Sulfasalazine-Induced Delayed Hypersensitivity Reaction Presenting as Fever, Aseptic Meningitis, and Mesenteric Panniculitis in a Patient with Seronegative Arthritis.

BACKGROUND An 82-year-old woman presented with acute pyrexial illness and mesenteric panniculitis and developed biochemical aseptic meningitis (cerebrospinal fluid pleocytosis with no identifiable pathogen). Investigation determined her illness was likely a delayed hypersensitivity reaction caused by sulfasalazine. Sulfasalazine-induced aseptic meningitis is a rare condition often diagnosed late in a patient's admission owing to initial non-specific illness symptomatology requiring the exclusion of more common "red flag" etiologies, such as infection and malignancy. CASE REPORT An 82-year-old woman with a history of recurrent urinary tract infections and seronegative arthritis presented with a 3-day history of fatigue, headache, dyspnea, and lassitude. On admission, she was treated as presumed sepsis of uncertain source owing to pyrexia and tachycardia. Brain computer tomography (CT) revealed no acute intracranial abnormality. Furthermore, CT of the chest, abdomen, and pelvis did not reveal any source of sepsis or features of malignancy. After excluding infective etiologies with serological and cerebrospinal fluid testing, sulfasalazine-induced aseptic meningitis (SIAM) was diagnosed. The patient was then commenced on intravenous steroids, resulting in immediate defervescence and symptom resolution. CONCLUSIONS SIAM remains a diagnostic challenge since patients present with non-specific signs and symptoms, such as pyrexia, headaches, and lassitude. These patients require a thorough investigative battery starting with anamnesis, physical examination, biochemical testing, and radiologic imaging. This case illustrates the need for a high suspicion index of drug-induced hypersensitivity reaction in a rheumatological patient with pyrexial illness where infective etiologies have been confidently excluded. Prompt initiation of intravenous steroids in SIAM provides a dramatic recovery and resolution of symptoms.

Delayed Severe Gingivitis After Placement of Orthodontic Braces in an Atopic Teenager: A Case Report and Literature Review.

We report a case of a 15-year-old atopic patient presenting with delayed, severe ulcerative hypertrophic gingivitis after placement of orthodontic braces, which required removal of braces and restorative laser surgical procedures. Patch testing to multiple metals and chemicals showed weak positive reactions to steel bands and formaldehyde. The patient experienced urticarial, gingivitis, and other intraoral symptoms after patch testing and re-exposure to nickel-containing products. In contrast, nickel, cobalt, and cobalt-chromium (Co-Cr) bracket patch testing sites were negative. Nickel-caused contact dermatitis is Type IV delayed hypersensitivity reaction occurring at least 24 h after exposure. This reaction can result in intraoral blisters, ulcerations, eczematous and urticarial reactions of the face and more distant skin areas. This case illustrates the intraoral delayed response, symptom resolution after removing the braces, and brackets and local reactions upon subsequent nickel exposure, despite negative patch testing and lymphocyte stimulation test to nickel. This case further illustrates the difficulty associated with diagnosing nickel allergy.

Delayed hypersensitivity reaction from microneedling twenty years after silicone fillers.

Skin rejuvenation procedures have increasingly flooded the aesthetic market, one of which includes microneedling. In microneedling, multiple fine punctures of the skin are performed with a needle to induce neocollagenesis. Microneedling has increasingly been used to treat inflammatory acne, acne scarring, photodamaged skin, and even radiation dermatitis. We present a patient with a stable history of liquid injectable silicone (LIS) given 20 years prior who developed chronic periocular and facial hypersensitivity after undergoing microneedling at a medi-spa. Long-term steroids and immunosuppressants were needed for control. The patient's severe reaction and resistance to treatment highlights the potential complications of microneedling administered by a non-medical professional in the setting of prior injectable silicone.

Carbamazepine-induced DRESS Syndrome: A Rare Delayed Hypersensitivity Reaction.

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but severe cutaneous drug hypersensitivity reaction. Delays in making a diagnosis of DRESS syndrome and lack of timely treatment may result in morbidity and mortality. However, the presentation can be misinterpreted as other pathologies because of a broad spectrum of clinical presentations, delayed reactions, and prolonged course. Despite the discontinuation of the medication that is the culprit, relapses of drug reactions frequently occur weeks to months later. Several drugs that are associated with DRESS syndrome are prescribed as psychotropic medications. This report describes the case of a patient with DRESS syndrome who was evaluated with the RegiSCAR scoring system as a "definite case," which was possibly induced by carbamazepine prescribed to treat bipolar I disorder. The young female patient was successfully treated with steroid medication after carbamazepine was discontinued. She was prescribed aripiprazole for mood stabilization without a subsequent recurrence of DRESS syndrome. We recommend that, in cases such as described here, clinicians take DRESS syndrome into consideration and provide proper timely management, particularly for patients receiving psychotropic drugs. A brief review of the literature concerning DRESS syndrome associated with psychotropic drugs and its pathogenesis are outlined and discussed.

Severe Immediate and Delayed Hypersensitivity Reactions to Biologics in a Toddler With Systemic Juvenile Idiopathic Arthritis.

Many pediatric rheumatic diseases can be safely managed with biologic therapy. Severe allergic reactions to these medications are uncommon. We report the case of a 2-year-old male with systemic-onset juvenile idiopathic arthritis and secondary macrophage activation syndrome (MAS), whose treatment was complicated by severe allergic reactions to biologics, including drug reaction with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity reaction (DIHR) likely due to anakinra, and anaphylactoid reaction to intravenous tocilizumab. These required transition to canakinumab, cyclosporine, and corticosteroids, with later development of interstitial lung disease and MAS flare needing transition from canakinumab to tofacitinib, which led to disease control. Whether lung disease is a manifestation of DRESS/DIHR to canakinumab remains unclear. High index of suspicion of hypersensitivity reactions for timely diagnosis and drug discontinuation is critical, especially in patients with active disease who might be at increased risk of these adverse events.

Risk of Chronic Rhinosinusitis With Nasal Polyps in Endotypes of Dermatophagoides pteronyssinus-Induced Rhinitis.

BACKGROUND: Observation of the natural history of two emerging endotypes of allergic rhinitis, local-sensitization rhinitis (LAR) and dual-allergic rhinitis (DAR), compared with systemic-sensitization rhinitis (AR), could improve knowledge of the role of allergy in chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: To test the hypothesis that endotypes of Dermatophagoides pteronyssinus (DP)-induced rhinitis were risk factors for CRSwNP and adult-onset asthma and to investigate whether delayed hypersensitivity to DP, assessed by atopy patch test, could be a contributing factor. METHODS: We conducted a prospective observational study over 15 years on a cohort of 999 patients: 468 with AR, 333 with LAR, and 198 with DAR. The latter endotype was characterized by the coexistence of seasonal disease caused by systemic sensitization to pollen in patients with DP-induced LAR. The study design included a physical visit; ear, nose, and throat examination with anterior rhinoscopy; skin prick test; serum-specific IgE; DP-atopy patch test; nasal allergen provocation test with DP; paranasal sinuses computed tomography scan; nasal endoscopy; and spirometry. RESULTS: During 15 years of follow-up, 194 patients developed CRSwNP with a higher rate of LAR (28.2%) and DAR (22.2%) than AR (12%). For LAR and DAR, 7.5% and 10.6% of patients developed adult-onset asthma temporally linked to CRSwNP in 68% and 71.4% of cases, respectively. A total of 858 patients with rhinitis had delayed hypersensitivity to DP. Moreover, DP-ATP was an independent predictive factor for CRSwNP and had elevated positive and negative predictive values for localized allergic disease of the nasal mucosa. CONCLUSIONS: Endotypes of DP-induced allergic rhinitis represent risk factors for CRSwNP. Patients with local-sensitization rhinitis and DAR are more at risk than those with AR. In these emerging endotypes, progression toward CRSwNP is often associated with the development of adult-onset asthma. Chronic rhinosinusitis with nasal polyps shows several possible indicators for type 2 endotype. Delayed hypersensitivity to DP is an independent predictive factor for CRSwNP.

Delayed hypersensitivity reaction after oral intake of non-ionic iodinated contrast medium.

Following intravenous contrast medium (CM) injection, a small proportion of patients acquires hypersensitivity reactions that occur either immediately or non-immediately (delayed). Although it is now claer that even oral applied CMs are able to cause adverse reactions, many radiologists as well as physicians of other disciplines, still believe that CM-application via the gastrointestinal route does not induce hypersensitivity reactions. Since this kind of misinterpretation may harm the patient, education on this topic is still necessary. Therefore, we describe a case who acquired a delayed hypersensitivity reaction following the oral intake of a non-ionic iodinated CM.

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.

Pediatric lichen planus pigmentosus possibly triggered by mercury dental amalgams.

Lichen planus pigmentosus is uncommon in childhood and its treatment is often challenging. We report a case of cutaneous lichen planus pigmentosus in a 10-year-old boy, without oral mucosal involvement, two months after an amalgam dental restoration. The diagnosis was based on the histopathological examination of a skin biopsy, the positive patch test to mercury, and the improvement after amalgam removal. Our case report suggests that metal allergy may play a role, and amalgam replacement may be followed by clinical improvement.

[Interstitial nephritis]. / Interstitielle Nephritis.

Acute interstitial nephritis (AIN) is a rare, often underdiagnosed condition and a common cause of renal failure. Drugs are the leading cause. The underlying pathophysiological condition is often a type IV hypersensitivity reaction. There are also rarer idiopathic forms, which often remain unrecognized. Additionally, the pathophysiological mechanisms are poorly understood, so that only very few promising forms of treatment are available. For some medications the overall risk is low but the side effects are relevant for the clinical routine due to the fact that they are frequently prescribed. In addition, the development of new approaches, such as immunotherapy also leads to side effects that cannot be completely predicted. For many diseases the occurrence of acute kidney injury increases the mortality and morbidity. A potentially irreversible chronic renal failure increases the incidence of further comorbidities and reduces the quality of life. Treatment is difficult and mostly empirical.

Oral Challenge without Skin Testing Safely Excludes Clinically Significant Delayed-Onset Penicillin Hypersensitivity.

BACKGROUND: Penicillins are the drug family most commonly associated with hypersensitivity reactions. Current guidelines recommend negative skin tests (ST) before re-administering penicillins to patients with previous nonimmediate reactions (NIR). OBJECTIVE: The objective of this study was to examine whether ST are necessary before re-administering penicillin to patients with NIR. METHODS: Patients with NIR to penicillins starting longer than 1 hour after last dose administration or starting any time after the first treatment day or patients with vague recollection of their reaction underwent penicillin ST. Disregarding ST results, patients were challenged with the relevant penicillins. One-tenth of the therapeutic dose followed by the full dose was administered at 1-hour interval and patients continued taking the full dose for 5 days. RESULTS: A total of 710 patients with alleged BL allergy were evaluated. Patients with a history of immediate reaction (52, 7.3%) or cephalosporin allergy (16, 2.2%) were excluded. Of the remaining 642 patients, 62.3% had negative ST, 5.3% positive ST, and 32.4% equivocal ST. A total of 617 (96.1%) patients were challenged. Immediate reaction was observed in 9 patients (1.5%): 1-positive ST, 7-negative ST, and 1-equivocal ST (P = .7). Late reaction to the first-day challenge occurred in 24 patients (4%). An at-home challenge was continued by 491 patients. Complete 5-day and partial challenges were well tolerated by 417 (85%) and 44 patients (8.9%), respectively, disregarding ST results. Thirty patients (6.1%) developed mild reactions to the home challenge regardless of their ST results. CONCLUSION: A 5-day oral challenge without preceding ST is safe and sufficient to exclude penicillin allergy after NIR developing during penicillin treatment.

Mechanisms of Drug-Induced Interstitial Nephritis.

Drug-induced acute interstitial nephritis (DI-AIN) is a drug hypersensitivity reaction (DHR) that manifests 7 to 10 days after exposure to the culprit drug. DHRs account for fewer than 15% of reported adverse drug reactions. The kidneys are susceptible to DHR because: (1) the high renal blood flow whereby antigens are filtered, secreted, or concentrated, and (2) it is a major site of excretion for drugs and drug metabolites. More than 250 different drugs from various classes have been incriminated as causative agents of DI-AIN, the third most common cause of acute kidney injury in the hospital. DI-AIN must be differentiated from drug-induced nephrotoxic acute tubular necrosis because of their differing pathophysiology and treatment. DI-AIN begins with antigen processing and presentation to local dendritic cells. The dendritic cells activate T cells, and the subsequent effector phase of the immune response is mediated by various cytokines. Incriminated antigenic mechanisms include response to a conjugation product of the drug or its metabolite with a host protein (eg, beta-lactam or sulfonamide antibiotic) or the direct binding of the drug to a particular host allele to elicit a hypersensitivity response (eg, certain anti-epileptic drugs). If the offending drug is not identified and discontinued in a timely manner, irreversible fibrosis and chronic kidney disease will occur. The core structure of each drug or its metabolite is an antigenic determinant, and the host interaction is termed the structure-activity relationship. Differing structure-activity relationships accounts for effect, hypersensitivity, and cross-reactivity among and between classes. The essence of management of DI-AIN lies with the four sequential steps: anticipation, diagnosis, treatment, and prevention. Corticosteroids are used in the treatment of DI-AIN because of their potent anti-inflammatory effects on T cells and eosinophils. Anticipation and prevention require notifying the patient that DI-AIN is an idiosyncratic, hypersensitivity reaction that recurs on re-exposure, and the drug should be avoided.

Nickel-associated delayed multiple white matter lesions after stent-assisted coil embolization of intracranial unruptured aneurysm.

Metal-induced encephalopathy after stent-assisted coil embolization is extremely rare. The present report describes two patients who presented with symptomatic intracranial parenchymal edematous lesions after stent-assisted coil embolization. A 64-year-old woman underwent stent-assisted coil embolization for a left internal carotid artery aneurysm; 21 days after the procedure she presented with right hand weakness and MRI revealed multifocal white matter lesions. Another woman aged 52 years underwent stent-assisted coil embolization for right vertebral artery aneurysm; 18 days after the procedure she presented with left-sided sensory disturbance and MRI demonstrated multiple white matter lesions. Treatment in both cases resulted in improvement of these lesions after steroid pulse therapy, and the patients had no associated morbidity 4 months after the procedures. Clinicians should monitor for neurologic symptoms and postoperative delayed radiologic parenchymal edematous changes associated with the metal allergic reaction after nitinol stent-assisted coil embolization.

Leprosy reactions in postelimination stage: the Bangladesh experience.

BACKGROUND: Leprosy reactions are immunologically mediated conditions and a major cause of disability before, during and after multidrug therapy (MDT). Little data have been published on the epidemiology of leprosy reactions in Bangladesh. OBJECTIVES: To describe the pattern and prevalence of leprosy reactions in the postelimination stage. METHODS: A descriptive retrospective cross-sectional study was carried out in Chittagong Medical College Hospital using the registered records of patients in the period between 2004 and 2013. RESULTS: Of the 670 patients with leprosy, 488 (73.38%) were males and 182 (27.37%) were females. The prevalence of reaction was in 300 (44.78%) patients with a male:female ratio of 3.55 : 1. The age-specific cumulative reaction cases at >40 years were 115 (38.33%) among all age groups. The prevalence of reaction was found to be in 166 (55.33%) patients for the reversal reaction, 49 (16.57%) for the erythema nodosum leprosum (ENL) and 85 (28.33%) for the neuritis. Borderline tuberculoid was most common (106, 35.33%)in the reversal reaction group, while lepromatous leprosy was most common (37, 12.33%) in ENL group. More than half of the patients (169, 56.33%) had reactions at the time of presentations, while 85 (28.33%) and 46 (15.33%) patients developed reaction during and after MDT, respectively. The reversal reaction group presented with ≥six skin lesions in 96 (57.83%) patients and ≥two nerve function impairments (NFIs) in 107 (64.46%) patients. The ENL was present chiefly as papulo-nodular lesions in 45 (91.84%) patients followed by pustule-necrotic lesions in four (8.16%), neuritis in 33 (67.35%), fever in 24 (48.98%), lymphadenitis in six (12.24%), arthritis in five (10.20%) and iritis in two (4.08%). Bacterial index ≥3 had been demonstrated in 34 (60.71%) patients in ENL group. CONCLUSION: The incidence of leprosy reaction seemed to be more than three times common in borderline tuberculoid (52.33%) group than in lepromatous leprosy (14%) group. Reactions with NFI and disability still occur among multibacillary patients during and after MDT. Early detection and management of leprosy reaction are very important in preventing disability and deformity, and patients should be educated to undergo regular follow-up examinations. Developing reinforced new therapies to curb leprosy reactions is crucial for improving leprosy healthcare services.

Comparison of atopic features between children and adults with eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a clinicopathological diagnosis seen in children as well as adults. Growing evidence suggests that EoE is strongly associated with atopic disorders. Presenting symptoms differ in children and adults and it is not known whether atopic features vary by age. This study was designed to compare atopic features and allergic sensitization between children and adults with EoE. We conducted a retrospective analysis of demographic and clinical data from 50 children (aged 2-18 years) and 50 adults (aged 21-75 years) with a biopsy-proven diagnosis of EoE referred to our allergy clinic. Data regarding patient characteristics, history of atopic diseases, and allergy test results were collected for analysis. The majority of children and adults were white and male patients. When compared with adults, a higher percentage of children had a history of asthma (52% versus 24%; p < 0.05). There was no statistically significant difference between adults and children regarding history of allergic rhinitis, atopic dermatitis, immunoglobulin E-mediated food allergy, and family history of atopy. There was no statistically significant difference between children and adults regarding immediate-type sensitization to foods and aeroallergens. Compared with adults, a higher percentage of children showed a positive reaction to one or more foods on patch testing (62% versus 31%; p = 0.01). A high prevalence of comorbid atopic diseases and sensitizations to food and environmental allergens was seen in both children and adults. Children had a significantly higher rate of asthma and positive patch test to foods compared with adults.

The development of a murine model for Forcipomyia taiwana (biting midge) allergy.

BACKGROUND: Forcipomyia taiwana (biting midge) allergy is the most prevalent biting insect allergy in Taiwan. An animal model corresponding to the human immuno-pathologic features of midge allergy is needed for investigating the mechanisms and therapies. This study successfully developed a murine model of Forcipomyia taiwana allergy. METHODS: BALB/c mice were sensitized intra-peritoneally with midge extract on days 0, 7, 14, 21 then intra-dermally on days 28, 31 and 35. Serum midge-specific IgE, IgG1, and IgG2a were measured every 14 days by indirect ELISA. The mice were challenged intradermally with midge extract at day 40 and then sacrificed. Proliferation and cytokine production of splenocytes after stimulation with midge extract were determined by MTT assay and ELISA, respectively. The cytokine mRNA expression in response to midge stimulation was analyzed by RT-PCR. RESULTS: Serum IgE, total IgG, and IgG1 antibody levels against midge extract were significantly higher in the midge-sensitized mice than in the control mice. After the two-step sensitization, all mice in the midge-sensitized group displayed immediate itch and plasma extravasation reactions in response to challenge with midge extract. Skin histology from midge-sensitized mice showed marked eosinophil and lymphocyte infiltrations similar to that observed in humans. Stimulation of murine splenocytes with midge extract elicited significant proliferation, IL-4, IL-10, IL-13 and IFN-γ protein production, and up-regulation of mRNA in a dose-dependent manner in the midge-sensitized group, but not in the control group. CONCLUSIONS: A murine model of midge bite allergy has been successfully developed using a two-step sensitization protocol. The sensitized mice have very similar clinical and immunologic reactions to challenge with midge proteins as the reactions of human to midge bites. This murine model may be a useful platform for future research and the development of treatment strategies for insect bite allergy.

Effects of inhaled corticosteroids on the dual asthmatic response.

Bronchial asthma patients develop various asthmatic response types to allergen challenge, such as immediate asthmatic response (IAR), late asthmatic response (LAR), or dual asthmatic response (DAR), the latter being a combination of an early phase (IAR) and a late phase (LAR). This study was designed to investigate (1) the features of the DAR thus identifying it as either a genuine two-phase compact clinical entity or a simultaneous appearance of two independent asthmatic response types, IAR and LAR, and (2) the protective effects of inhaled budesonide (BUD) on the DAR. Two protection tests (PTs) with BUD and a placebo (PL), in a single dose of 800 micrograms, were performed on 48 DAR patients, divided into four groups. Each test consisted of two treatments, one given 30 minutes before and the other at 1, 2, 3, or 4 hours after the bronchial challenge with allergen. The study design was randomized, double-blind, double-dummy, placebo-matched, crossover. A single dose of inhaled BUD did not affect the early phase (IAR) when applied 30 minutes before the challenge (p > 0.2), whereas it significantly prevented the late phase (LAR) when administered either 30 minutes before (p < 0.001) or up to 4 hours after the allergen challenge (p < 0.05). The different protective effects of BUD on both of the phases of DAR would suggest that this response does not exist as a compact clinical entity, but it may be a manifestation of two independent simultaneous responses, IAR and LAR, because of different immunologic mechanisms. Inhaled corticosteroids in a single dose administered shortly before or up to 4 hours after the allergen exposure contribute significantly to the prevention of the LAR, whereas they are unable to affect the IAR.