Systemic Reactions In Patients Research Articles

Basophil activation test to follow-up of patients treated with hymenoptera venom immunotherapy: a review of current evidence

Hymenoptera venom immunotherapy (HVI) is a long-term effective treatment to avoid new systemic reactions in patients with Hymenoptera allergy. The sting challenge test is considered the gold standard to confirm the tolerance. However, the use of this technique is not generalized in clinical practice, being the basophil activation test (BAT), which functionally explores allergen response, an alternative that does not entail any of the provocation risks associated with the sting challenge test. This study reviews the publications that used the BAT to follow up and evaluate the success of the HVI. Studies assessing the changes between a baseline BAT before the start and BATs performed between the starting and maintenance phases of the HVI were selected. Ten articles were found, comprising information from 167 patients, of which 29% used the sting challenge test. The studies concluded the importance of evaluating the responses with submaximal allergen concentrations, which reflect basophil sensitivity, to monitor the HVI using the BAT. It was also observed that changes in the maximum response (reactivity) could not reflect the clinical status of tolerance, particularly in the initial phases of HVI.

A single centre retrospective study of systemic reactions to subcutaneous immunotherapy

BackgroundSubcutaneous immunotherapy (SCIT) is the standard approach for treating patients with sensitizations to aeroallergens. However, immunotherapy can trigger severe systemic reactions if delivered inappropriately or to high risk patients. We sought to characterize and quantify SCIT systemic reactions requiring epinephrine administration during a 6-year period in a Canadian setting following the recommendations for components and dosages published in the 2010 Canadian Society of Allergy and Clinical Immunology (CSACI) Immunotherapy Manual.MethodsA single centre retrospective chart review was performed for all patients with systemic reactions to subcutaneous immunotherapy requiring intramuscular epinephrine injection between January 2011 and October 2017. Each systemic reaction requiring epinephrine was reviewed for baseline patient characteristics, details of the reaction, and reaction severity. Research ethics approval was obtained through McMaster University.Results28 of 380 patients experienced a systemic reaction requiring epinephrine administration, with an incidence rate of 1 per 1,047 injection visits (0.095%). 26 of the 28 reactions occurred within the mandatory 30-minute observation period post allergen immunotherapy. Of the 28 patients that experienced a systemic reaction to SCIT, 11 patients had asthma and 5 patients had a history of possible food allergy. All of the systemic reactions occurred during injections from vial number 4, and five patients reacted to their first shot of a re-ordered extract. 10 of the 28 patients required more than one intramuscular injection of epinephrine, and 20 of 28 patients were transferred to the hospital by ambulance.ConclusionsThis is the first Canadian study to review patients with systemic reactions to subcutaneous immunotherapy. Several best practice methods were employed throughout the study to optimize subcutaneous delivery of immunotherapy extract, and our recorded per injection incidence rate for systemic reactions was comparable or below the rate published in similar studies. The recommendations in the CSACI Immunotherapy Manual provide an approach to standardizing prescriptions for SCIT to maximize immunotherapy efficacy and reduce the risk of systemic reactions, though similar studies in larger multicenter settings are needed to confirm these observations. These observations provide important objective information to clinicians about the potential risks for systemic reactions in patients considering SCIT.

Comparison of two types of polyvalent snake antivenom used in treatment

Purpose: In this study; we aimed to compare the effectiveness of the two types of polyvalent snake antivenom and to determine the possible local and systemic reactions in patients who admitted to the emergency department with snake bite. Materials and Methods: We performed this retrospective study on 30 patients who complained of snakebite. We grouped the patients according to the antivenom type (PoliseraTM or Polivalan TM) which they received. Demographic characteristics of the patients, vital signs, local tissue findings, and laboratory parameters were recorded in the standard data form. The following data were also recorded; the number of vials of snake antivenom used in each group, additional doses of venom were administered, and whether any local or systemic reaction to antivenom has developed or not. Results: Thirty patients were included in the study. 16 patients were administered PoliseraTM (Group 1) snake antivenom and 14 patients were administered Polivalan TM (Group 2) snake antivenom. Patients in Group 1 were given an average of 9.1±7.3 vials, while patients in Group 2 were given an average of 11.6±12.7 vials. More allergic reactions-urticaria, fever, and cellulite were observed in the group receiving PolivalanTM antivenom. Conclusion: Different methodologies arising from the production of antivenom, pyrogen contamination, and differences in packaging can cause different effects and side effects even in products with the same dose and antivenom content.

Cytotoxicity of cobalt chloride in brain cell lines - a comparison between astrocytoma and neuroblastoma cells

High levels of circulating cobalt ions in blood have been reported to induce systemic reactions in patients with metal-on-metal (MoM) hip implants. We still lack information regarding these adverse effects, which may specifically impact on patients showing adverse neurological symptoms. To investigate this, we used a battery of in vitro viability and proliferation assays to identify toxic cobalt chloride (CoCl2) concentrations in two different brain cell types: SH-SY5Y neuroblastoma and U-373 astrocytoma cells. Cobalt cytotoxicity was characterised by MTT and Neutral Red (NR) assays at concentrations ranging from 0 to 500 μM after 24, 48, and 72 h exposure. MTT and NR showed a dose- and time-dependent toxicity with cobalt decreasing cell viability at high concentrations. IC50s for MTT at 72 h (astrocytes: 333.15 ± 22.88; neurons: 100.01 ± 5.91 μM) and for BrdU proliferation assays (astrocytes: 212.89 ± 9.84; neurons: 88.86 ± 19.03 μM) demonstrate that SH-SY5Y neurons are significantly more vulnerable to cobalt than astrocytes. Increased BrdU and MTT assay sensitivity suggested that DNA synthesis and metabolism disruption were involved in Co toxicity.Intracellular cobalt level measured by ICP-MS was significant after 100 μM treatment. Astrocytes displayed improved resistance to cobalt toxicity and higher uptake, which may reflect their neuroprotective nature. In summary, exposure to high concentrations of extracellular cobalt has deleterious effects in neurons and astrocytes, with neurons showing particular sensitivity.

The Effects of Low-Nickel Diet Combined with Oral Administration of Selected Probiotics on Patients with Systemic Nickel Allergy Syndrome (SNAS) and Gut Dysbiosis.

Background: Nickel (Ni) oral consumption may elicit systemic reactions in patients affected by systemic nickel allergy syndrome (SNAS), including gastrointestinal symptoms, which in turn are associated with gut dysbiosis. We evaluated the effects of a low-Ni diet alone or in combination with the oral consumption of appropriate probiotics on Ni-sensitivity and urinary dysbiosis markers in SNAS patients. Methods: n = 51 patients with SNAS and concomitant intestinal dysbiosis were enrolled in the study. According to the urinary indican/skatole levels, quantified through a colorimetric and a high-performance liquid chromatographic method, respectively, patients were assigned to a dysbiosis type/grade and followed a low-Ni diet for three months. Along with the diet, 22 patients also consumed probiotics based on the dysbiosis type. In particular, a Lactobacilli- or Bifidobacteria-containing formulation was administered to patients with fermentative or putrefactive dysbiosis, respectively, while a broad-spectrum probiotic formulation containing both Lactobacilli and Bifidobacteria was administered to patients with mixed dysbiosis. After three months, patients were invited to repeat the Ni-stimulation and the dysbiosis tests. Results: The fermentative dysbiosis group represented the largest group followed by the mixed dysbiosis group, while only two patients had putrefactive dysbiosis. Overall, at three months of treatment in general (diet alone with or without probiotics), the Ni-sensitivity and dysbiosis levels were strongly ameliorated. The association of a low-Ni diet with a specific probiotic oral supplementation was significantly more effective in decreasing dysbiosis levels or reaching eubiosis than with diet alone. Conclusion: Our results, while confirming the benefits of a low-Ni diet in SNAS patients, strongly support that appropriate adjuvant treatment with probiotics significantly helps to improve intestinal dysbiosis or restore a healthy microbiota.

Large local reaction to Hymenoptera stings: Sound studies are needed to change a shared concept.

The natural history of large local reactions to Hymenoptera stings allowed to estimate the risk to develop a systemic reaction after an initial large local reaction in about 4% of patients. A recently published study claimed that such risk concerns instead around one‐fourth of patients. However, such study is flawed by serious imprecision, particularly the unreliable identification by patients of the culprit insect, as well as the dubious identification of the causative venom in multisensitized patients. Also, the authors criticized previous studied because of the limited number of patients, while they included in the study 662 patients. Indeed, when only patients clearly restung by the same insect according to their history data were considered, the number of patients fell to 35. These data are unable to change the current shared concept on the low risk of systemic reactions in patients with initial large local reaction.

Investigation of the factors that determine the severity of allergic reactions to Hymenoptera venoms.

Introduction: Many risk factors that facilitate venom allergy and increase systemic reaction severity have been described in various studies, but the data are limited regarding this issue. We aimed to evaluate the impact of total immunoglobulin E (tIgE), specific IgE, and tryptase levels on the severity of systemic reactions in patients with a history of allergic reactions to Hymenoptera stings. Method: Eighty-two patients with a history of allergic reaction to Hymenoptera venom admitted to our outpatient clinic between March 2016 and August 2017 were included. Venom-specific IgE (Apis mellifera and Vespula vulgaris), total IgE, and basal tryptase levels were measured. Skin-prick tests were performed with inhalant allergens. The levels of specific IgE, total IgE, and tryptase were compared between patients with large local reactions and systemic reactions, and the relation of these parameters with the severity of systemic reaction was evaluated. Results: There were no significant differences in the specific IgE, total IgE, and tryptase values in patients with large local reactions and a history of systemic reactions (p > 0.05). The age, basal tryptase, and V. vulgaris-specific IgE levels of patients with a grade IV reaction history were higher than those with grades I-III reaction history (p < 0.05). An important finding was that high basal tryptase levels were a risk factor for grade IV reactions (p = 0.047, χ² = 4.512). There was a strong positive correlation between total IgE levels and V. vulgaris- and A. mellifera-specific IgE values in patients with a grade IV reaction history (r = 0.94, p = 0.005; and r = 0.88, p = 0.021, respectively). Conclusion: Baseline serum tryptase levels were a risk factor for the development of severe systemic reactions in venom allergy. This risk increases with increasing age in these patients. Another notable finding was the correlation between total IgE and venom-specific IgE values in patients with severe systemic reactions.

Systemic and erythrodermic reactions following repeated exposure to bites from the Common bed bug Cimex lectularius (Hemiptera: Cimicidae)

AbstractBed bugs (Cimex spp.) have undergone a global resurgence over the last 15–20 years. They readily bite humans, producing a range of cutaneous reactions. This article documents systemic reactions in two patients following repeated bites from the common bed bug, Cimex lectularius. Both patients had previously fed bed bugs on themselves without any serious complication, however upon feeding a new batch of the insects subsequently developed systemic urticarial reactions. Patient 1 fed 40–50 bed bugs on himself and after 8 min, he developed itch, swelling of the face, lethargy, profuse sweating and widespread wheals on the torso and limbs. The reaction disappeared in 5 h after treatment with systemic prednisone and antihistamines. Patient 2 developed a similar reaction after feeding five to six bed bugs on himself. In this case, the patient also developed chest tightness and breathing difficulties. Following a similar treatment, symptoms disappeared in 4 h. In light of the increasing exposure of this insect to the general public, systemic reactions in patients may present more commonly to the medical practitioner.

Manufacture of immunoglobulin products for patients with primary antibody deficiencies - the effect of processing conditions on product safety and efficacy.

Early preparations of immunoglobulin (Ig) manufactured from human plasma by ethanol (Cohn) fractionation were limited in their usefulness for substitution therapy in patients with primary antibody deficiencies (PAD), as Ig aggregates formed during manufacture resulted in severe systemic reactions in patients when given intravenously. Developments in manufacturing technology obviated this problem through the capacity to produce concentrated solutions of intact monomeric Ig, revolutionizing PAD treatment and improving patient life expectancy and quality of life. As the need for Ig has grown, manufacturers have refined further manufacturing technologies to improve yield from plasma and produce therapies, which are easier and less expensive to deliver. This has led to the substitution, partly or wholly, of ethanol precipitation by other techniques such as chromatography, and has also stimulated the production of highly concentrated solutions capable of rapid infusion. Ig products have been associated, since their inception, with certain adverse events, including infectious disease transmission, hemolysis, and thromboembolism. The introduction of standardized manufacturing processes and dedicated pathogen elimination steps has removed the risk of infectious disease, and the focus of attention has shifted to other problems, which appear to have increased over the past 5 years. These include hemolysis and thromboembolism, both the cause for substantial concern and the subject of recent regulatory scrutiny and actions. We review the development of manufacturing technology and the emerging evidence that changes for the optimization of yield and convenience has contributed to the recent incidents in certain adverse events. Industry measures under development will be discussed in terms of their potential to improve safety and optimize care for patients with PAD.

Systemic Reactions in Patients with Isolated Cardiac Sarcoidosis

Systemic Reactions in Patients with Isolated Cardiac Sarcoidosis

Grading local side effects of sublingual immunotherapy for respiratory allergy: Speaking the same language

Sublingual immunotherapy (SLIT) is increasingly used worldwide. Despite its safety being well ascertained, there is no universally accepted system to grade and classify its adverse events (AEs). According to the literature, it seems reasonable to classify and grade systemic side effects by using the previously published World Allergy Organization recommendations. On the other hand, local side effects are the most frequent with SLIT, sometimes leading to its discontinuation. Therefore grading of the severity of local side effects was perceived as necessary for the purpose of uniform reporting, classification, and quantification of this aspect. AWorld Allergy Organization Taskforce, after examining the available literature and the postmarketing surveillance data, proposed a clinically based grading of the severity of local AEs caused by SLIT. The use of the Medical Dictionary for Regulatory Activities nomenclature for AEs was also included in this context. The proposed grading system for SLIT-induced local reactions is expected to improve and harmonize surveillance and reporting of the safety of SLIT.

Rituximab may form a complex with iGmκ mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus–induced vasculitis

To report on 6 cases of hepatitis C virus (HCV)-induced mixed cryoglobulinemia (MC) vasculitis in patients who developed severe systemic reactions after rituximab infusion, and to report the results of the in vitro analysis of the underlying immunologic mechanisms. Twenty-two HCV-infected patients with MC vasculitis received rituximab infusions (a low-dose protocol cycle with 375 mg/m2/week for 4 consecutive weeks in 18 patients and a high-dose protocol cycle with 1,000 mg on days 1 and 15 in 4 patients). Systemic drug reactions following rituximab infusion were recorded and analyzed clinically and immunochemically. Six of 22 patients (27.3%) experienced systemic drug reactions after rituximab infusion. Four patients developed a severe flare of MC vasculitis 1 or 2 days after rituximab infusion. Two patients developed serum sickness syndrome 7 and 9 days after the first 1,000 mg rituximab infusion. Compared with patients without drug reactions, those with drug reactions had higher mixed cryoglobulin levels (mean+/-SD 1.4+/-0.82 gm/liter versus 0.71+/-0.77 gm/liter; P=0.0475) and lower C4 levels (mean+/-SD 0.02+/-0.006 gm/liter versus 0.07+/-0.07 gm/liter; P=0.02), and more of them received 1,000 mg high-dose rituximab protocol (50% versus 6.25%; P=0.046). In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgMkappa that had rheumatoid factor (RF) activity. Moreover, the in vitro addition of rituximab to serum containing an RF-positive IgMkappa type II mixed cryoglobulin was associated with visibly accelerated cryoprecipitation. In HCV-associated MC vasculitis, rituximab may form a complex with RF-positive IgMkappa, leading to accelerated cryoprecipitation and to severe systemic reactions. Rituximab should be administered with caution in MC vasculitis, with use of the 375 mg protocol and plasma exchanges prior to rituximab infusion in patients with high baseline levels of mixed cryoglobulin.

Immunotherapy for allergic rhinitis: clinical benefits and its working mechanisms

SummaryPollen immunotherapy exerts greater efficacy in the pollen season when the pollen count is not high than when it is high. Every pollen season, around half or more patients who have received pollen immunotherapy for &gt;5 years are judged as good responders; those who have received immunotherapy for &lt;5 years generally do less well. Therefore, the clinical response seems to depend on natural pollen counts and the duration of immunotherapy. In this study, peripheral blood mononuclear cells (PBMCs) were sampled before and during the pollen season to examine IL‐4, IL‐5, and IFN‐γ levels. It was revealed that pollen immunotherapy could decrease IL‐4 and ‐5 expression by pollen antigen‐stimulated PBMCs. When patients under immunotherapy were divided into good and poor response groups, clinical effectiveness was related to the depressed level of IL‐5 synthesis, but not to that of IL‐4 synthesis. Our study suggests that a decrease of IL‐5 expression during the pollen season is a key working mechanism of immunotherapy related to clinical effectiveness. In our patients, the incidence of systemic reactions was 5.8%/patient and &lt;0.1%/injection. A higher incidence of systemic reactions was observed in patients with the presence or a past history of asthma, the presence but not a past history of atopic dermatitis, and higher levels of total IgE (&gt;1000 U/mL). The incidence of systemic reactions in patients with 1 risk factor such as asthma, atopic dermatitis, and high IgE was 16.9%/patient and 0.1%/injection, whereas that in those without risk factors was 1.6%/patient and &lt;0.1/injection.

Frequency of acute systemic reactions in patients with allergic rhinitis and asthma treated with sublingual immunotherapy

Several studies have demonstrated the efficacy and safety of sublingual immunotherapy in the treatment of respiratory allergy. To determine the frequency of systemic adverse reactions in patients treated with standardized extracts of sublingual immunotherapy. Allergic patients with rhinitis with or without asthma and sensitized to at least 1 allergen were included. Increasing doses of standardized allergens were administered until reaching an average dose accumulated of 7,200 U after 26 weeks of treatment. Adverse events were graded according to the European Academy of Allergy and Clinical Immunology immunotherapy position paper. Forty-three patients with a median age of 11 years (interquartile range, 8-20 years) were included. All the patients had allergic rhinitis, and 63% had asthma; they were sensitized mostly to Dermatophagoides pteronyssinus and Dermatophagoides farinae. Four patients (9%) presented with an immediate and 1 (2%) with a late systemic reaction. In total, 7 systemic reactions occurred in 23,154 doses, and all were associated with wheezing or worsening of nasal symptoms (grade 2); in addition, 1 patient had angioedema and urticaria (grade 3). In this group, systemic reaction frequency was 11.6%, and all were classified as grade 2 or 3. Further assessments in larger samples of patients are required in the context of randomized controlled trials.

Risk Factors for Adverse Systemic Reactions Occurring during Immunotherapy with Standardized Dermatophagoides farinae Extracts

The most serious problem in practical immunotherapy is the risk of occasional, potentially life-threatening adverse systemic reactions. Elucidation of the incidence of, and possible risk factors for, systemic reactions would have a profound effect on the decision about how to manage allergic rhinitis. The aim of this retrospective study was to document the incidence and risk factors of adverse systemic reactions during immunotherapy using standardized Dermatophagoides farinae ( D. farinae ) extracts for perennial allergic rhinitis. This study included 386 patients (22,722 injections) with perennial allergic rhinitis who had received immunotherapy with standardized D. farinae extracts in our clinics for the past 5 years. The incidence of systemic reactions was 6.22% per patient and 0.12% per injection. The time of onset of systemic reactions ranged from 3 to 30 min (mean 11.3 min) after injections. Our study has demonstrated that asthma, atopic dermatitis and a high level of IgE in serum, but not a high level of specific IgE in serum, are important high risk factors that may induce severe adverse systemic reactions in patients who receive immunotherapy for perennial allergic rhinitis. The incidence of systemic reactions in those who had a high level of IgE (higher than 1000 U/ml) and asthma and/or atopic dermatitis was 66.67% (12/18) per patient. Conversely, the incidence of systemic reactions in those who had none of the risk factors was 1.64% per patient. Thus, the rate of systemic reactions is thought to be reduced by 75% if patients with high risk factors are strictly excluded from immunotherapy for allergic rhinitis.

Discontinuation of yellow jacket venom immunotherapy: Follow-up of 75 patients by means of deliberate sting challenge

Background: Venom immunotherapy is effective in preventing systemic reactions in patients with a history of an anaphylactic reaction to Hymenoptera stings. It is uncertain how long venom immunotherapy should be continued. Objective: We evaluated whether the duration of venom immunotherapy given to yellow jacket–sensitive patients related to the risk of an anaphylactic reaction to a later sting. Methods: Seventy-five yellow jacket–sensitive patients (29 male and 46 female) received a median number of three in-hospital sting challenges from a live insect in 3 subsequent years after discontinuation of venom immunotherapy. An anaphylactic reaction to one or more of the sting challenges was considered a relapse. We analyzed whether patients with and patients without a relapse differed in terms of gender, age, preimmunotherapy skin test data, preimmunotherapy level of venom-specific IgE, severity of the field-sting reaction that preceded immunotherapy, severity of the reaction to the sting challenge that preceded immunotherapy, adverse reactions to immunotherapy, changes in IgE and IgG 4 levels during immunotherapy, duration of immunotherapy, and presence of venom-specific IgE after cessation of therapy. Results: Venom immunotherapy was given for a median duration of 40 months (range, 7 to 120 months). Relapses were observed in six patients. In two of them, a rather severe anaphylactic reaction was observed after the second sting challenge. No relation was found between duration of venom immunotherapy and relapse risk. The relapse rate was higher among patients with high levels of specific IgE before and after immunotherapy. During therapy, the mean level of specific IgE decreased. This decline persisted in the 3 following years. No relapses of sting reactions were observed among patients without detectable specific IgE. Conclusion: Discontinuation of venom immunotherapy appears safe for patients with pretreatment IgE antibodies if these antibodies can no longer be detected during immunotherapy. For the remaining patients, a treatment period of 3 years may suffice. After discontinuation of immunotherapy, a clinical sting challenge can be considered to estimate the patient's current grade of hypersensitivity. (J Allergy Clin Immunol 1997;100:767-70.)

Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections

To learn whether patients taking beta-blocker (BB) drugs were at increased risk of having systemic reactions (SRs) from allergen immunotherapy, we prospectively studied 56,105 injection visits in 3178 patients during a 1-year interval. A total of 166 SRs occurred in 144 patients (4.5% of all patients) or 3.0 SRs occurred per 1000 injection visits. Sixty-eight patients were taking BB drugs throughout the year, and only one patient had an SR. By chance, 3.08 patients were expected to have had SRs. We conclude that BB drugs did not increase the frequency of SRs in the patients studied who were receiving immunotherapy (p greater than 0.95). Patients taking BB drugs may still be at increased risk, however, from more severe SRs or their SRs may be more refractory to therapy.

Melanoma, Growth Factors, and Cutaneous Paraneoplastic Syndromes

Paraneoplastic syndromes are systemic reactions in patients with cancers that are unrelated to tumor size or location. Cutaneous paraneoplastic syndromes include proliferative, metabolic, and inflammatory skin disorders. Both systemic and cutaneous paraneoplastic reactions may occur in patients with malignant melanoma. Cancers, including melanoma, may produce growth factors, which may be responsible for proliferative cutaneous paraneoplastic syndromes. A patient with malignant melanoma we previously reported, who had the sudden onset of acanthosis nigricans, skin tags (acrochordons), and seborrheic keratoses provides a model for proliferative cutaneous paraneoplastic syndromes. High levels of α‐TGF were found in the patient's urine prior to melanoma removal. The increased level of α‐TGF declined after the melanoma was removed, and a corresponding clinical improvement in his acanthosis nigricans, skin tags, and seborrheic keratoses occurred. In the skin lesions, EGF receptors were abnormally present throughout all epidermal layers prior to melanoma removal, and returned to their normal distribution in the basal layers after surgery. Ectopic growth factor production by malignant melanomas and other epithelial neoplasms may cause rare, but distinctive cutaneous paraneoplastic lesions. The model of melanoma, cutaneous paraneoplastic syndromes, and growth factors may provide understanding of both cutaneous lesions associated with neoplasia, and benign cutaneous lesions.