A Histologic Timeline of a Delayed Hypersensitivity Reaction after the COVID-19 Pfizer Booster.

A 54-year-old man presented with worsening bilateral rashes on legs and arms 7 days after receiving his BNT162b2 mRNA COVID-19 (Pfizer) vaccine booster. He developed burning on his palms about 5 days after receiving the booster. On day 6, he observed significant edema on his fingers and palms in addition to thin erythematous papules on his forearms. On day 7, he developed edema on his bilateral dorsal feet, and thin erythematous plaques on his shins. He stated that the rashes were pruritic. He had no rashes following the first two doses of the Pfizer vaccine. He denied having any history of skin disease, autoimmune disease, or allergies. Physical examination revealed multiple thin erythematous papules coalescing into thin plaques on his flexor forearms, and thin erythematous plaques on his dorsal feet (Figure 1). Three 4-mm punch biopsies were performed on his left flexor forearm. The biopsies were carried out at papules present for different lengths of time. Papules at biopsy sites "A," "B," and "C" were present for approximately 24-36 hours, 12-18 hours, and 3-6 hours, respectively (Figure 1).

Clinical and histopathological spectrum of delayed adverse cutaneous reactions following COVID-19 vaccination.

BACKGROUND: As more people become vaccinated against the SARS-CoV-2 virus, reports of delayed cutaneous hypersensitivity reactions are beginning to emerge. METHODS: In this IRB-approved retrospective case series, biopsy specimens of potential cutaneous adverse reactions from the Pfizer-BioNTech or Moderna mRNA vaccine were identified and reviewed. Clinical information was obtained through the requisition form, referring clinician, or medical chart review. RESULTS: Twelve cases were included. Histopathological features from two injection-site reactions showed a mixed-cell infiltrate with eosinophils and a spongiotic dermatitis with eosinophils. Three biopsy specimens came from generalized eruptions that showed interface changes consistent with an exanthematous drug reaction. Three biopsy specimens revealed a predominantly spongiotic pattern, consistent with eczematous dermatitis. Small-vessel vascular injury was seen in two specimens, which were diagnosed as urticarial vasculitis and leukocytoclastic vasculitis, respectively. There were two cases of new-onset bullous pemphigoid supported by histopathological examination and direct immunofluorescence studies. Eosinophils were seen in 10 cases. CONCLUSIONS: Dermatopathologists should be aware of potential cutaneous adverse reactions to mRNA-based COVID-19 vaccines. Histopathological patterns include mixed-cell infiltrates, epidermal spongiosis, and interface changes. Eosinophils are a common finding but are not always present. Direct immunofluorescence studies may be helpful for immune-mediated cutaneous presentations such as vasculitis or bullous pemphigoid.

Trunnionosis and metal wear causing metal hypersensitivity: 2 sides of the same coin?

Metal hypersensitivity (MHS) and trunnionosis are being looked at more frequently. Both entities pose a difficult concern for surgeons and patients alike. This commentary highlights the similarities and differences between the 2 conditions. When a surgeon suspects either MHS or trunnionosis, both should be considered in the differential diagnosis. Both conditions are rare and should be considered a diagnosis of exclusion. The commentary proposes an outline on how to diagnose and treat the 2 entities.

Lactoferrin as an Adjuvant for the Generation of Delayed Type Hypersensitivity to Orally Administered Antigen.

OBJECTIVE: The aim of this investigation was to evaluate the property of bovine lactoferrin (LF) in the generation of delayed type hypersensitivity (DTH) as an oral adjuvant during immunization with ovalbumin (OVA) and BCG. METHODS: LF admixed with OVA or BCG was used for immunization of CBA or C57BL/6 mice when given via oral or subcutaneous routes. Elicited DTH response was measured post immunization. Inhibition studies using mannose or galactose were accomplished by gavage prior to oral administration of antigens. LF was also examined for effects on BCG uptake by bone marrow derived macrophages (BMM). RESULTS: LF at doses of 1.0 mg and 10.0 mg, admixed with OVA (10.0 mg), significantly enhanced the antigen-specific DTH reaction. The stimulatory effects of LF were inhibited by the oral pretreatment of mice with 50.0 mg of mannose but not galactose. LF also enhanced the DTH reaction to orally administered BCG. LF enhanced uptake of BCG by BMM in a dose-dependent manner. CONCLUSION: LF was able to augment development of DTH when orally administered with OVA or BCG antigens. Inhibition studies suggest the involvement of the receptor with an affinity to mannose in mediation of the adjuvant effect. LF augmentation of the DTH response was partially effective when given in advance of oral delivery of the antigen; this effect could also be saturated by mannose. BCG studies provide preliminary evidence for LF in the potential augmentation of oral vaccination to prevent mycobacterial infection. In vitro experiments provide evidence that LF plays a role in modulation of antigen presenting cell activation.

Sea urchin injuries: a review and clinical approach algorithm.

Sea urchin injuries (SUIs) are among the most common marine injuries; however, there are no guidelines to dictate appropriate workup and treatment. Complications vary significantly depending on the extent of injury, site of injury and elapsed time to medical attention. Timely and appropriate management can prevent long-term morbidity despite the deceptively innocuous appearance of these injuries. We review the English literature on SUIs and offer an algorithm to aid in the management of affected patients. We found that superficially retained spines may trigger a local granulomatous inflammatory response, while spines retained near deep structures may induce sea urchin arthritis, inflammatory tenosynovitis, among other delayed complications. Therefore, we recommend immediate inactivation of pro-inflammatory compounds by hot water soaks at the time of injury, followed by extraction of all spines by a physician. Imaging is a valuable component of risk stratification to determine depth and location of spines, which guides selection of appropriate extraction technique to prevent long-term morbidity.

Sabra dermatitis: combined features of delayed hypersensitivity and foreign body reaction to implanted glochidia.

A striking dermatitis referred to by its colloquial designation of sabra dermatitis is associated with glochidia inoculation from the Opuntia cactus commonly known as the prickly pear. We report a 45-year-old woman who had an unexpected encounter with a cactus plant during a trip to Texas. She brushed up against the plant and was aware that she had been inoculated with several spines of the plant. Five days later she developed erythematous papules on the digits accompanied by swelling. The biopsy showed a very striking granulomatous reaction pattern within the dermis. There was a linear pattern of necrobiosis, likely representing a tract of inoculation injury palisaded by histiocytes including multinucleated forms. This necrobiotic tract demonstrated retained glochidia, each measuring roughly 40 to 70 microns in diameter. The nature of the inflammatory response is one that combines features of classic delayed hypersensitivity and an innate foreign body response. The glochidia are capable of eliciting a T cell mediated immune response; it is reasonable to assume that a Th1 cytokine signal is responsible for the unique pattern of inflammation including the secondary influx of neutrophils and relative lack of tissue eosinophilia.

Delayed-type Hypersensitivity to Metals in Newly Diagnosed Patients with Nonischemic Dilated Cardiomyopathy.

The causes of nonischemic dilated cardiomyopathy are classified as genetic or nongenetic, but environmental factors such as metal pollutants may interact with genetic susceptibility. The presence of metal particles has been detected in the myocardium, including in those patients with dilated cardiomyopathy. It is also known that hypersensitivity reactions can induce inflammation in tissue. The present study aimed to verify if metal-induced delayed-type hypersensitivity is present in patients with nonischemic dilated cardiomyopathy. The patient group consisted of 30 patients with newly diagnosed dilated cardiomyopathy; the control group comprised 41 healthy subjects. All patients and control subjects provided blood samples for lymphocyte transformation testing (MELISA®) to assess possible hypersensitivity to seven common metals. Specific exposure to metals was based on interview data. Results showed that exposure to cadmium and lead (p = 0.0002), aluminum (p = 0.0006), nickel (p = 0.0012), and chromium (p = 0.0065) was more often reported by patients than controls. The patients also had significantly more frequent hypersensitivity reactions to mercury (26.7% vs. 7.3%, p = 0.014624), nickel (40% vs. 12.2%, p = 0.02341), and silver (20% vs. 4.8%, p = 0.025468) than the control group. Patients with dilated cardiomyopathy had greater exposure to certain metals compared with healthy controls. Hypersensitivity to metals was more frequent in patients with dilated cardiomyopathy, suggesting a possible association that warrants further investigation.

Are Adverse Events Attributed to Essure Associated With Nickel Sensitization?

BACKGROUND: Essure is an effective method for hysteroscopic sterilization. Reports of adverse effects, the underlying mechanisms of which are unknown, have increased in recent years. OBJECTIVE: The aim of the study was to determine whether there is a relationship between adverse events attributed to Essure and nickel sensitization. METHODS: Patients presenting alleged adverse reactions to Essure were referred for nickel patch testing before removal. Data regarding medical history of nickel sensitization and symptoms attributed to Essure were collected. Dimethylglyoxime spot tests were performed on the explanted Essure. There was a follow-up at 3 months to evaluate whether there is improvement of the symptoms after Essure removal. CONCLUSIONS: Nickel sensitization via the classic delayed hypersensitivity pathway did not seem to be responsible for adverse events attributed to Essure. Among systemic symptoms reported, extracutaneous symptoms had the highest prevalence. Systemic contact dermatitis to nickel could not be ruled out in one case.

The Allergic Bone Marrow? The Immuno-Capacity of the Human Bone Marrow in Context of Metal-Associated Hypersensitivity Reactions.

Arthroplasty ranks among the greatest achievements of surgical medicine, with total hip replacement termed "the operation of the century." Despite its wide success, arthroplasty bears risks, such as local reactions to implant derived wear and corrosion products. Prevalence of allergies across Western society increases and along the number of reported hypersensitivity reactions to orthopedic implant materials. In this context the main focus is on delayed hypersensitivity (DTH). This mechanism is mainly attributed to T cells and an overreaction of the adaptive immune system. Arthroplasty implant materials are in direct contact with bone marrow (BM), which is discussed as a secondary lymphoid organ. However, the mechanisms of sensitization toward implant wear remain elusive. Nickel and cobalt ions can form haptens with native peptides to activate immune cell receptors and are therefore common T helper allergens in cutaneous DTH. The rising prevalence of metal-related allergy in the general population and evidence for the immune-modulating function of BM allow for the assumption hypersensitivity reactions could occur in peri-implant BM. There is evidence that pro-inflammatory factors released during DTH reactions enhance osteoclast activity and inhibit osteoblast function, an imbalance characteristic for osteolysis. Even though some mechanisms are understood, hypersensitivity has remained a diagnosis of exclusion. This review aims to summarize current views on the pathomechanism of DTH in arthroplasty with emphasis on BM and discusses recent advances and future directions for basic research and clinical diagnostics.

Sonographic features of vaccination granulomas in children with delayed-type hypersensitivity to aluminum.

In this article, we report the sonographic features of vaccination granulomas in three children sensitized to aluminum. Although the recognition of the vaccination granuloma relies on the clinical examination, misdiagnosis is frequent, leading to distressful procedures or prolonged antibiotic administration. In all our cases, sonography revealed a teardrop-shaped echogenic central structure, suggesting the deposition of aluminum crystals along the route of administration with consequent subcutaneous degenerative changes, and a surrounding hypoechoic cap, which reflects the changeable inflammatory reaction and the granuloma formation.

Type IV Cell-Mediated Hypersensitivity Reaction Caused by Titanium Implant Following Double Calcaneal Osteotomy and First Metatarsal-Cuneiform Arthrodesis: A Case Report and Review of the Literature.

Because of their inert character and desired biocompatibility, titanium implants have been universally accepted as safer alternatives to the conventional stainless steel orthopedic implants; however, recent emergence of type IV hypersensitivity reactions to titanium have included eczema, contact dermatitis, a prolonged febrile state, sterile osteonecrosis, and impaired fracture and wound healing. This report presents a patient with postoperative incision dehiscence and devascularization of surfaces in contact with titanium hardware after undergoing a double calcaneal osteotomy and a first metatarsal-cuneiform arthrodesis using titanium alloy implants. Titanium hypersensitivity was confirmed in this case through standard allergy patch testing by a board-certified immunologist. Complete healing occurred after diagnosis of the titanium allergy and hardware explant. To our knowledge, this is one of a few known allergies to titanium implants after foot and ankle surgery.

Quantitative, Absolute Count-Based T-Cell Analysis of CD69 Upregulation as a New Methodology for In Vitro Diagnosis of Delayed-Type Hypersensitivity Reaction to Nickel.

BACKGROUND: T cells play a major role in delayed-type hypersensitivity reactions. Their reactivity can be assessed by measuring the upregulation of the activation marker CD69, followed by assessment of proliferation and cytokine production. The aim of our study was to develop a novel, whole blood-based, quantitative, absolute count activation index (AI) for analysis of CD69 upregulation in various subsets of T cells in nickel-hypersensitive patients and compare it with previously reported approaches. METHODS: The study population comprised 10 patients with nickel allergy and 9 healthy controls. CD69 expression of CD3+, CD3+CD4+, and CD3+CD8+ T cells in heparinized blood was determined with flow cytometry after incubation with nickel sulfate for 48 hours. The absolute count of CD69+ cells was determined using microbeads. Production of the cytokines IL-2, IL-5, IL-13, and IFN-γ was determined after stimulation of peripheral blood mononuclear cells with nickel sulfate for 48 hours. RESULTS: We showed absolute AI to be the most sensitive approach. The index was calculated as the ratio of the absolute count of nickel-stimulated CD69-positive T cells to the absolute count of CD69-positive T cells in nonstimulated blood. This novel quantitative approach was more discriminative than previously reported approaches in which the T-cell CD69 percentage AI and cytokine production are measured. CONCLUSIONS: Our results demonstrated that measuring the absolute CD69 AI is a novel and accurate approach for quantification of antigen-specific T cells in the blood of patients with hypersensitivity reactions to nickel. This approach may be useful for better in vitro assessment of patients with delayed-type hypersensitivity reactions.