Acute Systemic Hypersensitivity Research Articles

NButGT Reinforces the Beneficial Effects of Epinephrine on Cardiac Mitochondrial Respiration, Lactatemia and Cardiac Output in Experimental Anaphylactic Shock.

Anaphylactic shock (AS) is the most severe form of acute systemic hypersensitivity reaction. Although epinephrine can restore patients' hemodynamics, it might also be harmful, supporting the need for adjuvant treatment. We therefore investigated whether NButGT, enhancing O-GlcNAcylation and showing beneficial effects in acute heart failure might improve AS therapy. Ovalbumin-sensitized rats were randomly allocated to six groups: control (CON), shock (AS), shock treated with NButGT alone before (AS+pre-Nbut) or after (AS+post-Nbut) AS onset, shock treated with epinephrine alone (AS+EPI) and shock group treated with combination of epinephrine and NButGT (AS+EPI+preNBut). Induction of shock was performed with an intravenous (IV) ovalbumin. Cardiac protein and cycling enzymes O-GlcNAcylation levels, mean arterial pressure (MAP), heart rate, cardiac output (CO), left ventricle shortening fraction (LVSF), mitochondrial respiration, and lactatemia were evaluated using Western blotting experiments, invasive arterial monitoring, echocardiography, mitochondrial oximetry and arterial blood samples. AS decreased MAP (-77%, p < 0.001), CO (-90%, p < 0.001) and LVSF (-30%, p < 0.05). Epinephrine improved these parameters and, in particular, rats did not die in 15 min. But, cardiac mitochondrial respiration remained impaired (complexes I + II -29%, p < 0.05 and II -40%, p < 0.001) with hyperlactatemia. NButGT pretreatment (AS+pre-Nbut) efficiently increased cardiac O-GlcNAcylation level as compared to the AS+post-Nbut group. Compared to epinephrine alone, the adjunction of NButGT significantly improved CO, LVSF and mitochondrial respiration. MAP was not significantly increased but lactatemia decreased more markedly. Pretreatment with NButGT increases O-GlcNAcylation of cardiac proteins and has an additive effect on epinephrine, improving cardiac output and mitochondrial respiration and decreasing blood lactate levels. This new therapy might be useful when the risk of AS cannot be avoided.

Depletion of interfering IgG and IgM is critical to determine the role of IgE in pegvaliase-associated hypersensitivity

Pegvaliase is an enzyme substitution therapy developed to lower blood phenylalanine (Phe) in adults with phenylketonuria (PKU). In phase 3 clinical studies, pegvaliase substantially reduced mean blood Phe in adult subjects with PKU. The most common type of adverse event observed in the pegvaliase clinical program was hypersensitivity adverse events (HAEs), which included occurrences of arthralgia, rash, and pruritis. The most clinically relevant HAEs were acute systemic hypersensitivity reactions consistent with anaphylaxis observed in 4.6% of phase 3 patients. HAEs were more commonly observed around the time of high circulating immune complex (CIC) levels and complement activation, and the majority of subjects that experienced acute systemic hypersensitivity events were able to continue treatment, which is atypical for a classical IgE-mediated anaphylactic event, but common for type III hypersensitivity reactions.To investigate the alternative mechanism of type III hypersensitivity, serum samples collected shortly after hypersensitivity events (in phase 2 and 3 studies) were tested for anti-pegvaliase IgE using custom radioallergosorbent test and/or ImmunoCAP® (ThermoFisher Scientific, Waltham, MA) assay methods. All subjects with acute systemic hypersensitivity that were tested for anti-pegvaliase IgE at or near the time of event with one or both assays tested negative for IgE. As presented here, an investigation using selected study samples with high anti-drug antibody (ADA) titers demonstrated that presence of IgM and/or IgG ADA can interfere with measurement of a human anti-pegvaliase IgE surrogate positive control. A depletion method was therefore developed using protein A- and G-conjugated Sepharose to remove interfering IgG and IgM in serum samples to low levels (<45 mg/dL) before IgE testing. A final 2× concentration step brought the IgE concentration in the depleted sample to approximately the same level of the starting serum. Phase 3 study samples with sufficient volume remaining that previously tested negative for anti-pegvaliase IgE were re-tested after depletion of IgG and IgM. All samples again tested negative, confirming the original test results. Taken together, the clinical presentation, temporal association of HAEs with CIC levels and complement activation, and lack of anti-pegvaliase IgE suggest pegvaliase-associated acute systemic hypersensitivity events were not IgE-mediated. Furthermore, we describe a universal method that is broadly applicable to enzyme therapies for detection of low concentrations of drug-specific IgE in the presence of high titer anti-drug antibodies of different isotypes.

Induction, titration, and maintenance dosing regimen in a phase 2 study of pegvaliase for control of blood phenylalanine in adults with phenylketonuria

BackgroundPhenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU. MethodsPegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 μmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 μmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment. ResultsBaseline mean blood Phe for Group A and Group B were 1135 μmol/L and 1198 μmol/L, respectively. Mean blood Phe ≤ 600 μmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ± 483 μmol/L) and for Group B by Week 48 (mean blood Phe of 557 ± 389 μmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B. ConclusionsPegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.

Pegvaliase for the treatment of phenylketonuria: Results of a long-term phase 3 clinical trial program (PRISM)

BackgroundPhenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency that results in phenylalanine (Phe) accumulation. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is a potential enzyme substitution therapy to lower blood Phe in adults with PKU. MethodsTwo Phase 3 studies, PRISM-1 and PRISM-2, evaluated the efficacy and safety of pegvaliase treatment using an induction, titration, and maintenance dosing regimen in adults with PKU. In PRISM-1, pegvaliase-naïve participants with blood Phe >600 μmol/L were randomized 1:1 to a maintenance dose of 20 mg/day or 40 mg/day of pegvaliase. Participants in PRISM-1 continued pegvaliase treatment in PRISM-2, a 4-part clinical trial that includes an ongoing, open-label, long-term extension study of pegvaliase doses of 5 mg/day to 60 mg/day. ResultsOf 261 participants who received pegvaliase treatment, 72.0% and 32.6% reached ≥12 months and ≥ 24 months of study treatment, respectively, and 65% are still actively receiving treatment. Mean (SD) blood Phe was 1232.7 (386.4) μmol/L at baseline, 564.5 (531.2) μmol/L at 12 months, and 311.4 (427) μmol/L at 24 months, a decrease from baseline of 51.1% and 68.7%, respectively. Within 24 months, 68.4% of participants achieved blood Phe ≤600 μmol/L, 60.7% of participants achieved blood Phe ≤360 μmol/L, below the upper limit recommended in the American College of Medical Genetics and Genomics PKU management guidelines, and 51.2% achieved blood Phe ≤120 μmol/L, below the upper limit of normal in the unaffected population. Improvements in neuropsychiatric outcomes were associated with reductions in blood Phe and were sustained with long-term pegvaliase treatment. Adverse events (AEs) were more frequent in the first 6 months of exposure (early treatment phase) than after 6 months of exposure (late treatment phase); 99% of AEs were mild or moderate in severity and 96% resolved without dose interruption or reduction. The most common AEs were arthralgia (70.5%), injection-site reaction (62.1%), injection-site erythema (47.9%), and headache (47.1%). Acute systemic hypersensitivity events consistent with clinical National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network anaphylaxis criteria were observed in 12 participants (17 events); of these, 6 participants remained on treatment. Acute systemic hypersensitivity events including potential events of anaphylaxis were not associated with immunoglobulin E, and all events resolved without sequelae. ConclusionResults from the PRISM Phase 3 program support the efficacy of pegvaliase for the treatment of adults with PKU, with a manageable safety profile in most participants. The PRISM-2 extension study will continue to assess the long-term effects of pegvaliase treatment.

Incidence of serum sickness after the administration of Australian snake antivenom (ASP-22)

Context: Serum sickness is a delayed immune reaction resulting from the injection of foreign protein or serum. Antivenom is known to cause serum sickness but the incidence and characteristics are poorly defined. Objective: To investigate the incidence and clinical features of serum sickness following the administration of Australian snake antivenoms. Materials and methods: This was a prospective cohort study of patients recruited to the Australian Snakebite Project who received snake antivenom from November 2012 to March 2014. Demographics, clinical information, laboratory tests and antivenom treatment were recorded prospectively. Patients administered antivenom were followed up at 7–10 days and 6 weeks’ post-antivenom. The primary outcome was the proportion with serum sickness, pre-defined as three or more of: fever, erythematous rash/urticaria, myalgia/arthralgia, headache, malaise, nausea/vomiting 5–20 days post-antivenom. Results: During the 16-month period, 138 patients received antivenom. 23 were not followed up (unable to contact, tourist, child, bee sting) and 6 died in hospital. Of 109 patients followed up, the commonest reason for antivenom was venom induced consumption coagulopathy in 77 patients. An acute systemic hypersensitivity reaction occurred post-antivenom in 25 (23%) and 8 (7%) were severe with hypotension. Serum sickness occurred in 32/109 (29%) patients, including 15/37 (41%) given tiger snake, 6/15 (40%) given polyvalent and 4/23 (17%) given brown snake antivenom. There was no association between the volume of antivenom and serum sickness, p = 0.18. The commonest effects were lethargy, headache, muscle/joint aches and fever. Discussion: The incidence of serum sickness after snake antivenom in Australia was higher than earlier investigations which failed to define symptoms or follow-up patients, but similar to more recent studies of antivenoms in the United States. Conclusion: Serum sickness is common with Australian snake antivenom but does not appear to be predictable based on the volume of antivenom administered.

Randomized Controlled Trial of Intravenous Antivenom Versus Placebo for Latrodectism: The Second Redback Antivenom Evaluation (RAVE-II) Study

Latrodectism is the most important spider envenomation syndrome worldwide. There remains considerable controversy over antivenom treatment. We aimed to investigate whether antivenom resulted in resolution of pain and systemic effects in patients with latrodectism who received standardized analgesia. In a multicenter randomized placebo-controlled trial of redback spider antivenom for latrodectism, 224 patients (>7 years) with a redback spider bite and severe pain, with or without systemic effects, were randomized to receive normal saline solution (placebo) or antivenom after receiving standardized analgesia. The primary outcome was a clinically significant reduction in pain 2 hours after trial medication compared with baseline. A second primary outcome for the subgroup with systemic features of envenomation was resolution of systemic features at 2 hours. Secondary outcomes were improved pain at 4 and 24 hours, resolution of systemic features at 4 hours, administration of opioid analgesics or unblinded antivenom after 2 hours, and adverse reactions. Two hours after treatment, 26 of 112 patients (23%) from the placebo arm had a clinically significant improvement in pain versus 38 of 112 (34%) from the antivenom arm (difference in favor of antivenom 10.7%; 95% confidence interval -1.1% to 22.6%; P=.10). Systemic effects resolved after 2 hours in 9 of 41 patients (22%) in the placebo arm and 9 of 35 (26%) in the antivenom arm (difference 3.8%; 95% confidence interval -15% to 23%; P=.79). There was no significant difference in any secondary outcome between antivenom and placebo. Acute systemic hypersensitivity reactions occurred in 4 of 112 patients (3.6%) receiving antivenom. The addition of antivenom to standardized analgesia in patients with latrodectism did not significantly improve pain or systemic effects.

Anaphylaxie

Anaphylaxis is an acute systemic hypersensitivity reaction with symptoms of immediate-type allergy, which involves particularly the skin, respiratory tract, cardiovascular system and gastrointestinal tract. The severity of anaphylactic reactions is variable but some are fatal. Hymenoptera venom anaphylaxis affects about 3% and food hypersensitivity 2.6-3.2% of the general population; drugs are the other frequent cause. Symptoms of anaphylaxis are characteristic, but none of them is obligatory--even urticaria is absent in about 10%--and each symptom may be found also in other conditions. Hence, there are numerous differential diagnostic considerations, and anaphylaxis may be overlooked in many cases. Diagnosis of anaphylaxis is based on the occurrence of characteristic symptoms, especially when they develop upon exposure to a potential trigger. It can be significantly supported by evidence of release of mediators in the course of the reaction. For clinical purposes, demonstration of an increase of mast cell tryptase serum concentration above the individual baseline value is useful. The correct diagnosis of anaphylaxis is not only important with regard to treatment of an acute reaction, but also for subsequent allergologic diagnostics and long-term management of the patient.

Fatal acute systemic hypersensitivity reaction during haemodialysis

Fatal acute systemic hypersensitivity reaction during haemodialysis

Clinical features and severity grading of anaphylaxis

Background Existing grading systems for acute systemic hypersensitivity reactions vary considerably, have a number of deficiencies, and lack a consistent definition of anaphylaxis. Objective The aims of this study were to develop a simple grading system and definition of anaphylaxis and to identify predictors of reaction severity. Methods Case records from 1149 systemic hypersensitivity reactions presenting to an emergency department were analyzed retrospectively. Logistic regression analyses of the associations between individual reaction features and hypotension and hypoxia were used to construct a grading system. Epinephrine use, etiology, age, sex, comorbidities, and concurrent medications were then assessed for their association with reaction grade. Results Confusion, collapse, unconsciousness, and incontinence were strongly associated with hypotension and hypoxia and were used to define severe reactions. Diaphoresis, vomiting, presyncope, dyspnea, stridor, wheeze, chest/throat tightness, nausea, vomiting, and abdominal pain had weaker, albeit significant, associations and were used to define moderate reactions. Reactions limited to the skin (urticaria, erythema, and angioedema) were defined as mild. These grades correlated well with epinephrine usage. Older age, insect venom, and iatrogenic causes were independent predictors of severity. Preexisting lung disease was associated with an increased risk of hypoxia. Conclusion This simple grading system has potential value for defining reaction severity in clinical practice and research settings. The moderate and severe grades provide a workable definition of anaphylaxis. Age, reaction precipitant, and preexisting lung disease appear to be the major determinants of reaction severity.

Occasional Review: Allergy to Coitus

Acute systemic hypersensitivity reactions to semen are rare but may be life-threatening. Chronic or recurrent local reactions are more common and may be misdiagnosed as infective or nonspecific vaginitis. The antigen(s) involved in these reactions reside in a glycoprotein fraction of seminal plasma. Allergic vulvovaginitis may also occur in sensitized women when they are exposed to exogenous allergens such as drugs, food and infective agents during sexual activity. Skin testing and other relevant investigations are indicated when these disorders are suspected. Condom usage will prevent symptoms of coital allergy. Desensitization has had variable success in acute systemic hypersensitivity. Precoital antihistamines may modify local reactions.