Immediate and delayed hypersensitivity reactions to corticosteroids - prevalence, diagnosis and treatment.

BACKGROUND: Corticosteroids, which are anti-inflammatory and immunosuppressive agents used for the treatment of various diseases including allergic disorders, can induce immediate and delayed hypersensitivity reactions. Although these reactions are not common, due to the wide usage of corticosteroid medications, corticosteroid hypersensitivity reactions are clinically important. OBJECTIVE: In this review, we summarise the prevalence, pathogenetic mechanism, clinical manifestations, risk factors, diagnostic and therapeutic approach for corticosteroid-induced hypersensitivity reactions. METHODS: An integrative review of the literature was conducted using PubMed searches (mainly large cohort-based studies) regarding the different aspects of corticosteroid hypersensitivity. RESULTS: Hypersensitivity reactions to corticosteroids can be immediate or delayed and can follow all modes of corticosteroid administration. Prick and intradermal skin tests are useful diagnostic tools for immediate hypersensitivity reactions, patch tests are useful for delayed hypersensitivity reactions. According to the diagnostic tests an alternative (safe) corticosteroid agent should be administered. CONCLUSION: Physicians of all medical disciplines should be aware that corticosteroids can cause (paradoxically) immediate or delayed allergic hypersensitivity reactions. The diagnosis of such allergic reactions is challenging since it is often difficult to distinguish between hypersensitivity reactions and deterioration of the basic inflammatory disease (e.g., worsening of asthma or dermatitis). Thus, a high index of suspicion is needed in order to identify the culprit corticosteroid.

Onset of occupational hand eczema among healthcare workers during the SARS-CoV-2 pandemic: Comparing a single surgical site with a COVID-19 intensive care unit.

BACKGROUND: As a result of the COVID-19 outbreak, hygiene regulations have been revised and hand sanitation has been intensified. OBJECTIVE: To investigate the onset of hand eczema during the COVID-19 pandemic in healthcare workers (HCWs) directly involved in intensive care of COVID-19 patients and HCWs without direct contact with COVID-19 patients. Hereby, we aim at increasing awareness about occupational hand eczema and preventive measures that can be adopted. METHOD: A survey was distributed amongst 114 HCWs at a single surgical centre and at a COVID-19 intensive care unit of the university hospital Ludwig Maximilian University Munich, Germany. Participants were questioned about the daily frequency of hand hygiene prior to and during the pandemic. Participants self-reported the onset of hand eczema and associated symptoms. RESULTS: Our study revealed a significant increase in hand washing, disinfection, and use of hand cream across all participants (P-value <.001), regardless of having direct contact with COVID-19 patients. A high prevalence of symptoms associated with acute hand dermatitis of 90.4% was found across all HCWs, whereas hand eczema itself was underreported (14.9%). CONCLUSION: The increase in hand sanitation during the COVID-19 pandemic impairs the skin of the hands across all HCWs, independent of direct intensive care of affected patients.

Higher Prevalence of Nickel and Palladium Hypersensitivity in Patients with Ulcerative Colitis.

BACKGROUND: The etiology of ulcerative colitis (UC) remains elusive even though many genetic and environmental pathogenic factors have been reported. Aberrant inflammatory responses mediated by specific subsets of T cells have been observed in ulcerative lesions of UC patients. OBJECTIVES: To elucidate the involvement of a delayed-type hypersensitivity reaction in UC, we focused on dental metal hypersensitivity, a T cell-mediated, delayed-type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. METHOD: We recruited 65 Japanese UC patients and 22 healthy controls (HC) and used the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium - the metals that have been widely used in dentistry. All subjects were users of metallic dental implants and/or prostheses containing zinc, gold, nickel, and/or palladium as major constituents. RESULTS: Sixty percent of the UC patients were hypersensitive to at least one metal species, whereas 32% of the HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for UC patients than for HC. Furthermore, a significantly greater proportion of UC patients were hypersensitive to nickel or palladium. The severity of the sensitivity to nickel and palladium was also significantly greater for UC patients than for HC. CONCLUSIONS: This pilot study demonstrates that UC patients have a significantly higher incidence of hypersensitivity to nickel and palladium, suggesting the possible involvement of dental metal hypersensitivity in UC pathogenesis.

Alcohol-Related Dermatitis: A Review.

: Wine, beer, liquor, and spirits are widely consumed in many cultures across the globe, and for some individuals, ingestion, cutaneous contact, or other exposure can lead to dermatologic findings. However, there currently exist no comprehensive reviews on alcohol-related dermatitis. Herein, we will provide an overview of alcohol-related dermatitis and contact urticaria, including the epidemiology and clinical manifestations, potential allergens found in alcoholic beverages, testing approaches, and strategies for allergen avoidance.

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.

A Systematic Review of the Literature of Delayed Inflammatory Reactions After Hyaluronic Acid Filler Injection to Estimate the Incidence of Delayed Type Hypersensitivity Reaction.

BACKGROUND: Hyaluronic acid (HA) dermal filler injection is believed to be a safe procedure. However, with the increase in the number of performed procedures and indications, the number of product-related complications, especially delayed inflammatory reactions, has also increased. Delayed-type hypersensitivity (DTH) reaction is one of these delayed inflammatory reactions, which is preventable by performing a pretreatment skin test. OBJECTIVES: The authors sought to find the incidence of delayed inflammatory reactions and DTH reaction after HA injection and to determine whether a pretreatment skin test is worthwhile to be performed. METHODS: The authors conducted a systematic literature review of all the relevant prospective studies, retrospective studies, and case reports on delayed inflammatory reactions and DTH reaction after HA filler injection. RESULTS: The incidence of delayed inflammatory reactions calculated from the prospective studies was 1.1% per year, and that of possible DTH reaction was 0.06% per year. Most retrospective studies estimated a percentage of delayed inflammatory reactions of less than 1% in 1 to 5.5 years. The incidence of DTH reaction would be lower than that. Among all the DTH cases reported, only about 5% of them were proven to be genuine DTH reactions. CONCLUSIONS: The incidence of both delayed inflammatory reactions and DTH reaction is low. There is evidence that genuine DTH reactions caused by HA fillers approved by the Food and Drug Administration do exist. This adverse event can be prevented by performing a pretreatment skin test. However, the incidence of DTH reaction is so low that the pretreatment skin test is not mandatory if Food and Drug Administration-approved HA fillers are used.

Immune dysregulation increases the incidence of delayed-type drug hypersensitivity reactions.

Delayed-type, T cell-mediated, drug hypersensitivity reactions are a serious unwanted manifestation of drug exposure that develops in a small percentage of the human population. Drugs and drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the drug-peptide complex to T cells. Multiple forms of drug hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many individuals expressing HLA risk alleles do not develop hypersensitivity when exposed to culprit drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether drug exposure will result in a health benefit, hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards drug hypersensitivity.

Epidemiology and Risk Factors for Severe Delayed Drug Hypersensitivity Reactions.

Severe delayed drug hypersensitivity reactions comprise different clinical entities and can involve different immune-mediated mechanisms. Common examples are severe cutaneous adverse reactions and druginduced internal organ injuries. The incidence of such reactions is overall low but seems to be on the rise reaching numbers as high as 9 per million individuals-years in the case of SJS/TEN and DRESS. Such conditions carry an important associated morbidity, and mortality can attain 40% in SJS/TEN patients, making these hypersensitivity reactions important targets when implementing preventive measures. Several risk factors have been identified for reaction severity; some are transverse, such as older age and underlying chronic diseases. The recent advances in pharmacogenetics allowed the identification of specific populations with higher risk and permitted strategic avoidance of certain drugs being HLA-B*57:01 screening in patients initiating abacavir the best successful example. In this work, we reviewed the epidemiology of SCARs and liver/kidney/lung drug-induced immune-mediated reactions. We focus on particular aspects such as prevalence and incidence, drugs involved, mortality and risk factors.

Family history of atopy in infants with cow's milk protein allergy: A French population-based study.

OBJECTIVES: This French multicenter, cross-sectional, observational study aimed to describe the family history of atopy in infants with cow's milk protein allergy (CMPA), and the related diagnostic approaches used by specialists in a real-life ambulatory setting. PATIENTS AND METHODS: In total, 1674 infants with suspected CMPA [median age 4.5 months (range: 0.1-18.0), males 54%] were enrolled in the study by 466 private physicians (pediatricians: 97%). Family history of atopy was defined as a known history of atopy in at least one first- (father, mother, and/or sibling) and/or second-degree relative (grandparents, uncles, and aunts), as reported by parents to physicians. RESULTS: Atopy in a first-degree relative was more common among infants with documented or high probability of CMPA (in 84% and 80% of cases, respectively, vs. the other subgroups, P=0.005). Most infants experienced digestive (92%) and skin (61%) symptoms suggestive of CMPA. Delayed reactions were reported in 64% of infants. According to a post-classification based on the results of previous diagnostic tests and procedures, 1133 infants (68%) had highly probable (52%) or documented CMPA (16%). In these infants, a history of atopy was reported in first- and/or second-degree relative(s) in 86% of cases (81% in first-degree relatives). Whatever the family history of atopy, the characteristics of the infants were similar, except for fewer pets in the case of negative family atopy (14% vs. 25%, P<0.001). Atopy in a parent was more frequent in infants who presented with the first signs suggestive of CMPA within the first 6 months of life vs. those with later first symptoms (75% vs. 65%, P=0.063). CONCLUSION: This French study confirms the high rate of family history of atopy in first-degree relatives of infants with probable or documented CMPA.

Differences in Adverse Reactions Among Iodinated Contrast Media: Analysis of the KAERS Database.

BACKGROUND: The various adverse drug reactions (ADRs) arise from different types of iodinated contrast media (ICM). OBJECTIVE: Thus, we investigated the occurrence rate and types of ADRs according to the total usage cases of the 7 most common ICM. METHODS: We retrospectively reviewed 74,242 causal ADRs caused by ICM from the Korea Adverse Event Reporting System database between January 2014 and December 2016. The 11,712,796 total usage cases that represent all administrations of ICM reported from individual medical institutions were received from the Health Insurance Review and Assessment Service. A proportionality test was used to examine the differences in the frequency ratio of causal ADRs to total usage cases. RESULTS: Immediate hypersensitivity (44,467 cases, 88.56%) occurred more frequently than delayed hypersensitivity (5,725 cases, 11.4%; P < .001). The overall occurrence rate of causal ADRs and serious ADRs considering total usage cases was 0.37% and 0.02%, respectively (P < .001). The ICM most commonly resulting in ADRs were iomeprol (0.7%) and iopromide (0.59%). The serious ADRs were most common for iomeprol (0.05%). When ADRs were classified according to the system organ class, "skin and appendages disorders" (47,065 cases, 63.4%) occurred most common. Iodixanol resulted in the highest frequency of "urinary system disorders." CONCLUSIONS: By comparison of the ADRs considering total usage cases, the incidence and classification of ADRs were different for each contrast medium. A prospective study is needed because the differences in these 7 major contrast media may assist in the selection of ICM tailored for each patient.

Exposure to Solar UVR Suppresses Cell-Mediated Immunization Responses in Humans: The Australian Ultraviolet Radiation and Immunity Study.

Animal and human studies show that exposure to solar-simulated UVR is immunomodulatory. Human studies that used natural sun exposure and controlled for confounding are rare. We immunized 217 healthy adults (age range = 18-40 years) with a T-cell-dependent antigen, keyhole limpet hemocyanin, and measured personal clothing-adjusted UVR exposure (for 5 days before and after immunization), lifetime cumulative UVR exposure, serum 25-hydroxyvitamin D concentration at immunization, and potential confounding factors. We tested cellular and humoral immune responses in relation to UVR exposure. The delayed-type hypersensitivity response to keyhole limpet hemocyanin recall challenge was lower in individuals with higher personal clothing-adjusted UVR exposure on the day before immunization (P = 0.015) and during intervals spanning the day before to 2-3 days after immunization. There was an incremental increase in T helper type 17 cells (as a proportion of CD4+ T cells) from preimmunization to postimmunization in the high, compared with the low, personal clothing-adjusted UVR exposure group (0.31% vs. -0.39%, P = 0.004). Keyhole limpet hemocyanin-specific antibody titers were not associated with acute or cumulative UVR exposure or serum 25-hydroxyvitamin D levels. Higher UVR exposure at antigen sensitization was associated with a reduced delayed-type hypersensitivity response and altered T helper type 17 kinetics. This has implications for the effectiveness of vaccinations and susceptibility to infections that rely on cell-mediated immune responses.

Low incidence of heparin-induced skin lesions in orthopedic surgery patients with low-molecular-weight heparins.

BACKGROUND: Heparins are widely prescribed for prevention and therapy of arterial and venous thromboembolic diseases. Heparin-induced skin lesions are the most frequent adverse effect of subcutaneous heparin treatment in non-surgical patients (7.5%-39.8%); no data exist on surgical patients. Commonly, they are due to a delayed-type hypersensitivity reaction (DTH), but may also be a manifestation of life-threatening heparin-induced thrombocytopenia (HIT). Lesions of both entities resemble initially. The risk of HIT is highest among heparin-anticoagulated orthopedic surgery patients. OBJECTIVE: To determine incidence and causes of heparin-induced skin lesions in major orthopedic surgery patients. METHODS: In a prospective cohort study, consecutive patients with subcutaneous low-molecular-weight heparin (LMWH) treatment were examined for cutaneous adverse effects. Further diagnostics (skin biopsy, clinical/laboratory assessment for thrombosis, bleeding, HIT, cross-allergies) were performed. RESULTS: Six of 316 enrolled patients (1.9%; 95% CI: 0.4%-3.4%) developed heparin-induced skin lesions. All were caused by a DTH reaction, and none was due to HIT or other rare heparin-associated skin diseases. Therapeutic use (dosage) of LMWH was identified as only risk factor (odds ratio: 3.1, 95% CI: 1.4-4.9; P = .00141). In addition to DTH, 5 thromboembolic, 4 major bleeding complications but no cases of HIT or cross-allergies were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Orthopedic surgery patients have-unlike non-surgical patients-a low risk for heparin-induced skin lesions during LMWH treatment; all lesions were due to a DTH reaction. The risk for DTH differs considerably between individual patient cohorts. No association with HIT was observed. These data help to tailor anticoagulatory treatment individually and to increase patient safety.

Occupational allergic contact dermatitis caused by antibiotics in healthcare workers - relationship with non-immediate drug eruptions.

BACKGROUND: Occupational allergic contact dermatitis (ACD) in healthcare workers (HCWs) is common, but systemic antibiotics are rarely reported as the cause. OBJECTIVES: Characterize occupational ACD by handling systemic antibiotics. METHOD: A retrospective analysis was performed of ACD caused by systemic antibiotics among HCWs patch tested between 2010 and 2016 with a series of systemic antibiotics. RESULTS: We studied 4 female nurses aged 28-47 years who developed ACD while working in surgical departments. They had eczema of the hands, and forearms or face, and 1 patient, who previously had exanthema caused by flucloxacillin, also developed a generalized rash following airborne exposure to systemic antibiotics. Patch tests showed positive reactions to ampicillin and cefazolin in 1 patient, to cefotaxime and ceftriaxone in 2 patients, and to several penicillins in another patient. Three patients also reacted to rubber allergens, fragrances, and/or preservatives. All patients admitted having direct and sporadic exposure to systemic antibiotic solutions. Avoidance resulted in a significant improvement of ACD, but 1 patient had to change job. CONCLUSIONS: Occupational ACD caused by ß-lactam antibiotics, particularly cephalosporins, is significant in HCWs. Cross-reactions between ß-lactams are similar to those described in non-immediate drug eruptions. A relationship between systemic delayed drug hypersensitivity and ACD, as observed in one case, suggests that patients should avoid future use of the antibiotic to which they are sensitized.

Association of non-immediate drug hypersensitivity with drug exposure: A case control analysis of spontaneous reports from a Tunisian pharmacovigilance database.

PURPOSE: To assess delayed-type cutaneous reactions (DTCRs) related to drugs, using a case-control approach to qualify drug risks. METHODS: The study used the Tunisian pharmacovigilance database of Monastir. The association between drugs and DTCRs was assessed using a case/non-case method. Drugs were grouped according to the ATC Classification System. Patients were defined as "cases" if they have developed DTCRs regardless of the causality assessment. All other reports were "non-cases". Association between reactions and drugs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals (CIs). A p value < 0.05 was considered significant. RESULTS: The analysis was carried out on 1798 reports, of which 867 concerned DTCRs (cases) and 931 concerned non-cases. The calculated risk estimates were significant for cefotaxime (ROR 2.1; 95% CI 1.5 to 3), pristinamycin (ROR 4; 95% CI 2 to 7.9), sulfamethoxazole (ROR 4.4; 95% CI 1.6 to 11.7), oxacillin (ROR 2.2; 95% CI 1.2 to 3.8), doxycycline (ROR 10.8; 95% CI 1.4 to 84.9), carbamazepine (ROR 3.3; 95% CI 1.7 to 6.2), phenobarbital (ROR 2.3; 95% CI 1.03 to 5.1), allopurinol (ROR 3.6; 95% CI 1.8 to 7.2), furosemide (ROR 2.4; 95% CI 1.3 to 6.3), hydrochlorothiazide(ROR 2.9; 95% CI 1.3 to 6.3) and candesartan (ROR 4.7; 95% CI 1.3 to 16.6). CONCLUSION: Our findings corroborate risks for a number of drugs, such as antibacterials, antiepileptics and allopurinol in inducing DTCRs. Given the widespread use of these drug classes, awareness should be raised among patients and prescribers about these risks.

Galactose-α-1,3-galactose syndrome: an Italian survey.

SUMMARY: Background. The term of α-Gal syndrome, which includes the delayed allergy to red meat and the allergic reactions following the administration of cetuximab, is associated to the presence of specific IgE to α-Gal. In Italy, only anecdotal cases were reported so far. The Association of Italian Allergists (AAITO) carried out a survey with the aim of evaluating presence, characteristics, clinical features, and distribution of the syndrome in Italy. Methods. A web structured questionnaire was made available on the website of AAIITO from July 2016 to January 2017. It included 31 multiple-choice questions concerning different items, including the site of physicians, the number of patients diagnosed as having cetuximab allergy and/or delayed red meat allergy, recall of tick bites, symptoms, time to reactions, elicitor foods, reactions with foods other than meat, and in-vivo and in-vitro tests used for the diagnosis. Results. Seventy-nine physicians completed the questionnaire. Nine cases of allergy to cetuximab and 40 cases of delayed red meat allergy were recorded across Italy. 22.5% of patients with cetuximab allergy and 62.5% of those with delayed red meat allergy recalled a tick bite. 75% of patients with delayed red meat allergy experienced symptoms after eating beef (butcher's cut in 72.5%). Urticaria was the most frequent clinical manifestation (65% of cases). In 60.6% of cases symptoms appeared 2 - 4 hours after meat ingestion, while in 7.9% symptoms appeared after > 4 hours. The most used diagnostic methods were the intradermal test for cetuximab allergy (88.9%) and the detection of IgE to α-Gal (55.5%) for red meat allergy. Most case reports came from Northern Italy. Conclusions. α-Gal syndrome is present in Italy and beef is the most frequent offending food. In most cases symptoms were not severe.

[Hypersensitivity reactions to beta-lactam antibiotics]. / Allergies aux bêtalactamines.

Allergy to beta-lactam antibiotics is a common condition and about 10% of patients report being allergic to penicillin. However, this diagnosis is largely overestimated. Two types of allergy should be distinguished and include immediate hypersensitivity that can lead to anaphylactic shock and delayed hypersensitivity, ranging from the most common maculopapular exanthema to severe bullous toxidermia or life-threatening DRESS. Allergy challenge with oriented skin tests according to the clinical features, supplemented with oral challenge in the absence of contraindication, will confirm or invalidate the diagnosis of beta-lactam allergy and will help to identify if necessary safe alternatives to beta-lactams.