Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.

Update on the use of immunoglobulin in human disease: A review of evidence

Importance Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. Objective To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. Design, Setting, and Participants A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). Exposures Rituximab administration. Main Outcomes and Measures The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. Results Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%;P  Conclusions and Relevance Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.

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Association of Immunoglobulin Levels, Infectious Risk, and Mortality With Rituximab and Hypogammaglobulinemia.

Immunoglobulin (Ig) replacement therapy dramatically changed the clinical course of primary hypogammaglobulinemias, significantly reducing the incidence of infectious events. Over the last two decades its use has been extended to secondary antibody deficiencies, particularly those related to hematological disorders as lymphoproliferative diseases (LPDs) and multiple myeloma. In these malignancies, hypogammaglobulinemia can be an intrinsic aspect of the disease or follow chemo-immunotherapy regimens, including anti-CD20 treatment. Other than in LPDs the broadening use of immunotherapy (e.g., rituximab) and immune-suppressive therapy (steroids, sulfasalazine, and mycophenolate mofetil) has extended the occurrence of iatrogenic hypogammaglobulinemia. In particular, in both autoimmune diseases and solid organ transplantation Ig replacement therapy has been shown to reduce the rate of infectious events. Here, we review the existing literature about Ig replacement therapy in secondary hypogammaglobulinemia, with special regard for subcutaneous administration route, a safe, effective, and well-tolerated treatment approach, currently well established in primary immunodeficiencies and secondary hypogammaglobulinemias.

/pdf/immunoglobulin-replacement-therapy-in-secondary-591gyqv4uk.pdf

Immunoglobulin Replacement Therapy in Secondary Hypogammaglobulinemia

Primary antibody deficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) and immunoglobulin replacement forms the mainstay of therapy for many patients in this category. Secondary antibody deficiencies (SAD) represent a larger and expanding number of patients resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal or gastrointestinal immunoglobulin losses. While there are clear similarities between primary and secondary antibody deficiencies, there are also significant differences. This review describes a practical approach to the clinical, laboratory and radiological assessment of patients with antibody deficiency, focusing on the factors that determine whether or not immunoglobulin replacement should be used. The decision to treat is more straightforward when defined diagnostic criteria for some of the major PADs, such as common variable immunodeficiency disorders (CVID) or X-linked agammaglobulinaemia (XLA), are fulfilled or, indeed, when there is a very low level of immunoglobulin production in association with an increased frequency of severe or recurrent infections in SAD. However, the presentation of many patients is less clear-cut and represents a considerable challenge in terms of the decision whether or not to treat and the best way in which to assess the outcome of therapy. This decision is important, not least to improve individual quality of life and reduce the morbidity and mortality associated with recurrent infections but also to avoid inappropriate exposure to blood products and to ensure that immunoglobulin, a costly and limited resource, is used to maximal benefit.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cei.12915

When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: a practical approach

Objective To define the incidence of and clinical practices associated with subcutaneous immunotherapy (SCIT)–related systemic reactions (SRs). Methods From 2008-2011, American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma & Immunology members completed an annual survey of SCIT-related SRs of varying severity (with grade 1 indicating mild; grade 2, moderate; and grade 3, severe anaphylaxis). From 2010-2011 (year 3) data were collected regarding SCIT-related procedures, including screening of patients with asthma, dose adjustment during peak pollen seasons, build-up regimens (conventional, cluster, or rush), and premedication. Results No fatal reactions were directly or indirectly reported from 2008-2011. The SR rates were similar for all 3 years (0.1% of injection visits; 83% of practices), as were severity grades. On average, for all 3 years, there were 7.1 grade 1, 2.6 grade 2, and 0.4 grade 3 SRs per 10,000 injection visits. Screening for worsening asthma symptoms was highly prevalent (86% always screened). Practices that always reduced doses during peak pollen season were significantly less likely to report grade 2 or 3 SRs (44% vs 65%; P  = .04). Cluster and rush build-up were associated with significantly more SRs ( P P Conclusion Fatal reactions to SCIT appear to be declining, possibly related to almost universal screening of asthmatic patients. Adjusting doses during the pollen season may be associated with decreased risk for severe SRs. Cluster and rush immunotherapy were associated with increased risk for SRs. Premedication by practices reporting SRs likely reflects past experience with SRs.

AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions?

Rituximab and immune deficiency: case series and review of the literature.

Background Allergists around the world have different practice styles when administering subcutaneous aeroallergen immunotherapy (IT) in peak pollen seasons, especially when changing doses or frequency of IT. The Immunotherapy practice parameters do not specifically address this issue. Objective Given the paucity of good data about adjustment of allergen immunotherapy during the pollen seasons, we examined whether a significant difference is present in the way allergists administer immunotherapy during allergy seasons. Methods To quantify the practice styles of allergists who are members of the American Academy of Allergy, Asthma and Immunology (AAAAI), a self-reported electronic survey was disseminated in September 2010 with the help of the AAAAI Needs Assessment Committee. The responses were tallied and analyzed according to demographic information. Results A total of 1,201 allergists in the AAAAI responded to the survey. Most responders practice in an urban or suburban nonacademic practice in the United States and have been in practice for more than 10 years. The size of their practice was variable. Those in practice for more than 10 years were more likely to adjust the dose and frequency of immunotherapy in pollen seasons. Conclusion This survey highlights the differences in the practice styles of AAAAI member allergists, and these differences may be associated with their demographic characteristics. Given the wide variability in how allergists adjust dose and frequency of immunotherapy during pollen seasons, establishing guidelines regarding this routine dilemma might help standardize the delivery of treatment to patients.

Yelena Kopyltsova

Papers

Rituximab and immune deficiency: case series and review of the literature.

Allergen immunotherapy practice patterns: a worldwide survey

Persistent Hypogammaglobulinemia After Rituximab Treatment