Serum Sickness Reaction Research Articles

P1058 Safety and effectiveness of subcutaneous infliximab formulation in difficult-to-treat Crohn’s Disease patients with previous exposure to intravenous infliximab: A case-series

Abstract Background Despite the increased therapeutic armamentarium for Crohn’s Disease (CD), a relevant proportion of patients fail to respond to multiple therapies and ultimately require surgery. Intravenous (IV) infliximab (IFX) reinduction after a drug holiday is associated with reduced drug efficacy and both acute and delayed infusion reactions, due to immunological mechanisms and development of antidrug antibodies, and is currently contraindicated. Recently, a subcutaneous (SC) formulation of IFX has been developed, demonstrating equal efficacy and safety with a better immunogenicity profile (i.e. biobetter). This study evaluated the safety and effectiveness of retreatment with SC IFX in CD patients previously exposed to IV IFX. Methods Data were retrospectively collected through the Electronic Medical Record. Patients included were IV IFX-experienced and subsequently treated with SC formulation after a period of drug holiday ≥ 1 year. Collected data included demographics, disease characteristics and activity, current and previous treatment, adverse events, and reasons for previous anti-TNFα discontinuation. Results 12 patients with CD were included. Mean age at diagnosis and disease duration were 16.2 (±6.7 SD) and 15.6 years (±7.4 SD) respectively. All patients had failed at least three biologics, and 7 patients underwent previous surgery. The main reason for IV IFX discontinuation was secondary failure (4 patients, 33%). Median time from IV suspension to SC treatment start was 106.5 months (IQR=98.5) with median treatment duration of 24 (IQR=37.5) and 7.5 (IQR=4.5) months for IV and SC IFX respectively. SC IFX was introduced as an add-on dual biologic therapy in 5 patients (3 treated with Ustekinumab, 2 with Vedolizumab). Overall, one adverse event with SC IFX was reported: a grade 2 serum sickness reaction, which led to treatment discontinuation. No immediate allergic reactions were reported. 10 patients had at least 6 months of follow-up. Median HBI reduction at 6 months from SC IFX begin was significant (p<0.05), varying from 7.5 (IQR=3.5) to 3.5 (IQR=4). C-Reactive Protein levels normalized in 3 (38%) patients, reduced in 2 (25%), and remained stable in 3 (38%). Faecal calprotectin normalized in 2 (29%) patients, reduced in 1 (14%), remained stable in 2 (29%), and increased in 2 (29%). At 6 months steroid free remission rate (HBI≤4) was 66%. Conclusion This is the first report showing that SC IFX reinduction in CD patients previously exposed to IV IFX is safe, even after a long drug holiday. It might be regarded as a rescue option in difficult-to-treat patients, either alone or combined with other immunosuppressants.

Serum Sickness Reaction to Rituximab with Positive Immediate Intradermal Skin Test: A Case Report

Background: Rituximab is a chimeric murine/human monoclonal antibody against CD20. It can be used off-label in autoimmune diseases. Its administration can lead to several types of reactions; immediate infusional reactions and also delayed reactions like Serum Sickness Reaction (SSR). Case presentation: This is a case study of a 48 years old woman diagnosed with rheumatoid arthritis/systemic lupus erythematosus who developed refractory immune thrombocytopenic purpura and received treatment with rituximab. After treatment, she developed erythematous-violet lesions accompanied with fever of 38ºC, dyspnea, joints arthralgia and edema. In the emergency department, hypotension, fever, dyspnea, and shivering were observed, for which, intramuscular epinephrine, intravenous corticosteroids, antibiotics and salbutamol nebulization were administered. In our allergy unit, we performed an intradermal test (IDT) with rituximab (1mg/ml), which was positive at immediate (20min) and late (48h) reading. Based on the clinical manifestations and test carried out, she was diagnosed with rituximab SSR. We also studied the molecular mass of the IgE-reactive proteins present in rituximab product by SDS-PAGE Immunoblotting method according to Laemmli, in reducing and non-reducing conditions, with high sensitivity and using three different polyvinylidene difluoride (PVDF) membrane blocking substances (skimmed cow's milk, fish collagen and egg white). We did not detect IgE-binding to rituximab product. Conclusion: The pathogenesis of SSR is not well known. The patients after reinfusion can develop immediate reactions suggesting involvement of IgE hypersensitivity. Nevertheless, there are patients who tolerated reinfusion. Further studies and assays are needed for a better understanding of these reactions and to lead to a safer re-administration if needed.

M035 SERUM SICKNESS-LIKE REACTION TO A VACCINATION: A CASE REPORT

Serum sickness-like reaction (SSLR) is an adverse reaction to an agent, typically a medication, that presents with symptoms similar to serum sickness reaction (SSR). Here we discuss a rare SSLR after routine vaccination administration.

Washed Equine Platelet Extract as an Anti-Inflammatory Biologic Pharmaceutical

Mammalian platelets participate in the immediate tissue injury response by initiating coagulation and further promoting tissue injury mitigation and repair. The latter properties are deployed following platelet release of presynthetized morphogens, cytokines, and growth and chemotactic factors, which launch a tissue regenerative, angiogenic, and anti-inflammatory program. Several blood-derived biologic products, like platelet-rich plasma (PRP) and platelet lysate (PL), are currently on the market to allow proper healing and tissue regeneration. However, not all growth factors are released from the platelets and the final products contain plasma proteins such as albumin, fibrinogen, complement, and immunoglobulins, increasing the risks of serum sickness or allergic reaction. To address this problem, we developed a new platelet extract where equine blood platelets are concentrated, washed, and thereafter lysed by detergent Triton X-114. Distinct from PRP, this extract is devoid of albumin, fibrinogen, and immunoglobulins and is 266-fold enriched in platelet-derived growth factor content relative to PRP. Washed equine platelet extract (WEPLEX) is amenable to lyophilization without loss of biological activity. In vitro, WEPLEX significantly inhibits human and equine T cell proliferative response to phytohemagglutinin and also polarizes murine CD45+/CD11b+ peritoneal macrophages to an IL-10+ M2-like phenotype. In vivo, WEPLEX substantially improves clinical outcome of murine experimental dextran sulfate sodium colitis. We propose that equine-sourced, zoonosis-free WEPLEX may serve as an anti-inflammatory biological therapy across mammalian species.

Rituximab Hypersensitivity: From Clinical Presentation to Management

Rituximab is a chimeric monoclonal antibody (mAb) against CD20 molecule which is expressed on human B cells. It has been used for the treatment of various lymphoid malignancies, lymphoproliferative diseases, and rheumatologic disorders. Rituximab is generally well tolerated. However, increased use of rituximab has been associated with hypersensitivity reactions (HSRs), which can be classified as infusion-related, cytokine-release, type I (IgE/non-IgE), mixed, type III, and type IV reactions. Immediate infusion-related reactions to rituximab are quite common and decrease in frequency with subsequent infusions. However, in about 10% of patients, severe infusion-related reactions develop, which prevent its use. Some of the immediate infusion reactions are due to a cytokine-release but some reactions raise concerns for type I (IgE/non-IgE) hypersensitivity. Recent studies have shown the presence of serum anti-rituximab antibodies, either represented by the IgG or IgE isotype. In some cases, clinical manifestations of IgE-mediated reactions and cytokine-release reactions partially overlap, which is called a mixed reaction. Classified as Type III reaction, rituximab-induced serum sickness reactions have been reported in patients with autoimmune diseases and hematological malignancies. The classic serum sickness triad (fever, rash, and arthralgia) has been observed in patients mainly with an underlying rheumatologic condition. Severe delayed type IV hypersensitivity reactions including non-severe maculopapular rash to severe reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis have been rarely reported following rituximab injection. Comprehensive reviews focused on rituximab-induced HSRs are scarce. We aimed to review clinical presentations, underlying mechanisms of rituximab hypersensitivity, as well as management including rapid drug desensitization.

Serum sickness reaction with skin involvement induced by bee venom injection therapy

Bee venom injection therapy is an alternative treatment sometimes used for chronic inflammatory diseases, including rheumatoid arthritis and multiple sclerosis, to reduce pain. Several chemical components of bee venom have anti-inflammatory effects, and apitoxin, one of the mixed components, has been used for pain prevention therapy. However, there have been no large-scale investigations regarding the efficacy or side effects or apitoxin. In this study, a case of serum sickness reaction that developed after receiving bee venom injection therapy is reported.

Great learning, much networking, and friendship.

Asia Pacific Allergy, the official journal of Asia Pacific Association of Allergy, Asthma, and Clinical Immunology (APAAACI), is proud of being one of the media partners of World Allergy Congress (WAC) 2015 in Seoul, Korea, which was very successful congress: great learning, much networking, and friendship in the Asia Pacific region and beyond. APAAACI also successfully held a sister society symposium during WAC 2015: important but neglected issues in allergy. The topics were 'eosinophilic esophagitis, gastroenteritis and colitis', 'angioedema without ur ticaria', and 'important but neglected food allergens: lessons from Asia'. Next year, we will have the most important congress in our region: the Joint Congress of APAAACI and Asia Pacific Association of Pediatric Allergy, Respiratory, and Immunology (APAPARI) in Kuala Lumpur, Malaysia during 18th-20th October, 2016 (http://www.apaaaci-kl2016.org). We are ready to invite participants from all over the world. International Classification of Diseases (ICD) is the global health information standard to capture mortality and morbidity statistics maintained by the World Health Organization (WHO) [1]. ICD 10th edition (ICD-10) is currently used by the majority of countries all around the world except some countries such as the United States and Australia which use the 9th edition [1]. However, the allergic and hypersensitivity conditions are not adequately classified and coded in the ICD-10 [2]. An international collaboration of Allergy Academies including first the World Allergy Organization, the American Academy of Allergy Asthma and Immunology and the European Academy of Allergy and Clinical Immunology has been coordinating tremendous efforts since 2013 to provide a better classification of these disorders in the new ICD-11 [1]. APAAACI as well as the Latin American Society of Allergy, Asthma and Immunology, and the American College of Allergy Asthma and Immunology joined the international collaboration for its importance. Tanno et al. [1] describe the journey to make the allergic and hypersensitivity conditions visible in the ICD-11 beta draft and the need of changes in the ICD framework. Readers of this journal will find the original articles on the treatment adherence and quality of life among adults with chronic urticaria in Singapore [3], and the attitudes, practices on allergic rhinitis of generalists and specialists in Philippine National Capital Region [4]. The readers will also find the first study on the pattern of anaphylaxis in Saudi Arabia [5] and the interleukin-10 and interleukin-5 balance in patients with active asthma, those in remission, and healthy controls from Japan, which showed a similar result from a murine asthma model of immunotherapy [6]. This issue contains an educational case report of serum sickness reaction with skin involvement induced by bee venom injection therapy from Korea [7], and a pilot study on the use of Yin Qiao San in children with conventional antipyretic hypersensitivity from Singapore [8]. Both of the articles are dealing with 'the traditional or complementary medicine and allergy' in our region.

A148: A Multi‐Center, Double‐Blind, Randomized‐Withdrawal Trial of Subcutaneous Golimumab in Pediatric Patients With Active Polyarticular Course Juvenile Idiopathic Arthritis Despite Methotrexate Therapy: Week 48 Results

Background/Purpose:To assess efficacy and safety of SC golimumab (GLM) in polyarticular pediatric juvenile idiopathic arthritis pts (aged 2 to <18 yrs) with active arthritis despite MTX for ≥3 months.Methods:In GO‐KIDS, a 3‐part randomized double‐blind, PBO‐controlled, withdrawal trial in pts with active JIA with a polyarticular course (≥5 active joints) and disease duration of ≥6 months despite current MTX (10–30 mg/m2/wk). In Part 1(wk 0–12), all pts received open‐label (OL) 30 mg/m2 GLM SC (max 50 mg) q4 wks with stable MTX dose. At wk 16, pts with ACR JIA 30 response entered Part 2 (wk 16–48). In Part 2, pts were randomized to continue GLM or switch to PBO q4 wks. Upon Part 2 completion at wk 48 or ACR JIA flare in Part 2, pts received OL GLM in Part 3. Primary endpoint was proportion of ACR JIA 30 responders at wk 16 without a JIA flare in Part 2 using wk 16 as baseline measurement. Secondary outcomes were ACR JIA 30/50/70/90 response rates and inactive disease rates at wk 16 and wk 48 by group and safety.Results:173 pts (Caucasian 87.9%, 75.7% females; age [median/range] 12 yrs/2–17 yrs) with moderately active disease were enrolled (Table ); 19 (11%) were d/c in Part 1 (lack of efficacy n = 14, AE n = 4, withdrawal of consent n = 1). In Part 1, 151 of 173 (87.3%) achieved an ACR JIA 30 response and 36.1% inactive disease status (Table ). There were 154 pts randomized double‐blind in Part 2 (PBO n = 76; continued GLM n = 78). At the end of Part 2, no significant differences between groups in JIA ACR non‐flare rates and trial did not meet primary endpoint [PBO‐grp vs. GLM‐grp: 52.6% vs. 59.0%, p = 0.41) nor were there differences for major secondary endpoints (Table 2). In contrast, sustained response in both groups (PBO, GLM) relative to wk 0 (Table 1 and 2). 6.5% (10 of 154) of pts d/c therapy after wk16 through wk 48. Through wk 48, AEs, serious AE (SAE), and serious infections were reported in 87.9%, 13.3%, and 2.9% of all randomized pts, respectively. Most common SAE was JIA exacerbation. No deaths, active TB or malignancies were reported (1). GLM‐treated pt experienced SAE of toxic hepatitis and 1 had SAE of hepatic enzyme increase. One pt switched from PBO to GLM experienced SAE of serum sickness reaction, resulting in GLM d/c. Proportion of pts with ≥1 injection site reaction was 8.1%. None of the reactions were serious, severe, or led to GLM d/c. At Baseline (All enrolled patients n=173) At wk16 (All randomized patients prior to randomization, n=154) At wk48 Values are medians (interquartile range) PBO + MTX (n=76) GLM + MTX (n=78) Physicians global assessment 5.40 (3.90; 7.00) 0.50 (0.10; 1.30) 0.30 (0.00; 1.00) 0.30 (0.00; 1.30) Patient/parent global assessment 4.50 (2.80; 6.10) 0.90 (0.30, 2.30) 0.60 (0.20; 1.65) 0.45 (0.10; 1.70) Number of active joints 12.0 (8.0; 18.0) 1.0 (0.0; 3.0) 1.0 (0.0; 3.0) 0.0 (0.0; 2.0) Number of joints with limited range of motion 8.0 (6.0; 15.0) 1.0 (0.0, 4.0) 0.5 (0.00; 4.0) 1.0 (0.0; 3.0) Physical function by CHAQ 0.94 (0.38; 1.50) 0.25 (0.00; 0.75) 0.13 (0.00; 0.63) 0.00 (0.00; 0.63) ESR (mm/hr) 16.00 (8.00; 28.00) 9.00 (5.00; 19.00) 9.50 (5.00; 16.50) 10.00 (5.00; 19.00) Methotrexate (mg/wk) 15t(5.00; 30.00) 15t(5.00; 30.00) 15t(5.00; 30.00) 15t(5.00; 30.00) ACR JIA response and flare rates PART 1 [WK 0ndash;16] Percentage of ACR JIA responders at end of Part 1 [WK 16] (n = 173) JIA ACR 30 87.3%t(151) JIA ACR 50 79.2%t(137) JIA ACR 70 65.9%t(114) JIA ACR 90 36.4%t(63) Inactive disease 36.1%t(62) PART 2 [WK 16ndash;48] Percentage of ACR JIA 30 responders without flare in Part 2 (n = 154) PBO + MTX (n=76) 52.6%t(40) P=0.41 GLM + MTXt(n=78) 59.0%t(46) Inactive disease 21.6%/39.7% Clinical remission 11.8%/12.8% Percentage of ACR JIA responders at WK48 (vs. wk0) by treatment in Part 2 [PBO +MTX/GLM +MTX] JIA ACR 30 95.9%/89.0% JIA ACR 50 91.8%/86.3% JIA ACR 70 78.1%/78.1% JIA ACR 90 53.4%/56.2% Pts experiencing flares/those considered treatment failures due to protocol violations are considered ACR non‐responders from the flair/failure visit to wk 48 Observed dataConclusion:JIA pts with active polyarticular dis ease demonstrated rapid response to GLM with 16 wks of OL treatment, resulting in inactive disease in 36% of the pts. The lack of differences in flare rates between GLM and PBO arms from wk 16 to 48 among OL GLM responders needs further evaluation. Safety profile was acceptable and injections well tolerated.

Infliximab Retreatment in Inflammatory Bowel Disease: A Single-center Experience

Purpose: Infliximab is an anti-tumor necrosis factor alpha (anti-TNF) agent used in Crohn's disease (CD) and ulcerative colitis (UC). Early data on episodic treatment with infliximab demonstrated increased risk of allergic reactions and reduced efficacy after interruptions in therapy. We aimed to characterize response rates and adverse events among patients with inflammatory bowel diseases (IBD) treated with a standardized infliximab retreatment protocol after a drug holiday. Methods: We retrospectively analyzed all cases of infliximab retreatment at a single tertiary care center, including individuals with both CD and UC, between 2011 and 2012. Re-treatment protocol included: prednisone taper, intravenous hydrocortisone, extended infusion duration, and initiation of concomitant immunomodulator when possible. We assessed the rationale for first discontinuation of infliximab, time interval since last infusion, adverse events associated with reinduction therapy, and overall response rates; defined as a.) clinical response with continuation of infliximab beyond induction therapy, and b.) clinical response with continuation of infliximab beyond 14 weeks. Results: A total of 19 patients underwent reinduction therapy with infliximab (n=17 with CD, n=2 with UC). Ages ranged from 20 to 72 years (mean 35.2 years), nine (47.4%) were female, five (26.3%) were smokers, and 13 (68.4%) had prior surgery. The interval between initial treatment and reinduction with infliximab ranged from 1 to 9 years (mean 4.7 years), and 15 (78.9%) were on other forms of immunosuppression prior to retreatment. A total of 13 (68.4%) had tried an alternate anti-TNF. The most common reason for discontinuation of first course of infliximab was patient preference (n=9, 47.4%). A total of 13 (68.4%) responded to reinduction at 6 weeks, with 12 (63.2%) meeting the endpoint of clinical response at week 14. Rates were higher for response at week 6 and 14 among those started on concomitant immunosuppression (72.7% and 63.6% respectively, as compared to 62.5% and 62.5% for those on no immunomodulator). There were three incidents of serious adverse events (SAEs), including two infusion reactions and one delayed serum sickness reaction. Of those with SAES, two (66.7%) had previously stopped infliximab due to preference, and one (33.3%) due to loss of response. Of these, two (66.7%) were on concomitant immunomodulators. Conclusion: We observed high re-treatment response rates with infliximab re-induction therapy in a group of individuals who largely initially stopped infliximab due to preference, although a substantial rate of severe adverse events occurred. Retreatment protocols should only be attempted with caution in a controlled setting.

Rituximab Combined with 3 Cycles of High Dose Dexamethasone Improves Response in Patients with Newly-Diagnosed, Persistent, and Chronic Immune Thrombocytopenia (ITP)

Abstract 3345 Introduction:Adults with newly-diagnosed ITP usually respond to initial prednisone treatment but typically relapse upon its tapering or discontinuation. Patients with persistent/chronic ITP treated with prednisone have an even lower likelihood of a lasting response. Dexamethasone (Dex) has been reported to have curative effects in newly diagnosed patients. Rituximab (Ritux) is thought to be effective in newly diagnosed patients but only yields a long term response in 20–25% of chronic ITP patients. Recently, newly-diagnosed previously-untreated patients received a single cycle of 4 days of Dex 40 mg/day or 4 infusions of 375mg/m2 Ritux combined with Dex. R+Dex in that study yielded a 63% response at 6 months and 34% at 3 years without additional treatment, which was more effective than Dex alone. Methods:Given the additive activity of these two drugs, 59 patients at Weill-Cornell Medical College with ITP of any duration were treated with 4 infusions of 375mg/m2 rituximab and three 4-day cycles of high-dose dexamethasone at 2-week intervals (R+Dex). Optimal response was assessed after 8 weeks as complete remission (CR, platelet count≥100×109/L) or partial remission (PR, 50–100×109/L). Long term outcome was also assessed and both were related to clinical variables. Data was compared to that of rituximab alone using the previous study from our center (Cooper BJH 2004). AIPF values were gathered prior to treatment until 12 weeks after treatment initiation. Results:All but 5 patients had been previously treated with a median of 2 therapies (range 0–7). Assessing optimal response achieved, 44/59 (74.5%) patients responded, with a CR in 64% and a PR in 10%. Only 1/28 patients with ITP < 1yr relapsed (at 12 months). Duration of ITP less than 24 months (p=0.0426) and being an adult predicted better optimal responses (p=0.0154).Of the original 44 responders, 33/59 patients [74% of responding adults and 77% of responding children] had ongoing responses at last f/u at a median of 14 months without the need for further ITP treatment (Figure). Eleven of the 44 relapsed (25%) including the one at 12 months mentioned above. Two additional patients relapsed who had ITP for 1–2 years prior to R+Dex and the other 8 patients who relapsed had ITP for greater than 3 years, 5 of whom had had ITP for 6+ years.Additionally, 53 of the 59 patients were genotyped for β1-tubulin gene. Of the ten patients with heterozygote genotypes, 9 (90%) responded to combination R+Dex treatment and 32 of the 43 wild type patients responded to treatment (p=0.46). There were no overt differences in the AIPF levels over the first 12 weeks between responders and non-responders. No AIPF differences were seen between the heterozygote and wild type patients for the β1-tubulin gene.In our previous study of rituximab alone, 54% of the 57 adult patients responded to rituximab treatment, compared to 86% of the 36 adult patients who responded to R+Dex treatment. R+Dex responders were found to have a longer duration of lower B cell numbers when compared with responders to rituximab alone, preliminarily demonstrating the additive effect of the 2 medications.Adverse events related to R+Dex generally were mild but one patient was hospitalized with colitis, two others experienced serum sickness reactions and dexamethasone was sometimes difficult to tolerate. Conclusion:R+Dex is active and appears clearly superior to rituximab alone in this single-center, pilot study. Adults and patients who have a shorter duration of ITP (< 1–2 years) fare better but children and those with a longer duration of ITP still have a 1/3 chance of a lasting response. The absence of homozygote β1-tubulin SNP’s in this population made interpretation of its effect difficult. High dose Dex is not always easy to tolerate but helps maintain the count during the treatment course of 32 days. A prospective, randomized trial is planned. [Display omitted] Disclosures:Basciano:Alexion: Consultancy. Ghanima:Roche Pharmaceuticals: Research Funding. Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

Serum sickness-like syndrome after immunoglobulin M-enriched polyclonal immunoglobulin

Medication reactions, infectious etiologies, graft vs. host disease, serum sickness, and serum sickness-like reaction are the most common conditions that cause skin fever and rashes in immunosuppressed patients. In addition to this long list of diseases, severity of the primary disease and deterioration in the patient's health status can make the diagnosis difficult. Furthermore, cutaneous and histological similarities in these mentioned conditions can be confounding. Here, we present a 16-year-old male patient with acute myeloid leukemia suffering from skin rashes and fever that appeared following a chemotherapy course leading to bone marrow suppression. We aim to discuss the differential diagnosis and share the diagnostic challenges that we already have experienced after immunoglobulin M-enriched polyclonal immunoglobulin.

Analysis of adverse reactions and its nursing countermeasures in Crohn's disease treated with infliximab

Objective To explore the adverse reactions of Infliximab and its relevant nursing countermeasures. Methods The clinical data from 13 patients were collected. Condition of adverse reaction was observed and nursing countermeasures were conducted. Results A total of 65 times of Infliximab-infusion were conducted in the 13 patients. Serum sickness reaction appeared 6 times, infection occurred 7 times and liver dysfunction occurred 2 times. According with those adverse reactions, nursing interventions including standard medication,infection prevention and observation were conducted. Conclusions The highest incidence of all adverse reactions is infection followed by serum sickness reaction. The key of nursing care is prevention and care of infection, observation of serum sickness reaction and liver function in order to insure effectiveness and safetyduring treatment. Key words: Crohn's disease; Infliximab; Adverse reactions; Nursing

Angioedema caused by bupropion treatment

Reports of urticaria and rash with bupropion are common, with an estimated incidence of 1-4%. Serious adverse reactions, including seizures and angioedema occur less commonly, but may be dose related. Rarely patients present with fever, arthralgia and myalgia resembling a serumsickness reaction. A case of a 30 year-old man presenting with a rash, angioedema, and arthralgia 19 days after commencing bupropion treatment to aid smoking cessation is described. Treatment with antihistamines and steroids, resulted in improvement within 3 hours, and complete resolution after 3 days. Management also included identifying and discontinuing the causative agent. Recent concerns over neuropsychiatric side effects of bupropion are highlighted. The literature is reviewed and recommendations for safer prescribing discussed.

Extra Renal Manifestations Of Acute Hepatitis “B” Virus Infection

Approximately 400 million people are chronic HBV carriers worldwide. The spectrum of chronic HBV infection ranges from asymptomatic hepatitis B surface antigen carrier state to chronic hepatitis with progression to cirrhosis and end-stage liver disease and carcinoma of liver. Several extrahepatic syndromes are associated with acute HBV infection like serum sickness reaction, polyarteritis nodosa due to ischemia of vasa nervosum of the nerves and glomerulonephritis. We present here the a case of a 38-year male with end stage renal disease due to diabetic nephropathy on maintenance haemodialysis with acute hepatitis B virus infection with extra hepatic, extra renal immunological manifestations.

Cetirizine‐induced anaphylaxis: a rare adverse drug reaction

A 30-year-old female patient was prescribed oral cetirizine 10 mg at night for the treatment of chronic idiopathic urticaria. Within 15 min of oral ingestion of cetirizine 10 mg, the patient experienced severe pruritis and urticarial eruption all over the body. She developed severe breathlessness and was unable to speak. The patient became restless, disoriented and lost consciousness. She was rushed to the emergency room. Her pulse and blood pressure were unrecordable and air entry was decreased in both lungs. A diagnosis of anaphylactic shock was made. Cardiopulmonary resuscitation was started and epinephrine 0.5 mg of 1:10 000 was given intravenously. She also received intravenous crystalloid. After approximately 30 min, the pulse rate increased to 100 beats min−1 and blood pressure to 124/80 mmHg. Hydrocortisone 100 mg was then given intravenously. The patient remained haemodynamically stable. She had no previous history of allergic reactions to any drug. There was no history of concomitant use of any other medication or alcohol intake, nor of previous exposure to cetirizine or any other piperazines. The patient received only one oral dose of cetirizine. The causality assessment of the adverse drug reaction (ADR) by Naranjo Algorithm was 7, putting it in a ‘probable’ ADR category [1]. The ADR was reported to the peripheral pharmacovigilance centre of the state under the National Pharmacovigilance Programme, India. Histamine-1 (H1) receptor antagonists have an established and valued place in the symptomatic treatment of various immediate hypersensitivity reactions. Nevertheless, it is a little known fact that although H1 receptor antihistamines are used in the treatment of drug-mediated allergy, they themselves can provoke allergic reactions. Although they have shown good tolerance in humans, no currently available antihistaminic is completely free from potential adverse effects under all circumstances [2]. There have been several reports of cetirizine causing multiple fixed drug eruptions and urticaria [3–6]. However, anaphylaxis due to oral ingestion of cetirizine is extremely rare. All the available H1 receptor antagonists are reversible competitive inhibitors of the interaction of histamine with H1 receptors. Cetirizine, a human metabolite of hydroxyzine, is a selective H1 receptor antagonist belonging to the second-generation piperazine class. Cetirizine is well absorbed orally and is excreted in the urine mainly in the unmetabolized form. Many drug reactions attributable to allergic phenomena respond to therapy with H1 antagonists, particularly those characterized by itch, urticaria, and angio-oedema; serum-sickness reactions also respond to intensive treatment. In humans, during hypersensitivity reactions, oedema formation and itch are effectively suppressed by histamine antagonists. Other effects, such as hypotension, are less well antagonized. This may be explained by the participation of other types of histamine receptors and by effects of other mast cell mediators such as prostaglandins, eicosatetratenoic acid derivatives, leukotrienes and others. Prophylactic treatment with a H1 antagonist may reduce symptoms of the hypersensitivity reaction to a tolerable level. However, in a patient with known hypersensitivity to cetirizine, repeat administration of cetirizine or hydroxyzine is contraindicated [7]. The exact mechanism by which cetirizine can cause anaphylaxis is not known, but may be linked to the piperazinic ring that is well known as an antigen [8]. Also, cetirizine has no effect on mast cell activation [9]. In conclusion, even though the safety of cetirizine has been widely established, there is an extremely rare chance of it causing anaphylaxis. Cetirizine may be used in the treatment of anaphylaxis. Hence this possibility (and similarly with other antihistamines) needs to be considered in the differential diagnosis of a patient not responding to treatment or deteriorating. Cetirizine may also mimic the underlying disease that led to its intake [10].

Transfusion‐induced serum sickness

Transfusion-induced serum sickness reactions are rarely reported in the literature. The Type III hypersensitivity reaction to heterologous proteins involves deposition of complement and immune complexes in small vessel walls resulting in a leukocytoclastic vasculitis. A case of a multiply transfused patient with several episodes of serum sickness reactions is presented. A 61-year-old man with myelodysplastic syndrome type refractory anemia presented with fever, rash, and polyarthralgia 5 days after transfusion of red blood cells (RBCs). By transfusing plasma-free "washed" RBCs, similar serum sickness reactions were avoided. Laboratory investigation showed an increase of serum creatinine, hematuria, and proteinuria. Levels of circulating immune complexes immunoglobulin G and immunoglobulin M were increased. Hypocomplementemia could not be demonstrated. Histopathologic examination of the skin showed leukocytoclastic vasculitis, compatible with serum sickness. The importance of early recognition of transfusion-induced serum sickness reactions is emphasized, because this can reduce unnecessary morbidity from this unusual complication of transfusion. To prevent this type of transfusion reaction, patients who experienced serum sickness-like reactions after transfusion should only receive plasma-free washed RBCs.

A prospective and randomized study of two conditioning regimens in treatment of severe systemic autoimmune diseases with autologous peripheral blood stem cell transplantation

To investigate the differences in immune reconstitution, hematopoietic reconstitution, efficacy, and complication between the two conditioning regimens with or without total body irradiation (TBI) in patients with refractory and severe autoimmune diseases (AID) who receiving autologous peripheral blood stem cell transplantation (APBSCT). Thirty-two AID patients, 5 males and 27 females, aged 29 (15 - 49), underwent APBSCT. The CD34(+) cells were mobilized with cytoxan (CTX) + granulocyte-colony stimulating factor (G-CSF) and selected by clinical magnetic activated cell sorting (CliniMACS). The conditioning regimen included CTX + antithymocyte globulin (ATG) in 11 patients and CTX + TBI in 21 patients. All the patients were followed up for more than 12 months. The median time of granulocyte recovery were 11 and 9 days in the CTX + TBI and CTX + ATG groups respectively (P = 0.003), the median time of platelet recovery were 13 and 8 days respectively (P = 0.001). In both groups, the lymphocyte subsets were recovered with the inverted CD4/CD8 ratio 12 months after transplantation. Relapse was seen in 3 cases of the CTX + TBI group (14.3%), and 2 cases of the CTX + ATG group (18.2%), and the rest of patients remained free of AID. During transplantation incidence of bacteria infection occurred in 5 of the 21 cases in the CTX + TBI group (23.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively; viral infection occurred in 1 of the 21 cases of the CTX + TBI group (4.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively. The number of radiated parotitis was 4 among the 21 patients of the CTX + TBI group (19%) and was 3 among the 12 patients of the CTX + ATG group (25%). Serum sickness reaction occurred in 3 of the 12 patients of the CTX + ATG group (25%). Bacterial and viral infections were cured soon after antibacterial or antiviral therapy, no fatal bleeding occurred due to thrombocytopenia in both groups. The conditioning regimen of TBI + CTX delays the hematopoietic reconstitution compared with the ATG + CTX regimen in treating AID. The regimen of CTX + TBI can be better tolerated, but there are no significant differences in efficacy and immune reconstitution among these two regimens.

Severe Serum Sickness Reaction to Oral and Intramuscular Penicillin

Serum sickness is a type III hypersensitivity reaction mediated by immune complex deposition with subsequent complement activation, small-vessel vasculitis, and tissue inflammation. Although the overall incidence of serum sickness is declining because of decreased use of heterologous sera and improved vaccinations, rare sporadic cases of serum sickness from nonprotein drugs such as penicillins continue to occur. Drug-induced serum sickness is usually self-limited, with symptoms lasting only 1-2 weeks before resolving. We report an unusual case of a severe and prolonged serum sickness reaction that occurred after exposure to an intramuscular penicillin depot injection (probable relationship by Naranjo score) and discuss how pharmacokinetics may have played a role. Clinicians should be familiar with serum sickness reactions particularly as they relate to long-acting penicillin preparations. Accurate diagnosis in conjunction with cessation of drug exposure and prompt initiation of antiinflammatory treatment with corticosteroids can produce complete recovery

8. Drug allergy

Drug reactions can be considered as being either predictable or unpredictable. A predictable reaction would be the result of the pharmacologic action of the medication. An unpredictable reaction might be idiosyncratic, might be drug intolerance, or might have or imply an immunologic basis, such as being IgE mediated. Immediate reactions that are not IgE mediated can be considered as pseudoallergic (non-IgE-mediated mast cell activation). This review will discuss allergic and immunologic reactions to immunomodulators, penicillins and cephalosporins, sulfonamides, aspirin, and nonselective nonsteroidal anti-inflammatory drugs and consider the serious drug-related conditions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The field of drug "allergy" has expanded to include adverse reactions associated with immunosuppressive medications, anticytokine therapies, and mAbs. The cytokine release reaction that occurs with anti-CD20 antibody infusions in patients with leukemia and white blood cell counts of greater than 50 x 10(9)/L is associated with high concentrations of TNF, IL-6, and IL-8. Because of the findings of fever, dyspnea, rigors, and hypotension, this reaction resembles the Jarisch-Herxheimer reaction that occurs 60 to 90 minutes after penicillin administration in patients with secondary syphilis. Furthermore, the care of the patient with penicillin allergy has been made more difficult in the absence of the major determinant, penicilloyl-polylysine, in that from 34% to 84% of patients who have positive skin test reactions to penicillin have exclusively positive reactions to the major determinant. SJS and TEN typically are caused by medications within 1 to 8 weeks of initiation of therapy. Evidence for death of the keratinocytes through (1) drug-specific cytotoxicity with the perforin-granzyme B-mediated killing and (2) activation of Fas on keratinocytes have provided explanations for the sloughing of skin. Unfortunately, intravenous immunoglobulin therapy for SJS and TEN has been disappointing.

Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria.

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.