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Abstract As many aspects of hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) cannot be explained with elevated bradykinin level alone, it has recently become clear that other factors also play an important role in the pathogenesis. One of these factors could be elevated neutrophil granulocyte (NG) counts, which are associated with increased NG activation in C1-INH-HAE patients; however, their origin has not been elucidated so far. Here, we aimed to investigate whether the excess of NGs is due to disturbed maturation, biased circulating/marginated pool equilibrium or decreased elimination. We enrolled 20 attack-free C1-INH-HAE patients together with 21 healthy controls and collected blood samples. We compared cell surface maturation markers, adhesion molecules, cytokine receptors, and Ca2+-mobilization of NG by flow cytometry, activation markers by ELISA, and NG/endothelial cell adhesion by automated pipetting system. Cell-surface markers showed normal maturation of NGs in C1-INH-HAE patients. Adhesion of NGs to endothelial cells pretreated with lipopolysaccharide or phorbol 12-myristate 13-acetate was significantly weaker in samples from C1-INH-HAE patients and bradykinin had no effect on the adhesion. NGs from C1-INH-HAE patients were in an activated state when assessed by soluble activation markers without any stimulation. Our data support that the maturation of NGs in C1-INH-HAE patients is normal, whereas adhesion properties of patient-derived NGs to the endothelium are reduced compared to those from healthy controls, indicating a bias between the circulating and marginated pools of NGs in patients. Bradykinin may not be responsible for reduced adhesion properties of NGs.

Abstract Background Autoantibodies against C1-inhibitor (C1-INH-Ab) have a diagnostic value in acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), even though antibodies can circulate in complexes, which can be undetectable by proven methods. Our aim was to measure C1-INH/C1-INH-Ab complexes (CAC) and investigate their connection to C1-INH-Ab and the changes in their titer over time. Results 19 patients were diagnosed with C1-INH-AAE in the Hungarian Angioedema Center of Reference and Excellence; 79% of them had an underlying disease. Samples were examined with a newly developed in-house complex ELISA method. Patients with high C1-INH-Ab titer had a CAC titer which did not exceed the normal level and the ones with high CAC titer had a C1-INH-Ab titer which did not exceed the normal level. In case of those patients who had C1-INH-Ab and CAC of the same type of immunoglobulin, the increasing titer of C1-INH-Ab went together with the decreasing level of CAC and vice versa. CAC titer was already increased before the diagnosis of the underlying disease. Conclusions Free circulating and complex antibodies are in a dynamically changing equilibrium. CAC measurements can help to predict the development of an underlying disease. The efficiency of the treatment for underlying disease can be monitored by the decreasing CAC titers. Our results show that the CAC can be of important additional information besides the complement panel examination in case of C1-INH-AAE. Measurement of CAC is recommended to be done parallelly with C1-INH-Ab, so as to detect both free and bound antibodies.

Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease, which often appears with hematological underlying diseases. It can be diagnosed by complement testing and its treatment consists of the management of the underlying disease and angioedema attacks.The patient (59 year-old male) who was taking angiotensin-converting-enzyme inhibitor, was referred to the Hungarian Angioedema Center of Reference and Excellence due to an upper airway edema which did not respond to conventional treatment and required tracheotomy. At our Center, C1-INH-AAE was diagnosed, and myeloma multiplex was found as an underlying disease. He have been followed up for the past 15 years.After the first treatment series (chemotherapy and stem cell transplantation), his complement parameters returned to normal, but 5 years later they started to deteriorate, and the angioedema attacks recurred. To avoid the recurrence of myeloma multiplex, and due to the frequent and serious angioedema attacks, the patient got another series of rituximab treatment. It resulted in the normalization of complement values, and he had no further angioedema attacks.Angiotensin-convertase-enzyme inhibitors can trigger C1-INH-AAE.The recurrence of the underlying disease or the angioedema attacks can be predicted by the regular follow up of the complement parameters. Thus, the treatment of the underlying disease can be started in time, before the onset of severe symptoms.

Acquired angioedema due to C1-inhibitor deficiency (C1–INH-AAE) is a rare disease that can be diagnosed via complement testing. It often accompanies lymphoproliferative underlying diseases. Our study aimed to examine if there is a connection between complement parameters and the clinical symptoms of C1–INH-AAE, and, in case of a known underlying disease, its activity. The other question is how a connection, if proven, could help in the development of the therapeutic strategy of C1–INH-AAE patients.In the past 30 years, out of the 3938 patients sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1–INH-AAE in 19 cases. An underlying disease was diagnosed in 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found.Angioedema specific long-term prophylaxis did not result in an improvement in neither the frequency of the attacks nor in the complement parameters.A connection has been found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Decreasing complement parameters warn about the appearance or the worsening of the underlying disease. The treatment of the underlying disease brings improvement in the complement parameters.Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Complement parameters supported the long-term efficacy of rituximab treatment for C1–INH-AAE.The change in complement parameters predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In C1–INH-AAE, it is essential to examine the patients for underlying diseases, and to regularly follow up the patient's complement parameters.

Abstract Background Angioedemas localized in the upper airway are potentially life threatening, and without proper treatment, they may lead to death by suffocation. Upper airway edemas (UAE) in bradykinin‐mediated angioedemas can even be the first symptoms of the disease. Methods Our survey was performed with a retrospective long‐term follow‐up method from the medical history of 197 hereditary (C1‐INH‐HAE) and 20 acquired C1‐inhibitor deficiency (C1‐INH‐AAE), 3 factor XII and 3 plasminogen gene mutation (FXII‐HAE, PLG‐HAE) patients treated at our center between 1990 and 2020. The UAE group included edemas localized to the mesopharynx, hypopharynx, and larynx, as narrowing of these anatomical regions can lead to suffocation. Results 98/197 C1‐INH‐HAE (47 families) and 13/20 C1‐INH‐AAE, 1/3 PLG‐HAE, 1/3 FXII‐HAE patients had experienced UAE at least once according to their medical history. In case of C1‐INH‐HAE patients, in 6/47 families who had undiagnosed ancestors had 13 members who died of suffocation. After the diagnosis, 1‐1 member of two families died of UAE. 44/64 C1‐INH‐HAE patients did not smoke, 20/64 did. The occurrence of UAE was significantly higher in smoker patients. We analyzed 7607 HAE attacks of 56/98 patients. Out of all attacks, the incidence of UAE in the C1‐INH‐HAE group was 4%, and 9.5% in the C1‐INH‐AAE group, respectively. Conclusion Early diagnosis is key in bradykinin‐mediated angioedemas cases, since the patient must be provided with adequate treatment; and also it is essential to inform patients about the importance of avoiding the trigger factors and the early symptoms of UAE, as these measures could significantly decrease the incidence of lethal UAEs.