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Background As of November 2020, SARS-CoV-2 has resulted in 55 million infections worldwide and over 1.3 million deaths from COVID-19. Outcomes following SARS-CoV-2 infection in individuals with primary immunodeficiency or symptomatic secondary immunodeficiency remain uncertain. Objectives To document the outcomes of individuals with primary or symptomatic secondary immunodeficiency following COVID-19 in the United Kingdom. Methods At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network (UK PIN) established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. Results 100 patients had been enrolled by 1st July 2020, 60 with primary immunodeficiency (PID), 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency and 33 with symptomatic secondary immunodeficiency (SID). In individuals with PID, 53.3% (n=32/60) were hospitalized, the infection fatality rate (IFR) was 20.0% (n=12/60), the case fatality rate (CFR) was 31.6% (n=12/38) and the inpatient mortality 37.5% (n=12/32). Individuals with SID had worse outcomes than those with PID. 75.8% (n=25/33) were hospitalized, the IFR was 33.3% (n=11/33), the CFR was 39.2% (n=11/28), and inpatient mortality 44.0% (n=11/25). Conclusions In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus.

Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody (ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents. This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2 g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein (CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3 months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively (p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2 weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group. A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3 months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with persistent disease activity after standard therapy.

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Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period, using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calcium-channel antibodies were measured by radioimmunoassay using 125I-omega-conotoxin MVIIC. Direct anti-idiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks. Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic neutralization by immunoglobulin was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated disorders may similarly be associated with decline in levels of pathogenic autoantibodies.

Hypogammaglobulinemia is a common finding in chronic lymphocytic leukemia (CLL). Its incidence increases with disease duration and stage such that it is present in up to 85 % of patients at some point in their disease course. It is therefore important to monitor patients for the development of an antibody deficiency. However, not all patients with antibody deficiency secondary to CLL are symptomatic with bacterial infections. In addition patients are susceptible to viral, fungal and opportunistic infections as a result of iatrogenic immunosuppression and through a variety of disease-related mechanisms, which affect cellular immunity and phagocytes. Published guidelines suggest that patients with a history of recurrent bacterial infections and a documented failure of antibody production should be treated with antibiotic prophylaxis in the first instance, with replacement immunoglobulin reserved for those who continue to suffer with significant bacterial infections. Here we present a review of the existing literature in order to provide a practical approach, based on best available evidence, to the investigation, monitoring and treatment of patients with antibody failure secondary to CLL; and we highlight areas in which further studies are needed.