A double-blind placebo-controlled pilot study of immunoglobulin for small fiber neuropathy associated with TS-HDS and FGFR-3 autoantibodies.

INTRODUCTION/AIMS: Small fiber neuropathies (SFN) have been associated with two autoantibodies, trisulfated heparin disaccharide (TS-HDS) and fibroblast growth factor receptor 3 (FGFR-3), and intravenous immune globulin (IVIG) has been suggested as a potential therapy. The study objective is to determine the efficacy of IVIG on nerve density, pain and neurologic examinations in patients with SFN associated with TS-HDS and FGFR-3 autoantibodies. METHODS: This was a double-blind placebo-controlled pilot study. Subjects with SFN confirmed by history, examination, and skin biopsy with elevated autoantibodies to TS-HDS and/or FGFR-3 received IVIG (or blinded placebo) 2 grams/kg followed by 1 gram/kg every 3 wk for a total of 6 treatments. All subjects had Utah Early Neuropathy Scores (UENS), questionnaires and skin biopsies with quantitation of intra-epidermal nerve fiber density (IENFD) taken from adjacent sites at the distal leg at baseline and 6 mo later. The primary outcome was the change in IENFD over 6 mo. RESULTS: Twenty subjects were enrolled; 17 completed treatment (8 IVIG, 9 placebo). Three did not have final data due to coronavirus disease 2019 (COVID-19). Skin biopsy IENFD improved by 0.5 ± 0.8 fibers/mm in the placebo group and improved by 0.6 ± 0.6 fibers/mm in the IVIG-treated group (p = NS).Over 24 wk the change in pain scores (11 point pain scale) was -1.9 ± 2.6 in the placebo group, and - 1.7 ± 0.9 in the IVIG group (p = NS), the UENS improved by 3.0 ± 5.8 in the placebo group and improved by 1.8 ± 3.9 in the IVIG group (p = NS). DISCUSSION: This pilot study did not detect a benefit of treatment with IVIG in patients with SFN and autoantibodies to TS-HDS and FGFR-3.

ASCENIV utilization in a primary immunodeficiency patient with recurrent viral infections.

Primary immunodeficiency (PI) patients may still experience persistent viral and bacterial respiratory infections with ongoing treatments. We report a challenging case of a PI patient who experienced recurrent viral respiratory infections despite receiving standard immunoglobulin replacement therapy. The patient was subsequently managed with immune globulin intravenous, human-slra (ASCENIV™) that contains elevated antibodies against multiple respiratory pathogens. The patient demonstrated significant clinical improvement with a resolution of persistent and debilitating viral respiratory infections and associated sequela.

Update on the treatment of multisystem inflammatory syndrome in children associated with COVID-19.

In late 2019, SARS-CoV-2 was detected in China and spread worldwide. In rare cases, children who were infected with COVID-19 may develop multisystem inflammatory syndrome (MIS-C), which could have higher mortality than COVID-19 itself. Therefore, diagnosis and management are critical for treatment. Specifically, most of the initial treatment options of MIS-C choose intravenous immunoglobulin (IVIG) and steroids as the first-line treatment for patients. Moreover, antagonists of some cytokines are used as potential future therapeutics. Of note, therapeutic plasmapheresis can be used as a treatment for refractory severe MIS-C. We believe that each patient, especially those with comorbid conditions, should have individualized treatment based on both multidisciplinary consensus approach and expert opinion.

Course and Treatment of a Rare Neurological Sequelae After COVID-19: Miller Fisher Syndrome.

Reports of COVID-19 infection detailing its symptoms and outcomes point to its effects systemically, including that of the nervous system, such as the rare Miller Fisher syndrome (MFS). In this report, we identified a 43-year-old Caribbean man who arrived in the USA with ataxia and ascending bilateral lower extremity weakness after COVID-19 infection. Before arrival, the patient was diagnosed with Guillain-Barré syndrome (GBS). He was treated with IV methylprednisolone and a round of IV immunoglobulin (IVIG); however, he showed a minimal response. Upon admission to our ED, he had severe tachypnea and flaccid symmetrical quadriparesis combined with areflexia. Moreover, he had begun to exhibit signs of multiple cranial nerve palsies, including ophthalmoplegia and facial diplegia. Additionally, his laboratory cerebrospinal fluid (CSF) analysis was grossly normal. Therefore, he was diagnosed with MFS. Furthermore, he developed acute depression and exhibited signs of mania. The patient was treated with IV methylprednisolone and the second round of a five-day course of IVIG, resulting in marked clinical improvement. This case highlights the need for a multidisciplinary care approach in patients with MFS. It also points to the possible benefit of multiple IVIG rounds in MFS patients who do not improve after the first course.

An Early Catch: Multisystem Inflammatory Syndrome in Adults (MIS-A) in a Young Adult Male With COVID-19 Exposure.

While severe acute respiratory syndrome (SARS) is the most common presentation of coronavirus disease 2019 (COVID-19) infection, several short- and long-term complications from COVID-19 infection are also being recognized. One such complication with life-threatening consequences is known as multisystem inflammatory syndrome in adults (MIS-A). While the phenomenon of multisystem inflammatory syndrome in children (MIS-C) is more recognized, the pathophysiology of both presentations remains a mystery currently. Several theories have been put forward however no consensus has been established yet. We present the case of a 20-year-old male who was admitted to the intensive care unit for a multisystem illness characterized by severe biventricular failure, profound shock, and acute liver and kidney injuries. The severity of illness necessitated the treatment with mechanical ventilation, extracorporeal membrane oxygenation (ECMO), vasopressors, and continuous veno-venous hemofiltration (CVVH). The patient was treated with one dose of intravenous immune globulin (IVIG). In association with the foregoing treatment, the patient made dramatic recovery and came off pulmonary, hemodynamic, and renal support within a week and made remarkably quick and full recovery. This case highlights a rare presentation of a COVID-19 complication that requires prompt recognition, supportive care, and empiric treatment that led to a favorable outcome in this case.

Immune globulin therapy and kidney disease: Overview and screening, monitoring, and management recommendations.

PURPOSE: This report calls attention to the potential risks of diminished kidney function when administering immune globulin (IG). The goal is to increase awareness of chronic kidney disease (CKD) and kidney function impairment in patients receiving IG and provide recommendations for screening, monitoring, and management to promote risk prevention and mitigation. SUMMARY: Human IG preparations for intravenous (IVIG) or subcutaneous (SCIG) administration are the mainstay of treatment in patients with primary immunodeficiency diseases. Increasingly, IVIG at high doses (1,000 to 2,400 mg/kg) is also used as a treatment for a variety of autoimmune and inflammatory conditions. Although some autoinflammatory disorders respond to a single course of IVIG therapy, the majority of patients require long-term, regular infusions, thereby increasing the overall risks. Often, both patients and physicians treating adults with IG are unaware of underlying CKD or kidney function impairment. This lack of awareness constitutes a major risk factor for potential worsening, particularly when using high doses of IVIG. Therefore, screening of all patients for CKD and kidney function impairment before the use of IG is essential. Identification of the cause of kidney impairment is strongly encouraged, as IG therapy may need to be modified. CONCLUSION: As detailed here, there are potential risks to patients with impaired kidney function with administration of IG, particularly at high doses. Product selection, volume, route of administration, and rate of infusion may impact those with compromised kidney function. Therefore, screening of all patients for CKD and kidney function impairment before the use of IVIG and SCIG, as well as ongoing monitoring and management, is critical. As with all potential adverse drug reactions, the best approach is to prevent them.

Treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT).

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel prothrombotic disorder characterized by thrombosis, thrombocytopenia, and disseminated intravascular coagulation identified in hundreds of recipients of ChAdOx1 nCoV-19 (Oxford/AstraZeneca), an adenovirus vector coronavirus disease 2019 (COVID-19) vaccine. VITT resembles heparin-induced thrombocytopenia (HIT) in that patients have platelet-activating anti-platelet factor 4 antibodies; however, whereas heparin typically enhances platelet activation by HIT antibodies, VITT antibody-induced platelet activation is often inhibited in vitro by pharmacological concentrations of heparin. Further, the thrombotic complications in VITT feature much higher frequencies of atypical thrombosis, most notably cerebral vein thrombosis and splanchnic vein thrombosis, compared with HIT. In this review, we outline the treatments that have been used to manage this novel condition since its recognition in March 2021, including anticoagulation, high-dose intravenous immune globulin, therapeutic plasma exchange, corticosteroids, rituximab, and eculizumab. We discuss the controversial issue of whether heparin, which often inhibits VITT antibody-induced platelet activation, is harmful in the treatment of VITT. We also describe a case of "long VITT," describing the treatment challenges resulting from platelet-activating anti-PF4 antibodies that persisted for more than 9 months.

Rapidly Increasing Severe Acute Respiratory Syndrome Coronavirus 2 Neutralization by Intravenous Immunoglobulins Produced From Plasma Collected During the 2020 Pandemic.

Immunoglobulin lots (N = 176) released since March 2020 were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies, with first positive results for September 2020 lots (mean, 1.7 IU/mL; 46% of lots positive). From there, values steadily increased, in correlation with the cumulative coronavirus disease 2019 (COVID-19) incidence, to reach a mean of 31.2 IU/mL and 93% of lots positive by January 2021. Extrapolating the correlation, immunoglobulins could reach an anti-SARS-CoV-2 potency of approximately 345 IU/mL by July 2021. At that stage, prophylactic immunoglobulin treatment for primary/secondary immunodeficiency could contain similar doses of anti-SARS-CoV-2 as convalescent plasma that is used for treatment of COVID-19.

Pharmacokinetics and Efficacy of Human Hyperimmune Intravenous Immunoglobulin Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Adult Syrian Hamsters.

BACKGROUND: After the failure of antibody therapies in treating hospitalized patients with coronavirus disease 2019 (COVID-19), we investigated the impact of viral replication on the pharmacokinetics and efficacy of a hyperimmune severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (CoVIG) product in treating SARS-CoV-2 infection using an adult Syrian hamster model. METHODS: The CoVIG was manufactured from plasma donors who had recovered from COVID-19. The dose used (400 mg/kg) was based on the dose given in clinical trials to hospitalized patients with COVID-19. Hamsters were given a single dose of CoVIG 2 days after challenge with the SARS-CoV-2 virus (isolate NY/PV08410/2020), followed by sampling of blood, nasal, tracheal, and lung tissues at different time points. The blood samples were assayed for anti-SARS-CoV-2 spike binding and used to calculate pharmacokinetic (PK) parameters. Nasal wash, tracheal, and lung tissue samples were assayed for viral replication by polymerase chain reaction (subgenomic messenger RNA). RESULTS: CoVIG-treated hamsters showed a reduction in viral replication in the lower respiratory tract, but minimal reduction in the upper respiratory tract, after challenge with SARS-CoV-2. Challenge resulted in altered PK parameters proportionate to viral replication, resulting in decreased area under the curve, accelerated clearance, and shorter half-life of CoVIG. CONCLUSIONS: These data indicate that in the presence of actively replicating SARS-CoV-2 virus, PK parameters are altered and should trigger an adjustment in CoVIG dosing.

A Case Report of Pediatric Kawasaki Disease and COVID-19 Association

Introduction: As COVID-19 spreads rapidly all over the world and nations struggle to control it, the novel presentations of SARS-CoV-2 infection and its possible triggering role for other diseases in pediatrics concern clinicians in frontlines. Case Presentation: We describe a 10-year-old child diagnosed with COVID-19 infection and concurrent Kawasaki disease. He pre-sented with prolonged fever and conjunctivitis. His initial echocardiogram showed coronary artery dilation in RCA. He was treated with IVIG and aspirin as per guidelines and discharged 48 hours after the completion of IVIG and diminishing fever. His follow-up echocardiogram showed improvement in a two weeks’ interval while he was quarantined in the meantime and showed no respiratory complications. Conclusions: In conclusion, we think that there might be a correlation between COVID-19 infection and hyperinflammatory condi-tions, like Kawasaki disease. Further investigations are needed to enlighten the complications caused by COVID-19 infection, espe-cially in pediatrics. In addition, we emphasize follow-up visits (in person or long-distance) in pediatrics presenting with inflammatory symptoms. © 2020, Author(s).

Highly Potent SARS-CoV-2 Neutralization by Intravenous Immunoglobulins manufactured from Post-COVID-19 and COVID-19-Vaccinated Plasma Donations.

From September 2020, some immunoglobulin lots from US plasma contained neutralizing antibodies against the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Paralleled by the increasing numbers of post-coronavirus disease 2019 (COVID-19) donors, immunoglobulin lot antibody positivity increased to 93% by January 2021, at a mean titer of approximately 30 IU/mL. The correlation predicted that anti-SARS-CoV-2 potency would reach 345 IU/mL by July 2021. In addition to post-COVID-19 donors, the rapidly increasing number of plasma donors vaccinated against COVID-19 resulted in a mean antibody titer of >600 IU/mL in July 2021 immunoglobulin lots, with SARS-CoV-2 antibody titers for several lots even higher than those of earlier produced hyperimmune globulin products.

Retrospective SARS-CoV-2 IgG screening during the first wave (March-June 2020) of the COVID-19 pandemic in the United Kingdom.

During the "first wave" of the coronavirus disease 2019 (COVID-19) pandemic in the United Kingdom (March-June 2020), the city of Leicester was particularly hard hit, resulting in reimposed lockdown measures. Although initial polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was attempted within the community, testing was soon abandoned due to an inability to keep up with demand by local laboratories. It is therefore feasible that undiagnosed transmission of COVID-19 in the community by asymptomatic individuals was a real possibility. Therefore, retrospective SARS-CoV-2 immunoglobulin G (IgG) testing of archived sera from out-patients visiting University Hospitals of Leicester NHS Trust service was performed to investigate the transmission of SARS-CoV-2 in the community. A total of 1779 sera samples were tested from samples collected between 16th March and 3rd June 2020, of which 202 (11.35%) were SARS-CoV-2 IgG positive. Positivity was lowest in March (2.54%) at the beginning of the pandemic before peaking in April (17.16%) before a decline in May and June (11.16% and 12.68%, respectively). This retrospective screening offers some insight into the early patterns of SARS-CoV-2 transmission within a sampled community population during the first wave of the COVID-19 pandemic; supporting the argument for more community screening during high incidences of pandemics.

COVID-19 induced immune thrombocytopenic purpura: case report.

Immune thrombocytopenic purpura (ITP) is an autoimmune state of decreased platelets caused by antibody or T-cell mediated destruction of platelets through the reticuloendothelial system and impairment of their production. Symptoms of ITP include bleeding usually from nose or gums, easy bruising, petechiae commonly of lower extremities, menorrhagia, hematuria, hematemesis, hematochezia and most dreadful, intra cranial hemorrhage. Molecular mimicry between viral antigens and host platelet antigens forming cross-reactive anti-platelet autoantibodies may lead to increased platelet clearance in ITP associated with viral infections. One of the many viruses associated with this is the Coronavirus disease 2019 (COVID-19). It has caused a devastating pandemic. It can activate innate and adaptive immune responses. It has numerous signs and symptoms including but not limited to dyspnea, fever, cough, fatigue, myalgias, loss of taste and smell. It leads to diseases such as pneumonia, acute respiratory distress syndrome, thrombosis and cardiomyopathy. Hematologic manifestations include thrombocytopenia and more commonly lymphopenia. Treatment includes steroids, immune globulin, romiplostim, eltrombopag, rituximab or splenectomy. Contact sports should be avoided due to risk of intra cranial bleeding with head impact. Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin should be used with caution since they impair platelet function. We discuss a patient with COVID-19 who developed thrombocytopenia thought to be due to ITP. Not much is known about the association between the two. It is important to keep this differential in mind when taking care of patients with COVID-19 who develop thrombocytopenia.

European stroke organization interim expert opinion on cerebral venous thrombosis occurring after SARS-CoV-2 vaccination.

Severe cases of cerebral venous thrombosis (CVT) with thrombocytopenia and anti-platelet factor 4 (PF4) antibodies occurring after adenoviral vector anti-SARS-CoV-2 vaccines have been recently reported. We aim to present a guidance document on the diagnosis and treatment of patients presenting with CVT after vaccination against SARS-CoV-2 infection. We reviewed the available evidence which consists on case reports, small case series, expert opinion and analogy with heparin-induced thrombocytopenia (HIT) management. Because of the low level of evidence, this is an interim document, based only on expert opinion consensus. In patients presenting with CVT after being vaccinated against SARS-CoV-2 infection, if there is thrombocytopenia a reliable HIT PF4 Antibody ELISA test should be performed, to confirm vaccine-induced immune thrombotic thrombocytopenia (VITT). In patients with CVT and thrombocytopenia, in whom VITT is suspected or confirmed, heparin (unfractionated or low molecular weight) should be avoided and non-heparin anticoagulants are preferred. If possible, platelet transfusions should be avoided. If the diagnosis of VITT is confirmed or suspected, early intravenous immunoglobulins are indicated. This expert opinion is supported by low quality evidence. It should be periodically updated, or changed to a formal guideline, as new and higher quality evidence is eventually produced. Because of their potential unfavourable clinical course, patients developing symptoms and signs suggestive of CVT after being vaccinated against SARS-CoV-2 virus should undergo urgent clinical and neuroimaging evaluation. In cases of suspected or confirmed VITT, non-heparin anticoagulants should be used, platelet transfusions avoided and intravenous immunoglobulin started early.

Closing the serological gap in the diagnostic testing for COVID-19: The value of anti-SARS-CoV-2 IgA antibodies.

During coronavirus disease 2019 (COVID-19) pandemic, the early diagnosis of patients is a priority. Serological assays, in particular immunoglobulin (Ig)M and IgG anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have today several applications but the interpretation of their results remains an open challenge. Given the emerging role of the IgA isotype in the COVID-19 diagnostics, we aimed to identify the SARS-CoV-2 IgA antibodies in a COVID-19 population seronegative for IgM. A total of 30 patients hospitalized in San Giovanni di Dio Hospital (Florence, Italy) for COVID-19, seronegative for IgM antibodies, have been studied for anti-SARS-CoV-2 antibodies. They all had a positive oro/nasopharyngeal swab reverse transcription-polymerase chain reaction result. Assays used were a chemiluminescent assay measuring SARS-CoV-2 specific IgM and IgG (S + N) and an ELISA, measuring specific IgG (S1) and IgA antibodies against SARS-CoV-2. Among the 30 patients, eight were positive for IgA, seven were positive for IgG (N + S), and two for IgG (S1), at the first point (5-7 days from the onset of symptoms). The IgA antibodies mean values at the second (9-13 days) and third (21-25 days) time points were even more than twice as high as IgG assays. The agreement between the two IgG assays was moderate (Cohen's K = 0.59; SE = 0.13). The inclusion of the IgA antibodies determination among serological tests of the COVID-19 diagnostic is recommended. IgA antibodies may help to close the serological gap of the COVID-19. Variations among anti-SARS-CoV-2 IgG assays should be considered in the interpretation of results.

Production of anti-SARS-CoV-2 hyperimmune globulin from convalescent plasma.

BACKGROUND: In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. Prior to the development of specific drug therapies or a vaccine, more immediately available treatments were sought including convalescent plasma. A potential improvement from convalescent plasma could be the preparation of anti-SARS-CoV-2 hyperimmune globulin (hIVIG). STUDY DESIGN AND METHODS: Convalescent plasma was collected from an existing network of plasma donation centers. A caprylate/chromatography purification process was used to manufacture hIVIG. Initial batches of hIVIG were manufactured in a versatile, small-scale facility designed and built to rapidly address emerging infectious diseases. RESULTS: Processing convalescent plasma into hIVIG resulted in a highly purified immunoglobulin G (IgG) product with more concentrated neutralizing antibody activity. hIVIG will allow for the administration of greater antibody activity per unit of volume with decreased potential for several adverse events associated with plasma administration. IgG concentration and IgG specific to SARS-CoV-2 were increased over 10-fold from convalescent plasma to the final product. Normalized enzyme-linked immunosorbent assay activity (per mg/ml IgG) was maintained throughout the process. Protein content in these final product batches was 100% IgG, consisting of 98% monomer and dimer forms. Potentially hazardous proteins (IgM, IgA, and anti-A, anti-B, and anti-D) were reduced to minimal levels. CONCLUSIONS: Multiple batches of anti-SARS-CoV-2 hIVIG that met regulatory requirements were manufactured from human convalescent plasma. The first clinical study in which the hIVIG will be evaluated will be Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) [NCT04546581].

Histobulin as a complementary but essential therapeutic for Intravenous Immune Globulin Therapy of Pfeiffer-Weber-Christian disease with multiple allergic diseases and its effects on allergic disease: A case report.

Histobulin is complementary to IVIG therapy but is an essential therapeutic for PWCD. Histoublin is recommended not only in atopic dermatitis and multiple food allergies but also in patients with multiple allergic diseases.

Mitigating the risk of COVID-19 exposure by transitioning from clinic-based to home-based immune globulin infusion.

PURPOSE: Intravenous immune globulin (IVIG) therapy is used in patients with hypogammaglobulinemia to lower the risk of infections. IVIG and subcutaneous IVIG (SCIG) therapy have been to shown to be safe and effective when administered as clinic-based infusions. Concern from both patients and providers for increased transmission of the coronavirus disease 2019 (COVID-19) virus to immunosuppressed patients with scheduled medical visits and procedures made it necessary for us to reassess our process of how we manage patient care in general and chronic clinic infusions in particular. Here we describe our experience of transitioning patients from clinic-based to home based IVIG and/or SCIG infusions to decrease the risk of COVID-19 exposure. METHODS: Criteria were developed to identify high-risk immunosuppressed patients who would be appropriate candidates for potential conversion to home based IVIG infusions. Data were collected via chart review, and cost analysis was performed using Medicare Part B reimbursement data. A patient outcome questionnaire was developed for administration through follow-up phone calls. RESULTS: From March to May 2020, 45 patients met criteria for home-based infusion, with 27 patients (60%) agreeing to home-based infusion. Posttransition patient outcomes assessment, conducted in 26 patients (96%), demonstrated good patient understanding of the home-based infusion process. No infusion-related complications were reported, and 24 patients (92%) had no concerns about receiving future IVIG and/or SCIG doses at home. No patient tested positive for COVID-19 during the study period. Clinic infusion visits decreased by 26.6 visits per month, resulting in a total of 106 hours of additional available infusion chair time per month and associated cost savings of $12,877. CONCLUSION: Transition of clinic based to home based IVIG/SCIG infusion can be successfully done to decrease potential exposure during a pandemic in a high-risk immunosuppressed population, with no impact on patient satisfaction, adherence, or efficacy. The home-based infusion initiative was associated with a reduction in costs to patients and an increase in available chair time in the infusion clinic.

Passive immunization and its rebirth in the era of the COVID-19 pandemic.

The COVID-19 pandemic, caused by SARS-CoV-2, has led to a rapid search for therapeutic and preventive measures because of the potentially severe course of infection. The antiviral drug, remdesivir, and the anti-inflammatory agent, dexamethasone, have shown beneficial effects. As the current COVID-19 vaccines are not yet fully available to everyone, or they may not be readily and universally accepted, various treatment options are being evaluated and will still be needed under these conditions. One of these treatment options, passive immunization, has shown promise in some studies. Further research is needed to determine the utility of immunotherapy with convalescent plasma or artificially produced monoclonal antibodies for the treatment of symptomatic patients, and potentially for use as post-exposure prophylaxis, at least until more effective drugs are available or safe and effective vaccines are distributed and administered to everyone.