Quantification of human intravenous immunoglobulin from plasma and in process samples by affinity chromatography.

Advances in affinity chromatography now make it possible to analyze immunoglobulin G from plasma and its fractions with a simple chromatographic method. Ligands derived from camelid antibodies have been developed which have affinity to all 4 subclasses of human IgG without a cross reactivity to other immunoglobulins. The commercially available Capture Select FcXL is the basis for a simple method for direct quantification of immunoglobulin G from plasma or from fractions from cold ethanol precipitation. After direct injection of the sample into the column the unbound proteins are washed out with equilibration buffer and eluted with a pH-step. The elution the peak is integrated, and quantity is derived form a standard curve. The limit of detection with 40 µg/mL, and a linearity up to 250 µg/mL allows an analysis of samples ranging from 0.04 to 50 mg/mL using varying injection volume without further dilution and the two-wavelength detection. A full cycle is completed within five minutes. This method can serve as orthogonal method for in-process control but also for process development.

Serum immunoglobulin levels in group E of chronic obstructive pulmonary disease: insights for clinical management and immunoglobulin therapy strategies.

OBJECTIVE: The study aimed to characterize serum immunoglobulin (Ig) concentrations and their relationship with clinical and paraclinical features in patients with COPD group E in the stable stage. Additionally, the study focused on evaluating the relationship between serum Ig levels and the risk of exacerbations over the next 12 months, thereby clarifying the role of serum Ig deficiency in affecting the future risk for these patients. METHODS: A prospective observational study assessed IgG, IgA, IgM, and IgE levels in 67 COPD patients and 30 healthy controls at Military Hospital 103 from October 2017 to August 2020. Primary outcomes included Ig isotype levels in COPD patients, with secondary outcomes exploring differences compared to controls and associations with clinical variables. RESULTS: COPD patients showed significantly lower IgG concentrations and higher IgA levels than controls. IgM and IgE levels did not differ significantly. Subgroup analysis revealed notable decreases in IgG1 and IgG3 concentrations, with 10.4% of patients exhibiting reduced IgG levels and 0.3% diagnosed with common variable immunodeficiency. No significant associations were found between Ig levels and exacerbation risk or clinical variables. CONCLUSIONS: Serum IgG and IgM concentrations were significantly reduced in COPD patients compared to normal individuals, with IgG1 and IgG3 concentrations notably low. Serum IgA levels were significantly higher in COPD patients compared with normal controls. However, no significant association was found between Ig concentrations, particularly serum IgG deficiency and its subclasses, with the frequency and risk of exacerbations during 12 months of longitudinal follow-up. Caution is warranted in the use of immunoglobulin therapy in the treatment of COPD patients. TRIAL REGISTRATION: An independent ethics committee approved the study (Ethics Committee of Military Hospital 103 (No. 57/2014/VMMU-IRB), which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice.

Treatment of Immune Thrombocytopenia: Contextualization from a Historical Perspective.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated decrease in platelet count and an increased risk of bleeding. The pathogenesis is complex, affecting multiple components of the immune system and causing both peripheral destruction of platelets and inadequate production in the bone marrow. In this article, we review the treatment of ITP from a historical perspective, discussing first line and second line treatments, and management of refractory disease.

Emerging treatment landscape for Guillain-Barré Syndrome (GBS): what's new?

INTRODUCTION: Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder characterized by acute paralysis. A significant portion of patients are left with residual deficits, which presents a considerable global healthcare challenge. The precise mechanisms underlying GBS pathogenesis are not fully elucidated. Recent studies have focused on postinfectious molecular mimicry and identified involvement of IgG autoantibodies and innate immune effectors in GBS. Intravenous immunoglobulins (IVIg) and plasma exchange (PE) are two established evidence-based immunomodulatory treatments for GBS, but a significant proportion of GBS patients fails to respond adequately to either therapy. This emphasizes an urgent need for novel and more potent treatments. AREAS COVERED: We discuss novel immunomodulatory therapies presently at different phases of preclinical and clinical investigation. Some drugs in development target pathophysiologic mechanisms such as IgG autoantibody catabolism and complement activation, which are relevant to GBS. EXPERT OPINION: There is an unmet need for more effective immune therapies for GBS. New immunomodulatory therapies under development may provide more potent options for GBS patients who do not respond to IVIg or PE. Future directions may include incorporating neuroprotective interventions based on evolving understanding of mechanisms underlying nerve injury and axonal degeneration.

Upper Gastrointestinal (GI) Manifestations of Inflammatory Myositis: A Tale of Two Patients.

Myositis is a group of rare autoimmune disorders characterized by chronic inflammation of skeletal muscles that leads to a hallmark triad of muscle weakness, fatigue, and myalgia. Extra-muscular manifestations are sometimes seen and involve various organ systems, including the gastrointestinal (GI) tract. In this case series, two patients with polymyositis (PM) and dermatomyositis (DM), both of whom developed dysphagia as a complication of myositis, are discussed. Case 1 was a female with a known history of biopsy-proven dermatomyositis who presented with progressive peripheral edema and weakness affecting all extremities. Concurrently, she displayed symptoms of pneumonia and dysphagia associated with frequent spontaneous or self-induced vomiting to alleviate retrosternal discomfort. Esophagogastroduodenoscopy (EGD) revealed esophageal dilatation and an absence of a contractile response, consistent with myositis. Treatment comprised intravenous immunoglobulin (IVIG), mycophenolate, and lifestyle modifications, including dietary adjustments and maintaining an upright position postprandial. The second case was a female with muscle weakness and dysphagia. Video-fluoroscopic swallow assessment was significant for pharyngeal dysfunction without a sensory response to penetrated material, and the patient was at high risk of aspiration with any oral intake. The presence of pharyngeal dysfunction and dysphagia prompted treatment with IVIG, mycophenolate, and percutaneous endoscopic gastrostomy (PEG) tube placement. These cases have highlighted the upper GI complications observed in patients with myositis, accentuating the necessity for a personalized treatment approach. Timely intervention has shown promising results in symptomatic relief and improving patient outcomes. This emphasizes the importance of a multidisciplinary approach when addressing myositis-related upper GI manifestations.

International collaborative study to assess new stocks of candidate reference preparations to control the level of anti-D in IVIG

The level of anti-D antibodies in human immunoglobulin products for intravenous administration (IVIG) is controlled by the direct haemagglutination method prescribed by the European Pharmacopoeia (Ph. Eur.) that requires 2 control reference reagents. The World Health Organization (WHO) positive control International Reference Reagent (IRR; 02/228) with a nominal titre of 8 defines the highest acceptable titre, while the negative control preparation (02/226) has a nominal titre of <2. Working reference preparations (04/132 and 04/140) were subsequently established as Biological Reference Preparations (BRPs) for the Ph. Eur., and for distribution by the United States Food and Drug Administration (US FDA) and the National Institute for Biological Standards and Control (NIBSC). Due to diminishing stocks of these working reference preparations across the 3 institutions, a joint international study was organised to establish harmonised replacement batches. Sixteen laboratories contributed data to the study to evaluate positive and negative candidate replacement batches (13/148 and 12/300, respectively) against the WHO positive and negative control IRRs and the current working reference preparations (BRPs). The results show that the candidate reference preparations (13/148 and 12/300) are indistinguishable from the corresponding IRRs and current BRPs. The candidate preparations 13/148 and 12/300 were adopted by the Ph. Eur. Commission as Immunoglobulin (anti-D antibodies test) BRP batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 with nominal haemagglutination titres of 8 and <2, respectively. The same materials were also adopted as NIBSC and US FDA reference preparations, thus ensuring full harmonisation.

Limitations in the clinical utility of vaccine challenge responses in the evaluation of primary antibody deficiency including Common Variable Immunodeficiency Disorders.

Vaccine challenge responses are an integral component in the diagnostic evaluation of patients with primary antibody deficiency, including Common Variable Immunodeficiency Disorders (CVID). There are no studies of vaccine challenge responses in primary hypogammaglobulinemia patients not accepted for subcutaneous/intravenous immunoglobulin (SCIG/IVIG) replacement compared to those accepted for such treatment. Vaccine challenge responses in patients enrolled in two long-term prospective cohorts, the New Zealand Hypogammaglobulinemia Study (NZHS) and the New Zealand CVID study (NZCS), were compared in this analysis. Almost all patients in the more severely affected SCIG/IVIG treatment group achieved protective antibody levels to tetanus toxoid and H. influenzae type B (HIB). Although there was a highly significant statistical difference in vaccine responses to HIB, tetanus and diphtheria toxoids, there was substantial overlap in both groups. In contrast, there was no significant difference in Pneumococcal Polysaccharide antibody responses to Pneumovax® (PPV23). This analysis illustrates the limitations of evaluating vaccine challenge responses in patients with primary hypogammaglobulinemia to establish the diagnosis of CVID and making decisions to treat with SCIG/IVIG. The conclusion from this study is that patients with symptoms attributable to primary hypogammaglobulinemia with reduced IgG should not be denied SCIG/IVIG if they have normal vaccine responses.

Treatment intensification in Kawasaki disease - current perspectives.

INTRODUCTION: Intravenous immunoglobulin is the standard of care in Kawasaki disease. However, a subset of patients exhibits resistance to intravenous immunoglobulin treatment, even when Kawasaki disease is promptly diagnosed and managed. While intravenous immunoglobulin reduces the occurrence of coronary artery abnormalities from 15-25% to 3-5%, it does not entirely eliminate the risk. Besides, management guidelines for non-coronary complications of Kawasaki disease, for instance, myocarditis, remain speculative. AREAS COVERED: Recent literature suggests that a subset of patients with Kawasaki disease may benefit from treatment intensification with drugs, such as corticosteroids, infliximab, anakinra, and/or ciclosporin. In this manuscript, we have reviewed recent advances in the management of Kawasaki disease, especially with regard to preemptive intensification of therapy in children at high risk of cardiac complications. A comprehensive search was made using Web of Science, Scopus, and PubMed databases to gather English articles published from 1967 to 2023 on the treatment of Kawasaki disease. We incorporated the following words in the search strategy: 'Kawasaki disease,' 'intravenous immunoglobulin/IVIg,' 'intravenous immunoglobulin/IVIg-resistant Kawasaki disease,' 'treatment intensification,' or 'primary intensification of treatment/therapy.' EXPERT OPINION: The 'high-risk' group in Kawasaki disease needs to be identified with early intensification of primary therapy for better coronary and myocardial outcomes.

Retrospective Evaluation of Survival and Prognostic Factors in Immune Thrombocytopenia: A Single-Center and Cross-Sectional Study.

Background and Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the autoantibody-mediated destruction of platelets. The treatment of ITP aims to maintain a sufficient platelet count to prevent bleeding. First-line treatment options include corticosteroids and intravenous immunoglobulin (IVIg), while second-line treatments include splenectomy, rituximab and other immunosuppressive agents, and thrombopoietin (TPO) receptor agonists. This study aims to discuss the treatment methods and results from 100 patients with ITP at the Mugla Training and Research Hospital through a pharmacological approach. Materials and Methods: Demographic characteristics, clinical findings, bone marrow aspiration and biopsy results, and treatments and treatment responses at the time of diagnosis of the 100 patients with ITP who were treated and followed up in the period 2015-2023 were evaluated retrospectively. Results: In the third month after treatment, the overall response percentage was 100% in patients who received steroids only and 88% in patients who received IVIg treatment alone or in combination with steroids (p > 0.05). The most preferred second-line treatments were splenectomy (41%), eltrombopag (26%), and rituximab (10%). Bone marrow biopsy was performed in 54% of patients, where 35.1% showed increased megakaryocytes, 44.4% adequate megakaryocytes, and 14.8% decreased megakaryocytes. It is noted that eltrombopag and rituximab, in particular, yield higher complete remission rates than immunosuppressive drugs. Conclusions: Considering the side effects of immunosuppressive medications, IVIg, splenectomy, and steroid therapy, the use of new agents such as eltrombopag, which are easily tolerated and have a lower risk of side effects, is expected to increase.

Effect of intravenous immunoglobulin on mortality in hospitalized patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials.

Background and Aims: We performed a meta-analysis of randomized controlled trials (RCTs) to summarize the overall effect of intravenous immunoglobulin (IVIG) on mortality outcomes among hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: We systematically searched electronic databases up to June 1, 2023. Pooled odds ratio (OR) of mortality with a 95% confidence interval (CI) was generated using a random-effects model. The risk of bias was appraised using the Cochrane risk-of-bias Version 2 tool for randomized trials. Results: Nine RCTs were included: three RCTs had an overall low risk of bias, four RCTs had some concerns in the overall risk of bias, and two RCTs trials had an overall high risk of bias. The use of IVIG indicated a significant reduction in the odds of mortality (pooled OR = 0.69; 95% CI 0.50-0.96) relative to nonuse of IVIG. Subgroup analysis in patients with a severe course of COVID-19 revealed no significant reduction in the odds of mortality (pooled OR = 0.58; 95% CI 0.29-1.16). Conclusions: We suggest exercising caution when interpreting effectiveness of IVIG in reducing mortality among hospitalized patients with COVID-19. Our findings emphasize for larger trials with rigorous study designs to better understand the impact of IVIG, particularly in those with severe COVID-19.

Going Outside the Gut: Immune Thrombocytopenia Presenting as a Rare Extraintestinal Manifestation of Ulcerative Colitis.

A 26-year-old male with no significant medical history presented with hematochezia and was diagnosed with ulcerative colitis (UC) accompanied by immune thrombocytopenia (ITP) as an extraintestinal manifestation (EIM) of UC. This case report delves into the uncommon overlap between UC, a subtype of inflammatory bowel disease primarily affecting the colon and rectum, and ITP, an autoimmune condition leading to platelet destruction. The patient's atypical presentation and subsequent positive response to a treatment regimen targeting both UC and ITP underscores the necessity for a thorough and multifaceted diagnostic approach in individuals with UC, especially when faced with non-gastrointestinal symptoms like unexplained thrombocytopenia. The findings from this study enhance the understanding of UC's diverse manifestations and highlight its potential intersection with other autoimmune diseases, advocating for integrated care strategies in managing such intricate clinical cases.

An Interesting Case of Refractory Kawasaki Disease With Co-infection.

Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the common vasculitides of childhood. KD most commonly occurs in children over six months up to five years of age, although it can occur in young infants, older children, and adults. Early diagnosis is critical to achieving optimal treatment. We present a case of a three-year-old female child who was admitted with a fever for five days and fulfilled the diagnostic clinical criteria for KD. She was given intravenous immunoglobulin (IVIG) and aspirin. However, the fever persisted, and a urine culture showed the growth of Klebsiella pneumoniae. We started an antibiotic based on her sensitivity. Since fever spikes were not subsiding, she was given a repeat dose of IVIG along with an oral corticosteroid for refractory KD, after which she showed clinical improvement. This case highlighted that refractory KD can coexist with infection.

Variable Expression Common Immune Deficiency: A Report of Five Cases.

We present five cases of common variable immunodeficiency (CVID), comprising three women and two men with a mean age of 23.8 ± 9.2 years. All our patients suffered from recurrent bronchopneumonitis, with complications of purulent pleurisy in two cases, requiring decortication in one case, and resulting in bronchiectasis in three cases. Digestive tract infections were observed in four patients, while two patients presented with ENT infections. One case was complicated by bacterial meningitis. All patients presented with global hypogammaglobulinemia, with CVID and granulomatous manifestation in one case. Treatment consisted of monthly immunoglobulin infusions.

Treatment response in patients with clinical and supportive laboratory features of chronic inflammatory demyelinating polyneuropathy without demyelinative findings on nerve conduction studies: A retrospective study.

INTRODUCTION/AIMS: Not all patients with chronic inflammatory demyelinating polyneuropathy (CIDP) have evidence of demyelination on nerve conduction studies (NCS). Patients with "supportive" evidence of CIDP on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), ultrasound (US), or nerve biopsy but not on NCS, often receive immunomodulating therapy. We evaluated the treatment response of patients with clinical and supportive features of CIDP lacking NCS evidence of demyelination. METHODS: Retrospective chart review was conducted on 232 patients who met CIDP clinical criteria and were treated with disease-modifying therapy. Patients included did not have NCS criteria of demyelination, but did have supportive CSF, MRI, or US findings consistent with CIDP. A positive treatment response was defined as at least a one-point improvement in the modified Rankin scale (mRS), or a four-point increase in the Medical Research Council sum score (MRCSS). RESULTS: Twenty patients met criteria: 17 of the 18 (94%) patients with CSF protein >45 mg/dL, 6 of the 14 (43%) with MRI lumbosacral root or plexus enhancement, and 4 of the 6 (67%) with enlarged proximal nerves on US. Eighteen patients received intravenous immunoglobulin, 10 corticosteroids, one plasma exchange, and six other immunomodulatory therapies. Twelve patients had a positive treatment response on the MRCSS or mRS. The presence of MRI lumbosacral root or plexus enhancement was associated with a positive treatment response. DISCUSSION: A trial of immunomodulating treatment should be considered for patients with clinical features of CIDP in the absence of NCS evidence of demyelination, particularly when there is MRI lumbosacral root or plexus enhancement.

A Novel Variant of the PIK3R1 Gene Mutation Associated With SHORT Syndrome and Agammaglobulinemia.

Primary immunodeficiencies are disorders of the immune system often caused by mutations of genes required for lymphocyte development. Phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) gene mutations are associated with SHORT syndrome, a rare multisystem disease. The name stands for Short stature, Hyperextensibility, Ocular depression, Rieger anomaly and Teething delay. Our case describes a child who presented with agammaglobulinemia with phenotypical features of SHORT syndrome. Upon further investigation, he was found to have a rare variant of the PIK3R1 gene mutation. This new mutation combines two distinct diseases with the same gene defect, which otherwise has been reported as two separate entities. The objective of this report is to identify a new gene mutation associated with SHORT syndrome along with agammaglobulinemia and to highlight the importance of recognizing the features of SHORT syndrome. We describe a nine-year-old male who presented with developmental delay and recurrent infections at the age of 12 months. Immunological evaluation revealed agammaglobulinemia and he has been scheduled for regular intravenous immunoglobulin replacement therapy. In view of characteristic syndromic physical features, speech and teething delay, we investigated further for the underlying genetic reason for agammaglobulinemia. The molecular analysis demonstrated a rare homozygous variant, c.244dup, in the PIK3R1 gene. This case reveals the association of the PIK3R1 gene mutation with agammaglobulinemia and SHORT syndrome. It further demonstrates the discovery of a new pathological variant of the gene. A detailed history and examination along with an immunological and genetic workup should be carried out for children with certain distinct phenotypical features. SHORT syndrome has specific characteristics that call for awareness and early recognition for prompt diagnosis and intervention. Emphasis is placed on genetic counseling as the disease is inherited in an autosomal recessive pattern, as demonstrated by molecular genetic studies.

Post-Viral Longitudinally Extensive Transverse Myelitis: A Case Report.

Longitudinally extensive transverse myelitis is a rare neurological manifestation caused by dengue infection. Here, we describe the uncommon presentation of a 24-year-old male with fever and maculopapular rash followed by flaccid quadriparesis with acute urinary retention. Magnetic resonance imaging of the whole spine with contrast revealed a long-segment ill-defined hyperintense signal noted in the cord. The patient was managed conservatively with intravenous steroids and later intravenous immunoglobulins. The patient is on regular follow-up and doing well. Currently, the patient is on tablet prednisolone with a tapering dose.

Subacute Cutaneous Lupus Erythematosus Secondary to Intravenous Immunoglobulin Infusions.

Subacute cutaneous lupus erythematosus (SCLE) is a variant of cutaneous lupus erythematosus (CLE) characterized by distinct skin lesions. Clinical manifestations typically include annular or psoriasiform skin lesions, often localized in sun-exposed areas such as the chest and back. The pathogenesis of SCLE is largely unknown, and contributing factors include genetics, environmental exposures, and immunological dysregulation. SCLE may be idiopathic or drug-induced, with common triggers being calcium channel blockers, thiazide diuretics, and terbinafine. Intravenous immunoglobulin (IVIG) treatment, frequently used in various autoimmune conditions, has a rare association with SCLE. We report a case in which this condition arose during IVIG treatment for chronic inflammatory demyelinating polyneuropathy (CIDP). Knowledge of this rare effect is beneficial to all providers who prescribe IVIG, including neurology, rheumatology, and dermatology.

Acute-Onset Quadriplegia Presenting With Hyperreflexia: A Dilemma in Diagnosis.

An autoimmune polyradiculoneuropathy, Guillain-Barré syndrome (GBS) is an acute, rapidly progressive, and fulminant one. Rapidly developing motor weakness along with absent reflexes, with or without sensory impairment, is the hallmark of GBS. GBS is never a hereditary entity; it is always acquired by the individual. Here, we present an interesting case of GBS in a 37-year-old male patient presenting with lower limb weakness for one day which had progressed to upper limb weakness in a day. There was a history of fever and loose stools four days back. On examination, vitals were within normal limits including single breath count. Central nervous system (CNS) examination revealed as follows: bicep jerk, tricep jerk, and supinator jerk were National Institute of Neurological Disorders and Stroke (NINDS) scale grade 2 in bilateral upper limbs. Knee jerk was NINDS scale grade 3 in bilateral lower limbs, which was unusual considering that GBS presents with areflexia or reduced reflexes. Ankle jerk was absent in bilateral lower limbs. Plantars were mute bilaterally. Nerve conduction study was suggestive of axonal and demyelinating motor neuropathy involving all four limbs. The patient was planned for intravenous immunoglobulin at a dose of 2 g/kg/day for five days but developed an allergic reaction to the first dose; hence, the therapy was discontinued, and the option of plasmapheresis was given to which the patient refused. This is a report of a case of GBS with hyperreflexia which is an uncommon entity in the Indian subcontinent.

Corrigendum: Low rates of headache and migraine associated with intravenous immunoglobulin infusion using a 15-minute rate escalation protocol in 123 patients with primary immunodeficiency.

[This corrects the article DOI: 10.3389/fimmu.2022.1075527.].

A Unique Case of Non-paraneoplastic Lambert-Eaton Myasthenic Syndrome Treated With Subcutaneous Immunoglobulin: A Case Report and Review of Literature.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular disorder caused by pathogenic autoantibodies directed against voltage-gated calcium channels present on the presynaptic nerve terminal. For LEMS patients refractory to initial symptomatic treatment with amifampridine, immunomodulatory therapy with intravenous immunoglobulin (IVIG) is often utilized. However, in the authors' review of literature, the utility of subcutaneous immunoglobulin (SCIG) in the treatment of LEMS has been scarcely reported. Here, we present a unique case of non-paraneoplastic LEMS managed with SCIG with excellent clinical response and improvement on electromyography. SCIG therapy may be a reasonable alternative for patients with LEMS who do not tolerate the intravenous formulation.