Serum Immunoglobulin G Levels Research Articles

Analysis of Risk Factors of Urinary Tract Infection in Acute Glomerulonephritis Children: A Single-Center Cross-Sectional Study.

This study aimed to explore the risk factors of urinary tract infection (UTI) in acute glomerulonephritis (AGN) children. It selected 175 children (86 cases with AGN and 89 cases with AGN and UTI) in Yantai Mountain Hospital from January 2021 to January 2022 for clinical research, comparatively analysed the clinical data, such as urine protein, serum protein, cholesterol, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein (a) (Lp (a)), and used logistic regression analysis to screen out the independent risk factors of AGN with UTI. The univariate analysis showed that UTI was not related to gender, use of angiotensin converting enzyme inhibitor, cholesterol, HDL, IgM and immunoglobulin A (p > 0.05) but related to age, dosage of dopamine, urine protein, serum protein, LDL, IgG and Lp (a) (p < 0.05). The multivariate logistic regression analysis indicated that age, dosage of dopamine ≥3 µg/kg/min, urine protein, serum protein, LDL, IgG and Lp (a) were independent risk factors of UTI in AGN children. Age, dosage of dopamine, urine protein, serum protein, LDL, IgG and Lp (a) were correlated with the occurrence and development of UTI. The use of high-dose dopamine in younger children could lead to higher levels of urinary protein, LDL and Lp (a), resulting in a higher risk of UTI in AGN patients with lower levels of serum protein and IgG. Therefore, attention should be paid to such patients, and intervention measures should be taken promptly in clinic.

The Significance of Serum IgG4/IgG and IgG4/IgG1 Ratio in the Diagnosis Value of IgG4-Related Diseases.

Elevated serum immunoglobulin G4 (IgG4) is one of the important features of patients with IgG4-related diseases (IgG4-RD). But diagnosing these diseases using IgG4 alone is tricky because the tests can sometimes give inaccurate results. Our research is focused on studying the ratio of IgG4 to two other substances, immunoglobulin G (IgG) and immunoglobulin G1 (IgG1), in the blood. We hope this approach will lead to more accurate diagnoses of IgG4-RD. We conducted a study on 68 patients diagnosed with IgG4-related diseases (IgG4-RD) and 160 individuals suffering from other autoimmune diseases (AID) at our hospital between June 2018 and June 2022. Eighty healthy people who underwent physical examination in our hospital at the same time were randomly selected as controls, and medical records were collected for all subjects. The serum IgG and IgG subclasses were detected, and the IgG4/IgG and IgG4/IgG1 ratios were calculated. We found that patients with IgG4-RD have significantly higher average levels of serum IgG4 and more elevated IgG4/IgG and IgG4/IgG1 ratios compared to individuals with other AID patients and those in good health (p < 0.001). The receiver operating characteristic (ROC) curve analysis showed that the diagnostic effectiveness area under the curve (AUC) of the serum IgG4/IgG ratio for IgG4-RD was 0.906 (95% confidence interval [CI], 0.865-0.947) and 0.921 (95% CI, 0.876-0.965) when comparing with other AID patients and healthy individuals, respectively. The optimal cut-off value for the IgG4/IgG ratio was 0.147 (with 72.1% sensitivity and 94.4% specificity) compared with AID patients and 0.129 (with 77.9% sensitivity and 96.2% specificity) compared with healthy individuals. Similarly, the AUC of the serum IgG4/IgG1 ratio for diagnosing IgG4-RD was 0.919 (95% CI, 0.882-0.956) and 0.916 (95% CI, 0.870-0.962) when compared with patients with other AID and healthy individuals, respectively. When we divided our study participants into a high IgG4/IgG ratio group (>0.129) and a normal IgG4/IgG ratio group (≤0.129) using a cut-off point of 0.129, we found through logistic regression analysis that those with a high IgG4/IgG ratio were more likely to be associated with IgG4-RD (odds ratio [OR], 31.25; 95% CI, 15.31-63.79; p < 0.001). Likewise, a high IgG4/IgG1 ratio was also significantly linked to an increased risk of IgG4-RD (OR, 36.39; 95% CI, 17.57-75.38; p < 0.001). The serum's IgG4/IgG and IgG4/IgG1 ratios are independently linked to IgG4-RD and are valuable in its diagnosis.

Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria

To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m2 and proteinuria≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. Forty-four participants were randomized into placebo (n= 14), telitacicept 160 mg (n= 16), and telitacicept 240 mg (n= 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval,-1.57 to-0.20; P= 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval,-0.95 to 0.37; P= 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.

Revisiting the cytologic features of autoimmune pancreatitis: An institutional experience.

Autoimmune pancreatitis (AIP) is a known mimicker of pancreatic ductal adenocarcinoma both clinically and radiologically. In this study, the authors present their institutional experience in diagnosing AIP on cytology and correlate results with the histologic findings. A 14-year computerized search for patients who had histologically confirmed AIP with concurrent or prior cytology was performed. Clinical data, cytology findings, and surgical pathology results were reviewed for analysis. Eighteen patients were identified. The patients showed a male predominance, with a mean age of 59years. Jaundice, weight loss, and abdominal pain were the most common clinical presentation. Five of 12 patients who were tested for serum immunoglobulin G4 had elevated levels. Cytologic findings of 16 cases that were available for review showed markedly inflamed fibrous stroma (54%) and cytologic atypia (50%). The final cytologic diagnoses were suspicious for adenocarcinoma (n=1), atypical (n=8), and benign/negative (n=9). The corresponding surgical pathology diagnoses were classified as type 1 (n=10), type 2 (n=6), and AIP, not otherwise specified (n=2). All type 2 AIP cases had at least atypical cytologic diagnoses, with one called suspicious for adenocarcinoma and another called adenocarcinoma at the time of rapid on-site evaluation. In contrast, eight of 10 type 1 AIP cases were negative/benign, and two of 10 were atypical. In these two atypical cases, the possibility of AIP was raised because of the presence of inflamed stroma. AIP is a pitfall in cytology because moderate-to-marked atypia can be present, especially in type 2 AIP. Because atypia can be severe, the presence of cellular fibrous stroma with lymphocytic stromal infiltrates and the integration of serum immunoglobulin G4 levels could be helpful in avoiding diagnostic overcall in AIP.

Detecting immunoglobulin G4-related intracranial arteriopathy with magnetic resonance vessel wall imaging: a preliminary experience in two cases

BackgroundDetecting immunoglobulin G4 (IgG4)-related intracranial arteriopathy, a rare neurovascular complication of IgG4-related disease, is challenging. While magnetic resonance (MR) vessel wall imaging (VWI) can visualize various neurovascular pathologies, its application to this arteriopathy has not been reported as of this writing.Case presentationA 74-year-old male and a 65-year-old female manifested multiple cranial nerve palsy and neck pain, respectively. Both cases exhibited multiorgan masses with markedly elevated serum IgG4 levels and were clinically diagnosed with IgG4-related disease. Three-dimensional T1-weighted black blood VWI with and without contrast agent identified intracranial vascular lesions characterized as nearly-circumferential mural thickening with homogeneous contrast enhancement in the internal carotid and vertebral arteries; some of the lesions had been unrecognized with screening MR angiography due to expansive remodeling. The former patient underwent corticosteroid therapy, and VWI after treatment revealed decreased mural thickening and enhancement.ConclusionFurther studies to elucidate characteristic findings of VWI might contribute to early detection of this treatable pathology.

Prevalence of theDirect Antiglobulin Test and Its Clinical Impact on Multiply Transfused Thalassemia Patients: AProspective Study Conducted at aTertiary Care Center in Northern India.

This study was conducted to estimate prevalence of direct antiglobulin test (DAT) positivity and its impact on transfusion support in patients with thalassemia. The DAT testing was performed for patients with β-thalassemia who received transfusion from November 2021 to March 2022. Elution was done for DAT-positive samples. Of 180 patients, 21 (11.6%) were DAT positive. Immunoglobulin G (IgG) was present in 4 (19%) and IgG+C3d was present in 8 (38%). Only complement was present in 9 (42.8%) patients. The IgG-reactive DATs were associated with pan-reactive eluate. Patients who were DAT-positive had significantly higher levels of serum bilirubin, ferritin, and IgG than those who were DAT-negative. Autoantibody formation in multiply transfused thalassemia patients is common and merits equal attention as alloimmunization. It is particularly important as DAT-positive red bloodcells may undergo clinically significant hemolysis, which may increase the transfusion requirements with associated sequalae such as increased serum ferritin and splenomegaly.

Clinical Images: Dacryoadenitis in eosinophilic granulomatosis with polyangiitis mimicking immunoglobulin G4-related disease.

The patient, a 26-year-old woman, presented with a 2-week history of acute swelling in both lacrimal glands (A). She had recently developed uncontrolled asthma and nasal polyps. The laboratory test results were notable for an absolute eosinophil count of 5300 cells per μl (reference range 100-400 μl), exceeding 50% of circulating leukocytes. The antineutrophil cytoplasmic antibody test result was negative. Magnetic resonance imaging of the head confirmed swelling of the bilateral lacrimal glands (B, yellow arrowheads) and rhinosinusitis. A biopsy of her lacrimal gland revealed eosinophil-rich necrotizing granulomatous inflammation with vasculitis (C). Her serum immunoglobulin G4 (IgG4) level was slightly elevated (265 mg/dl, normal upper limit is 121 mg/dl), but IgG4 immunostaining of the biopsy specimen did not show a significant finding. A diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was made. Treatment with 30 mg of prednisone was initiated, which was gradually tapered without glucocorticoid-sparing agents over 12 months. The swelling of her lacrimal glands resolved, and she was free of symptoms, including asthma and lacrimal gland swelling, at the 12-month follow-up. In summary, EGPA can present with lacrimal gland swelling and mimic IgG4-related Mikulicz disease (1, 2). A histopathological examination of the swollen lacrimal gland is the key to differentiating EGPA from IgG4-related Mikulicz disease in such cases. Disclosureform Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Association between serum baseline C1q and IgG levels and the efficacy of combined immunotherapy in patients with esophageal squamous cell carcinoma: a retrospective study

Background To assess the clinical value of serum complement component 1q (C1q) and immunoglobulin G (IgG) levels in predicting the response to combined immunotherapy in patients with esophageal squamous cell carcinoma. Methods We conducted a retrospective study of 44 patients with esophageal squamous cell carcinoma who received combined immunotherapy in our hospital. Serum IgG and C1q levels were collected before and three weeks after immunotherapy treatment, together with other data on clinical and demographic characteristics. Results Twenty seven patients (61.4%) showed partial response (PR), 13 (29.5%) stable disease (SD), and 4 (9.1%) progressive disease (PD). None of the patients presented complete response (CR). The PR group displayed lower IgG and higher C1q levels both before and after immunotherapy than patients showing SD or PD. The IgG reduction (59.3%) and C1q increment (70.3%) in the PR group three weeks post-treatment were significantly larger than those in patients showing SD or PD. Moreover, the pretreatment C1q level and the post-treatment change of C1q levels were strongly associated with the immunotherapy response. Conclusions High pre- and post-treatment C1q levels and reduced post-treatment IgG levels correlate with efficacy of combined immunotherapy in patients with esophageal squamous cell carcinoma. Serum baseline C1q level may predict immunotherapy response in such patients.

Immunoglobulin G4-related disease diagnosed by prostate biopsy: a case report

BackgroundImmunoglobulin G4-related disease is characterized by swelling of various organs throughout the body and nodules/hypertrophic lesions. However, its cause remains unknown. We report a case of immunoglobulin G4-related disease that was diagnosed based on the histopathological findings of prostate biopsy.Case presentationA 72-year-old Japanese man had been treated by a nearby doctor for hypertension, but subsequently developed lower urinary tract symptoms and was prescribed an α1 blocker for 1 year. However, the patient was subsequently referred to our department because his symptoms did not improve. Prostate-specific antigen was 1.258 ng/ml; however, the nodule was palpable in the right lobe on digital rectal examination, and magnetic resonance imaging suggested Prostate Imaging and Reporting and Data System category 3. Therefore, transrectal prostate needle biopsy (12 locations) under ultrasound was performed. Histopathological examination revealed no malignant findings, although infiltration of lymphocytes and plasma cells, and partial fibrosis were observed. No remarkable findings of obstructive phlebitis were observed. Immunoglobulin G4-related disease was suspected, and immunoglobulin and immunoglobulin G4 immunostaining was performed. Immunoglobulin G4 positive plasma cells were observed in a wide range, immunoglobulin G4 positive cells were noted at > 10 per high-power field, and the immunoglobulin G4 positive/immunoglobulin G positive cell ratio was > 40%. Serum immunoglobulin G4 levels were high at 1600 mg/dl. Enhanced abdominal computed tomography findings suggested periaortitis. Additionally, multiple lymphadenopathies were observed around the abdominal aorta. The patient was accordingly diagnosed with immunoglobulin G4-related disease definite, diagnosis group (definite). We proposed steroid treatment for periaortic soft tissue lesions and lower urinary tract symptoms; however, the patient was refused treatment. A computed tomography scan 6 months after diagnosis revealed no changes in the soft tissue lesions around the aorta. Follow-up computed tomography examinations will be performed every 6 months.ConclusionIf immunoglobulin G4-related disease is suspected and a highly invasive examination is required for histopathological diagnosis, this can be performed by a relatively minimally invasive prostate biopsy for patients with lower urinary tract symptoms. Further evidence is needed to choose an optimal candidate for prostate biopsy for lower urinary tract symptoms patients with suspicion of immunoglobulin G4-related disease. For patients with lower urinary tract symptoms with immunoglobulin G4-related disease or a history, performing a prostate biopsy may avoid unnecessary treatment. However, if steroid therapy is ineffective, surgical treatment should be considered.

It Melts Like Snow: Steroid Responsiveness of Immunoglobulin G4-Related Disease

Dear Editor, A 35-year-old male presented with insidious onset gradually progressive bilateral painless submandibular swelling, followed by periorbital swelling [Figure 1] for the past 7 years. He had no constitutional or sicca symptoms. He had no history of addiction or autoimmunity in the family. Systemic examination was unremarkable. On evaluation, he had raised inflammatory markers with a negative autoimmune panel. Magnetic resonance imaging orbit showed bilateral orbital extraconal soft-tissue masses with contrast enhancement. Incisional biopsy from the extraconal mass was suggestive of fibrocollagenous stroma with aggregation of lymphocytes, plasma cells, and histiocytes without any necrosis or granuloma. On further evaluation, submandibular gland biopsy showed chronic sialadenitis with immunoglobulin G4 (IgG4)-positive plasma cell >10/hpf and IgG4: IgG ratio >40% [Figure 2] without any major organ involvement on imaging. The diagnosis of IgG4-related disease was kept. He was started on oral steroid 0.5 mg/kg/day and observed a rapid clinical response within 15 days of steroid therapy. Later, he was started on azathioprine and continued with tapering dose of steroid. He was followed up every month for first 3 months and then every 3 monthly upto 16 months without any signs of recurrence. For a long-standing indolent disease of 7 years, drastic steroid response with resolution of clinical symptoms was quite evident in our case.Figure 1: (a) Pretreatment bilateral upper eyelid swelling, (b) pretreatment bilateral submandibular swelling, (c and d) during glucocorticoid therapy (day 15) resolution of orbital and submandibular swelling, respectivelyFigure 2: Salivary gland with seromucinous acini and ducts embedded in mildly fibrotic stroma with numerous lymphoid follicles with germinal centers (a and b: H and E). Clusters of plasma cells are highlighted with CD138 immunohistochemical stain (c). IgG4 positive cells, >10/hpf (d)IgG4-related disease (IgG4-RD) is a chronic, systemic, fibroinflammatory condition with variable organ manifestation. CD4+ T-cells and B-cells are central to the pathogenesis causing organ damage and fibrosis. Marked expansion of IgG4-secreting plasmablast in the blood is usually seen in active and untreated cases.[1] Key to diagnosis is the classical histopathological hallmarks of lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. IgG4 RD usually has a good response to steroids but a variable relapse rate. Factors associated with lesser treatment response and relapse were well analyzed in a Japanese multicenter study. Multivariate analysis from the study revealed that intermediate steroid initial dose (0.4–0.69 mg/day), slow tapering regimen (<0.4 mg/day), and shorter disease duration were associated with a significantly lower rate of disease relapse.[2] The study of isolated IgG4 ophthalmic disease also echoed similar results regarding steroid response and relapse, with more relapse in those with elevated serum IgG4 levels and a shorter duration of initial steroid treatment (<5 months). Low-dose steroid maintenance should be considered to avoid recurrence in patients with elevated serum IgG4 levels.[3] Later on, rituximab therapy showed promising results in inducing remission[4] and steroid-free long-term maintenance.[5] Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Immunoglobulin G4-Related Disease of The Larynx Mimicking Malignancy: A Case Report and Review of the Literature

Immunoglobulin G4–related disease is characterized by increased serum immunoglobulin G4 level, enlargement in the relevant organs and histopathologically intense storiform fibrosis, lymphoplasmacytic infiltration rich in immunoglobulin G4 positive plasma cells, and obliterative phlebitis. In this report, a patient who underwent a laryngeal biopsy with a pre-diagnosis of malignancy, but had findings consistent with immunoglobulin G4–related disease in the biopsy sample, is described. Immunoglobulin G4–related disease can be seen in very rare localizations. It should be kept in mind in differential diagnosis when tissues especially containing inflammation rich in plasma cells are encountered. Clinical, laboratory and pathological correlation is extremely important in the diagnosis of an immunoglobulin G4-related disease.

Serologic Response of SARS-CoV-2 mRNA-based Vaccines in Patients with Autoimmune Diseases

Background: In the spring of 2021, coronavirus disease 2019 (COVID-19) vaccines were approved and distributed in the United States for the public to combat the COVID-19 pandemic, but their rapid development leaves some questions unanswered. Vaccine efficacy has always been a point of interest for individuals with rheumatological diseases that take immunosuppressants. This study investigates the vaccine efficacy of two COVID-19 mRNA-based vaccines, Moderna and Pfizer, in subjects in West Texas patients with autoimmune diseases. Materials and Methods: Blood was collected from Texas Tech University employees who received both doses of COVID-19 vaccines within the past nine months. Subjects were separated into either a group with a known history of rheumatic disease (n=18) or those without (n=18). The samples were analyzed for serum immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels using specific enzyme-linked immunoassay kits, and a neutralizing antibody test using a surrogate virus was conducted as well. Results were analyzed using the Mann-Whitney U test (unpaired, two-tailed). Results: There was no significant difference in serum IgG and IgA levels between the control and rheumatologic disease groups, but there were significant differences in serum IgM levels. All subjects cleared the threshold for the neutralizing antibody test. Conclusion: The relatively similar serum IgG levels and the 100% detection rate of effective neutralizing antibodies across both groups indicate promising signs of serological response for subjects with autoimmune conditions, but the relatively low serum IgA and IgM levels of the study the group warrants further investigation.

Development of IgG4-related pancreatitis and kidney disease 7 years after the onset of undiagnosed lymphadenopathy: A case report.

This report describes a patient diagnosed with immunoglobulin G4 (IgG4)-related pancreatitis and kidney disease 7 years after the onset of undiagnosed lymphadenopathy. A 48-year-old Japanese woman presented with fatigue and leg oedema. Computed tomography showed perigastric lymphadenopathy, for which she underwent a laparoscopic biopsy of the perigastric lymph nodes. Although histopathological examination of the lymph nodes did not lead to a definitive diagnosis, serological tests revealed elevated serum IgG4 levels (558 mg/dl) and IgG4 immunostaining of the lymph nodes showed IgG4-positive plasma cell infiltration, leading to the suspicion of IgG4-related disease. Further workup revealed no organ lesion other than lymphadenopathy. At age 55 years, despite having no subjective symptoms, contrast-enhanced computed tomography showed low-density lesions in the tail of the pancreas and the left kidney. Histopathological examination showed lymphocyte infiltration, consisting of a mixture of plasma cells and eosinophils, in both organs and obliterative phlebitis in the pancreas. IgG4 immunostaining of the kidney specimens showed 160 IgG4-positive cells per high-powered field, with the IgG4+/IgG+ cell ratio being almost 100%, leading to a diagnosis of IgG4-related pancreatitis and kidney disease. Treatment with prednisolone for 2 months resulted in lesion improvement. Although the diagnosis of IgG4-related lymphadenopathy is often challenging in patients with lymphadenopathy alone, findings in the present patient emphasise the importance of long-term follow-up, as it may allow early detection of involvement of other organs by IgG4-related disease.

Effects of low-dose intravenous immunoglobulin as the adjunctive therapy in septic shock patients with and without hypogammaglobulinemia: a retrospective cohort study

Intravenous immunoglobulin (IVIG) therapy has a reported adjunctive effect in the treatment of sepsis, but in light of results from a large-scale randomized control trial (RCT), evidence for improved prognosis with IVIG therapy is currently deemed insufficient. In recent years, there have been many reports of low serum immunoglobulin G (IgG) as a poor prognostic factor in septic patients. Under Japan's national health insurance system, IVIG is administered for severe infections at a dose of 5 g/day for three days (total 15 g or 0.3 g/kg). At present, IVIG administration is not specifically formulated for septic patients with hypogammaglobulinemia. It is clinically significant to investigate whether serum IgG levels can serve as a biomarker to predict the efficacy of IVIG treatment for septic shock and help to identify those patients who might benefit from an adjunctive IVIG treatment. The purpose of this study was to compare the efficacy of this low-dose IVIG as an adjunctive therapy in septic shock patients with and without hypogammaglobulinemia. In this retrospective cohort study, patients who received low-dose IVIG (5 g/day for 3 days) as adjuvant therapy for septic shock were enrolled. These patients were divided into two groups based on a median serum IgG level of 829 mg/dL (<830 mg/dL defined as hypogammaglobulinemia) prior to IVIG administration. To assess the efficacy of low-dose IVIG administration (0.3 g/kg), 28-day survival probability as the primary outcome, and the lengths of artificial ventilation and intensive care unit (ICU) stays as the secondary outcomes were compared using the Kaplan-Meier method, the log-rank test, the Wilcoxon or Mann-Whitney U test. A total of 80 patients with septic shock that underwent IVIG treatment in the ICU were enrolled. These patients were divided into two groups based on a median serum IgG level. Survival probabilities at 28 days were 90.0% and 85.0% in the high- and low-level groups, respectively, and there was no significant difference between the two groups (P=0.457). There are not also significant differences in median lengths of artificial ventilation (6 vs. 9 days, P=0.215) and ICU stays (10 vs. 12 days, P=0.199) after IVIG administration. Logistic regression revealed that these clinical outcomes were not associated with serum IgG after adjusting for confounding factors as the antibiotics. Serum IgG levels was not associated with the clinical outcomes by low-dose IVIG treatment. Our results suggest that the prognosis of low-dose IVIG as adjunctive therapy in patients with septic shock might be no different with and without hypogammaglobulinemia.

Immunogenicity and safety of SARS-CoV-2 mRNA vaccine in patients with nephrotic syndrome receiving immunosuppressive agents.

BackgroundAs there are no large-scale reports of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccination in patients with nephrotic syndrome using immunosuppressive agents, we conducted the prospective study.MethodsSARS-CoV-2 mRNA vaccines were administered to patients with nephrotic syndrome receiving immunosuppressive agents. The titers of SARS-CoV-2 spike protein receptor–binding domain antibodies were measured before and after vaccination. We evaluated factors associated with antibody titers after vaccination and analyzed adverse events.ResultsWe enrolled 40 patients and evaluated vaccine immunogenicity in 35 of them. Seroconversion (> 0.8 U/mL) was achieved in all patients, and the median antibody titer was 598 U/mL (interquartile range, 89–1380 U/mL). Patients using mycophenolate mofetil (MMF) showed lower antibody titers than those who were not (median: 272 U/mL vs. 2660 U/mL, p = 0.0002), and serum immunoglobulin G (IgG) levels showed a weak linear relationship with antibody titers (R2 = 0.16). No breakthrough infections were noted. Three patients (7.5%) suffered from a relapse of nephrotic syndrome (2 and 3 days, respectively, after the first dose and 8 days after the second dose), two of whom had a history of relapse within 6 months before the vaccination.ConclusionsThe SARS-CoV-2 mRNA vaccine was immunogenic in patients with nephrotic syndrome using immunosuppressive agents, although the use of MMF and low levels of serum IgG were associated with lower antibody titers after vaccination. Patients with high disease activity may experience a relapse of nephrotic syndrome after vaccination.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information Supplementary InformationThe online version contains supplementary material available at 10.1007/s00467-022-05633-y.

Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis

Antagonism of the neonatal Fc receptor (FcRn) by efgartigimod has been studied in several autoimmune diseases mediated by immunoglobulin G (IgG) as a therapeutic approach to remove pathogenic IgGs. Whereas reduction of pathogenic titres has demonstrated efficacy in multiple autoimmune diseases, reducing total IgG could potentially increase infection risk in patients receiving FcRn antagonists. The objective of this study was to analyse the effect of FcRn antagonism with efgartigimod on existing protective antibody titres and the ability to mount an immune response after vaccine challenge. Serum levels of total IgG and protective antibodies against tetanus toxoid (TT), varicella zoster virus (VZV), and pneumococcal capsular polysaccharide (PCP) were measured in all patients enrolled in an open-label trial of efgartigimod for the treatment of pemphigus. Vaccine specific-responses were assessed by measuring changes in IgG titres in patients with generalised myasthenia gravis (gMG) who were treated with efgartigimod and who received influenza, pneumococcal, or coronavirus disease 2019 (COVID-19) vaccines during participation in the double-blind trial ADAPT or open-label extension, ADAPT+ (n = 17). FcRn antagonism reduced levels of protective anti-TT, anti-VZV, and anti-PCP antibodies and total IgG to a similar extent; anti-TT and anti-VZV titres remained above minimally protective thresholds for the majority of patients, (10/12) 83% and (14/15) 93% respectively. Protective antibodies returned to baseline values upon treatment cessation. Antigen-specific IgG responses to influenza, pneumococcal, and COVID-19 immunisation were detected in patients with gMG who received these vaccines while undergoing therapy with efgartigimod. In conclusion, FcRn antagonism with efgartigimod did not hamper generation of IgG responses but did transiently reduce IgG titres of all specificities.

Population Pharmacokinetic Modelling of Intravenous Immunoglobulin Treatment in Patients with Guillain-Barré Syndrome.

Background and ObjectiveIntravenous immunoglobulin (IVIg) at a standard dosage is the treatment of choice for Guillain–Barré syndrome. The pharmacokinetics, however, is highly variable between patients, and a rapid clearance of IVIg is associated with poor recovery. We aimed to develop a model to predict the pharmacokinetics of a standard 5-day IVIg course (0.4 g/kg/day) in patients with Guillain–Barré syndrome.MethodsNon-linear mixed-effects modelling software (NONMEM®) was used to construct a pharmacokinetic model based on a model-building cohort of 177 patients with Guillain–Barré syndrome, with a total of 589 sequential serum samples tested for total immunoglobulin G (IgG) levels, and evaluated on an independent validation cohort that consisted of 177 patients with Guillain–Barré syndrome with 689 sequential serum samples.ResultsThe final two-compartment model accurately described the daily increment in serum IgG levels during a standard IVIg course; the initial rapid fall and then a gradual decline to steady-state levels thereafter. The covariates that increased IgG clearance were a more severe disease (as indicated by the Guillain–Barré syndrome disability score) and concomitant methylprednisolone treatment. When the current dosing regimen was simulated, the percentage of patients who reached a target ∆IgG > 7.3 g/L at 2 weeks decreased from 74% in mildly affected patients to only 33% in the most severely affected and mechanically ventilated patients (Guillain–Barré syndrome disability score of 5).ConclusionsThis is the first population-pharmacokinetic model for standard IVIg treatment in Guillain–Barré syndrome. The model provides a new tool to predict the pharmacokinetics of alternative regimens of IVIg in Guillain–Barré syndrome to design future trials and personalise treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01136-z.

Immunological factors associated with discordant virological response postcombination antiretroviral therapy in pediatric human immunodeficiency virus infection.

Evaluation of immunological factors responsible for discordant virological responses postcombination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-positive children aged &lt;5 years. Immunological profiling of enrolled 30 HIV-positive children was done at enrollment, 6 and 12 months. Flow cytometric analysis was performed for enumeration of counts and percentage of CD4⁺, CD8⁺, and CD19⁺ cells; expression of CD19, CD86, PD-1, CD3, CD8 and CD28 on lymphocytes was evaluated using whole blood staining technique with monoclonal antibodies. HIV-1 viral load was quantified using a real-time polymerase chain reaction. Serum levels of immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin (IgM), and interleukin (IL)-7 were quantitated using quantitative enzyme-linked immunosorbent assay kits. The HIV-infected children were categorized into virological responders (VRs; HIV-1 plasma viral load &lt;47 copies/mL) and virological nonresponders (VNRs; HIV-1 plasma viral load &gt;1000 copies/mL) following 1-year cART. The frequency of CD28⁺ CTLs cells was higher (P &lt; 0.0001), and the frequency of CD28-CTLs cells was lower (P &lt; 0.0001) in VRs than VNRs. CD28⁺ and CD28-CTLs cells correlated with HIV-1 plasma viremia (r = -0.4695, P = 0.01; r = 0.40, P = 0.03, respectively). VRs had higher CD19 percentage (P = 0.04) and count (P = 0.01) than VNRs. CD19⁺ B cells in the VRs had lower expression of CD86 (P = 0.03) and PD-1 (P = 0.002) than VNRs. VR had lower levels of serum IgG (P = 0.03), IgM (P = 0.04), and IL-7 (P = 0.01) than VNRs. High baseline B-cell counts, lower serum IgG, IgM, IL-7 levels, lower activation and exhaustion of B cells, and higher frequency of CD28⁺ CTLs are associated with positive virological response, whereas elevated CD28-CTLs are associated with the poor virological outcomes in HIV-infected children.

Rituximab in myasthenia gravis: efficacy, associated infections and risk of induced hypogammaglobulinemia

The aim of this study is to evaluate the long-term efficacy, safety, and impact on immunoglobulin G (IgG) levels of rituximab in patients with myasthenia gravis (MG). A retrospective, observational study of drug-refractory MG patients treated with rituximab was done. The MG Foundation of America postintervention status (MGFA-PIS) was used to evaluate clinical response. Serum IgG levels were determined at baseline and post-treatment. Hypogammaglobulinemia was defined as IgG<7g/L. Thirty patients were included, 12 with anti-MuSK and 18 with anti-AChR antibodies. Mean (SD) follow-up was 85.5 (48) months. All 12 MuSK+ patients but only six (33%) AChR+ patients achieved minimal manifestations or remission (p<0.01). Nine severe infections were observed in five patients (17%). One patient was diagnosed with progressive multifocal leukoencephalopathy. At baseline, two patients (2/24; 8%) had hypogammaglobulinemia. During follow-up, hypogammaglobulinemia was observed in 60% (3/5) of patients who developed an infection and in 33% (7/21) who did not. Two of these patients died of infection-related complications. This study supports the effectiveness of rituximab in patients with MG, especially those with anti-MuSK antibodies. Severe infections may appear after rituximab treatment and hypogammaglobulinemia might play a role on it. A standard protocol would be needed to closely monitor IgG levels in MG patients treated with rituximab.

Norcantharidin alleviates cyclophosphamide-induced immunosuppression via circBCL2L1/miR-30c-3-3p/TRAF6 axis

Cyclophosphamide is a widely used antitumor drug, with induced adverse effects, such as intestinal mucosal injury and immunosuppression. Norcantharidin possesses anticancer activity through enhancement of antitumor immunity. We investigated the role of norcantharidin in cyclophosphamide-induced immunosuppression. Mice were treated with cyclophosphamide, and exposed to norcantharidin. Enzyme-linked-immunosorbent serologic assay was performed to assess the levels of immunoglobulin and cytokines in serum, and the splenic T lymphocytes were analyzed by immunohistochemistry. Incubation with norcantharidin increased the serum levels of immunoglobulin G (IgG), interleukin (IL)-12, interferon-gamma (IFN-γ), and IL-6, and enhanced the percentage of CD4+ and CD8+ T lymphocytes in cyclophosphamide-induced mice. Expression of circBCL2L1 was down-regulated in the spleen of cyclophosphamide-induced mice, while up-regulated by norcantharidin incuba-tion. Norcantharidin attenuated cyclophosphamide-induced up-regulation of miR-30c-3-3p and down-regulation of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in mice. Over-expression of circBCL2L1 increased serum levels of immunoglobulin and cytokines, and enhanced the percentage of splenic CD4+ and CD8+ T lymphocytes in cyclophosphamide-induced mice. Moreover, over-expression of circBCL2L1 increased TRAF6 in cyclophosphamide-induced mice through down-regulation of miR-30c-3-3p. Knockdown of TRAF6 attenuated norcantharidin-induced increase of serum levels of IgG, IL-12, IFN-γ, and IL-6, and up-regulation of CD4+ and CD8+ T lymphocytes in cyclophosphamide-induced mice. Norcantharidin exhibited protective effect against cyclophosphamide-induced immunosuppression in mice through regulation of circBCL2L1/miR-30c-3-3p/TRAF6 axis.