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Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Altres ajuts: Generalitat de Catalunya's Department de salut (SLD015); Consorcio Centro de Investigación Biomédica en Red (CB-2021) Background. Prophylactic vaccination has proven to be the most effective strategy to fight the COVID-19 pandemic. Methods. This was a prospective observational cohort study involving 30 predominantly antibody deficiency disorders (ADD)-afflicted adult patients on immunoglobulin replacement therapy vaccinated with three doses of the mRNA-1273 COVID-19 vaccine, and 10 healthy controls. Anti-RBD IgG antibodies were determined in plasma samples collected just before the first dose of mRNA-based COVID-19 vaccine and on weeks 4, 8, 24, and 28 following the first vaccination. Patients were categorized based on the levels of anti-RBD antibodies determined on w8 as non-, low-, and responders. Chi-square and Kruskal-Wallis tests were used to see if any variables correlated with humoral response levels. Any adverse effects of the mRNA-based vaccine were also noted. Results. The COVID-19 vaccine was safe and well-tolerated. The humoral response elicited at w8 after vaccination depended on the type of ADD, the type of immunoglobulin deficiency, the presence of granulomatous lymphocytic interstitial lung disease, recent use of immunosuppressive drugs, and the switched memory B cells counts. The third vaccine dose boosted humoral response in previous responders to second dose but seldom in non-responders. Conclusions: The humoral response of patients with predominant ADD depends mostly on the type of immunodeficiency and on the frequency of B and T cell populations.

Patients with antibody deficiency disorders, such as primary immunodeficiency (PID) or secondary immunodeficiency (SID) to B-cell lymphoproliferative disorder (B-CLPD), are two groups vulnerable to developing the severe or chronic form of coronavirus disease caused by SARS-CoV-2 (COVID-19). The data on adaptive immune responses against SARS-CoV-2 are well described in healthy donors, but still limited in patients with antibody deficiency of a different cause. Herein, we analyzed spike-specific IFN-γ and anti-spike IgG antibody responses at 3 to 6 months after exposure to SARS-CoV-2 derived from vaccination and/or infection in two cohorts of immunodeficient patients (PID vs. SID) compared to healthy controls (HCs). Pre-vaccine anti-SARS-CoV-2 cellular responses before vaccine administration were measured in 10 PID patients. Baseline cellular responses were detectable in 4 out of 10 PID patients who had COVID-19 prior to vaccination, perceiving an increase in cellular responses after two-dose vaccination (p < 0.001). Adequate specific cellular responses were observed in 18 out of 20 (90%) PID patients, in 14 out of 20 (70%) SID patients and in 74 out of 81 (96%) HCs after vaccination (and natural infection in some cases). Specific IFN-γ response was significantly higher in HC with respect to PID (1908.5 mUI/mL vs. 1694.1 mUI/mL; p = 0.005). Whereas all SID and HC patients mounted a specific humoral immune response, only 80% of PID patients showed positive anti-SARS-CoV-2 IgG. The titer of anti-SARS-CoV-2 IgG was significantly lower in SID compared with HC patients (p = 0.040), without significant differences between PID and HC patients (p = 0.123) and between PID and SID patients (p =0.683). High proportions of PID and SID patients showed adequate specific cellular responses to receptor binding domain (RBD) neoantigen, with a divergence between the two arms of the adaptive immune response in PID and SID patients. We also focused on the correlation of protection of positive SARS-CoV-2 cellular response to omicron exposure: 27 out of 81 (33.3%) HCs referred COVID-19 detected by PCR or antigen test, 24 with a mild course, 1 with moderate symptoms and the remaining 2 with bilateral pneumonia that were treated in an outpatient basis. Our results might support the relevance of these immunological studies to determine the correlation of protection with severe disease and for deciding the need for additional boosters on a personalized basis. Follow-up studies are required to evaluate the duration and variability in the immune response to COVID-19 vaccination or infection.

IntroductionHigh-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers.MethodsPeripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots.ResultsQuantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells.ConclusionQuantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

INTRODUCTION: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers. METHODS: Peripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed ex vivo using flow cytometry. Additionally, B cell function was assessed with T cell dependent (TD) and T cell independent (TI) stimulation assays, analyzing proliferation and differentiation of B cells by flow cytometry and numbers of immunoglobulin secreting cells in ELISpots. RESULTS: Quantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells. CONCLUSION: Quantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

The Coronavirus disease 2019 (COVID-19) pandemic has represented an unprecedented challenge for humankind from health, economic, and social viewpoints. In February 2020, Italy was the first western country to be deeply hit by the pandemic and suffered the highest case/fatality rate among western countries. Brand new anti-COVID-19 vaccines have been developed and made available in

Immunodeficiencies (IDs) are disorders of the immune system that increase susceptibilityto infections and cancer, and are therefore associated with elevated morbidity and mortality. IDs can be primary (not caused by other condiciono or exposure) or secondary due to the exposure to different agents (infections, chemicals, aging, etc.). Most primary immunodeficiencies (PIDs) are of genetic origin, caused by mutations affecting genes with key roles in the development or function of the cells of the immune system. A large percentage of PIDs are associated with a defective development and/or function of ymphocytes and, especially, B cells, the ones in charge of generating the different types of antibodies. B-cell development is a tightly regulated process in which many different factors participate. Among the regulators of B-cell differentiation, a correct epigenetic control of cellular identity is essential for normal cell function. With the advent of next-generation sequencing (NGS) techniques, more and more alterations in different types of epigenetic regulators are being described at the root of PIDs, both in humans and in animal models. At the same time, it is becoming increasingly clear that epigenetic alterations triggered by the exposure to environmental agents have a key role in the development of secondary immunodeficiencies (SIDs). Due to their largely reversible nature, epigenetic modifications are quickly becoming key therapeutic targets in other diseases where their contribution has been known for more time, like cancer. Here, we establish a parallelism between IDs and the nowadays accepted role of epigenetics in cancer initiation and progression, and propose that epigenetics forms a ¿third axis¿ (together with genetics and external agents) to be considered in the etiology of IDs, and linking PIDs and SIDs at the molecular level. We therefore postulate that IDs arise due to a variable contribution of (i) genetic, (ii) environmental, and (iii) epigenetic causes, which in fact form a continuum landscape of all possible combinations of these factors. Additionally, this implies the possibility of a fully epigenetically triggered mechanism for some IDs. This concept would have important prophylactic and translational implications, and would also imply a more blurred frontier between primary and secondary immunodeficiencies., FEDER, the “Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III” (PI14/00025), MINECO (SAF2017-83061-R), the “Fundación Ramón Areces,” the “Federación Española de Enfermedades Raras,” the “Asociación Muévete por los que no Pueden,” and a Research Contract with the “Fundación Síndrome de Wolf-Hirschhorn o 4p-.” Institutional grants from the “Fundación Ramón Areces” and “Banco de Santander

Қазіргі кездегі иммунологиялық жетістіктеріне қарамай, клиникалық иммунология алдында екіншілік иммунды тапшылықтар мәселелеріне қатысты сұрақтар әлі де дәрігермамандардың назарын алуда. Екіншілік иммунды тапшылықтар жағдайларын анықтау және дер кезінде коррекциялау, негізгі аурулардың емдеу нәтижелерін айтарлықтай жақсартады., Despite the present immunological progress, questions regarding secondary immunоdeficiencies in clinical immunology still face the attention of health professionals. Identification and timely adequate correction of secondary immunodeficiency states will significantly improve the results of treatment of major diseases.

Установлено, что ассоциативные желудочно-кишечные заболевания свиней регулярно регистрируются в хозяйствах края, поражая молодняк в возрасте от 1 до 3 месяцев. Заболеваемость поросят в различных хозяйствах составляет от 20% до 60%. Характер таких заболеваний в большинстве случаев зачастую имеет бактериальную и вирусно-бактериальную этиологию и возникают как на фоне вторичных иммунодефицитов, так и могут являться причиной этих иммунодефицитов. Неполноценное питание животных, неблагоприятные условия содержания, воздействие химических, физических факторов, болезни обмена веществ и многие других причины могут вызывать вторичные иммунодефициты, характеризующиеся нарушением специфических факторов защиты организма. Впервые месяцы жизни состояние неспецифической резистентности играет ключевую роль в защите организма животных от инфекционных агентов. В отличие от гуморального иммунитета, неспецифические факторы защиты у молодняка сельскохозяйственных животных имеет большую физиологическую зрелость и не так значительно отличается от показателей взрослых животных. Это обусловлено тем, что синтез всех ее компонентов генетически детерминирован, и они присутствуют в организме к моменту рождения. Определена терапевтическая эффективность комплексного препарата при ассоциативных желудочно-кишечных заболеваниях свиней на фоне вторичных иммунодефицитов. Изучены ингибирующие свойства сыворотки крови животных до и после применения препарата в реакции ингибирования активности антител и рассчитан индекс ингибирования (ИИ). Установлено, что ИИ равный 1,1 и более показывает наличие иммунологической недостаточности в организме, что способствует возникновению ассоциативных заболеваний животных. Терапевтическая эффективность лекарственного средства составила 90%. Использование препарата в схеме профилактических и лечебных мероприятий, направленных на борьбу с ассоциативными желудочно-кишечными заболеваниями свиней бактериальной этиологии на фоне вторичных иммунодефицитов, стимулирует бактерицидную и лизоцимную активность сыворотки крови у поросят, что позволяет сократить гибель животных и увеличить сохранность поголовья., It has been established that associative gastrointestinal diseases of pigs are regularly recorded in the farms of the region, affecting young animals between 1 and 3 months of age. The incidence of piglets in various farms ranges from 20% to 60%. The nature of such diseases in most cases has a bacterial and viral­bacterial etiology and occurs both against the background of secondary immunodeficiencies and may be the cause of these immunodeficiencies. Inadequate nutrition of animals, adverse conditions of exposure, exposure to chemical, physical factors, metabolic diseases and many other factors can cause secondary immunodeficiencies characterized by violation of specific body resistance factors. During the first months of life, the state of nonspecific resistance plays a key role in protecting the animal’s body against infectious agents. Unlike humoral immunity, non­specific protective factors in young farm animals have greater physiological maturity and are not so significantly different from those of adult animals. This is due to the fact that the synthesis of all its components is genetically determined, and they are present in the body at the time of birth. The therapeutic efficacy of a complex drug in associative gastrointestinal diseases of pigs on the background of secondary immunodeficiency was determined. The inhibitory properties of the blood serum of animals before and after the use of the drug in the reaction of inhibiting antibody activity were studied and the index of inhibition (II) was calculated. It is established that II equal to 1.1 and more indicates the presence of immunological deficiency in the body, which contributes to the emergence of associative diseases of animals. The therapeutic efficacy of the drug was 90%. The use of the drug in the scheme of preventive and therapeutic measures aimed at combating associative gastrointestinal diseases of pigs of bacterial etiology against the background of secondary immunodeficiencies stimulates the bactericidal and lysozyme activity of blood serum in piglets, which allows to reduce the animals’ death and increase the safety of livestock., №8 (2019)

Intravenous immunoglobulins (IVIg) are therapeutic preparations of normal human IgG that have been used for more than 20 years for substitutive therapy in patients with primary antibody deficiencies. Recent studies pointed out the need to obtain normal residual levels of IgG (i.e. 8 g/L) in order to reduce the number and severity of bacterial infections in these patients. The IVIg are also prescribed for the substitutive therapy of secondary immunodeficiencies such as chronic lymphoid leukemia and multiple myeloma with hypogammaglobulinemia and severe and/or recurrent infections, and human immunodeficiency virus (HIV)-infected children with recurrent bacterial infections before the era of highly active antiretroviral agents. However, in the latter situation, no recent study has evaluated IVIg therapy in acquired immunodeficiency syndrome (AIDS) children receiving highly active antiretroviral agents (HAART), and the use of IVIg must probably be restricted to the currently rare clinical situation in Western Europe of children with AIDS who develop recurrent infections despite the administration of HAART and prophylactic cotrimoxazole. IVIg have also been reported to prevent infections, interstitial pneumonia and graft-vs. host disease during the first 90 days post-transplant in allogeneic bone-marrow transplant recipients. However, this result was not confirmed by two recent studies and IVIg therapy should probably only be proposed for a subgroup of bone-marrow allografted patients such as those with hypogammaglobulinemia and sepsis. With the exception of erythrovirus B19 infection with erythroblastopenia, no clear benefit of IVIg therapy has been reported for the curative management of other infectious diseases.

Patients with secondary immunodeficiencies are at a high risk of infection. Currently some of these infections are preventable through specific immunization. Prevention of these diseases can diminish morbidity and mortality amongst these patients. In this review we describe the use of vaccines in persons with secondary immunodeficiencies.

Patients with secondary immunodeficiencies are at a high risk of infection. Currently some of these infections are preventable through specific immunization. Prevention of these diseases can diminish morbidity and mortality amongst these patients. In this review we describe the use of vaccines in persons with secondary immunodeficiencies.