Immunomodulatory and anti-inflammatory properties of immunoglobulin G antibodies.

Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.

Restoring immune tolerance in pemphigus vulgaris.

Intravenous immunoglobulin (IVIg), a preparation of polyclonal serum IgG pooled from numerous blood donors, has been used for nearly three decades and is proving to be an efficient treatment for many autoimmune blistering diseases, including pemphigus vulgaris (PV). Despite its widespread use and therapeutic success, its mechanisms of action are not completely understood. Some of its anti-inflammatory and immunomodulatory actions have been studied. In this study, the authors present a twenty-year follow-up of 21 patients with clinical and immunopathological confirmed PV, treated with IVIg as monotherapy, according to an established published protocol. IVIg therapy produced long-term sustained, clinical, serological, and immunopathological remission. For 20 y, these patients received no drugs and experienced no disease. This observation suggests that there was the establishment of immune balance or restoration of immune regulation in these PV patients. Twelve (57%) patients experienced no relapse during follow-up. Six (29%) patients experienced a relapse due to acute stress or post-coronavirus infection and/or vaccination. Reinstitution of IVIg resulted in prompt sustained recovery. Three (14.2%) patients, in clinical and serological remission, died due to unrelated causes. No severe adverse effects from IVIg were documented in all 21 patients. The simultaneous or sequential anti-inflammatory and immunomodulatory effects of IVIg may have influenced the long-term clinical remission observed. This study provides a human prototype to examine the pathophysiology of autoimmunity and a model to study immune regulation and mechanisms that can facilitate restoring immune tolerance.

When is the use of intravenous immunoglobulin appropriate in immune thrombocytopaenia?

Intravenous immunoglobulin (IVIg) is the gold standard treatment for severe cases of immune thrombocytopaenia (ITP). However, its cost, limited duration of efficacy and market supply tension have led French guidelines to reserve IVIg for ITP patients with formal contra-indications to corticosteroids, with French bleeding score ('Khellaf score') > 8, and corticosteroid-resistant patients either with Khellaf score ≤ 8 or in preparation for an invasive procedure or during pregnancy. We studied the prescribing practices of IVIg for ITP in real-life conditions and assessed their compliance with French guidelines. A monocentric retrospective study was conducted between 2016 and 2020 among 114 patients hospitalized in our unit, for a total of 208 IVIg treatments. In 37% of cases, the Khellaf score was >8, validating IVIg prescription according to French guidelines. In the remaining cases, reasons noted for use of IVIg included corticosteroid resistance (33.7%), preparation for an invasive procedure (8.5%), context of pregnancy (6.6%) and contra-indication to corticosteroids (3.3%). After analysis, IVIg prescription was considered valid according to current French guidelines in 84.4% of cases. Non-compliant IVIg prescription was more frequent in younger patients (p = 0.027). Concomitant anti-coagulation was also noted as an argument for IVIg prescription outside of the current French guidelines.

Clinical efficacy of SARS-CoV-2 Omicron-neutralizing antibodies in immunoglobulin preparations for the treatment of agammaglobulinemia in patients with primary antibody deficiency.

Immunocompromised individuals are at significantly elevated risk for severe courses of coronavirus disease 2019 (COVID-19). In addition to vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (nAbs) have been applied throughout the pandemic, with time of treatment onset and potency against the currently prevailing virus variant identified as relevant factors for medical benefit. Using data from the European Society for Immunodeficiencies (ESID) registry, the present study evaluated COVID-19 cases in three groups of patients with inborn errors of immunity (IEI; 981 agammaglobulinemia patients on immunoglobulin replacement therapy (IGRT); 8960 non-agammaglobulinemia patients on IGRT; 14 428 patients without IGRT), and the neutralizing capacity of 1100 immunoglobulin lots against SARS-CoV-2 ("Wuhan" and Omicron strains), throughout 3 years. From the first (2020/2021) to the second (2021/2022) cold season, i.e., during the virus drift to the more contagious Omicron variants, an increase in case numbers was recorded that was comparable (~2- to 3-fold) for all three study groups. During the same period, immunoglobulin lots showed a profound nAb increase against the archetypal SARS-CoV-2 strain, yet only low levels of Omicron nAbs. Notably, shortly before the third (2022/2023) cold season, Omicron-neutralizing capacity of released immunoglobulin lots had plateaued at high levels. From the second to the third cold season, COVID-19 cases dropped markedly. While a ~6-fold case reduction was recorded for the groups of non-agammaglobulinemia patients on IGRT and IEI patients not receiving IGRT, the decline was ~30-fold for the group of agammaglobulinemia patients on IGRT. These findings suggest a substantial COVID-19-protective effect of IGRT, at least for distinct groups of antibody-deficient patients.

Type 2 herpes simplex virus-induced anti-N-methyl-D-aspartate receptor encephalitis responsive to immunoglobulin monotherapy.

Herpes simplex virus-2 encephalitis (HSV2E) in immunocompetent adults is exceptionally rare, and the subsequent onset of autoimmune encephalitis after HSV2E is even less common. This report presents the inaugural Chinese case of anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) induced by HSV2E, confirmed via metagenomic next-generation sequencing (mNGS). The patient demonstrated a favorable response to intravenous immunoglobulin (IVIG) monotherapy. This case emphasizes the importance of considering autoimmune encephalitis in patients exhibiting new or recurrent neurological symptoms after HSV2E recovery. Comprehensive mNGS and neuronal antibody testing are essential for timely diagnosis. Moreover, IVIG monotherapy can serve as an effective treatment for NMDARE induced by HSV2, providing a viable alternative, particularly when steroid therapy is contraindicated.

Sialylated IVIg promotes clinical improvements in a rabbit dry eye model by regulating inflammatory cytokines.

Dry eye disease (DED) is caused by a loss of homeostasis of the tear film, which results in visual disturbance, ocular surface inflammation and damage, and neurosensory abnormalities. Although it is prevalent in 5-50% of the global population, there are limited clinical options for its treatment. This study explored the potential use of human intravenous immunoglobulin (IVIg) and its enriched fractions of sialylation, sialylated IVIg (sIVIg), as a treatment for DED. Fifteen female New Zealand white rabbits were topically instilled with 0.2% benzalkonium chloride (BAC) twice daily for five consecutive days to induce experimental dry eye. Saline, 0.4% IVIg, or 0.04% sIVIg eye drops were instilled twice daily for 20 consecutive days. Clinical evaluations, such as non-invasive tear break-up time (NIBUT) and corneal fluorescein staining (CFS), were conducted. mRNA levels of mucin 4, mucin 16, TNF-α, IL-1ß, MMP9, IL-10, TGF-ß, and CD209 in rabbit conjunctival tissues were examined using reverse transcription polymerase chain reaction (RT-PCR) or quantitative RT-PCR (qRT-PCR). The relationships between CD209 family members in rabbits and various mammalian species were analyzed using a phylogenetic tree. IVIg or sIVIg treatment resulted in clinical improvements in the rabbit DED model. The inflammatory cytokines, TNF-α and IL-1ß, were increased and mucin 4 and mucin 16, cell surface-associated mucins, were decreased in BAC-induced dry eye. Following IVIg or sIVIg treatment, inflammatory cytokines decreased, whereas the anti-inflammatory cytokine, IL-10, increased substantially. Moreover, a 10-fold lower sIVIg treatment dose resulted in prolonged IL-10 production, representing a significantly improved DED compared to IVIg. Furthermore, the expression of rabbit CD209 mRNA in the rabbit conjunctiva and its close relationship with primate homologs suggest that it may interact with IVIg or sIVIg to promote IL-10 expression, as previously described in humans. At a lower dosage, sIVIg showed a more efficient improvement in DED, making it a promising new candidate medication for DED.

Elevated Serum IL-17A in Kawasaki Disease Patients Predicts Responsiveness to Intravenous Immunoglobulin Therapy.

INTRODUCTION: This study aimed to investigate the correlation between serum interleukin (IL)-17A levels and responsiveness to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD) patients. METHODS: A retrospective analysis on data from 192 KD patients admitted to the Anqing Municipal Hospital between January 2021 and January 2024 was conducted. Patients were categorized into IVIG-nonresponsive and IVIG-sensitive groups as per the treatment outcomes. Outcome measures included serum IL-17A levels, left coronary artery (LCA) Z scores, and relevant laboratory parameters. Logistic regression analysis was performed to identify predictive factors for IVIG responsiveness, and diagnostic performance was assessed using receiver operating characteristic (ROC) curves and calculation of the area under the curve (AUC). RESULTS: A total of 40 IVIG-nonresponsive cases and 152 IVIG-sensitive cases were included. Prior to intervention, IVIG-nonresponsive patients had significantly higher serum IL-17A levels compared to IVIG-sensitive patients, with a statistically significant difference. After intervention, serum IL-17A levels significantly decreased in IVIG-sensitive patients while remaining elevated in IVIG-nonresponsive patients. IVIG-nonresponsive patients exhibited significantly higher levels of C-reactive protein (CRP), white blood cell count (WBC), NE, and ALT compared to IVIG-sensitive patients, whereas no significant differences in LCA Z scores between the two groups existed. Multivariable logistic regression analysis identified pre-IL-17A, CRP, WBC, and ALT as independent predictors of IVIG-nonresponsiveness in KD. When pre-IL-17A was ≥39.96 pg/mL, the specificity and sensitivity for predicting IVIG-nonresponsive KD were 63.9% and 71.9%, respectively, with an AUC of 0.637. The combined diagnosis of IL-17A, CRP, WBC, and ALT yielded an AUC of 0.780. CONCLUSION: Serum IL-17A levels were remarkably elevated in IVIG-nonresponsive KD patients both before and after intervention. A serum IL-17A level (≥39.96 pg/mL) demonstrated good predictive profile for IVIG-nonresponsive KD, and combining IL-17A with CRP, WBC, and ALT improved diagnostic performance.

A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 Syndrome.

Intravenous immunoglobulin (IVIG) is an immunomodulatory therapy that has been studied in several neuroimmune conditions, such as Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and multiple sclerosis. It has also been proposed as a potential treatment option for acute COVID-19 infection and post-acute sequelae of SARS-CoV-2 infection (PASC). IVIG is thought to function by providing the recipient with a pool of antibodies, which can, in turn, modulate immune responses through multiple mechanisms including neutralization of cytokines and autoantibodies, saturation of neonatal fragment crystallizable receptors, inhibition of complement activation, and regulation of T and B cell mediated inflammation. In acute COVID-19, studies have shown that early administration of IVIG and plasmapheresis in severe cases can reduce the need for mechanical ventilation, shorten ICU and hospital stays, and lower mortality. Similarly, in PASC, while research is still in early stages, IVIG has been shown to alleviate persistent symptoms in small patient cohorts. Furthermore, IVIG has shown benefits in another condition which has symptomatic overlap with PASC, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), though studies have yielded mixed results. It is important to note that IVIG can be associated with several potential adverse effects, such as anaphylaxis, headaches, thrombosis, liver enzyme elevations and renal complications. In addition, the high cost of IVIG can be a deterrent for payers and patients. This review provides a comprehensive update on the use of IVIG in multiple neuroimmune conditions, ME/CFS, acute COVID-19, and PASC, as well as covers its history, production, pricing, and mechanisms of action. We also identify key areas of future research, including the need to optimize the use of Ig product dosing, timing, and patient selection across conditions, particularly in the context of COVID-19 and PASC.

Autoantibody profiles in intravenous immunoglobulin preparations: A possible cause of mistaken autoimmunity diagnosis.

BACKGROUND: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. STUDY DESIGN AND METHODS: Using binding-capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor-derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. RESULTS: Anti-thyroglobulin (Tg), anti-thyroidperoxidase (TPO), and anti-Sjögren's-syndrome-related antigen A (SS-A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. DISCUSSION: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false-positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy.

Hepatitis B screening in hematology patients receiving intravenous immunoglobulin.

BACKGROUND: Transient positivity for hepatitis B core antibody (Anti-HBc) following intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin exposure is a well-described phenomenon. The aim of this study was to retrospectively review Hepatitis B viral screening practices in IVIG recipients in a hematology specific cohort at a single center. METHODS: Electronic databases were analyzed to identify all hematology patients who received IVIG from September 2022 to March 2022 at a single Irish center (n = 43). The proportion of patients that had a baseline anti-HBc tested prior to IVIG receipt was assessed as well as the proportion of patients that developed a transiently positive anti-HBc following IVIG exposure. Data were also collected relating to signal cut-off ratios in patients with detectable anti-HBc post-IVIG. RESULTS: 58.1% of patients had at least one serological hepatitis B viral test sent prior to IVIG exposure. Anti-HBc was the least common serological investigation performed prior to IVIG exposure (21% of recipients). A positive or equivocal "low level antibody" was identified in 15% of recipients and this was proven to be transient in all cases. CONCLUSION: The minority of hematology patients had a baseline anti-HBc assessed prior to IVIG exposure. All patients in this study had the potential to require further immunosuppressive therapies, which could be limited by a misleading anti-HBc result. We therefore advocate for baseline anti-HBc testing to be performed prior to IVIG exposure in hematology patients and for cautious interpretation of anti-HBc results taking into account signal cut-off ratios post-IVIG exposure.

Hypogammaglobulinemia and infection risk in myotonic dystrophy type 1.

INTRODUCTION/AIMS: Hypogammaglobulinemia is a common yet under-recognized feature of myotonic dystrophy type 1 (DM1). The aims of our study were to determine the frequency of immunoglobulin G (IgG) deficiency in our cohort, to examine the association between immunoglobulin levels and cytosine-thymine-guanine (CTG) repeat length in the DMPK gene, and to assess whether IgG levels are associated with an increased risk of infection in DM1 patients. METHODS: We conducted a single-center, retrospective cross-sectional study of 65 adult patients with DM1 who presented to the Neuromuscular Clinic at Concord Repatriation General Hospital, Sydney, Australia, between January 2002 and January 2022. We systematically collected and analyzed clinical, laboratory, and genetic data for all patients with available serum electrophoresis and/or IgG level results. RESULTS: Forty-one percent of DM1 patients had IgG deficiency despite normal lymphocyte counts, IgA, IgM, and albumin levels. There was an association between CTG repeat expansion size and the degree of IgG deficiency (F = 6.3, p = .02). There was no association between IgG deficiency and frequency of infection in this group (p = .428). DISCUSSION: IgG deficiency is a frequent occurrence in DM1 patients and is associated with CTG repeat expansion size. Whether hypogammaglobulinemia is associated with increased infection risk in DM1 is unclear. A prospective multicenter cohort study is needed to evaluate this.

Timing of intravenous immunoglobulin treatment and outcome in Guillain-Barré syndrome: Is time nerve?

INTRODUCTION/AIMS: Despite treatment, a considerable proportion of patients with Guillain-Barré syndrome (GBS) experience poor recovery, highlighting a therapeutic need. There is a lack of evidence that treatment timing affects recovery. This study aims to investigate the effects of intravenous immunoglobulin (IVIg) timing on disability and speed of recovery in GBS. METHODS: We performed a retrospective study of 136 IVIg-treated GBS patients admitted to two Korean centers between 2010 and 2021. We analyzed the effect of time to IVIg on the GBS disability scale (GBS-DS) and the degree of improvement from nadir (∆GBS-DS) at 1, 3, 6, and 12 months, as well as the time to regain the ability to walk or run unaided. Time to IVIg was treated either as a continuous variable or categorized into 1-week intervals to explore critical time windows. Known prognostic factors, the modified Erasmus GBS Outcome Scores on admission and pre-treatment serum albumin levels were adjusted as covariates. RESULTS: Shorter time to IVIg was independently associated with better GBS-DS, greater ∆GBS-DS, and shorter time to walk or run unaided at all time points. The therapeutic effect of IVIg was notably diminished when administered beyond the first 2 weeks of onset. DISCUSSION: Our study highlights the timing of IVIg as a modifiable prognostic factor in GBS. The earlier IVIg is initiated, the better the outcomes, with the ideal time window being within the first 2 weeks. These findings underscore the importance of prompt diagnosis and early intervention to optimize recovery in GBS patients.

Intravenous immunoglobulin and plasma exchange prescribing patterns for Guillain-Barre Syndrome in the United States-2001 to 2018.

INTRODUCTION/AIMS: Randomized controlled trials show that repeat intravenous immunoglobulin (IVIG) dosing and plasma exchange (PLEX) followed by IVIG (combination therapy) have no additional therapeutic benefit in Guillain-Barre Syndrome (GBS) non-responders. Furthermore, the delineation between GBS and Acute Onset CIDP (A-CIDP) can be particularly challenging and carries therapeutic implications. We aimed to evaluate the presence of repeat IVIG, combination therapy, and diagnostic reclassification from GBS to CIDP. METHODS: We performed a retrospective study of a large healthcare database for patients with GBS in the US from 2001 to 2018. We identified individuals initially diagnosed with GBS and later re-classified as CIDP. Multivariable logistic regression models were developed to determine associations between patient factors and repeat IVIG dosing, combination therapy, and diagnostic re-classification from GBS to CIDP. RESULTS: We identified 2325 patients with GBS. A total of 39.7% received repeat IVIG and 6.1% received combination therapy. The proportion of individuals initially diagnosed with GBS and then re-classified as CIDP was 32.0%. Repeat IVIG, combination therapy, and diagnostic reclassification remained stable over time. Female sex (OR 0.79, 95% CI 0.65-0.96) and medium-high net worth (OR 0.64, 95% CI 0.45-0.90) associated with repeat IVIG therapy, while Asian ethnicity associated with diagnostic re-classification from GBS to CIDP (OR 1.77, 95% CI 1.09-2.86). DISCUSSION: Repeat IVIG dosing was quite common in GBS before newer trials suggesting harm in non-responders, and IVIG/PLEX combination therapy continues to persist despite strong evidence against use in non-responders. Further, nearly one in three patients initially diagnosed with GBS is subsequently diagnosed with CIDP, but the reasons are unclear.

Antibodies against glutamic acid decarboxylase in intravenous immunoglobulin preparations can affect the diagnosis of type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIgs) contain various autoantibodies, including those against glutamic acid decarboxylase (GADAb), a valuable biomarker of type 1 diabetes mellitus. Passive transfer of GADAb from IVIgs to patients poses a risk of misdiagnosis, and information on the specific titres of GADAb and their impact on diagnostic accuracy remains limited. This study aimed to provide further insights into the origin of GADAb detected in patient serum following IVIg infusion. MATERIALS AND METHODS: GADAb titres in IVIg products from Japan and the United States were measured using enzyme-linked immunosorbent assay-based assays. For reliable quantification, GADAb titres in pooled plasma were quantified and compared with those in the IVIg products. The determined titres were used to estimate the likelihood of passively detecting acquired GADAb in individuals receiving IVIgs. RESULTS: GADAbs were prevalent in IVIg products; however, the titres varied significantly among different lots and products. Importantly, IVIg-derived GADAb was estimated to remain detectable in patient serum for up to 100 days following a dosage of 2000 mg/kg. CONCLUSION: Clinicians should consider that IVIg preparations may contain GADAb, which can lead to false-positive results in serological assays. Careful interpretation of the assay results is key to the definitive diagnosis of type 1 diabetes mellitus.

Impact of 2021 European Academy of Neurology/Peripheral Nerve Society diagnostic criteria on diagnosis and therapy of chronic inflammatory demyelinating polyradiculoneuropathy variants.

BACKGROUND AND PURPOSE: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated. METHODS: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP. RESULTS: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory-predominant CIDP (7%), 10 motor CIDP (3%), and eight motor-predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F-wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor-predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory-predominant CIDP did. CONCLUSIONS: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.

Transfusion-related acute lung injury (TRALI) following intravenous immunoglobulin infusion in a rituximab immunosuppressed patient with long-shedding SARS-CoV-2.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. CASE PRESENTATION: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. CONCLUSION: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.

Motor polyradiculoneuropathy as an unusual presentation of neurobrucellosis: a case report and literature review.

Brucellosis, a zoonotic disease caused by Brucella species, poses a significant global health concern. Among its diverse clinical manifestations, neurobrucellosis remains an infrequent yet debilitating complication. Here, we present a rare case of neurobrucellosis with unusual presentations in a 45-year-old woman. The patient's clinical course included progressive lower extremity weakness, muscle wasting, and double vision, prompting a comprehensive diagnostic evaluation. Notable findings included polyneuropathy, elevated brucella agglutination titers in both cerebrospinal fluid and blood, abnormal EMG-NCV tests, and resolving symptoms with antibiotic therapy. The clinical presentation, diagnostic challenges, and differentiation from other neurological conditions are discussed. This case underscores the importance of considering neurobrucellosis in regions where brucellosis is prevalent and highlights this rare neurological complication's distinctive clinical and radiological features. Early recognition and appropriate treatment are crucial to mitigate the significant morbidity associated with neurobrucellosis.

Successful management of severe Kell alloimmunization in pregnancy with intravenous immune globulin.

Hemolytic Disease of the Fetus and Newborn (HDFN) is a condition that affects 1 to 2 out of 1000 patients during pregnancy (1). When an alloantibody is present, it is essential to identify its nature in order to organize appropriate follow-up. Kell-mediated HDFN is rare; it occurs in about 5% of Kell alloimmunized pregnant women. It is important to note that in case of anti-Kell immunization, the severity of HDFN is not correlated with maternal antibody titers, and anemia tends to occur earlier and more severely. Therefore, early diagnosing and management of this condition is crucial. In the management of severe fetal anemia due to Kell immunization, available treatments include in utero transfusion (IUT), immunoglobulin therapy. Other alternative treatments exist, such as plasmapheresis. Intravenous immunoglobulin (IVIG), a noninvasive therapeutic approach, acts through multiple mechanisms. IVIG has been evaluated in cases of RhD immunization with high maternal antibody titers and a history of pregnancies involving early hydrops or intrauterine death. Regarding the potential benefits of intravenous IgG therapy, it may delay the need for early IUT, reduce the overall reliance on IUT, and have a positive impact on obstetric outcomes. This case of IV IgG therapy of anti-Kell immunization offers a thought-provoking avenue for future exploration.

Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups.   Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

Trends in intravenous immunoglobulin use in New South Wales, Australia.

BACKGROUND: Intravenous immunoglobulin (IVIg) is a critical replacement therapy for immunodeficiencies and immunomodulatory treatment for autoimmune and inflammatory diseases. Adequate supply of IVIg is a global issue, necessitating supply restrictions. In Australia, despite strict criteria for use, demand for IVIg has increased over time and exceeds domestic supply. OBJECTIVE: Factors associated with the upward trend in overall IVIg use were examined, including in the number of unique patients, IVIg dosing and treatment frequency and variations by prescribing discipline and disease group. METHODS: De-identified data of IVIg dispensed in the largest Australian state (New South Wales) from 2007 to 2013 were provided by Australian Red Cross Lifeblood. Trends and projections were calculated using log-linear regression of unique patients, treatment episodes and grams of IVIg for overall use and use stratified by discipline and disease group. RESULTS: During the study period, 169 453 treatment episodes were recorded for 12 547 unique patients accounting for 5 827 787 g of IVIg use. Overall, IVIg use increased by 12.0% (11.5-12.6%) per year representing a 97.7% increase (91.6-104%) over the study period. The highest growth was among neurological conditions (16.0% (14.9-17.1%) per year). An increase in the number of unique patients was the primary driver of this growth, augmented by increases in the frequency and average dose per treatment. CONCLUSIONS: Clinically acceptable measures to improve management of IVIg supply are needed including optimising dose, frequency and duration of treatment. Formal evaluation of IVIg versus alternatives, including cost-effectiveness and comparative efficacy, is warranted.