Significance of individual management plan for the patients with hereditary lymphangioedema during pregnancy and lactation, and in newborns

Hereditary angioedema (HAE) is a genetically caused orphan disease with a high risk of developing life-threatening attacks, thus requiring availability for up-to-date information on this problem for the doctors of any specialties. A limited number of observations determine the value of the analysis for each clinical case. Many facets of clinical manifestations, a list of predisposing and triggering factors, as well as limitations of some diagnostic and therapeutic algorithms, require the development of individual management schemes under distinct clinical situations. In this paper, we present the unique clinical cases with certain limitations, describing unexpected onset of the disease in the course of pregnancy, management aspects during delivery and post-delivery periods in a women with a previously confirmed HAE diagnosis. Adapted diagnostic algorithms of postnatal diagnostic verification are presented for children with burdened genetic history. We express some assumptions about involvement of a multidisciplinary team of specialists, personalized approach to building a management plan with an “online” correction depending on observation stage of НАЕ patient

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Сравнительный анализ применения тоцилизумаба при тяжелых COVID-19-ассоциированных пневмониях у пациентов разных возрастных групп

According to accumulated clinical data, one of the causes of severe damage to lung epithelial cells associated with SARS-CoV-2 (2019-nCoV) is an acute, timely underestimated "cytokine storm" (cytokine cascade, hypercytokinaemia) with characteristic signs of an expressed hyper-inflammatory syndrome with subsequent polyorganic failure. The study presents the results of the analysis of the effectiveness of tocilizumab therapy (TCZ) in patients (n = 181) of different age groups with developed pneumonia caused by SARS-CoV-2. The aim of the study was to evaluate the effectiveness of TCZ therapy in patients of different age groups with developed pneumonia in the frame of COVID-19. Methods. Patients (n = 181) with community-acquired pneumonia caused by coronavirus SARS-CoV-2 are included in a one-center, non-randomized, prospective study to evaluate the effectiveness of TCZ therapy conducted at the State Public Health Institution "City Clinical Hospital No.52" of the Moscow City Health Department. Patients were divided into 3 age subgroups – up to 50 years, 50–70 years and over 70 years. Patients with community-acquired SARS-CoV-2-induced pneumonia receiving non-invasive oxygen support and patients who had artificial lung ventilation (ALV) were given a single dose of 400 mg of TCZ in addition to basic therapy. Results. There are no significant differences between age groups in the severity of pneumonia according to the data of the computed tomography (CT), however, a more severe condition and a higher mortality rate (p < 0.001) were reliably observed in patients over 70 age compared to the other age groups. After TCZ treatment in patients of each age group, the severity of the condition assessed on the National Early Warning Score (NEWS2) has been significantly reduced compared to the baseline. Conclusion. According to the data of the pilot study the efficacy and safety of TCZ in patients of all presented age groups with COVID-associated pulmonary tissue lesion and signs of "cytokine storm" was demonstrated. At the same time, patients up to 50 years after the therapy of TCZ managed to achieve greater clinical efficiency compared to patients in other groups. According to the severity of the state and laboratory criteria, the lowest clinical efficacy of TCZ therapy was observed in patients over 70 years of age; as a consequence, the highest mortality rate was observed in the same group. At the same time, the TCZ therapy has not had a positive impact on the change of laboratory values and the severity of the disease in case of unfavorable outcome. Согласно накопленным клиническим данным, одной из причин тяжелых повреждений клеток эпителия легких, ассоциированных с SARS-CoV-2 (2019-nCoV), является острый, вовремя недооцененный синдром «цитокинового шторма» (цитокиновый каскад, гиперцитокинемия) с характерными признаками выраженного гипервоспалительного синдрома с последующей полиорганной недоста - точностью. В работе представлены результаты анализа эффективности терапии тоцилизумабом (ТЦЗ) у пациентов (n = 181) разных возрастных групп с развившейся пневмонией в рамках COVID-19. Целью исследования явилась оценка эффективности терапии ТЦЗ у пациентов разных возрастных групп с развившейся пневмонией, вызванной SARS-CoV-2. Материалы и методы. В одноцентровом нерандомизированном проспективном исследовании оценки эффективности терапии ТЦЗ, проведенном на базе Государственного бюд жетного учреждения здравоохранения «Городская клиническая больница № 52» Департамента здравоохранения города Мос - квы, приняли участие пациенты (n = 181) с внебольничной пневмонией, вызванной коронавирусом SARS-CoV-2. Больные были распределены в 3 возрастные подгруппы: до 50 лет, 50–70 лет, старше 70 лет. Пациентам с внебольничной пневмонией, вызванной SARS-CoV-2, получающим неинвазивную кислородную поддержку, и больным, у которых проводилась искусственная вентиляция легких (ИВЛ), в до полнение к основной терапии назначен ТЦЗ однократно в дозе 400 мг. Результаты. Достоверных различий между возрастными группами по тяжести пневмонии по данным компьютерной томографии (КТ) не выявлено, однако отмечено достоверно более тяжелое состояние и более высокий уровень смертности (p < 0,001) у больных старше 70 лет по сравнению с остальными возрастными группами. После терапии ТЦЗ у больных каждой из возрастных групп тяжесть состояния, оцененная по шкале National Early Warning Score (NEWS2), достоверно снизилась по сравнению с исходными показателями. Заключение. По данным пилотного исследования продемонстрирована эффективность и безопасность применения ТЦЗ у пациентов всех представленных возрастных групп с COVID-ассоциированным повреждением легочной ткани и признаками «цитокинового шторма». При этом у пациентов до 50 лет после терапии ТЦЗ удалось добиться бόльшей клинической эффективности по сравнению с больными остальных групп. По степени тяжести состояния и лабораторным критериям самая низкая клиническая эффективность терапии ТЦЗ отмечена у пациентов старше 70 лет; как следствие, в этой же группе отмечен самый высокий уровень смертности. При этом в случае неблагоприятного исхода терапия ТЦЗ не оказывала положительного влияния на изменение лабораторных показателей и степень тяжести заболевания.

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination : results of the UCARE COVAC-CU study

Background: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy. Objective: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. Methods: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. Results: Across 2769 COVID-19–vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination–induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination–induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine–related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. Conclusions: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination:Results of the UCARE COVAC-CU study

Background: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy.Objective: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. Methods: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. Results: Across 2769 COVID-19–vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination–induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started &lt;48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination–induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine–related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. Conclusions: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated.</p