg, RR 1.34, 95% CI 1.19-1.52) were associated with risk of granulomas; the timing of vaccination appointments was not. Among child-level factors, female sex (vs. males, RR 1.12, 95% CI, 1.02-1.22), prematurity (vs. term birth, RR 0.71, 95% CI, 0.54-0.93) and having sibling(s) with granulomas (vs. no siblings with granulomas, RR 46.15, 95% CI, 33.67-63.26) were associated with risk of granulomas. Among maternal-level factors, non-Danish ethnicity (vs. Danish, RR 0.51, 95% CI, 0.42-0.63) and young maternal age (<20 years vs. 20-39 years, RR 0.46, 95% CI 0.25-0.83) were associated with risk of granulomas. CONCLUSIONS: Several risk factors for vaccination granulomas at the vaccine, child and maternal levels, were identified. Reducing the dose of aluminium or replacing aluminium hydroxide with aluminium phosphate could reduce the risk of granulomas. However, this must be balanced against the potential for reduced immunogenicity.

Aluminium adjuvants versus placebo or no intervention in vaccine randomised clinical trials: a systematic review with meta-analysis and Trial Sequential Analysis.

OBJECTIVES: To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development. DESIGN: Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). DATA SOURCES: We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021. ELIGIBILITY CRITERIA: Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias with Cochrane's RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I2 statistic. We GRADE assessed the certainty of the evidence. RESULTS: We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants' seroprotection. CONCLUSIONS: Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.

Post-vaccination aluminium granulomas in children. / Aluminiumsgranulomer etter barnevaksinasjon.

BACKGROUND: Persistent itching subcutaneous granulomas related to aluminium-containing vaccines are poorly recognised in health care. They are often associated with aluminium hypersensitivity. CASE PRESENTATION: An intensely itching subcutaneous nodule appeared on the left thigh of a 17-month-old girl at the injection site for an aluminium adsorbed diphtheria-tetanus-pertussis-polio-HiB vaccine given at 3, 5 and 12 months. Ultrasound suggested a vascular malformation among other differential diagnoses. An MR investigation under general anaesthesia was planned, but the diagnosis was confirmed prior to this by a positive epicutaneous test with aluminium. INTERPRETATION: Despite a typical history of an itchy vaccination granuloma, the child underwent a thorough hospital workup to rule out malignancy. The diagnosis was delayed for two years. Vaccination granulomas have a good prognosis but can persist for many years. It is important to recognise the condition early in primary health care to avoid unnecessary anxiety and investigations.

Salivary Glands after Prolonged Aluminum Exposure: Proteomic Approach Underlying Biochemical and Morphological Impairments in Rats.

Aluminum (Al) is one of the most abundant elements on Earth, and its high extraction rate and industrial use make human exposure very common. As Al may be a human toxicant, it is important to investigate the effects of Al exposure, mainly at low doses and for prolonged periods, by simulating human exposure. This work aimed to study the effects of low-dose exposure to chloride aluminum (AlCl3) on the oxidative biochemistry, proteomic profile, and morphology of the major salivary glands. Wistar male rats were exposed to 8.3 mg/kg/day of AlCl3 via intragastric gavage for 60 days. Then, the parotid and submandibular glands were subjected to biochemical assays, proteomic evaluation, and histological analysis. Al caused oxidative imbalance in both salivary glands. Dysregulation of protein expression, mainly of those related to cytoarchitecture, energy metabolism and glandular function, was detected in both salivary glands. Al also promoted histological alterations, such as acinar atrophy and an increase in parenchymal tissue. Prolonged exposure to Al, even at low doses, was able to modulate molecular alterations associated with morphological impairments in the salivary glands of rats. From this perspective, prolonged Al exposure may be a risk to exposed populations and their oral health.

Delayed allergic skin reactions to vaccines.

Background: Recent advances in vaccination against the severe acute respiratory syndrome coronavirus 2 pandemic have brought allergists and dermatologists to the forefront because both immediate and delayed hypersensitivity reactions have been reported. Objective: This literature review focused on delayed reactions to vaccines, including possible causative agents and practical information on how to diagnose, evaluate with patch testing, and manage subsequent dose administration. Methods: Currently published reviews and case reports in PubMed, along with data on vaccines from the Centers for Disease Control and Prevention web site. Relevant case reports and reviews that focused on delayed reactions to vaccines were selected. Results: Most delayed hypersensitivity reactions to vaccines include cutaneous manifestations, which vary from local persistent pruritic nodules to systemic rashes. The onset is usually within a few days but can be delayed by weeks. Multiple excipients have been identified that have been implicated in delayed vaccine reactions, including thimerosal, formaldehyde, aluminum, antibiotics, and gelatin. Treatment with antihistamines, topical corticosteroids, or systemic corticosteroids alleviates symptoms in most patients. Such reactions are generally not contraindications to future vaccination. However, for more-severe reactions, patch testing for causative agents can be used to aid in diagnosis and approach further vaccination. Conclusion: Delayed-type hypersensitivity reactions to vaccines are not uncommon. If needed, patch testing can be used to confirm agents, including antibiotics, formaldehyde, thimerosal, and aluminum. In most cases, delayed cutaneous reactions are not contraindications to further vaccine administration.