Normal Immunoglobulin Research Articles

Innate immunodeficiencies: a group of primary immunodeficiencies predisposing exclusively to common diseases

Abstract Background Innate immune deficiencies can impair both cellular and humoral immune responses. In contrast, other immune functions may appear normal, leading to increased susceptibility to specific pathogens, such as severe viral infections or Mendelian Susceptibility to Mycobacterial Disease (MSMD). Studying these deficiencies is essential for understanding the pathophysiology of these infectious diseases. Main body While primary immunodeficiencies (PIDs) generally cause vulnerability to multiple infections, innate immunodeficiencies increase susceptibility to specific pathogens, despite normal immune responses to others. Patients with these deficiencies show normal immunoglobulins and lymphocyte subpopulations, complicating diagnosis. This review highlights genetic susceptibility to mycobacteria, pneumococci, herpes simplex virus, and candidiasis, emphasizing recognizing this subset of PIDs. Conclusion This review highlights the diverse spectrum of genetic mutations contributing to defects in innate and intrinsic immunity, including Mendelian susceptibility to mycobacterial disease (MSMD), chronic mucocutaneous candidiasis, and predispositions to invasive bacterial and viral infections. Identifying key mutations in pathprovideh such as TLR3, IFN signaling, and IL-17A/F immunity provides valuable insights into the pathogenesis of these conditions. Our findings underscore the need for early genetic diagnosis and targeted interventions, particularly in regions with high undiagnosed cases, to reduce the morbidity and mortality associated with defects in innate and intrinsic immunity.

P35 Pyrexia of unknown origin in a patient with long standing rheumatoid arthritis

Abstract Introduction Pyrexia of unknown origin (PUO) can be challenging in treated rheumatic auto-immune disease. Many conditions may have fever as part of the symptom complex, treatment may mask signs and symptoms and can also make opportunistic infection more likely. Unusual or fastidious infections can be particularly difficult to diagnose. We describe a case of ureaplasma infection that evaded detection for a prolonged period in a female with long standing rheumatoid arthritis (RA). Case description 47 year old female presented January 2023 with fevers, weight loss and persistently high CRP. RA diagnosed in 1998. Erosive wrist and MTP disease, initial RF 32, CCP 8. Treatment- 5-10 mg prednisolone since 1998, adalimumab 2010, rituximab 2013-2022. Normal Ig levels, IgG lamda paraprotein since 2016 (too low to quantify). Frequency and dysuria March 2022. Cystoscopy- small bladder; biopsies in May 2022 and August 2023 showed acute on chronic inflammatory infiltrate with granulation tissue. Interstitial cystitis diagnosed. She had recurrent episodes of pyuria and was given several courses of antibiotics, including meropenem, temocillin, fluconazole, gentamicin. Despite the recurrent pyuria no organisms were cultured. CT CAP February 2023 -ground glass opacity right lower lobe. Later CXR clear. Quantiferon negative, also negative 2016, 2019. Other normal / negative tests- TTG, HIV, Hep ABCE, TFTs, EBV viral load. EBV, CMV IgG +ve. CMV titres 696 c/ml June 2023. CD 19 undetectable. IgG4 0.02 g/L. MPO, PR3 negative. BK virus was detected in urine. There was no sustained response to iv methylprednisolone and a course of filgotinib given for possible systemic RA symptoms. She developed a dry cough and shortness of breath. PET-CT July 2023 - bilateral FDG avid large confluent areas of consolidation. Urine + bronchial washings were negative for TB growth at 42 days. However, in view of deterioration empirical TB treatment was started July 2023. CT urogram in September 2023 showed likely bilateral renal abcesses, as well as bilateral hydronephrosis. Left renal cyst aspirate was performed and empirical doxycycline started at 100 mg bd. Ureaplasma detected from the aspirate on PCR. 3 weeks doxycyline given with rapid resolution of fevers and CRP. February 2024- cystectomy and ileal conduit in for refractory interstitial cystitis with a poorly compliant, small capacity, thick walled fibrotic bladder which had caused bilateral ureteric obstruction. She has made a good recovery. TB treatment course was completed. Discussion This case shows the difficulties in diagnosing infection from a little known and difficult to detect organism, ureaplasma. Discovered in the 1950s, it has no cell wall and very small genome and is therefore an obligate parasite /saprophyte. Together with mycoplasma it belongs to the bacterial class of Mollicutes. It cannot be routinely cultured nor gram stained. PCR or specialist culture is required. It may be present as a commensal but has been implicated in symptomatic genitourinary infections. It has also been implicated in native and non-native joint infections, and in infants can cause a pneumonic illness. Empirical treatment may be indicated due to long turn around times for diagnosis. There is some evidence that reduced humoral immunity may be a contributory factor to infection. We have found a previous case described of ureaplasma renal abcesses in a patient with MS and neurogenic bladder treated with rituximab. Our patient had normal immunoglobulin levels though still had profound CD19 suppression. Further immune suppression resulted from methylprednisolone and course of filgotinib, which may have accelerated the course of infection. Ureaplasma and mycoplasma do not have a cell wall, thus making beta-lactam antibiotics and vancomycin ineffective. Cyclines, josamycin and fluroquinolones are effective, though there is increasing resistance developing. We gave a relatively long course of doxycycline as our patient was very unwell and had apparent extensive urinary tract involvement. BK virus seropositivity is present in 90% of the normal population and asymptomatic viruria in up to 20%. However, it is a cause of renal tract inflammation in the immunosuppressed – in particular post-transplant. We felt it was unlikely to be significant in our patient in view of the clinical picture, lack of BK viraemia and negative viral findings on bladder biopsy. Key learning points • Ureaplasma should be on the list of organisms to consider in cases of PUO when the more common infective causes have been ruled out, particularly in immune suppressed patients. Patience and close collaboration with colleagues is essential. This patient had multiple MDT meetings involving infectious disease, respiratory, secondary and tertiary care urology and rheumatology specialists. The collaboration was invaluable. A course of doxycycline may be considered as a relatively low risk approach while awaiting microbiological confirmation in such cases.

Measuring the impact of automated dispensing cabinets implementation on data and inventory management of human normal immunoglobulin in an acute teaching hospital: A pre- and post- intervention study

BackgroundHuman Normal Immunoglobulin (HNIg) is a complex plasma-derived blood product used to treat a variety of medical conditions. Global supply problems have increased focus on HNIg stewardship, including mandatory recording of HNIg usage on the National Immunoglobulin Database (NIgD). Local departmental audits identified significant inconsistencies in data uploaded to NIgD. Inventory management issues caused a number of stock losses in the last financial year. A paper-based HNIg batch number recording system was replaced with the use of Automated Dispensing Cabinets (ADCs), which generated an electronic batch number report, with matching fields required for electronic upload to NIgD. AimTo measure the impact of ADC implementation on the accuracy of data uploaded to NIgD, HNIg stock control and staff time associated with processes of HNIg data and inventory management. MethodThree months of pre- and post-implementation HNIg dispensing data was compared to the data uploaded to the NIgD for discrepancies. Inventory reports were used to identify unexplained stock adjustments. Time and motion methods were used to quantify staff time associated with HNIg activities. ResultsPre-implementation: 20.7 % (3762.5 g/18,217 g) of HNIg by volume (23.7 % of dispensing episodes; 66/279) were inaccurately uploaded or absent on the NIgD and three stock adjustments were made (loss of >£15 k). Post-implementation: 12 % (2325 g/19,347 g) of HNIg by volume (10.8 % of dispensing episodes; 31/286) were inaccurately uploaded or absent on the NIgD and zero stock adjustments were observed; Mean time for dispensing per HNIg prescription reduced from 17 min to 8 min; Time spent uploading data to NIgD per month reduced from 5 h to 1.75 h. Discussion/ConclusionThe use of ADCs improved accuracy of NIgD data upload. Following implementation direct observations have cited unregistered or finished patient episodes, dispensing procedural compliance, and user familiarity with the system as common reasons for incomplete data uploads to NIgD. The new ADC process had consequences of forcing dispensing procedure compliance to improve uploads, whilst reducing dispensing times. It led to improved stock control and removed upload burden from dispensers. ADC stock discrepancy alerts allowed staff to proactively resolve discrepancies in real time. Time taken for additional processes to support management of stocks in ADCs, including monthly stock cycle counts, were important considerations for implementation. The key advantage of using ADC batch number reports is the ability to upload as a single monthly batch without having to manually access individual patient records on the NIgD. It facilitates early identification of failed upload attempts and supports resolution of stock discrepancies.

Long-Term Survival and Immune Reconstitution of Donor-Derived Chimeric Antigen Receptor T-Cell Therapy for Childhood Molecular Relapse of B-Cell Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an independent risk factor for relapse in patients with acute lymphoblastic leukemia (ALL). This study aimed to assess the efficacy, safety, and immune reconstitution of chimeric antigen receptor T-cell (CAR-T) therapy in patients with molecular relapse after allo-HSCT. Eleven patients with molecular relapse of B-cell-ALL who underwent CAR-T therapy after allo-HSCT were enrolled. The rate of MRD negativity after a month of CAR-T infusion was 81.8%. Patients who bridged to second-HSCT after CAR-T therapy (n = 3) showed a trend of higher 3-year leukemia-free survival and 3-year overall survival than those who did not (n = 8; 100% vs. 75.0%; 95% CI, 45.0–104.9%; p = 0.370). No treatment-related mortalities were observed. Among patients who did not bridge to second-HSCT and remained in complete remission until the last follow-up (n = 6), five of them had not recovered normal immunoglobulin concentrations with a median follow-up of 43 months. CAR-T therapy may be a safe and effective treatment strategy to improve survival after allo-HSCT; however, the problem of prolonged hypogammaglobulinemia in patients who do not bridge to second-HSCT is worth noting.

An unusual case of HHV-8 negative, idiopathic, multicentric Castleman disease following chronic lymphocytic leukaemia

Background: Castleman disease is a rare condition characterised by polytypic lymphocytes proliferation and lymphadenopathy generally with a benign course. Whereas high grade lymphoma (Richter syndrome) is a classical complication seen in chronic lymphocytic leukaemia with a poor outcome, benign conditions mimicking this entity are infrequent. Case description: We describe the case of an 81-year-old Caucasian male who developed a human herpesvirus-8 (HHV-8)–negative, idiopathic multicentric Castleman disease (iMCD) following a treated Binet C chronic lymphocytic leukaemia (CLL). The clinical and radiological pattern raised initially the suspicion of a classical Richter transformation. Blood analysis showed auto-immune haemolytic anaemia and thrombocytopenia. He had normal immunoglobulin levels. The anatomopathological analysis of a cervical adenomegaly showed hypervascularisation and a polytypic plasmocytic proliferation compatible with a plasmocytic iMCD type. Interestingly, bone marrow examination showed reticuline fibrosis but, in the absence of anasarca or generalised oedema, we were not allowed to conclude to the diagnosis of a TAFRO syndrome. We exclude all other mimicking conditions, comprising haematological malignancies, infections, and auto-immune diseases He was first treated with corticosteroids with poor results but dramatically responded to tocilizumab (anti-Il6). Conclusion: To our knowledge, this the first case described of a Castleman disease following CLL and surprisingly mimicking Richter syndrome. Clinicians should be aware of this rare misleading condition.

Allergy and Adenoids: Is There any Correlation?

To determine the association of adenoid hypertrophy with allergic rhinitis in pediatric patients based on Simplified Visual Analog Scale and serum IgE levels. The present study was conducted in our tertiary care centre on 130 patients planned for adenoidectomy from May 2022 to June 2023. Children were divided into two groups based on IgE levels and Allergic history- Group I: who had raised immunoglobulin E levels with allergic rhinitis (according to ARIA guidelines) before adenoidectomy (n = 69) and Group II: who had normal immunoglobulin E levels pre-operatively (n = 72). VAS scoring was done in both groups and compared pre and post operatively. In our study it was found that the adenoid volume was more in patients with allergic history and increased IgE levels as compared to those with normal IgE levels (p < 0.05) pre-operatively. Also, the difference between pre-operative VAS score among Group I and Group II was statistically significant (p = 0.046). Also, the difference between postoperative VAS score among Group I and group II was also statistically significant (p = 0.043). There was statistically significant higher change in VAS score in Group II post-operatively (p = 0.027). sOur study demonstrates that children with allergic rhinitis tend to present earlier with symptoms of adenoid hypertrophy. In addition, children without allergic history show better post-operative VAS scores as the allergic component still prevails in children with allergic history.

A Cross-Sectional Study of Measles-Specific Antibody Levels in Australian Blood Donors-Implications for Measles Post-Elimination Countries.

Passive immunisation with normal human immunoglobulin (NHIG) is recommended as post-exposure prophylaxis (PEP) for higher-risk measles contacts where vaccination is contraindicated. However, the concentration of measles-specific antibodies in NHIG depends on antibody levels within pooled donor plasma. There are concerns that measles immunity in the Australian population may be declining over time and that blood donors' levels will progressively decrease, impacting levels required to produce effective NHIG for measles PEP. A cross-sectional study of Australian plasmapheresis donors was performed using an age-stratified, random sample of recovered serum specimens, collected between October and November 2019 (n = 1199). Measles-specific IgG antibodies were quantified by ELISA (Enzygnost anti-measles virus IgG, Siemens), and negative and equivocal specimens (n = 149) also underwent plaque reduction neutralisation testing (PRNT). Mean antibody levels (optical density values) progressively decreased from older to younger birth cohorts, from 2.09 [±0.09, 95% CI] to 0.58 [±0.04, 95% CI] in donors born in 1940-1959 and 1990-2001, respectively (p < 0.0001). This study shows that mean measles-specific IgG levels are significantly lower in younger Australian donors. While current NHIG selection policies target older donors, as younger birth cohorts become an increasingly larger proportion of contributing donors, measles-specific antibody concentrations of NHIG will progressively reduce. We therefore recommend monitoring measles-specific antibody levels in future donors and NHIG products in Australia and other countries that eliminated measles before the birth of their youngest blood donors.

Novel Mutation in the Moesin (MSN) Gene Leads to Immunodeficiency with Epstein-Barr Virus (EBV) Infection and Dermatomyositis-Like Symptoms.

Moesin (MSN) deficiency is a recently reported combined immunodeficiency, and few cases have been reported to date. We describe a Chinese patient with a novel mutation causing MSN deficiency and a novel phenotype. Clinical and immunological data were collected. Whole-exome sequencing was performed to identify gene mutations. MSN protein expression and T cell proliferation and activation were determined by flow cytometry. Cell migration was confirmed with a Transwell assay. Autoantibody levels were analyzed using antigen microarrays. The patient was a 10-year-old boy who presented with recurrent fever, oral ulcers and dermatomyositis-like symptoms, such as periorbital edema, facial swelling, elevated creatine kinase levels, and abnormal electromyography and muscle biopsy results. Epstein-Barr virus (EBV) DNA was detected in the serum, cells and tissues of this patient. He further developed nasal-type NK/T-cell lymphoma. A novel hemizygous mutation (c.68A > G, p.N23S) in the MSN gene was found. The immunological phenotype of this patient included persistent decreases in T and B lymphocyte counts but normal immunoglobulin IgG levels. The patient had attenuated MSN protein expression and impaired T-cell proliferation and migration. The proportions of Tfh cells and CD21low B cells in the patient were higher than those in the controls. Moreover, 82 IgG and 102 IgM autoantibodies were more abundant in the patient than in the healthy controls. The novel mutation N23S is pathogenic and leads to a severe clinical phenotype. EBV infection, tumor, and dermatomyositis-like autoimmune symptoms may be associated with MSN deficiency, further expanding the understanding of the disease.

Clinical efficacy of prophylactic intravenous immunoglobulin for elderly DLBCL patients with hypogammaglobulinemia in the COVID-19 pandemic era.

Elderly patients diagnosed with diffuse large B-cell lymphoma (DLBCL) undergoing reduced intensity R-CHOP therapy are at a heightened risk of acquiring infections, notably coronavirus disease 2019 (COVID-19) infection. This study aimed to evaluate the efficacy of intravenous immunoglobulin (IVIG) as prophylaxis against COVID-19 in this vulnerable population. A total of 125 elderly patients with DLBCL undergoing reduced intensity R-CHOP therapy were analyzed in this prospective, multicenter study. Patients with hypogammaglobulinemia were categorized into IVIG and non-IVIG groups, while those with normal immunoglobulin levels constituted the observation group. The study evaluated COVID-19 infection rates, therapy response, and safety outcomes. Among the enrolled patients (median age: 77 years), 89 patients (71.2%) presented with hypogammaglobulinemia at diagnosis, and 56 patients enrolled in the IVIG administration group. IVIG administration remarkably reduced COVID-19 infection rates compared to non-IVIG recipients (8.9% vs. 24.6%; p =0.040). Notably, patients over 80 years old were more susceptible to COVID-19. Patients on IVIG exhibited good tolerance with manageable adverse events. Among patients with hypogammaglobulinemia who received IVIG, 40.5% of patients developed additional immunoglobulin deficiencies during chemotherapy. One or more new hypogammaglobulinemia occurred during chemotherapy in 72% of patients with hypogammaglobulinemia who did not receive IVIG, and in 61.3% of patients who did not have hypogammaglobulinemia at diagnosis. IVIG showed promise in reducing COVID-19 infections among elderly patients with DLBCL receiving reduced intensity R-CHOP therapy. This highlights IVIG's potential as a prophylactic measure, necessitating further investigation to optimize dosing, administration schedules, and potential interactions with vaccination strategies.

Second- and third-line treatment agents in autoimmune hepatitis (AIH): Where do we stand?

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology that can lead to end stage liver disease if left without treatment. Corticosteroids with or without azathioprine (AZA) are considered the recommended standard first-line treatment option for the induction and maintenance of remission. The aim of treatment is to achieve complete biochemical response (CBR), defined by normal transaminases and immunoglobulin G (IgG) within 6–12 months after treatment initiation. However, response rates to standard treatment vary widely as approximately 10–25% of cases develop intolerance, insufficient response, or rarely non-response to AZA. Mycophenolate mofetil (MMF) is an effective and safe alternative first-line treatment in AIH, based on its high rates of CBR among treatment-naive patients, but can also be considered as second-line drug in patients with poor response or intolerance to AZA. However, even after the administration of second line treatment there is a small proportion of patients with refractory disease that bear the highest probability of developing decompensated cirrhosis and hepatocellular carcinoma. For this difficult to treat subgroup of patients third-line treatments are warranted. Therefore, the aim of this review is to summarize the current evidence on second- and third-line therapies for AIH, as well as, to set the background for future perspectives on safer and more efficient treatment strategies.

Justification of Intensive care management of children with severe COVID19 (а case study)

the unprecedented COVID-19 pandemic that spread across the world and lasted for more than 3 years had significant medical and social consequences. Despite the fact that in the children's population the coronavirus infection has a milder course and a much lower risk of mortality, there are individual cases with pre-existing comorbidities that cause severe acute respiratory distress syndrome. Thus, in most cases, severe COVID-19 developed in children with pre-existing conditions, including: immunodeficiency, diabetes mellitus, bronchial asthma, etc. Therefore, comorbidities disposed children to progress to severe Covid-19 which requires treatments with more aggressive therapeutic tactics and personalised management. The article presents a clinical case of severe acute respiratory distress syndrome caused by the SARS-CoV-2 virus in an early age child. The patient was observed in the Anesthesiology and Intensive Therapy Department of the Chernivtsi Regional Children's Clinical Hospital. Due to acute respiratory infection, the child has been developing signs of respiratory failure. The available instrumental findings confirmed right lung pneumonia, complicated by pneumothorax. Laboratory tests confirmed leukocytosis, thrombocytopenia, hypertransfusion, increased procalcitonin, increased level of C-reactive protein, D-dimer and interleukin-6 as well as circulating immune complexes. The treatment regimen included respiratory protection (oxygen therapy), support of hemodynamics (infusion of glucose-saline solutions), administration of intravenous normal human immunoglobulin, a short course of parenteral glucocorticosteroids, the use of step-by-step combined antibacterial therapy and a direct-acting antiviral drug (remdesivir), and thromboembolism prophylaxis (low-molecular-weight heparin). Following intensive treatment, the child's condition was characterised by a slow positive dynamics, leading to full recovery. This case demonstrates the need for timely detection of life-threatening conditions caused by COVID-19 and requires an aggressive management of child's condition using a complex intensive therapy.

Итоги открытого многоцентрового неинтервенционного наблюдательного проспективного исследования влияния на качество жизни препарата Кипферон®, применяемого у детей 0–7 лет с острыми респираторными вирусными инфекциями в условиях рутинной амбулаторно- поликлинической практики

Objective. To evaluate the dynamics of the quality of life of children aged 0 to 7 years with acute respiratory viral infections (ARVI) of mild and moderate severity when adding the drug Kipferon® (a mixture of normal human immunoglobulin and recombinant interferon α-2b) to standard therapy, as well as to determine the effect of this drug on the infectious morbidity of patients during 3 months following the course of treatment. Patients and Methods. A multicenter observational clinical study conducted at 19 clinical centers in Russia in routine outpatient and polyclinic practice included 855 children aged 0 to 7 years; the mean age was 3.5 ± 1.7 years. There were 460 (53.8%) boys and 395 (46.2%) girls. There were 89 children aged 0 to 1 year; older children were 766. Patients were divided into 2 groups: the main group (n = 656), children from which received Kipferon® (rectal suppositories, according to the instructions for use) for 7 days in addition to standard symptomatic therapy, and the control group (n = 199). The children were examined on admission, on the 3–5th and 6-8th day from the beginning of treatment; 1 and 3 months after the end of the course of therapy. The severity of the main clinical symptoms was evaluated using a 10-point system. The legal representatives of all patients signed informed consent. Statistical analysis of the results was performed using the methods of descriptive and variation statistics, Student and Mann–Whitney criteria; differences were considered reliable at p &lt; 0.05. Results. The initial general level of discomfort, as well as the degree of severity of 11 main symptoms of acute respiratory infection were comparable in both groups and significantly improved by the end of the treatment course. On the 3-5th day from the beginning of treatment in patients receiving Kipferon® preparation, statistically significant (p &lt; 0.05) improvement in all leading manifestations of ARVI was revealed, while in the control group improvement was registered only in 8 symptoms out of 11. In infants of the main group by the 3–5th day of treatment, difficulties in feeding and falling asleep significantly (p &lt; 0.05) decreased; older patients significantly better ate and slept, and were more physically active. Bacterial complications of ARVI in the main group developed 2 times less frequently: 36 (5.7%) cases vs. 20 (10.3%); the differences are reliable (p = 0.026) according to the χ2 criterion. Repeated acute respiratory viral infections during 3 months of follow-up were significantly (p &lt; 0.05) more frequent in children who did not receive Kipferon® (47.5% vs. 20.3%). No serious adverse events were detected during the use of Kipferon® preparation. Adverse events were recorded in 2 patients, none of them was classified as related to the use of the study drug; serious adverse events were absent during the entire observation period. Conclusion. The efficacy and safety of the immunomodulating drug Kipferon® allows us to recommend it as an important addition to symptomatic agents in the treatment of acute respiratory infections in pediatrics. Key words: children, interferons, Kipferon®, acute respiratory viral infections

An Unusual Case of HHV-8 Negative, Idiopathic, Multicentric Castleman Disease Following Chronic Lymphocytic Leukaemia.

Castleman disease is a rare condition characterised by polytypic lymphocytes proliferation and lymphadenopathy generally with a benign course. Whereas high grade lymphoma (Richter syndrome) is a classical complication seen in chronic lymphocytic leukaemia with a poor outcome, benign conditions mimicking this entity are infrequent. We describe the case of an 81-year-old Caucasian male who developed a human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) following a treated Binet C chronic lymphocytic leukaemia (CLL). The clinical and radiological pattern raised initially the suspicion of a classical Richter transformation. Blood analysis showed auto-immune haemolytic anaemia and thrombocytopenia. He had normal immunoglobulin levels. The anatomopathological analysis of a cervical adenomegaly showed hypervascularisation and a polytypic plasmocytic proliferation compatible with a plasmocytic iMCD type. Interestingly, bone marrow examination showed reticuline fibrosis but, in the absence of anasarca or generalised oedema, we were not allowed to conclude to the diagnosis of a TAFRO syndrome. We excluded all other mimicking conditions, comprising haematological malignancies, infections, and auto-immune diseases He was first treated with corticosteroids with poor results but dramatically responded to tocilizumab (anti-Il6). To our knowledge, this the first case described of a Castleman disease following CLL and surprisingly mimicking Richter syndrome. Clinicians should be aware of this rare misleading condition. Castleman disease can mimic a Richter transformation in a CLL patient.

Genetically corrected RAG2-SCID human hematopoietic stem cells restore V(D)J-recombinase and rescue lymphoid deficiency

AbstractRecombination-activating genes (RAG1 and RAG2) are critical for lymphoid cell development and function by initiating the variable (V), diversity (D), and joining (J) (V(D)J)-recombination process to generate polyclonal lymphocytes with broad antigen specificity. The clinical manifestations of defective RAG1/2 genes range from immune dysregulation to severe combined immunodeficiencies (SCIDs), causing life-threatening infections and death early in life without hematopoietic cell transplantation (HCT). Despite improvements, haploidentical HCT without myeloablative conditioning carries a high risk of graft failure and incomplete immune reconstitution. The RAG complex is only expressed during the G0-G1 phase of the cell cycle in the early stages of T- and B-cell development, underscoring that a direct gene correction might capture the precise temporal expression of the endogenous gene. Here, we report a feasibility study using the CRISPR/Cas9-based “universal gene-correction” approach for the RAG2 locus in human hematopoietic stem/progenitor cells (HSPCs) from healthy donors and RAG2-SCID patient. V(D)J-recombinase activity was restored after gene correction of RAG2-SCID-derived HSPCs, resulting in the development of T-cell receptor (TCR) αβ and γδ CD3+ cells and single-positive CD4+ and CD8+ lymphocytes. TCR repertoire analysis indicated a normal distribution of CDR3 length and preserved usage of the distal TRAV genes. We confirmed the in vivo rescue of B-cell development with normal immunoglobulin M surface expression and a significant decrease in CD56bright natural killer cells. Together, we provide specificity, toxicity, and efficacy data supporting the development of a gene-correction therapy to benefit RAG2-deficient patients.

Initial observations on the impact of implementation of automated dispensing cabinets for Human Normal Immunoglobulin on data and inventory management

Abstract Introduction Human Normal Immunoglobulin (HNIg) is a plasma-derived blood product used to treat a variety of diseases. Global supply problems1 have increased focus on HNIg stewardship, including mandatory recording of HNIg usage on the National Immunoglobulin Database2 (NIgD). This is a dispensary-based process and determines HNIg stock allocation and remuneration. Departmental audits identified significant delays and inconsistencies in data uploaded to NIgD. Inventory management issues caused a number of stock losses in the last financial year. A paper-based HNIg recording system was replaced with the use of Automated Dispensing Cabinets (ADCs). This enabled the development of an electronic ADC batch number report, from dispensing data, that matched fields required for electronic upload to NIgD, making the process more robust and proficient. Aim To measure the impact of implementation of ADCs for HNIg on data and inventory management. Objectives included identifying: Percentage of HNIg dispensed uploaded accurately to NIgD within one month of dispensing; Number of HNIg stock adjustments; Staff time required for activities associated with HNIg management. Methods Approval was obtained from the Trust Pharmacy Research and Audit Committee. The need for ethical submission was waived. Pre-implementation (May-July 2022) and post-implementation (February-April 2023) HNIg dispensing data was compared to the data uploaded to the NIgD for discrepancies. Electronic inventory reports were generated to identify the number of unexplained stock adjustments made. Time and motion methods were used to observe staff time associated with dispensing, stock management of HNIg in ADCs and data upload activities. Results Pre-implementation: 20.7% (3762.5g/18,217g) of HNIg (23.7% of dispensing episodes; 66/279) were inaccurately uploaded or absent on the NIgD and three stock adjustments were made. Post-implementation: 12% (2325g/19,347g) of HNIg (10.8% of dispensing episodes; 31/286) were inaccurately uploaded or absent on the NIgD and zero stock adjustments were observed; Mean time for dispensing HNIg reduced from 17 minutes/prescription to 8 minutes/prescription; Time spent uploading data to NIgD reduced from 5 hours to 1.75 hours/month. Discussion/Conclusion The use of ADCs has improved accuracy and completeness of data upload to NIgD. Direct observations have cited unregistered or finished patient episodes, dispensing procedural compliance, and user familiarity with the system as common reasons for incomplete data uploads to NIgD. Training is vital in assuring data quality and completeness. The new ADC process had unexpected consequences of forcing dispensing procedure compliance to improve uploads, whilst reducing dispensing times. It led to improved stock control and removed upload burden from dispensers. ADC stock discrepancy alerts allowed staff to proactively resolve discrepancies in real time. Time taken for additional processes to support management of stocks in ADCs, including monthly cycle counts, were important considerations for implementation. The key advantage of using ADC batch number reports is being able to upload as a single batch monthly without having to log into individual patient records on the system. It facilitates early identification of failed upload attempts, supporting resolution. Further work focusing on fully aligning naming conventions to NIgD should deliver additional efficiencies; minimising manipulations currently required prior to upload.

Liver inflammation activity in patients with autoimmune hepatitis with normal alanine aminotransferase and immunoglobulin G levels

Background and aimsNormal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. MethodsTwo hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. ResultsOne hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. ConclusionsHigh proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Impact of COVID 19 on Patients with Multiple Myeloma : A National Inpatient Sample Analysis

Introduction: Multiple myeloma (MM) is characterized by the proliferation of clonal immunoglobulins and suppression of normal immunoglobulins. These patients are susceptible to infections due to multiple factors such as hypogammaglobulinemia, impaired lymphocyte function, steroid-related immunosuppression, and neutropenia secondary to chemotherapy. There is limited data on the association of COVID-19 infection with in-hospital outcomes of MM. We hypothesize that COVID-19 infection is associated with adverse outcomes. Methodology: We queried the National Inpatient Sample (NIS) Database 2020 for adult (aged ≥ 18 years) hospitalizations with a primary diagnosis of MM. The cohort was subcategorized based on the presence of COVID-19 infection. The primary outcome studied was in-hospital mortality. Multiple secondary outcomes were analyzed including length of stay, cost of hospital stay, and individual organ system failures. Multivariable logistic regression was performed adjusting for patient and hospital level characteristics to evaluate outcomes. An alpha error of 0.05 was accepted for all analyses. Results: A total of 111,540 MM hospitalizations were included in the study, of which 2,195 (1.96%) had concomitant COVID-19 infection. The mean age was almost similar in both groups. Patients with MM and concurrent COVID-19 infection, had significantly higher in-hospital mortality [adjusted odds ratio (aOR) 6.54, 95% CI 5.25-8.20, p&amp;lt;0.001], length of stay [aOR 4.12 (2.92-5.32), p&amp;lt;0.001] and hospitalization cost [$54,940 ($34,688-$75,191), p&amp;lt;0.001]. They had higher rates of cardiac arrest (2.9% vs 1.1%, p&amp;lt;0.001), acute renal failure (48.8% vs 31.3%, p&amp;lt;0.001), acute liver failure (2.5 % vs 1.1%, p&amp;lt;0.001), acute respiratory failure (50.8% vs 17.3%, p&amp;lt;0.001). They also required higher levels of care in terms of hemodialysis (14.8% vs 8.8%, p&amp;lt;0.001), non-invasive ventilation (8.4% vs 3.3%, p&amp;lt;0.001), and invasive ventilation (1.6 % vs 0.3%, p&amp;lt;0.001). Discussion: Patients with MM who were admitted with COVID-19 had higher odds of in-hospital mortality, and developing (end-organ)complications such as cardiac arrest, respiratory failure, renal failure, and liver failure. They also had longer and costlier stays. The development of COVID-19 in patients with MM causes such poor outcomes likely due to shared endothelial dysfunction, thrombosis, and hyperinflammation. Prior studies have also shown impaired response to mRNA vaccination in this population. Thus, as COVID-19 restrictions are now at ease, increased vigilance is required in this vulnerable population. The limitations of our study are retrospective use of the administrative database with a potential of missing or inaccurate data, lack of information on specific treatments in MM patients limiting the ability to assess treatment-related outcomes, and unknown vaccination status.

Selektif IgE Eksikliği ve Otoimmun Hastalık İlişkisi

Abstract&#x0D; Introduction and Aim: Selective IgE deficiency (SIgED) is currently defined as a significant decrease in serum levels of IgE (≤2 kIU/L) in a patient whose other immunoglobulin levels are normal. The clinical spectrum of SIgED is unknown still. This study aimed to determine the relationship between SIgED and autoimmune diseases in an allergy and immunology clinic of a university hospital.&#x0D; Methods: A retrospective study of the data obtained from medical records of 40 patients, 27 were female (67.5%), and the mean age was 39 years (range 20–69 years) and IgE levels of ≤2.0 kIU/L with normal immunoglobulin (Ig) IgG, IgA, and IgM levels.&#x0D; Results: A total of 40 patients , 27 females (67.5 %) and 13 males (32.5%), were included in the study. The mean age of the patients was 39 ±13.06 years (range 20–69). In the present study, 35% of patients had an autoimmune disease (N:14), however 65% of patients did not have any autoimmune disease (N:26). Hashimoto’s thyroiditis being the most frequent (N:6) in 15% which is followed by systemic lupus erythematosus (SLE) (N:3) in 7.5%, celiac disease (N: 2) in 5%, chronic spontaneous urticaria (CSU) (N:1) in 2.5%, vitiligo (N:1) in 2.5%, type 1 diabetes mellitus (DM) (N:1) in 2.5%. &#x0D; Conclusion: SIgED, should be defined clearly with cut-off values of IgE. Physicians should show more attention to the low IgE values and investigate patients about autoimmune diseases which can be seen together with SIgED. More studies should be conducted to investigate associated diseases with SIgED.

Combined deficient response to polysaccharide-based and protein-based vaccines predicts a severe clinical phenotype.

Antibody response on polysaccharide- and protein-based vaccines is useful to test Bcell functionality. As only few studies have explored the value of studying immune response to both vaccines, we evaluated the clinical value of anti-polysaccharide and anti-protein Luminex-based multiplex assays in context of primary immunodeficiency (PID) diagnosis. A 10-plex Luminex-based assay detecting antibodies to ten pneumococcal polysaccharide (PnPS) serotypes [present in unconjugated Pneumovax, not in 13-valent pneumococcal conjugated vaccine (PCV)] and a 5-plex assay detecting antibodies to five protein antigens (present in DTap/Tdap) were clinically validated in healthy individuals (n=99) and in retrospective (n=399) and prospective (n=108) patient cohorts. Clinical features of individuals with impaired response to PnPS and/or proteins were compared to those with normal response. Antigen-specific antibody thresholds were determined in healthy individuals. Individuals with impaired anti-PnPS responses and deficient immunoglobulin levels suffered more from autoimmune diseases and had lower Bcell levels compared to individuals with impaired anti-PnPS response with normal immunoglobulin levels. Individuals with combined impaired response to PnPS and proteins showed more severe clinical manifestations compared to individuals with isolated impaired response to PnPS or proteins. Eight of the 11 individuals with severely impaired responses to both PnPS and proteins had common variable immunodeficiency. Evaluation of the anti-PnPS response to four serotypes not contained in 20-valent PCV was comparable to evaluation to ten serotypes not contained in 13-valent PCV. Multiplexed assessment of anti-PnPS and anti-protein responses combined with immunoglobulin quantification provides useful clinical information to support PID diagnosis.

Determination of optimum nanofiltration conditions for the manufacturing process of human normal immunoglobulin G for intravenous administration

Scientific relevance. Medicinal products based on immunoglobulin class G (IgG) from human plasma are widely used in clinical practice to treat bacterial and viral infections, primary and secondary immunodeficiencies, and autoimmune diseases. Nanofiltration is a way to mitigate the risk of in-process contamination of raw materials with various pathogens, including viruses. Therefore, it is relevant to investigate the development and implementation of additional viral inactivation and/or elimination steps.Aim. This study aimed to develop and validate optimum nanofiltration conditions and to scale up the nanofiltration step for the manufacturing of human IgG for intravenous administration.Materials and methods. The study used a solution of IgG from plasma fractions II and III. The authors paired nanofilters manufactured by Planova 20N and BioEx (Asahi Kasei, Japan), Viresolve Pro (Merck Millipore, USA), Virosart HC and HF (Sartorius, Germany), and Pegasus SV4 and Prime (Pall, USA) with Sartopore polyethersulphone prefilters by Sartorius (Germany), Virosart MAX polyamide prefilters by Sartorius (Germany), and EKX-P regenerated cellulose prefilters by Pall (Germany). Virus reduction validation studies were performed with model viruses (human immunodeficiency virus type 1, porcine transmissible gastroenteritis virus, porcine parvovirus, murine encephalomyocarditis virus, and bovine viral diarrhoea virus) in the laboratories of the N.F. Gamaleya centre. The sample data analysis involved calculating mean values with 95% confidence intervals.Results. For all the selected combinations of prefilters and filters, the maximum nanofiltration throughput depended on the IgG concentration in the test solution. With the combination of an EKX-P filter with a Pegasus SV4 nanofilter, the maximum throughput and the IgG yield reached 6300 g/m2 and 95%, respectively. When combined with a Planova 20N nanofilter, EKX-P and Sartopore (polyethersulphone) filters provided a maximum throughput of up to 2980 g/m2 and an IgG yield of almost 100%, provided that the test solution had an IgG concentration of 10 g/L. With different filter combinations, virus reduction levels ranged from 4.00±0.05 to 4.75±0.04 log10 for human immunodeficiency virus type 1, from 4.30±0.04 to 4.55±0.06 log10 for porcine transmissible gastroenteritis virus, from 5.38±0.08 log10 to 5.57±0.04 log10 for murine encephalomyocarditis virus, 5.12±0.10 log10 to 5.25±0.08 log10 for porcine parvovirus, and exceeded 5.00 log10 for bovine viral diarrhoea virus. The virus reduction levels achieved were not statistically associated with prefilter brands.Conclusions. The study demonstrated that nanofiltration was effective at removing viruses with various virion sizes and physicochemical characteristics, including viruses as small as parvovirus B19. The levels of virus reduction exceeded 4 log10 and met the acceptance criteria.The laboratory-scale nanofiltration parameters and the corresponding filtration times, as well as IgG yields, did not change when the process was scaled up. Therefore, nanofiltration is an effective and productive technique that helps eliminate various types of viruses and considerably improve viral safety without affecting the quality of biological medicinal products.