Clinical and experimental treatment of primary humoral immunodeficiencies.

Selective IgA deficiency (sIgAD), common variable immunodeficiency (CVID), and transient hypogammaglobulinemia of infancy (THI) are the most frequent forms of primary antibody deficiencies. Difficulties in initial diagnosis, especially in the early childhood, the familiar occurrence of these diseases, as well as the possibility of progression to each other suggest common cellular and molecular patomechanism and a similar genetic background. In this review, we discuss both similarities and differences of these three humoral immunodeficiencies, focusing on current and novel therapeutic approaches. We summarize immunoglobulin substitution, antibiotic prophylaxis, treatment of autoimmune diseases, and other common complications, i.e. cytopenias, gastrointestinal complications, and granulomatous disease. We discuss novel therapeutic approaches such as allogenic stem cell transplantation and therapies targeting-specific proteins, dependent on the patient's genetic defect. The diversity of possible therapeutics models results from a great heterogeneity of the disease variants, implying the need of personalized medicine approach as a future of primary humoral immunodeficiencies treatment.

Management of humoral secondary immunodeficiency in hematological malignancies and following hematopoietic stem cell transplantation: Regional perspectives.

Secondary immunodeficiency (SID) can occur as a result of multiple factors, including hematological malignancies, hematopoietic stem cell transplantation (HSCT), immunosuppressive treatment, biologics, and anti-inflammatory drugs. SID includes disorders resulting from impairment of both cellular and humoral immunity. This review focuses on the current risk factors, implications, and challenges in managing SID patients with impaired humoral immunity, which includes quantitative (hypogammaglobulinemia) and/or functional antibody and B-cell deficiencies specifically related to hematological malignancies and post-HSCT. Increased physician awareness is needed surrounding the disease presentation and early risk factors, as SID may be caused by several etiologies. Careful clinical assessment is then required to optimize management, which encompasses close monitoring of clinical parameters, vaccination, antibiotic prophylaxis, and immunoglobulin replacement therapy (IGRT). Novel methods of IGRT administration are associated with enhanced pharmacokinetics, IgG trough level stability, no need for venous access, as well as fewer systemic adverse events and better administration flexibility compared with traditional methods. Published international guidelines supported by observations from clinical data are broadly followed; however, best practices within each country have nuances that underline the need to tailor treatment plans to the individual patient.

A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review.

INTRODUCTION: Deficiency of adenosine deaminase 2 (DADA2) is a rare monogenic autoinflammatory disease, whose clinical phenotype was expanded since the first cases, originally described as mimicker of polyarteritis nodosa, with immunodeficiency and early-onset stroke. METHODS: A systematic review according to PRISMA approach, including all articles published before the 31st of August 2021 in Pubmed and EMBASE database was performed. RESULTS: The search identified 90 publications describing 378 unique patients (55.8% male). To date 95unique mutations have been reported. The mean age at disease onset was 92.15 months (range 0-720 months), 32 (8.5%) showed an onset of the first signs/symptoms after 18 years old and 96 (25.4%) after 10 years old. The most frequent clinical characteristics described were cutaneous (67.9%), haematological manifestations (56.3%), recurrent fever (51.3%), neurological as stroke and polyneuropathy (51%), immunological abnormalities (42.3%), arthralgia/arthritis (35.4%), splenomegaly (30.6%), abdominal involvement (29.8%), hepatomegaly (23.5%), recurrent infections (18.5%), myalgia (17.9%), kidney involvement (17.7%) etc. Patients with skin manifestations were older than the others (101.1 months SD ± 116.5, vs. 75.3 SD ± 88.2, p 0.041), while those with a haematological involvement (64.1 months SD ± 75.6 vs. 133.1 SD ± 133.1, p < 0.001) and immunological involvement (73.03 months SD ± 96.9 vs. 103.2 SD ± 112.9, p 0.05) are younger than the others. We observed different correlations among the different clinical manifestations. The use of anti-TNFα and hematopoietic cell stems transplantation (HCST) has improved the current history of the disease. CONCLUSION: Due to this highly variable phenotype and age of presentation, patients with DADA2 may present to several type of specialists. Given the important morbidity and mortality, early diagnosis and treatment are mandatory.

Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency - Three consecutive cases and review of the literature.

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.

Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency – Three consecutive cases and review of the literature / Tratamiento de la COVID-19 con plasma de convalecientes en pacientes con inmunodeficiencia humoral. Tres casos consecutivos y revisión de la literatura

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.(AU)

Se ha sugerido que los pacientes carentes de respuesta inmune humoral desarrollan una forma menos severa de COVID-19, pero existen algunos casos de curso prolongado, recurrente o incluso mortal. Desde abril de 2020 existen evidencias de los beneficios del plasma de convalecientes de COVID-19 (PCC) en los pacientes con inmunodeficiencia humoral. La mayoría tienen una inmunodeficiencia congénita primaria o están recibiendo tratamiento con anticuerpos anti-CD20. Describimos tres pacientes con inmunodeficiencia humoral y COVID-19 tratados con PCC en nuestro centro y revisamos los 31 casos más descritos en la literatura. Todos resolvieron el cuadro clínico con PCC, salvo tres. Una dosis de 200-800 mL fue suficiente en la mayoría de los casos. Los niveles de anticuerpos tras la transfusión fueron negativos o bajos, sugiriendo el consumo de los mismos en la neutralización del SARS-CoV-2. Estos pacientes tienen un curso clínico prolongado que se acorta tras la administración del PCC. El PCC podría ser de utilidad en los pacientes con inmunodeficiencia humoral. Evita las recaídas y la cronificación de la COVID-19. El PCC debería transfundirse lo antes posible en los pacientes con COVID-19 e inmunodeficiencia humoral.(AU)

Respiratory microbiota as a good predictor of outcome in humoral immunodeficiency. Methodological and conceptual difficulties in comprehensive microbiome analysis.

The microbiome as a broad term defines the most dynamic ecological system in which, apart from the biocenosis, there is unique niche for its development, equally dynamic, because host-derived, contrary to physical environment in ecology. Although for years, antibodies, was recognized as a key element of the mucosal barrier, there is still no progress in comprehensive linking microbes and humoral elements. Which organism is a pathogen and which is a commensal - there are still no exact answers (and criteria). Also the discrepancy between experimental research, using more and more sophisticated techniques -showing the existence of nearly 900 bacterial species in our mouth was observed. On the contrary, bacterial infections caused by novel species have not been recognised in patients with humoral immunodeficiencies, apart from the capsular cocci and H. influenzae. Research on human virome, including CMV, is also focused on the cellular immunity, but in many situations in the clinic the humoral compartment are the exclusive, still effective, barrier against viral replication. AIM: The aim of study was to perform an integrated microbiome analysis (microbiota and host) for strict linking various microbiota constelation and end-stage clinical manifestation in humoral immunodeficiency. MATERIALS AND METHODS: This cross-study based on own clinical experience reveal crucial gap in the literature. RESULTS: It indicate the natural competition: why the sentinel microorganism in humoral deficiency - S. pneumoniae dominates in some patients, and in others - Viridans Group Streptococci. Crucial role of high specific IgM level in several CVID complication was described. Furthermore, respiratory microbiota translocation with cancer regression and influence of therapeutic regimen on clinical sequel (predominantly infectious or malignant) were presented. The studies indicates numerous methodological and microecological classification difficulties, which are the source of inadequate, often contradictory conclusions from experimental research. CONCLUSIONS: Microecology describe ecosystem that consists of all the organisms and the abiotic physical environment with which they interact: i.e. biocenosis and biotope but clinical immunology -microorganisms in biotic (cellular) niche in host. Unfortunately, these studies are focused on the anecdotal "healthy" biocenosis (healthy microbiome), without analyzing other elements of the niche, for example cancer. Overall, focusing on the gut microbiota clearly restrict our knowledge on the manifestation of humoral deficiencies in respiratory system. The work is a summary of the search for representative clinical models and microbiological methods (diagnostic chain) in clinical immunology practice.

Inmunodeficiencias humorales en pacientes adultos. Cuatro décadas de seguimiento / Antibody deficiencies in adults. Forty years of follow up

Resumen Las inmunodeficiencias humorales (IDH) comprenden un grupo de enfermedades caracterizadas por una deficiente respuesta mediada por anticuerpos. Se clasifican en primarias (IDHP), causa das por defectos propios del sistema inmune, o secundarias (IDHS) a otras enfermedades o fármacos. Nuestro objetivo fue revisar la evolución de las IDH asistidas en la Unidad Inmunología del Hospital Durand entre 1982 y 2020, dividido en dos periodos, Periodo I (1982-2009) y Periodo II (2010-2020); para evaluar el crecimiento de éstas, sus características epidemiológicas y las formas de tratamiento. Se evaluaron 205 pacientes, 176 (85.8%) IDHP y 29 (14.2%) IDHS. Las IDHP más diagnosticadas fueron: inmunodeficiencia común variable en 104 (59%) pacientes, agammaglobulinemia ligada al cromosoma X en 17 (9.6%) y deficiencia selectiva de IgA en 26 (14.8%). En 25 (14.2%) IDHP se realizó un diagnóstico molecular. Las causas de IDHS fueron: secundaria a rituximab en 21 (72.4%) pacientes, enfermedades hematológicas en tres (10.2%) y fármacos antiepilépticos en tres. Un total de 161 (78.5%) pacientes recibieron gammaglobulina, 140 (87%) IDHP y 21 (13%) IDHS; 152 (94.4%) fueron tratados con gammaglobulina endovenosa y nueve (5.6%) con gammaglobulina subcutánea. De los tratados inicialmente con forma endovenosa, 30 (19.7%) cambiaron a subcutánea. El crecimiento en la can tidad de pacientes entre ambos periodos del estudio fue mayor al 250%, y al 700% en pacientes incorporados por año. El crecimiento de las IDHS con relación al de las IDHP fue más del doble. Al finalizar el estudio 125 pacientes continuaban en seguimiento, 80% IDHP y 20% IDHS, y 14 fallecieron.

Abstract Antibody deficiencies (AD) are characterized by low or absent immunoglobulin levels or the inability to develop a specific antibody response. They are classified in primary (PAD) when there is an intrinsic immune defect, or secondary (SAD) to other dis eases or drugs. The aim of our study was to review the evolutio n of AD assisted at the Immunology Unit, Hospital Durand between 1982 and 2020, divided into two periods: Period I (1982-2009) and Period II (2010-2020); to evaluate their growth, epidemiologic features and treatment options. A total of 205 patients were identified, 176 (85.8%) with PAD and 29 (14.2%) with SAD. The most frequent PAD were common variable immunodeficiency in 104 (59%) patients, X linked agammaglobulinemia in 17 (9.6%) and selective IgA deficiency in 26 (14.8%). Genetic defects were found in 25 (14.2%) patients with PAD. SAD cases were associated with rituximab in 21 (72.4%) subjects, haematological disease in three (10.2%) and with antiepileptic drugs in other three; 161 (78.5%) patients were treated with immunoglobulins, 140 (87%) PAD y 21 (13%) SAD; 152 (94.4%) received intravenous immunoglobulins and nine (5.6%) subcutaneous immunoglobulins. Thirty (19.7%) patients treated at first with intravenous immunoglobulins changed to subcutaneous formulations. The increase in number of patients between both periods was greater than 250%, and more than 700% in patients added per year. SAD growth was greater than twice times comparing with PAD. By the end of the study 125 patients continued in follow up, 80% PAD y 20% SAD and 14 died.

[Antibody deficiencies in adults. Forty years of follow up]. / Inmunodeficiencias humorales en pacientes adultos. Cuatro décadas de seguimiento.

Antibody deficiencies (AD) are characterized by low or absent immunoglobulin levels or the inability to develop a specific antibody response. They are classified in primary (PAD) when there is an intrinsic immune defect, or secondary (SAD) to other diseases or drugs. The aim of our study was to review the evolutio n of AD assisted at the Immunology Unit, Hospital Durand between 1982 and 2020, divided into two periods: Period I (1982-2009) and Period II (2010-2020); to evaluate their growth, epidemiologic features and treatment options. A total of 205 patients were identified, 176 (85.8%) with PAD and 29 (14.2%) with SAD. The most frequent PAD were common variable immunodeficiency in 104 (59%) patients, X linked agammaglobulinemia in 17 (9.6%) and selective IgA deficiency in 26 (14.8%). Genetic defects were found in 25 (14.2%) patients with PAD. SAD cases were associated with rituximab in 21 (72.4%) subjects, haematological disease in three (10.2%) and with antiepileptic drugs in other three; 161 (78.5%) patients were treated with immunoglobulins, 140 (87%) PAD y 21 (13%) SAD; 152 (94.4%) received intravenous immunoglobulins and nine (5.6%) subcutaneous immunoglobulins. Thirty (19.7%) patients treated at first with intravenous immunoglobulins changed to subcutaneous formulations. The increase in number of patients between both periods was greater than 250%, and more than 700% in patients added per year. SAD growth was greater than twice times comparing with PAD. By the end of the study 125 patients continued in follow up, 80% PAD y 20% SAD and 14 died.

Las inmunodeficiencias humorales (IDH) comprenden un grupo de enfermedades caracterizadas por una deficiente respuesta mediada por anticuerpos. Se clasifican en primarias (IDHP), causadas por defectos propios del sistema inmune, o secundarias (IDHS) a otras enfermedades o fármacos. Nuestro objetivo fue revisar la evolución de las IDH asistidas en la Unidad Inmunología del Hospital Durand entre 1982 y 2020, dividido en dos periodos, Periodo I (1982-2009) y Periodo II (2010-2020); para evaluar el crecimiento de éstas, sus características epidemiológicas y las formas de tratamiento. Se evaluaron 205 pacientes, 176 (85.8%) IDHP y 29 (14.2%) IDHS. Las IDHP más diagnosticadas fueron: inmunodeficiencia común variable en 104 (59%) pacientes, agammaglobulinemia ligada al cromosoma X en 17 (9.6%) y deficiencia selectiva de IgA en 26 (14.8%). En 25 (14.2%) IDHP se realizó un diagnóstico molecular. Las causas de IDHS fueron: secundaria a rituximab en 21 (72.4%) pacientes, enfermedades hematológicas en tres (10.2%) y fármacos antiepilépticos en tres. Un total de 161 (78.5%) pacientes recibieron gammaglobulina, 140 (87%) IDHP y 21 (13%) IDHS; 152 (94.4%) fueron tratados con gammaglobulina endovenosa y nueve (5.6%) con gammaglobulina subcutánea. De los tratados inicialmente con forma endovenosa, 30 (19.7%) cambiaron a subcutánea. El crecimiento en la cantidad de pacientes entre ambos periodos del estudio fue mayor al 250%, y al 700% en pacientes incorporados por año. El crecimiento de las IDHS con relación al de las IDHP fue más del doble. Al finalizar el estudio 125 pacientes continuaban en seguimiento, 80% IDHP y 20% IDHS, y 14 fallecieron.

Response to Severe Acute Respiratory Syndrome Coronavirus 2 Initial Series and Additional Dose Vaccine in Patients With Predominant Antibody Deficiency.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with predominant antibody deficiency (PAD) is associated with high morbidity, yet data regarding the response to SARS-CoV-2 immunization in PAD patients, including additional dose vaccine, are limited. OBJECTIVE: To characterize antibody response to SARS-CoV-2 vaccine in PAD patients and define correlates of vaccine response. METHODS: We assessed the levels and function of anti-SARS-CoV-2 antibodies in 62 PAD patients compared with matched healthy controls at baseline, at 4 to 6 weeks after the initial series of immunization (a single dose of Ad26.COV2.S [Janssen] or two doses of BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]), and at 4 to 6 weeks after an additional dose immunization, if received. RESULTS: After the initial series of SARS-CoV-2 vaccination, PAD patients had lower mean anti-spike antibody levels compared with matched healthy controls (140.1 vs 547.3 U/mL; P = .02). Patients with secondary PAD (eg, B-cell depletion therapy was used) and those with severe primary PAD (eg, common variable immunodeficiency with autoinflammatory complications) had the lowest mean anti-spike antibody levels. Immune correlates of a low anti-spike antibody response included low CD4+ T helper cells, low CD19+ total B cells, and low class-switched memory (CD27+IgD/M-) B cells. In addition, a low (<100 U/mL) anti-spike antibody response was associated with prior exposure to B-cell depletion therapy, both at any time in the past (odds ratio = 5.5; confidence interval, 1.5-20.4; P = .01) and proximal to vaccination (odds ratio = 36.4; confidence interval, 1.7-791.9; P = .02). Additional dose immunization with an mRNA vaccine in a subset of 31 PAD patients increased mean anti-spike antibody levels (76.3 U/mL before to 1065 U/mL after the additional dose; P < .0001). CONCLUSIONS: Patients with secondary and severe primary PAD, characterized by low T helper cells, low B cells, and/or low class-switched memory B cells, were at risk for low antibody response to SARS-CoV-2 immunization, which improved after an additional dose vaccination in most patients.

Case Report: Zellweger Syndrome and Humoral Immunodeficiency: The Relevance of Newborn Screening for Primary Immunodeficiency.

Background: Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs). Case Presentation: We report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected. Conclusion: In this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.

A Patient with Kabuki Syndrome Mutation Presenting with Very Severe Aplastic Anemia.

Kabuki syndrome (KS) is a rare congenital disorder commonly complicated by humoral immunodeficiency. Patients with KS present with mutation in the histone-lysine N-methyltransferase 2D (KMT2D) gene. Although various KMT2D mutations are often identified in lymphoma and leukemia, those encountered in aplastic anemia (AA) are limited. Herein, we present the case of a 45-year-old Japanese man who developed severe pancytopenia and hypogammaglobulinemia. He did not present with any evident malformations, intellectual disability, or detectable levels of autoantibodies. However, B-cell development was impaired. Therefore, a diagnosis of very severe AA due to a hypoplastic marrow, which did not respond to granulocyte colony-stimulating factor, was made. The patient received umbilical cord blood transplantation but died from a Pseudomonas infection before neutrophil engraftment. Trio whole-exome sequencing revealed a novel missense heterozygous mutation c.15959G >A (p.R5320H) in exon 50 of the KMT2D gene. Moreover, Sanger sequencing of peripheral blood and bone marrow mononuclear cells and a skin biopsy specimen obtained from this patient identified this heterozygous mutation, suggesting that de novo mutation associated with KS occurred in the early embryonic development. Our case showed a novel association between KS mutation and adult-onset AA.

Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency.

PURPOSE: Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. METHODS: In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. RESULTS: The median age of the patients was 10 years (mean 20.7 years, range 1-44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. CONCLUSION: Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

The 13-Valent Pneumococcal Conjugate Vaccine Elicits Serological Response and Lasting Protection in Selected Patients With Primary Humoral Immunodeficiency.

Background: Patients with primary humoral immunodeficiency are more prone to invasive as well as recurrent pneumococcal infections. Therefore, anti-pneumococcal vaccination including the 13-valent conjugate vaccine is recommended. Nevertheless, to date, no data is available on immunogenicity of this vaccine in this population. Objective: To assess the immunogenicity and the persistence of protection up to one year after a 13-valent pneumococcal conjugate vaccine in patients with primary humoral immunodeficiency. Methods: Twenty-nine patients with common variable immunodeficiency or IgG subclass deficiency were vaccinated. Immune response and immune protection at baseline as well as at one, six and twelve months after vaccination were evaluated by measuring specific IgG serum concentrations (ELISA), and opsonophagocytic activities directed against selected pneumococcal (MOPA). Results: By ELISA, half of the patients had protective IgG concentrations before vaccination, 35.7% showed an immune response one month after vaccination, 71.4%, 66.7% and 56.0% of the patients were protected at one, six and twelve months respectively. Conversely, by MOPA, 3.4% of the patients were protected at baseline, 10.7% showed an immune response and 28.6%, 48.2% and 33.3% were protected at one, six and twelve months respectively. IgG subclass deficiency, Ig replacement therapy and higher IgG2 concentrations at diagnosis were associated with long-term protection. Conclusion: Pneumococcal conjugate vaccine improves immune protection and antibodies' functionality in a subset of patients with primary immunodeficiency. Prime-boost vaccine strategy needs to be better and individually adapted.

Pneumococcal serotype-specific cut-offs based on antibody responses to pneumococcal polysaccharide vaccination in healthy adults.

Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naïve adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4-6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.

Lessons Learned From the Clinical Presentation of Common Variable Immunodeficiency Disorders: A Systematic Review and Meta-Analysis.

Background: Diagnostic delay in common variable immunodeficiency disorders (CVID) is considerable. There is no generally accepted symptom-recognition framework for its early detection. Objective: To systematically review all existing data on the clinical presentation of CVID. Methods: PubMed, EMBASE and Cochrane were searched for cohort studies, published January/1999-December/2019, detailing the clinical manifestations before, at and after the CVID-diagnosis. Results: In 51 studies (n=8521 patients) 134 presenting and 270 total clinical manifestations were identified. Recurrent upper and/or lower respiratory infections were present at diagnosis in 75%. Many patients had suffered severe bacterial infections (osteomyelitis 4%, meningitis 6%, septicemia 8%, mastoiditis 8%). Bronchiectasis (28%), lymphadenopathy (27%), splenomegaly (13%), inflammatory bowel disease (11%), autoimmune cytopenia (10%) and idiopathic thrombocytopenia (6%) were also frequently reported. A bimodal sex distribution was found, with male predominance in children (62%) and female predominance in adults (58%). 25% of CVID-patients developed other manifestations besides infections in childhood, this percentage was much higher in adults (62%). Immune-dysregulation features, such as granulomatous-lymphocytic interstitial lung disease and inflammatory bowel disease, were more prominent in adults. Conclusions: The shift from male predominance in childhood to female predominance in adults suggests differences in genetic and environmental etiology in CVID and has consequences for pathophysiologic studies. We confirm the high frequency of respiratory infections at presentation, but also show a high incidence of severe bacterial infections such as sepsis and meningitis, and immune dysregulation features including lymphoproliferative, gastrointestinal and autoimmune manifestations. Early detection of CVID may be improved by screening for antibody deficiency in patients with these manifestations.

Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency - Three consecutive cases and review of the literature.

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.

Kinetics of immune reconstitution after anti-CD19 chimeric antigen receptor T cell therapy in relapsed or refractory acute lymphoblastic leukemia patients.

INTRODUCTION: Anti-CD19 chimeric antigen receptor (CAR) -T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti-CD19 CAR-T cell therapy. METHODS: Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti-CD19 CAR-T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow-up within 60 days post-infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. RESULTS: CD8+ cells were the first to recover with a median time on day 21(7-87), followed by CD16/CD56+ cells on day 28(14-87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post-infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41-118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post-infusion. IgG recovered in 6 patients with a median time on day 184(89-346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. CONCLUSIONS: Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti-CD19 CAR-T cell therapy.

Chronic Lymphocytic Leukemia-Induced Humoral Immunosuppression: A Systematic Review.

Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact of humoral immunity deficiency on the clinical and therapeutic approach. A systematic literature review was carried out by two independent authors who searched PubMed databases for studies published up to January 2020. Additionally, Google Scholar was used to evaluate search results and support manual research. The search resulted in 240 articles eligible for analysis. After all criteria and filters were applied, 22 studies were finally applied to the analysis. The data analysis showed that the clinical heterogeneity of CLL patients correlates with the diversity of molecular abnormalities determining the clinical picture of the disease, the analysis of which enables setting therapeutic targets. Additionally, in improving the therapeutic method, it is worth introducing supportive therapies with the use of vaccines, antibiotics and/or immunoglobins. Moreover, humoral immunodeficiency in CLL has a strong influence on the risk of infection in patients for whom infections are a major cause of morbidity and mortality.

Evaluation of pulmonary findings in patients with humoral immunodeficiency.

AIM: To determine the frequency of sinopulmonary infections, detect changes in the respiratory system, and measure functional capacity of the lungs in our patients with humoral immunodeficiency. MATERIAL AND METHODS: Fifty-six patients with humoral immunodeficiency were enrolled in this study. The clinical, laboratory, and radiologic data, and pulmonary function tests of the subjects were evaluated from their file records, retrospectively. RESULTS: The distribution of our patients was as follows: 25 patients had common variable immune deficiency, three patients had X-linked agammaglobulinemia, five patients had hyper immunoglobulin M syndrome, 19 patients had deficiency of immunoglobulin G subset, and four patients had selective immunoglobulin A deficiency. The most common symptom of the patients was chronic cough (n=47, 83.9%). The most common pathologies on high-resolution computed tomography of the chest were atelectasis and bronchiectasis (27.7%). The most common pathology in pulmonary function tests was the presence of moderate obstructive patterns along with restrictive patterns (n=6,12.5%). The FEV 1, FVC, and FEF 25-75 values were significantly lower in patients with common variable immunodeficiency compared with the patients who had IgG subset deficiencies (p=0.001, p=0.01, p=0.01). Among the patients who were treated with intravenous immunoglobulin, the age at the diagnosis of immunodeficiency was higher in patients with bronchiectasis (14.2±8.4 years) compared with those without bronchiectasis (10.1±11.4 years) (p=0.04). CONCLUSION: Clinical findings are not sufficient to monitor the structural and functional changes in the respiratory system, and patients should be evaluated using high-resolution computed tomography of the chest and pulmonary function tests.

Focusing on Good Responders to Pneumococcal Polysaccharide Vaccination in General Hospital Patients Suspected for Immunodeficiency. A Decision Tree Based on the 23-Valent Pneumococcal IgG Assay.

Background and Aim: Recently, the 23-valent IgG-assay was suggested as screening assay to identify poor responders to pneumococcal polysaccharide (PnPS)-vaccination with the serotype-specific assay as a second-line test. However, in a low pre-test probability general hospital setting predicting good responders could be more valuable to reduce the number of samples needing serotyping. Methods: Serotype-specific PnPS antibody-assays were performed for suspected immunodeficiency in two Dutch general hospitals (Jeroen Bosch Hospital, 's-Hertogenbosch; Elisabeth Tweesteden Hospital, Tilburg). 23-Valent PnPS antibody-assays were subsequently performed in archived material. Data were analyzed using receiver operating characteristic curves (AUC) and agreement indices (ICC). Results: Sera of 284 patients (348 samples) were included; 23-valent IgG-titres and the corresponding sum of PnPS-serotype specific antibodies showed moderate correlation (ICC = 0.63). In 232 conjugated-pneumococcal-vaccine-naïve patients (270 samples), a random 23-valent IgG-titer could discriminate between samples with and without ≥7/11, ≥7/13, or ≥6/9 pneumococcal serotypes when both cut-off values 0.35 and 1.0 µg/ml were used (AUC 0.86 and 0.92, respectively). All patients with a pre-immunization-titer ≥38.2 µg/ml and/or post-immunization-titer ≥96.1 µg/ml and none with a post-immunization-titer ≤38.5 µg/ml exhibited a good response to PnPS vaccination. Using these breakpoints as screening test to predict good responders, only 24% of patients would require further serotyping, as opposed to 68% if breakpoints to predict poor responders would have been used. Conclusion: In a low pre-test probability setting, the 23-valent IgG-assay proved to be a reliable screening test for good responders in conjugated-pneumococcal-vaccine-naïve patients, reducing the overall number of patient samples needing further serotyping, thus reducing overall costs of pneumococcal vaccination response assessment.