RESUMO
A small fraction of people vaccinated with mRNA-lipid nanoparticle (mRNA-LNP)-based COVID-19 vaccines display acute or subacute inflammatory symptoms whose mechanism has not been clarified to date. To better understand the molecular mechanism of these adverse events (AEs), here, we analyzed in vitro the vaccine-induced induction and interrelations of the following two major inflammatory processes: complement (C) activation and release of proinflammatory cytokines. Incubation of Pfizer-BioNTech's Comirnaty and Moderna's Spikevax with 75% human serum led to significant increases in C5a, sC5b-9, and Bb but not C4d, indicating C activation mainly via the alternative pathway. Control PEGylated liposomes (Doxebo) also induced C activation, but, on a weight basis, it was ~5 times less effective than that of Comirnaty. Viral or synthetic naked mRNAs had no C-activating effects. In peripheral blood mononuclear cell (PBMC) cultures supplemented with 20% autologous serum, besides C activation, Comirnaty induced the secretion of proinflammatory cytokines in the following order: IL-1α < IFN-γ < IL-1ß < TNF-α < IL-6 < IL-8. Heat-inactivation of C in serum prevented a rise in IL-1α, IL-1ß, and TNF-α, suggesting C-dependence of these cytokines' induction, although the C5 blocker Soliris and C1 inhibitor Berinert, which effectively inhibited C activation in both systems, did not suppress the release of any cytokines. These findings suggest that the inflammatory AEs of mRNA-LNP vaccines are due, at least in part, to stimulation of both arms of the innate immune system, whereupon C activation may be causally involved in the induction of some, but not all, inflammatory cytokines. Thus, the pharmacological attenuation of inflammatory AEs may not be achieved via monotherapy with the tested C inhibitors; efficacy may require combination therapy with different C inhibitors and/or other anti-inflammatory agents.
Assuntos
COVID-19 , Inativadores do Complemento , Nanopartículas , Humanos , Lipossomos , Vacinas contra COVID-19/efeitos adversos , Leucócitos Mononucleares , Citocinas , Fator de Necrose Tumoral alfa , Vacina BNT162 , Ativação do Complemento , LipídeosRESUMO
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed and effective medication to treat hypertension. Although generally well tolerated, about 1% of patients will experience angioedema, a potentially life-threatening adverse drug reaction. This reaction is thought to be mediated via a buildup of bradykinin and does not typically respond to epinephrine, corticosteroids, or antihistamines. Alternative treatment strategies have been investigated, the bulk of which surround the use of therapies approved for hereditary angioedema. OBJECTIVE: Utilization of C1 esterase inhibitors at our institution was reviewed between 2016 and 2018 for treatment of ACE inhibitor-induced angioedema. We describe the clinical course of case series, along with a review of current literature. DISCUSSION: Utilization of C1 esterase inhibitors for treating ACE inhibitor-induced angioedema is an uncommon therapy and has limited efficacy in our case series. Treatment did not result in rapid improvement of swelling, prevention of intubation, or prevention of intensive care unit admission. CONCLUSIONS: Based on our case series, C1 esterase therapy should not be utilized routinely for ACE inhibitor-induced angioedema and is not expected to prevent intubation in severe cases.
Assuntos
Angioedema , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Proteína Inibidora do Complemento C1/uso terapêutico , Angioedema/induzido quimicamente , Angioedema/tratamento farmacológico , Bradicinina , HumanosRESUMO
Angioedema is a non-inflammatory oedema of the subcutaneous tissue and/or mucosal membranes. It most commonly coexists with urticaria wheals and is considered to be a deep form of urticaria. Less commonly, it occurs in isolation and can take two basic forms: acquired angioedema and hereditary angioedema. Currently, there are 4 defined types of acquired angioedema and 7 types of hereditary angioedema. Treatment of angioedema depends on its form and etiological factors. Especially the genetic form, i.e. hereditary angioedema, is a considerable challenge for medical specialists, particularly dermatologists and allergists.
RESUMO
Hereditary angioedema is characterized by severe, episodic edema of the subcutaneous and mucosal tissue. The disease carries significant morbidity and mortality due to involvement of the gastrointestinal tract and upper airway. Recent advances in the treatment of hereditary angioedema include new techniques used to isolate and purify human-derived C1 inhibitor, the production of a recombinant form of C1 inhibitor, and the development of drugs that target the kallikrein-kinin pathway. This paper reviews the mechanisms, efficacy, and adverse reactions associated with these medications.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Bradicinina/análogos & derivados , Bradicinina/uso terapêutico , Proteína Inibidora do Complemento C1/uso terapêutico , Humanos , Peptídeos/uso terapêuticoRESUMO
BACKGROUND: Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long-term prophylaxis with twice-weekly intravenous injections of plasma-derived C1-inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE. METHODS: This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity. RESULTS: After SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event. CONCLUSIONS: Subcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Adulto , Angioedemas Hereditários/imunologia , Proteína Inibidora do Complemento C1/administração & dosagem , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/farmacocinética , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
Presently, medications approved for children with Hereditary Angioedema (HAE) are extremely limited. This is especially the case for children under 12 years of age. For this reason we reviewed and summarized the data on treatment of children with HAE. Available data indicate that plasma derived C1-inhibitor is a safe, effective treatment option for HAE in pediatric patients, including those below 12 years of age. Other therapies are also appear safe for the under 12 year of age, but less data are available. Importantly, home-based treatment of HAE in this age group appears to be safe and effective and can improve quality of life. These findings support current HAE consensus guidelines which strongly recommend the use of plasma derived C1-inhibitor as a first-line treatment in children and encourage home and self-treatment.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Fatores Imunológicos/uso terapêutico , Plasma/química , Adolescente , Fatores Etários , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/imunologia , Criança , Pré-Escolar , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/isolamento & purificação , Serviços de Assistência Domiciliar , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/isolamento & purificação , Guias de Prática Clínica como Assunto , Autocuidado , Resultado do TratamentoRESUMO
The disfunction or deficiency of the C1 esterase inhibitor (C1INH) is associated with hereditary or acquired angioedema (HAE/AAE), a rare life-threatening condition characterized by swelling in the skin, respiratory and gastrointestinal tracts. The current treatment options may carry the risks of either viral infection (plasma-derived Berinert®) or immune reaction (human recombinant C1INH from rabbit milk, Ruconest®). This study describes the physicochemical and biological characterization of a novel recombinant human C1 esterase inhibitor (rhC1INH) from Chinese hamster ovary (CHO) cells for the treatment of hereditary angioedema compared to the marketed products Berinert® and Ruconest®. The mass spectrometry results of total deglycosylated rhC1INH revealed a protein with a molecular mass of 52,846 Da. Almost full sequence coverage (98.6%) by nanoLC-MS/MS peptide mapping was achieved. The purity and C1s inhibitory activity of rhC1INH from CHO cells are comparable with Ruconest®, although we found differences in charge isoforms distribution, intact mass values, and N-glycans profile. Comparison of the specific activity (IC50 value) of the rhC1INH with human C1 esterase inhibitor from blood serum showed similar inhibitory properties. These data allow us to conclude that the novel rhC1INH molecule could become a potential therapeutic option for patients with HAE/AAE.
RESUMO
OBJECTIVE: To describe 2 cases of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema treated with C1 esterase inhibitor (human) [Berinert]. SUMMARY: Case 1 is a 60-year-old Caucasian male with angioedema from lisinopril. He was initially treated with a conventional regimen of an antihistamine, methylprednisolone, epinephrine, and fresh frozen plasma. When symptoms did not resolve, intravenous C1 peptide esterase inhibitor (C1INH) was administered, with clinical improvement. Four hours later, symptoms returned and the patient underwent emergency tracheostomy. Case 2 is a 64-year-old Caucasian male who presented with angioedema due to enalapril. In the emergency department, he received conventional treatment. Endotracheal tube placement was unsuccessful. While the patient was undergoing intubation in the operating room, intravenous C1INH was administered resulting in quick improvement of symptoms. DISCUSSION: Angioedema from ACEI occurs at an incidence of 0.7%. Conventional treatment may be of limited benefit due to the mechanism of the reaction. C1INHs, which are indicated for hereditary angioedema, have been utilized in treating ACEI-induced angioedema. According to the Naranjo algorithm scale, the patient in case 1 experienced angioedema that is probably related to lisinopril. C1INH was administered intravenously when symptoms progressed, despite conventional treatment. In case 2, the patient experienced angioedema, which is possibly related to enalapril, and was treated with C1INH. CONCLUSION: C1INH (human) was a successful addition to the traditional management of 2 patients with angioedema due to ACEI.
Assuntos
Angioedema/induzido quimicamente , Angioedema/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Proteína Inibidora do Complemento C1/uso terapêutico , Angioedema/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hereditary angioedema (HAE) is a rare genetic disorder characterised by episodes of swelling without urticaria. Berinert® (CSL Behring) is a plasma-derived human C1 inhibitor (C1-INH) concentrate, approved for the treatment of HAE with C1-INH deficiency (C1-INH-HAE), however, it is often used off-label in Europe to treat HAE with normal C1-INH. To report the clinical characteristics of patients with HAE with normal C1-INH (with F12 gene mutation; FXII-HAE) or of unknown origin (U-HAE), and their response to Berinert®. Data from 2007 to 2016 (obtained retrospectively from the French Cohort BeRinert AngiÅdème [COBRA] registry of HAE patients with everyday use of Berinert®) were analysed; no control group was included. Diagnostic criteria for FXII-HAE and U-HAE included a normal C1-INH antigenic level and function and refractoriness to high-dose antihistamines. For FXII-HAE, diagnosis also included F12 gene mutation, and U-HAE a positive family history for the disease. To date, 28 patients with FXII-HAE or U-HAE were identified (mean age: 27 years; first angioedema attack at 19.8 years; 85.7% female) with 78 documented Berinert®-treated attacks, the majority occurring in the laryngeal and abdominal regions. Efficacy assessment of Berinert® was available for 38 of 78 documented Berinert®-treated attacks; 22 improved within 60 minutes of treatment initiation, nine within 60-180 minutes, four after 180 minutes, and three showed no improvement. No severe or serious adverse effects were reported. Data to date suggest that Berinert® may be a safe and efficacious treatment option for the majority of HAE patients.
Assuntos
Angioedemas Hereditários/sangue , Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/metabolismo , Proteína Inibidora do Complemento C1/uso terapêutico , Adolescente , Adulto , Angioedemas Hereditários/genética , Proteína Inibidora do Complemento C1/efeitos adversos , Fator XII/genética , Feminino , França , Humanos , Masculino , Mutação , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; "pnfC1-INH") is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis. OBJECTIVE: The objective of this study was to describe safety and usage patterns of pnfC1-INH. METHODS: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason. RESULTS: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (n = 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation. CONCLUSIONS: The findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedemas Hereditários/prevenção & controle , Criança , Pré-Escolar , Proteína Inibidora do Complemento C1/efeitos adversos , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products, typically with off-label use or at supratherapeutic doses. OBJECTIVES: Active surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events. METHODS: A registry was initiated in April 2010 at 27 US and 4 EU sites to obtain both prospective and retrospective safety and usage data on subjects who were administered C1-INH (Berinert). RESULTS: As of May 10, 2013, data were available for 135 subjects and 3196 infusions. By subject, 67.4% were using C1-INH as on-demand therapy and 23.0% as both on-demand therapy and prophylactic administration. Approximately half of the infusions (49.5%) were administered for prophylaxis and >90% were given by the patient or a caregiver in the home setting. A total of 299 adverse events were reported, for an overall rate of 0.09 events per infusion with only 6 considered related to C1-INH. Two thromboembolic events were reported, both in patients with prothrombotic risk factors. CONCLUSION: This large pool of real-world clinical usage data in HAE further supports the extensive safety profile of 2 Berinert formulations when used on demand and/or for prophylaxis in both home and health care settings. No evidence was found to suggest that Berinert is an independent, causative risk factor for thromboembolic events.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Angioedemas Hereditários/prevenção & controle , Proteína Inibidora do Complemento C1/efeitos adversos , Adolescente , Adulto , Idoso , Criança , Proteína Inibidora do Complemento C1/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Tromboembolia/induzido quimicamente , Adulto JovemRESUMO
Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.
RESUMO
Hereditary angioedema (HAE) is a relatively rare autosomal dominant disorder that is typically characterized by recurrent episodes of edema in various body locations. It is most commonly caused by an inherited deficiency of functionally active C1 esterase inhibitor (C1-INH). Replacement therapy with a human plasma-derived C1-INH concentrate is recommended for the treatment and prophylaxis of acute attacks of HAE due to C1-INH deficiency (HAE-C1-INH). This article will discuss the current therapies available for the treatment of HAE-C1-INH, latest treatment guidelines, results of several studies demonstrating the efficacy and safety of the plasma-derived, pasteurized and nanofiltered C1-INH concentrate Berinert(®) (CSL Behring GmBH, Marburg, Germany), and future perspectives for the treatment and management of HAE-C1-INH.
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Angioedemas Hereditários/terapia , Proteína Inibidora do Complemento C1/uso terapêutico , Plasma/química , Proteína Inibidora do Complemento C1/química , Humanos , Pasteurização/métodos , Guias de Prática Clínica como AssuntoRESUMO
Consensus guidelines on hereditary angioedema (HAE) recommend that all patients have access to on-demand treatment of acute attacks. A recent patientcentric guideline recommended that at least 2 on-demand therapies be available because patients often have heterogeneous responses to different medications. Self-administration of therapeutic agents, or administration under supervision by a health care provider in the home setting, is the preferred treatment approach. Future studies are needed to show the benefits of acute on-demand therapies at improving quality of life and reducing morbidity and mortality in patients with HAE.