Contact Dermatitis from Biomedical Devices, Implants and Metals- Trouble from Within.

Allergic contact dermatitis is characterized by its appearance of red, raised and infiltrated, scaling or scabbed skin and intense pruritus, and distinguished from irritant contact dermatitis by its specific immune process and histopathology. Many contact allergens are low molecular weight chemicals including metals such as nickel, cobalt, and chromium, preservatives, and adhesives. When such materials are used internally in biomedical devices, they are similarly capable of causing sensitization and an inflammatory response. Sometimes the reaction remains internal, and presents as swelling, pain, stiffness, decreased range of motion, and internal itching around the implant. Such reactions may, in some cases, also extend to include a localized or, rarely, systemic contact dermatitis indicative of the same process. This review will present an overview of reported skin and local internal reactions to orthopedic implants, which are the largest category of implanted internal metal devices. Immune reactions to smaller categories of medical appliances include cardiac devices and vascular stents, neuromodulation devices, diabetic appliances, Nuss bar surgery for pectus excavatum, and dental and spinal implants. We will review the available diagnostic tools, the consensus on interpretation, and reported strategies for treatment.

How Allergists Can Perform an Occupational History in Every Patient.

The occupational history is often neglected in the routine evaluation of new patients with asthma, chronic rhinitis, or dermatologic complaints. Such omissions are inadvertent because work-related conditions are often not prioritized. There also may be lack of awareness of the scope of respiratory or cutaneous allergens capable of inducing occupational asthma (OA) or work-related contact dermatitis. Evidence exists suggesting that the occupational history is often neglected among primary care physicians and specialists. Failure to diagnose OA in a timely fashion by identifying occupational sources of exposure, for example, may result in unnecessary morbidity in workers whose exposure is not modified. In this commentary, we propose a brief intake survey to be administered to all patients coming to an allergy practice to quickly screen for possible work-related respiratory symptoms and another for occupational dermatitis. This would require minimal physician time and could be self-administered at the initial encounter and incorporated into the medical record. A positive response to either survey should trigger a more detailed evaluation by the allergy specialist. More detailed approaches for stepwise clinical evaluation of the worker suspected of OA and contact dermatitis are discussed.

Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility.

Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis.

The Emerging Spectrum of Respiratory Diseases in the U.S. Cannabis Industry.

While the cannabis industry is one of the fastest growing job markets in the United States and globally, relatively little is known about the occupational hazards that cannabis production workers face. Based on the closely related hemp industry and preliminary studies from recreational cannabis grow facilities, there is concern for significant respiratory exposures to bioaerosols containing microbial and plant allergens, chemicals such as pesticides, volatile organic compounds, and other irritant gases. Components of the cannabis plant have also recently been identified as allergenic and capable of inducing an immunoglobulin E-mediated response. Accumulating evidence indicates a spectrum of work-related respiratory diseases, particularly asthma and other allergic diseases. Disentangling causal relationships is difficult given the heterogeneity of mixed exposures, diagnostic challenges, and confounding by personal cannabis use. Despite and because of these uncertainties, better regulatory guidance and exposure controls need to be defined in order to reduce the risk of work-related disease.

Autoantibody profile in sarcoidosis, analysis from the GRADS sarcoidosis cohort.

BACKGROUND: Sarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls. STUDY DESIGN AND METHODS: We analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers. RESULTS: Sarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs. CONCLUSION: Sarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.

Synovial Fluid Cytokines, Chemokines and MMP Levels in Osteoarthritis Patients with Knee Pain Display a Profile Similar to Many Rheumatoid Arthritis Patients.

BACKGROUND: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA (n = 21) to those with RA (n = 27) and normal knees (n = 3). METHODS: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active (n = 20) or controlled (n = 7) based upon SF white blood cell counts (> or <300 cells/mm3). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing. RESULTS: Only six biomarkers were significantly higher in SF from active RA compared to OA-TNF-α, IL-1-ß IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts (p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum (p < 0.05). CONCLUSION: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

Sensitization to Implant Components Is Associated with Joint Replacement Failure: Identification and Revision to Nonallergenic Hardware Improves Outcomes.

BACKGROUND: Over 90% of one million annual US joint replacements are highly successful. Nonetheless, 10% do poorly owing to infection or mechanical issues. Many implant components are sensitizers, and sensitization could also contribute to implant failure. OBJECTIVE: To determine the prevalence of implant sensitization in joint failure patients, their clinical characteristics, and implant revision outcomes. We hypothesized that sensitized patients would improve when revised with nonallergenic materials. METHODS: We prospectively enrolled 105 joint failure patients referred by orthopedic surgeons who had already excluded infection or mechanical causes. Patients provided informed consent, completed a history and physical examination, patch testing to metals and bone cement, and a nickel lymphocyte proliferation test. A study coordinator was able to contact 64% of patients (n = 67) 9 to 12 months later to evaluate outcomes. RESULTS: A total of 59% were sensitized to an implant component: 32% to metal and 37% to bone cement. The nickel lymphocyte proliferation test was 60% sensitive and 96% specific in diagnosing nickel sensitization. Most sensitized subjects reported no or uncertain histories of reactions to a specific material. Implant sensitized patients were younger and reported previous eczema, joint itching, and implant loosening. By 9 to 12 months later, most patients with a revised implant (revised) described significant improvement (16 of 22 revised for sensitization [P = .0003] vs 9 of 13 revised without sensitization [P = .047]) compared with patients without implant revision). All revised patients with sensitization used components to which they were not sensitized. Pain (P = .001), swelling (P = .035), and instability (P = .006) were significantly reduced in the revised sensitized group. CONCLUSIONS: Sensitization to implant components is an important cause of unexplained joint replacement failure. Joint revisions based on sensitization information resulted in significant improvements.

The T Cell Repertoires from Nickel Sensitized Joint Implant Failure Patients.

Nickel (Ni2+) is one of the most common allergens, affecting around 10-15% of the general population. As the demand for orthopedic implant surgery rises, the number of surgical revisions due to joint implant failure also increases. There is evidence that some patients develop joint failure due to an immune response to a component of the implant, and we have found that Ni2+ is an especially important cause. Hence, understanding the mechanisms by which Ni2+ allergy induces joint implant failure becomes a critical research question. The structural basis of Ni2+ activation of pathogenic T cells is still not clear. The purpose of this study was to characterize Ni2+-reactive T cell repertoires derived from the peripheral blood of joint failure patients due to Ni2+ sensitization using single-cell sequencing techniques. We stimulated the proliferation of Ni2+ -reactive T cells from two implant failure patients in vitro, and sorted them for single-cell VDJ sequencing (10× genomics). We identified 2650 productive V-J spanning pairs. Both TCR α chains and ß chains were enriched. TRBV18 usage is the highest in the P7 CD4+ population (18.1%), and TRBV5-1 usage is the highest in the P7 CD8+ population (12.1%). TRBV19 and TRBV20-1 segments are present in a high percentage of both P7 and P9 sequenced T cells. Remarkably, the alpha and beta chain combination of TRAV41-TRBV18 accounts for 13.5% of the CD4+ population of P7 patient. Compared to current Ni specific T cell repertoire studies of contact dermatitis, the Vα and Vß usages of these joint implant failure patients were different. This could be due to the different availability of self-peptides in these two different tissues. However, TRBV19 (Vß17) was among frequently used TCR ß chains, which are common in previous reports. This implies that some pathogenic T cells could be similar in Ni2+ hypersensitivities in skin and joints. The alignment of the TCR CDR3ß sequences showed a conserved glutamic acid (Glu) that could potentially interact with Ni2+. The study of these Ni2+ specific TCRs may shed light on the molecular mechanism of T cell activation by low molecular weight chemical haptens.

Occupational Allergies to Cannabis.

Within the last decade there has been a significant expansion in access to cannabis for medicinal and adult nonmedical use in the United States and abroad. This has resulted in a rapidly growing and diverse workforce that is involved with the growth, cultivation, handling, and dispensing of the cannabis plant and its products. The objective of this review was to educate physicians on the complexities associated with the health effects of cannabis exposure, the nature of these exposures, and the future practical challenges of managing these in the context of allergic disease. We will detail the biological hazards related to typical modern cannabis industry operations that may potentially drive allergic sensitization in workers. We will highlight the limitations that have hindered the development of objective diagnostic measures that are essential in separating "true" cannabis allergies from nonspecific reactions/irritations that "mimic" allergy-like symptoms. Finally, we will discuss recent advances in the basic and translational scientific research that will aid the development of diagnostic tools and therapeutic standards to serve optimal management of cannabis allergies across the occupational spectrum.

Isocyanate induced allergic contact dermatitis in a university undergraduate student: An occupational dermatitis case report, review of laboratory safety regulations, and implications for campus research.

A 19-year-old female college undergraduate developed an intensely swollen, erythematous and pruritic rash on the face and hands while working in an optical fabrication lab producing photosensitive polymers. She had no respiratory symptoms. The rash was consistent with contact dermatitis and there was no clinical evidence of respiratory involvement with normal spirometry. A review of the safety data sheets of chemicals used in the laboratory revealed several known sensitizers, including 6-hexamethylene diisocyanate (HDI), dibutyl phthalate, and 2,4,6-tribromophenyl acrylate. Patch testing confirmed the patient's sensitization to HDI. A subsequent worksite visit identified several hazardous chemicals that were used without appropriate hazard communication, training, standard operating procedures, or personal protective equipment. Simple exposure controls were recommended and instituted, and the patient was able to return to work in the laboratory without the recurrence of symptoms. This case demonstrates the importance of hazard identification, communication, and safety training in academic laboratories, for students and workers. A medical evaluation can identify hazards as well as lead to improvements in exposure controls and safe return to research.

Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis.

Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.

Allergy to Surgical Implants.

Surgical implants are essential elements of repair procedures to correct worn out joints, damaged spinal components, heart and vascular disease, and chronic pain. However, many of the materials that provide stability, flexibility, and durability to the implants are also immunogenic. Fortunately, allergic responses to surgical implants are infrequent. When they do occur, however, the associated pain, swelling, inflammation, and decreased range of motion can significantly impair the implant function. Given the high numbers of joint replacements performed in the developed world, allergic reactions to orthopedic implants form the largest category of allergic responses. The most important allergens in this category include nickel, cobalt, chromium, and bone cement. These allergens are also the most important in reactions to spinal surgeries. Multiple cardiac and neurostimulatory devices are constructed of metals and adhesives that can be sensitizing in some individuals. Implantable pulse generators, important in cardiac pacemakers, gastric stimulators, and neurostimulators, may include components made of stainless steel, titanium alloy, platinum and iridium, epoxy resins, poly methyl methacrylates, and isocyanates, all of which are immunogenic in some patients. Cardiac stents and patches are often made of Nitinol, a composite of nickel and titanium. More surgical procedures are closed using skin glues, which are also capable of triggering a blistering contact dermatitis. Patch testing is the gold standard to determine sensitization, and this review provides a list of standard allergens to test for different implants. The patients most appropriate for testing include (1) pre-operative joint replacement patients with a prior history of skin reactions to metal jewelry, jean snaps, watch bands, metal glass frames, artificial nails, or skin glue; (2) post-operative joint replacement failure patients needing revision without an obvious cause such as infection or mechanical incompatibility; and (3) post-operative cardiac or neurological patients with localized rash, pain, swelling, or inflammation near or over the implant.

Using DR52c/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure.

T cell mediated hypersensitivity to nickel (Ni2+) is one of the most common causes of allergic contact dermatitis. Ni2+ sensitization may also contribute to the failure of Ni2+ containing joint implants, and revision to non-Ni2+ containing hardware can be costly and debilitating. Previously, we identified Ni2+ mimotope peptides, which are reactive to a CD4+ T cell clone, ANi2.3 (Vα1, Vß17), isolated from a Ni2+ hypersensitive patient with contact dermatitis. This T cell is restricted to the major histocompatibility complex class II (MHCII) molecule, Human Leukocyte Antigen (HLA)-DR52c (DRA, DRB3*0301). However, it is not known if Ni2+ induced T cell responses in sensitized joint replacement failure patients are similar to subjects with Ni2+ induced contact dermatitis. Here, we generated DR52c/Ni2+ mimotope tetramers, and used them to test if the same Ni2+ T cell activation mechanism could be generalized to Ni2+ sensitized patients with associated joint implant failure. We confirmed the specificity of these tetramers by staining of ANi2.3T cell transfectomas. The DR52c/Ni2+ mimotope tetramer detected Ni2+ reactive CD4+ T cells in the peripheral blood mononuclear cells (PBMC) of patients identified as Ni2+ sensitized by patch testing and a positive Ni2+ LPT. When HLA-typed by a DR52 specific antibody, three out of four patients were DR52 positive. In one patient, Ni2+ stimulation induced the expansion of Vß17 positive CD4+ T cells from 0.8% to 13.3%. We found that the percentage of DR52 positivity and Vß17 usage in Ni2+ sensitized joint failure patients are similar to Ni sensitized skin allergy patients. Ni2+ independent mimotope tetramers may be a useful tool to identify the Ni2+ reactive CD4+ T cells.

Work-Related Asthma.

OBJECTIVE: Summarize developed evidence-based diagnostic and treatment guidelines for work-related asthma (WRA). METHODS: Comprehensive literature reviews conducted with article critiquing and grading. Guidelines developed by a multidisciplinary expert panel and peer-reviewed. RESULTS: Evidence supports spirometric testing as an essential early test. Serial peak expiratory flow rates measurement is moderately recommended for employees diagnosed with asthma to establish work-relatedness. Bronchial provocation testing is moderately recommended. IgE and skin prick testing for specific high-molecular weight (HMW) antigens are highly recommended. IgG testing for HMW antigens, IgE testing for low-molecular weight antigens, and nitric oxide testing for diagnosis are not recommended. Removal from exposure is associated with the highest probability of improvement, but may not lead to complete recovery. CONCLUSION: Quality evidence supports these clinical practice recommendations. The guidelines may be useful to providers who diagnose and/or treat WRA.

Allergy to Surgical Implants.

Surgical implants have a wide array of therapeutic uses, most commonly in joint replacements, but also in repair of pes excavatum and spinal disorders, in cardiac devices (stents, patches, pacers, valves), in gynecological implants, and in dentistry. Many of the metals used are immunologically active, as are the methacrylates and epoxies used in conjunction with several of these devices. Allergic responses to surgical components can present atypically as failure of the device, with nonspecific symptoms of localized pain, swelling, warmth, loosening, instability, itching, or burning; localized rash is infrequent. Identification of the specific metal and cement components used in a particular implant can be difficult, but is crucial to guide testing and interpretation of results. Nickel, cobalt, and chromium remain the most common metals implicated in implant failure due to metal sensitization; methacrylate-based cements are also important contributors. This review will provide a guide on how to assess and interpret the clinical history, identify the components used in surgery, test for sensitization, and provide advice on possible solutions. Data on the pathways of metal-induced immune stimulation are included. In this setting, the allergist, the dermatologist, or both have the potential to significantly improve surgical outcomes and patient care.

Contact dermatitis: a practice parameter-update 2015.

This parameter was developed by the Joint Task Force on Practice Parameters, which represents the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Contact Dermatitis: A Practice Parameter-Update 2015." This is a complete and comprehensive document at the current time. The medical environment is changing and not all recommendations will be appropriate or applicable to all patients. Because this document incorporated the efforts of many participants, no single individual, including members serving on the Joint Task Force, are authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information or interpretation of this practice parameter by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by the pharmaceutical industry in drug development or promotion. Previously published practice parameters of the Joint Task Force on Practice Parameters for Allergy & Immunology are available at http://www.JCAAI.org or http://www.allergyparameters.org.