II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies

In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1 st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil.RESUMONos ultimos anos, novas imunodeficiencias primarias e defeitos geneticos tem sido descritos. Recentemente, produtos de imunoglobulina, com aprimoramento em sua composicao e para uso por via subcutanea, tornaram-se disponiveis em nosso meio. Com o objetivo de orientar o medico no uso da imunoglobulina humana para o tratamento das imunodeficiencias primarias, os membros do Grupo de Assessoria em Imunodeficiencias da Associacao Brasileira de Alergia e Imunologia produziram um documento que teve por base uma revisao narrativa da literatura e sua experiencia profissional, atualizando o I Consenso Brasileiro publicado em 2010. Apresentam-se novos conhecimentos sobre indicacoes e eficacia do tratamento com imunoglobulina nas imunodeficiencias primarias, aspectos relevantes sobre a producao, II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies II Consenso Brasileiro sobre o uso de imunoglobulina humana em pacientes com imunodeficiencias primarias ; in name of Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology einstein. 2017;15(1):1-16 forma de utilizacao (vias de administracao, farmacocinetica, doses e intervalos), efeitos adversos (principais efeitos, prevencao, tratamento e notificacao), monitorizacao do paciente, apresentacoes disponiveis e forma de obtencao deste recurso terapeutico em nosso meio.Descritores: Doencas do sistema imune; Imunoglobulinas; Imunoglobulinas intravenosas; Sindromes de imunodeficiencia; Imunizacao passivaABOUT THIS PAPERThis document was collaboratively prepared by members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology, based on a narrative literature review and their professional experience, to guide Brazilian physicians on the use of human immunoglobulin (Ig) to treat primary immunodeficiencies.(1)
Since the 1960's, different preparations for intravenous administration have been developed and put to use, but it was only in the late 1970's and early 1980's that this route became the route of choice for Ig replacement in PID patients. [bib_ref] Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and..., Wasserman [/bib_ref] [bib_ref] Long-term efficacy and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous infusion of..., Wasserman [/bib_ref] In the 1980's, improvements were made to the production process and composition of this immunobiological for intravenous infusion, allowing the use of higher Ig doses with better infection control, but still with many adverse effects. [bib_ref] Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and..., Wasserman [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency..., Skoda-Smith [/bib_ref] At that point in time, subcutaneous administration started to be reported by several services. [bib_ref] Immunoglobulin replacement therapy by slow subcutaneous infusion, Berger [/bib_ref] [bib_ref] Home treatment in patients with antibody deficiency by slow subcutaneous infusion of..., Roord [/bib_ref] [bib_ref] Subcutaneous infusion of gammaglobulins in management of agammaglobulinaemia, Ugazio [/bib_ref] [bib_ref] Treatment of antibody deficiency syndromes with subcutaneous infusion of gamma globulin, Roord [/bib_ref] [bib_ref] Immunoglobulin replacement therapy by selfinfusion at home, Chapel [/bib_ref] [bib_ref] Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion, Gardulf [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] It has been increasingly used in the last 10 to 15 years, with good clinical results, few adverse effects and other advantages when compared to intravenous, as described later. [bib_ref] Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs, Gardulf [/bib_ref] [bib_ref] The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin..., Chapel [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement in primary immunodeficiencies, Berger [/bib_ref] [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route, Gardulf [/bib_ref] [bib_ref] Subcutaneous immunoglobulin: opportunities and outlook, Misbah [/bib_ref] [bib_ref] VIRTUE Trial Investigators. Improved quality of life, immunoglobulin G levels, and infection..., Berger [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Kobrynski [/bib_ref] [bib_ref] Comparative study of subcutaneous versus intravenous IgG replacement therapy in pediatric patients..., Bezrodnik [/bib_ref] [bib_ref] Illustrative cases on individualizing immunoglobulin therapy in primary immunodeficiency disease, Bonagura [/bib_ref] [bib_ref] Oksenhendler E; DEFI study group. Efficiency of immunoglobulin G replacement therapy in..., Gouilleux-Gruart [/bib_ref] [bib_ref] Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review, Lingman-Framme [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] Products for subcutaneous use have been available in Brazil since 2015.
In the context of major advancements in the knowledge of PIDs and the production of human Ig, and with new products available in the market, we must update the first consensus published in 2010, which is currently in use in Brazil.

## Objective
To update the 1 st Brazilian Consensus on the Use of Human Immunoglobulin in Patients with Primary Immunodeficiencies, published in 2010. The text presents advancements in knowledge of indications and efficacy of Ig replacement in primary immunodeficiencies, in addition to relevant facts about production, mode of use (administration routes, pharmacokinetics, doses and intervals), adverse events (major effects, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapy in Brazil. The use of human Ig in secondary immunodeficiencies or as an immunomodulator in autoimmune and inflammatory diseases is not addressed in this paper.

# Methods
A foundation text was prepared by the coordinators of the advisory group, based on scientific publications on the use of Ig in primary immunodeficiencies in the last 10 years, retrieved from PubMed and Google Scholar, as well as relevant textbooks and guidelines, in the form of a narrative literature review.
The text was sent by e-mail to the other 14 members of the group, to be expanded and modified so as to reflect the technical and literature-based knowledge as well as the clinical experience of all involved.

# Introduction
Primary immunodeficiencies (PID) are a very heterogeneous group currently made up of more than 300 diseases caused by genetic mutations, leading to abnormal development and function of the immune system, and are characterized by recurrent infections (either severe or caused by unusual or low-pathogenicity agents), autoimmune or inflammatory manifestations, and a greater predisposition to cancer. [bib_ref] The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies, Bousfiha [/bib_ref] [bib_ref] Different brands of intravenous immunoglobulin for primary immunodeficiencies: how to choose the..., Abolhassani [/bib_ref] [bib_ref] Primary immunodeficiency diseases: an update on the classification from the nternational Union..., Picard [/bib_ref] In the past few years, new diseases and new genetic defects have been described.
Several registries around the world, including the Latin American, show that at least 50% of PIDs predominantly affect antibody production, which is also impaired in other types of immune system defects. [bib_ref] Advances in primary immunodeficiency diseases in Latin America: epidemiology, research, and perspectives, Errante [/bib_ref] [bib_ref] Prevalence and morbidity of primary immunodeficiency diseases, Kobrynski [/bib_ref] [bib_ref] Joris van Montfrans, The Netherlands) and the ESID Society. The European Society..., Mahlaoui [/bib_ref] [bib_ref] Primary immunodeficiencies worldwide: an updated overview from the Jeffrey Modell Centers Global..., Modell [/bib_ref] The use of serum from animals or convalescent humans in the treatment and prevention of infectious diseases started at the end of the 19 th century. Purification of Immunoglibulin G (IgG) became possible in the 1940's with the Cohn-Oncley fractionation method, used to produce albumin for the injured during World War II. [bib_ref] History of immunoglobulin replacement, Eibl [/bib_ref] Human Ig replacement therapy was performed for the first time in 1952, by Bruton, in the first patient described with agammaglobulinemia, using the subcutaneous route.In the years that followed, the intramuscular route became the most widely used for Ig replacement. However, this mode of administration is painful, reaches serum concentrations in about 24 hours, and has low bioavailability and less than 50% recovery. [bib_ref] Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and..., Wasserman [/bib_ref] With the use of higher doses, side effects, such as chills, fever or even anaphylaxis, occur more frequently. [bib_ref] History of immunoglobulin replacement, Eibl [/bib_ref] A final review of the text was carried out by two specialists in the field who were not part of the group.

## Indications and efficacy of human immunoglobulin in primary immunodeficiencies
Treatment with Ig is currently the leading therapeutic approach in almost 75% of PDIs, i.e. those in which antibody production is impaired,promoting the replacement of immunoglobulin G or IgG. The objectives are to maintain stable and adequate serum concentrations of this type of Ig and achieve good clinical management of patients. [bib_ref] Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis..., Bonilla [/bib_ref] [bib_ref] Dose and outcomes in primary immunodeficiency disorders, Bonagura [/bib_ref] [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] The target serum IgG concentration had been set at 500mg/dL in blood samples collected immediately before the infusion, [bib_ref] Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis..., Bonilla [/bib_ref] [bib_ref] High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease, Roifman [/bib_ref] [bib_ref] Inter-University Working Party for the Study of Immune Deficiencies. The effect of..., Eijkhout [/bib_ref] [bib_ref] Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes, Bonilla [/bib_ref] [bib_ref] Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary..., Yong [/bib_ref] but the clinical monitoring of patients has shown that higher values, approximately 700 to 1,000mg/dL, are more efficient to control infections, particularly pneumonia. [bib_ref] High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease, Roifman [/bib_ref] [bib_ref] Evaluating and managing hypogammaglobulinemia, Rose [/bib_ref] [bib_ref] Management of primary antibody deficiency with replacement therapy: summary of guidelines, Roifman [/bib_ref] [bib_ref] Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin..., Lucas [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] The use of immunoglobulin therapy for patients with primary immune deficiency: an..., Shehata [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] Higher target IgG concentrations are especially important in patients with chronic pulmonary disease and bronchiectasis, promoting improved lung function. [bib_ref] Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin..., Lucas [/bib_ref] [bib_ref] Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in..., Roifman [/bib_ref] [bib_ref] Pulmonary abnormalities in patients with primary hypogammaglobulinemia, Kainulainen [/bib_ref] [bib_ref] Genetic causes of bronchiectasis: primary immune deficiencies and the lung, Notarangelo [/bib_ref] [bib_ref] Serial lung function tests in primary immune deficiency, Rich [/bib_ref] It is important to note that the IgG concentrations required for infection prevention vary among individuals, and the treatment must be individualized to find the doses and serum IgG concentrations leading to good clinical responses in each patient (also known as biological IgG level). [bib_ref] Illustrative cases on individualizing immunoglobulin therapy in primary immunodeficiency disease, Bonagura [/bib_ref] [bib_ref] Dose and outcomes in primary immunodeficiency disorders, Bonagura [/bib_ref] [bib_ref] Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin..., Lucas [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] Biologic IgG level in primary immunodeficiency disease: the IgG level that protects..., Bonagura [/bib_ref] [bib_ref] Using intravenous immunoglobulin (IVIG) to treat patients with primary immune deficiency disease, Bonagura [/bib_ref] [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] "Good clinical control" is defined as a decrease in the number and severity of infectious and inflammatory conditions, and a decrease in hospitalizations and use of antibiotics, preventing certain complications and improving general health and quality of life. [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Children and adults with primary antibody deficiencies gain quality of life by..., Gardulf [/bib_ref] [bib_ref] Subcutaneous administration of IgG, Berger [/bib_ref] [bib_ref] Intravenous and subcutaneous immunoglobulin replacement: a two-way road. Optimizing healthcare quality in..., Soler-Palacin [/bib_ref] In patients with normal IgG concentrations before initiating treatment (specific antibody deficiencies, for example), the clinical response alone is used for adjustment of Ig therapy. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] The recommendations of the European Society for Primary Immunodeficiencies (ESID) regarding human Ig replacement are [bib_ref] Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency, Berger [/bib_ref] serum IgG<200mg/dL is always an indication, except for patients with transient hypogammaglobulinemia of infancy with no severe infections; serum IgG between 200 and 500mg/dL is an indication in case of antibody production deficiency or recurrent and/or severe infections; serum IgG>500mg/dL is an indication for Ig replacement only when abnormal production of specific antibodies is verified, and recurrent and severe infections are present.
According to these recommendations, the use of human Ig is indicated in all PIDs in case of documented impairment in the production of IgG antibodies. [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] However, there are evidence-based indications in some PIDs: abnormal antibody production related to B-cell defects (X-linked agammaglobulinemia, common variable immunodeficiency, defective production of specific antibodies, defects of IgG subclasses with abnormal antibody production), except for selective IgA deficiency, as well as combined immunodeficiencies with or without associated syndromes (severe combined immunodeficiencies, X-linked hyper-IgM syndrome, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, NEMO deficiency, Warts syndrome, WHIM syndrome -warts, hypogammaglobulinemia and immunodeficiency), and after hematopoietic stem cell transplant in PID patients. [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Use of intravenous immunoglobulin in human disease: a review of evidence by..., Orange [/bib_ref] [bib_ref] Therapeutic use of immunoglobulins, Stiehm [/bib_ref] [bib_ref] Prioritization of evidence-based indications for intravenous immunoglobulin, Orange [/bib_ref] [bib_ref] An update on the use of immunoglobulin for the treatment of immunode..., Albin [/bib_ref] [bib_ref] Joint Task Force on Practice Parameters, representing the American Academy of Allergy,..., Bonilla [/bib_ref] There is some evidence of benefits in hyper-IgE syndrome, ataxia-telangiectasia, DiGeorge syndrome and anticytokine-autoantibodymediated disorders (Chart 1). [bib_ref] An update on the use of immunoglobulin for the treatment of immunode..., Albin [/bib_ref] [bib_ref] Joint Task Force on Practice Parameters, representing the American Academy of Allergy,..., Bonilla [/bib_ref] The immunoglobulin may also be used as an immunomodulator, at higher doses, to treat autoimmune manifestations associated with some PIDs, such as thrombocytopenia or hemolytic anemia. [bib_ref] Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long..., Kerr [/bib_ref] [bib_ref] Mechanisms of action of Ig preparations: immunomodulatory and anti-inflammatory effects, Matucci [/bib_ref] 

## Chart 1. primary immunodeficiencies in which immunoglobulin replacement is indicated

## Ig indication level primary immunodeficiencies
Required and immediate start X-linked and autosomal recessive agammaglobulinemia Despite having increased in recent years, the use of Ig in patients with secondary hypogammaglobulinemia (Chart 2) [bib_ref] Evaluating and managing hypogammaglobulinemia, Rose [/bib_ref] [bib_ref] The genetics of hypogammaglobulinemia, Grimbacher [/bib_ref] [bib_ref] Immunoglobulin replacement therapy in children, Garcia-Lloret [/bib_ref] [bib_ref] Secondary antibody deficiencies, Dhalla [/bib_ref] must be further investigated and is indicated in case of lower levels of serum IgG and/or documented impairment of antigen-specific antibody production and/or presence of relevant infections. [bib_ref] Immunoglobulin replacement therapy in secondary hypogammaglobulinemia, Compagno [/bib_ref] A condition that has become more frequent in recent years is hypogammaglobulinemia associated with the use of rituximab, an anti-CD20 monoclonal antibody indicated for some autoimmune diseases, lymphoproliferative syndromes, or refractory nephrotic syndrome. This type of hypogammaglobulinemia affects up to 50% of patients, especially those on regular use of rituximab; is symptomatic in less than 10% of cases, and can persist for a long time [bib_ref] Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous..., Casulo [/bib_ref] [bib_ref] Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience..., Compagno [/bib_ref] [bib_ref] Use of Rituximab in systemic lupus erythematosus: a single center experience over..., Aguiar [/bib_ref] [bib_ref] Late-onset adverse events after a single dose of rituximab in children with..., Fujinaga [/bib_ref] requiring Ig replacement, either intravenous or subcutaneous. [bib_ref] Intravenous versus subcutaneous immunoglobulin replacement in secondary hypogammaglobulinemia, Spadaro [/bib_ref] Persistent hypogammaglobulinemia may occur in a small group of genetically predisposed patients on rituximab. [bib_ref] FCGR3A-158V/F polymorphism may correlate with the levels of immunoglobulin in patients with..., Nishio [/bib_ref] [bib_ref] Rituximab and immune deficiency: case series and review of the literature, Kaplan [/bib_ref] Numerous studies showed a reduction in infections and mortality rates, and an overall improvement of health status and quality of life promoted by intravenous Ig replacement in PID patients. [bib_ref] Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis..., Bonilla [/bib_ref] [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] [bib_ref] Use of intravenous gama-globulin in antibody immunodeficiency: results of a multicenter trial, Ammann [/bib_ref] [bib_ref] Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease, Roifman [/bib_ref] [bib_ref] The use of intravenous immunoglobulin in immunodeficiency diseases, Buckley [/bib_ref] [bib_ref] Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with..., Busse [/bib_ref] [bib_ref] Immunoglobulin treatment in primary antibody deficiency, Maarschalk-Ellerbroek [/bib_ref] We searched the literature and found a number of studies with similar or even better results with the use of subcutaneous Ig, especially in regard to improved quality of life. [bib_ref] Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency..., Skoda-Smith [/bib_ref] [bib_ref] The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin..., Chapel [/bib_ref] [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] VIRTUE Trial Investigators. Improved quality of life, immunoglobulin G levels, and infection..., Berger [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Kobrynski [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] [bib_ref] Children and adults with primary antibody deficiencies gain quality of life by..., Gardulf [/bib_ref] [bib_ref] Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency, Berger [/bib_ref] [bib_ref] The life situations of patients with primary antibody deficiency untreated or treated..., Gardulf [/bib_ref] [bib_ref] Subcutaneous IgG Study Group. Safety and efficacy of self-administered subcutaneous immunoglobulin in..., Ochs [/bib_ref] [bib_ref] Vivaglobin Study Group. Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions..., Hoffmann [/bib_ref] [bib_ref] Experience with a 20% subcutaneous immunoglobulin (Hizentra  ) in children with..., Gregory [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency in routine clinical..., Vultaggio [/bib_ref] This route has also been shown effective and safe in children, [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] Comparative study of subcutaneous versus intravenous IgG replacement therapy in pediatric patients..., Bezrodnik [/bib_ref] [bib_ref] Rapid subcutaneous immunoglobulin infusions in children, Thomas [/bib_ref] [bib_ref] Immunoglobulin replacement treatment by rapid subcutaneous infusion, Gaspar [/bib_ref] [bib_ref] Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency, Fasth [/bib_ref] [bib_ref] Subcutaneous Immunoglobulin Replacement Therapy in Infants and Children with Primary Immunodeficiencies, Church [/bib_ref] [bib_ref] Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics, Shapiro [/bib_ref] elderly (even those on anticoagulation and antiplatelet therapy), [bib_ref] Subcutaneous immunoglobulin replacement in primary immunodeficiencies, Berger [/bib_ref] [bib_ref] Subcutaneous administration of IgG, Berger [/bib_ref] [bib_ref] Safety and efficacy of homebased subcutaneous immunoglobulin G in elderly patients with..., Stein [/bib_ref] pregnant women [bib_ref] Subcutaneous administration of IgG, Berger [/bib_ref] [bib_ref] Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women, Gardulf [/bib_ref] and obese patients, [bib_ref] Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency:..., Shapiro [/bib_ref] [bib_ref] Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body..., Hodkinson [/bib_ref] at the same dose recommended for intravenous use.
Although replacement therapy with human Ig showed to be effective in a specific group of PIDs, it must also be considered for other PIDs in case of documented impairment of antibody production and presence of recurrent and/or severe infections. This therapy is safe and effective when administered either intravenously or subcutaneously.

## Production
Ever since the first method for plasma protein fractionation using ethanol was introduced by Cohn-Oncley in the 1940's, a series of improvements have been made to the production of Ig, leading to enhanced safety and tolerability. [bib_ref] Intravenous immunoglobulins: evolution of commercial IVIG preparations, Hooper [/bib_ref] This process allowed for higher doses to be used intravenously with better clinical management of patients.
The immunoglobulin is purified from human plasma obtained from thousands of donors, ensuring a broad spectrum of protective antibodies. On the other hand, this could increase the theoretical risk for transmission of blood-borne pathogens, but this risk is eliminated by quarantining the donated blood and applying multiple purification steps. Different manufacturers use different combinations of precipitation, filtration, and chromatography to improve product purity (reaching an IgG concentration over 95%). [bib_ref] On the dark side of therapies with immunoglobulin concentrates: the adverse events, Spath [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] The diverse preparations also contain a small amount of IgA and traces of IgM.
The products available differ in their physicochemical characteristics (presentation, concentration, osmolarity and pH) and excipients (preservatives and IgG aggregation inhibitors). [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Immunoglobulin replacement therapy: a twentyyear review and current update, Saeedian [/bib_ref] The latest products are safe from the standpoint of infection transmission; they are stabilized with amino acids rather than sugars, have lower sodium concentrations and IgA content under 50mg/ml. [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] [bib_ref] Intravenous immunoglobulins: evolution of commercial IVIG preparations, Hooper [/bib_ref] The immunoglobulins are not generic products. The characteristics of each product must be considered at the time of prescription, as shown below, and switching must be avoided, except when indicated by the physician. [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] 

## Chart 2. causes of secondary hypogammaglobulinemia

# Disease-related

## Mode of use (administration routes, doses and intervals)
Human Ig can be administered as intramuscular, intravenous and subcutaneous injections. Considering the rate of adverse effects and the limited volume that can be used, the intramuscular route is no longer used. The standard loading dose of intravenous Ig is 400 to 600mg/kg/dose, starting at every 21 days. [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] The relation between intravenous Ig doses, serum IgG concentrations and clinical control was demonstrated in several studies, [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] but we must remember that the metabolism of the administered IgG varies among different individuals. [bib_ref] Oksenhendler E; DEFI study group. Efficiency of immunoglobulin G replacement therapy in..., Gouilleux-Gruart [/bib_ref] [bib_ref] High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease, Roifman [/bib_ref] [bib_ref] Inter-University Working Party for the Study of Immune Deficiencies. The effect of..., Eijkhout [/bib_ref] [bib_ref] Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long..., Kerr [/bib_ref] [bib_ref] Pharmacokinetics of intravenous immunoglobulin: a systematic review, Koleba [/bib_ref] Considering the importance of individualizing therapy, the doses and infusion intervals must be adjusted according to the clinical response and IgG concentrations obtained for each patient. [bib_ref] Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long..., Kerr [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Human intravenous immunoglobulin in primary and secondary antibody deficiencies, Stiehm [/bib_ref] Higher doses between 600 and 800mg/kg/dose (or up to 1,200mg/kg) may be required and are particularly indicated in case of chronic lung and/or sinus disease. [bib_ref] Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin..., Lucas [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in..., Roifman [/bib_ref] [bib_ref] Biologic IgG level in primary immunodeficiency disease: the IgG level that protects..., Bonagura [/bib_ref] [bib_ref] Benefit of intravenous IgG replacement in hypogammaglobulinemic patients with chronic sinopulmonary disease, Roifman [/bib_ref] [bib_ref] Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with..., Busse [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] Moreover, Ig is better metabolized during infections and autoimmune/ inflammatory diseases, as well as with losses due to comorbidities or PID complications, or yet, in patients with neonatal Fc receptor promoter gene polymorphisms. [bib_ref] Illustrative cases on individualizing immunoglobulin therapy in primary immunodeficiency disease, Bonagura [/bib_ref] [bib_ref] Oksenhendler E; DEFI study group. Efficiency of immunoglobulin G replacement therapy in..., Gouilleux-Gruart [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] Therefore, greater doses of Ig may be required, even if temporarily, in acute infections (increased IgG catabolism), severe and/or persistent diarrhea (gastrointestinal loss) or hypersplenism (sequestration). [bib_ref] Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long..., Kerr [/bib_ref] Increase of serum concentrations with intravenous administration occurs within a few hours at about 100 to 200mg/dL for every 100mg/kg immunoglobulin administered, decreasing rapidly through tissue redistribution within the first few days, with half life around 21 to 28 days [fig_ref] Figure 1: Post-infusion serum concentration of immunoglobulin G in patients on regular use of... [/fig_ref]. [bib_ref] Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes, Bonilla [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] Pharmacokinetics of intravenous immunoglobulin: a systematic review, Koleba [/bib_ref] [bib_ref] Product equivalence study comparing the tolerability, pharmacokinetics, and pharmacodynamics of various human..., Andresen [/bib_ref] As good clinical control and stable serum IgG concentrations are established, intravenous Ig infusions can be performed every 28 days. [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Immunoglobulin treatment in primary antibody deficiency, Maarschalk-Ellerbroek [/bib_ref] [bib_ref] Comparison of American and European practices in the management of patients with..., Hernandez-Trujillo [/bib_ref] Stable IgG values are usually achieved within 3 (or up to 6) months of infusions. [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes, Bonilla [/bib_ref] Patients with very low IgG concentrations (<200mg/ dL) are initially treated with intravenous Ig, often at initial doses of 800 to 1,000mg/kg, leading to a faster increase in serum concentrations. [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] Subcutaneous Ig is used at the same dose as intravenous Ig  about 400 to 600mg/kg/month, i.e., approximately 100 to 150mg/kg every week. [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a meta-analysis..., Orange [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] The increase in serum IgG concentrations was estimated at 84.4mg/dL for each 100mg/kg/month increase in the subcutaneous Ig dose. [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] Blood IgG concentrations increase less rapidly than with intravenous infusions, [bib_ref] Comparison of American and European practices in the management of patients with..., Hernandez-Trujillo [/bib_ref] peaking at 2 to 4 days. [bib_ref] Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes, Bonilla [/bib_ref] [bib_ref] Bioavailability of gammaglobulin after subcutaneous infusions in patients with common variable immunodeficiency, Waniewski [/bib_ref] When starting subcutaneous administration, shorter intervals are recommended as follows: 100mg/kg for 5 consecutive days in the first week, [bib_ref] Efficacy and safety of subcutaneous vivaglobin (R) replacement therapy in previously untreated..., Borte [/bib_ref] [bib_ref] Subcutaneous immunoglobulin loading regimens for previously untreated patients with primary antibody deficiency, Rojavin [/bib_ref] or twice-weekly in the first 2 weeks. [bib_ref] Experience with subcutaneous loading of vivaglobin or hizentra in primary immunodeficiency patients..., Koterba [/bib_ref] [bib_ref] Initiation of immunoglobulin therapy by subcutaneous administration in immunodeficiency patients naive to..., Koterba [/bib_ref] Serum IgG concentrations are more stable with subcutaneous Ig [bib_ref] Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG..., Berger [/bib_ref] and reached within 6 to 10 weeks of use [fig_ref] Figure 1: Post-infusion serum concentration of immunoglobulin G in patients on regular use of... [/fig_ref]. [bib_ref] Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency, Wasserman [/bib_ref] [bib_ref] Bioavailability of gammaglobulin after subcutaneous infusions in patients with common variable immunodeficiency, Waniewski [/bib_ref] The interdose interval may go from fortnightly to daily, using infusion pumps or push. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics, Shapiro [/bib_ref] There has been recent evidence showing that higher doses of subcutaneous Ig, as has been established for intravenous Ig, are related with superior clinical control of patients. [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] In patients who wish to switch from intravenous to subcutaneous, we must use a quarter of the previous monthly dose, starting subcutaneous infusions one to two weeks after the last intravenous infusion. [bib_ref] The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin..., Chapel [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Vivaglobin Study Group. Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions..., Hoffmann [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency in routine clinical..., Vultaggio [/bib_ref] [bib_ref] Subcutaneous immunoglobulin loading regimens for previously untreated patients with primary antibody deficiency, Rojavin [/bib_ref] [bib_ref] Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy..., Berger [/bib_ref] Subcutaneous administration should be preferably in the abdomen, but can also be given in the arms or thighs, [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] without the need for site rotation. [bib_ref] Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route, Gardulf [/bib_ref] Local skin hygiene must be performed with alcohol or chlorhexidine. Local anesthetics or ice may be applied to reduce pain if necessary. [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] There is no need to use gloves, but proper hand washing is critical. [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] The infusion can be administered in two to four sites, simultaneously or sequentially, weekly or every two weeks. [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] [bib_ref] Rapid subcutaneous immunoglobulin administration every second week results in high and stable..., Gustafson [/bib_ref] When using infusion pumps, the infusion rate must be 0.1 to 0.25mL/kg/hour/site, reaching up to 15mL/hour/site initially, and then a maximum of 25mL/hour/site. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] In case of more frequent administration by push, doses can be daily, twice or three times per week, or even weekly, with adequate safety and a shorter administration time when compared with pumps. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump:..., Shapiro [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a..., Shapiro [/bib_ref] Administration requires 1 to 10mL syringes with 25 to 23 gauge wing sets, 4 to 6mm needles for children and 9 to 15mm needles for adults, [bib_ref] Subcutaneous Immunoglobulin Replacement Therapy in Infants and Children with Primary Immunodeficiencies, Church [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] [bib_ref] Nurse Advisory Committee Immune Deficiency Foundation. Nursing guidelines for administration of immunoglobulin..., Younger [/bib_ref] or special perpendicular needles, [bib_ref] Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion, Gardulf [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20% SCIG preparation: a..., Jolles [/bib_ref] at a rate of 1ml/minute. [bib_ref] Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Kobrynski [/bib_ref] The total volume applied per site depends largely on the individual tolerability and also varies according to the product, dose and administration time. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a..., Shapiro [/bib_ref] [bib_ref] Nurse Advisory Committee Immune Deficiency Foundation. Nursing guidelines for administration of immunoglobulin..., Younger [/bib_ref] In children, depending on the weight and age group, it is usually possible to give up to 10 to 20mL per site, whereas in adults, 30 to 40mL/site or up to 80mL, in some cases. [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy: ensuring success, Younger [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump:..., Shapiro [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a..., Shapiro [/bib_ref] A recent survey in Europe showed that most patients receive about 20mL per site with good tolerability. [bib_ref] Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump:..., Shapiro [/bib_ref] A new product for subcutaneous use, already commercially available though not in Brazil, includes the application of hyaluronidase first and then (10 minutes later) the Ig solution, using the same route, allowing for a higher infusion volume per site. [bib_ref] Facilitated subcutaneous immunoglobulin (fSCIg) therapy--practical considerations, Ponsford [/bib_ref] In this setting, it is possible to inject subcutaneous Ig every 21 to 28 days, just like intramuscular injections, with appropriate safety and good clinical results. [bib_ref] Long-term efficacy and safety of recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous infusion of..., Wasserman [/bib_ref] Doses must be gradually increased over 7 weeks, which limits the use of this product when initial IgG levels are too low (<200mg/dL). In countries where this product is available, it has not yet been released for use in pregnant women and patients under 18 years of age. [bib_ref] Current treatment options with immunoglobulin G for the individualization of care in..., Jolles [/bib_ref] Studies indicate that Ig therapy is safe during pregnancy, both intravenously or subcutaneously. [bib_ref] Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women, Gardulf [/bib_ref] [bib_ref] Intravenous immunoglobulin in pregnancy, Smith [/bib_ref] Doses should be increased according to the clinical control and serum IgG concentrations achieved. Although the IgG given to pregnant women can cross the placenta and passively protect the fetus, the dose must be increased (20 to 30%) in the last trimester of pregnancy, to ensure adequate levels of antibodies to the newborn. [bib_ref] Rapid subcutaneous IgG replacement therapy at home for pregnant immunodeficient women, Gardulf [/bib_ref] [bib_ref] IgG replacement therapy for primary hypogammaglobulinaemia during pregnancy: report of 9 pregnancies..., Williams [/bib_ref] Therapy must continue throughout the patient's life, except in those subjected to hematopoietic stem cell transplantation, and in patients with unspecified hypogammaglobulinemia, who can regain the ability to produce Ig. [bib_ref] Joint Task Force on Practice Parameters, representing the American Academy of Allergy,..., Bonilla [/bib_ref] In those cases, infusions can be given at increasingly longer intervals, with close monitoring of the patient and serum IgG values, until they can be discontinued. [bib_ref] Does intravenous immunoglobulin therapy prolong immunodeficiency in transient hypogammaglobulinemia of infancy?, Memmedova [/bib_ref] However, there is no consensus in the literature on how to proceed in these situations.

## Adverse effects, prevention, treatment and reporting
Treatment with Ig is quite safe, but adverse effects have been described in 1 to 81% of patients or infusions; 30 to 40% of patients; and 5 to 15% of infusions. [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] They can be mild, moderate or severe, [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] immediate (during or shortly after infusion) or late (hours to days after infusion). [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] Those considered mild do not cause any changes to vital signs and are resolved with symptomatic drugs without the need to stop the infusion. If signs and symptoms progress and/or persist requiring interruption of the infusion, the adverse effects are considered moderate. Severe adverse effects require immediate discontinuation of the drug and implementation of urgent therapeutic measures. [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] Most adverse events are mild and immediate, occur within the first infusions, are related to the rate of infusion, and are rapidly reversible. [bib_ref] On the dark side of therapies with immunoglobulin concentrates: the adverse events, Spath [/bib_ref] [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Safety of intravenous immunoglobulin (IVIG) therapy, Katz [/bib_ref] [bib_ref] Safety of IGIV therapy and infusion-related adverse events, Ballow [/bib_ref] [bib_ref] Adverse reactions of prophylactic intravenous immunoglobulin; a 13-year experience with 3004 infusions..., Dashti-Khavidaki [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] [bib_ref] Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of..., Bichuetti-Silva [/bib_ref] Headache, fever, malaise, flu-like symptoms, nausea, chills, fatigue, myalgia, low back pain, tachycardia, blood pressure changes and erythroderma are the most common events. [bib_ref] On the dark side of therapies with immunoglobulin concentrates: the adverse events, Spath [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Safety of IGIV therapy and infusion-related adverse events, Ballow [/bib_ref] [bib_ref] Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of..., Bichuetti-Silva [/bib_ref] Severe reactions occur in less than 1% of infusions and usually with higher doses indicated for autoimmune and inflammatory diseases. [bib_ref] Use of intravenous immunoglobulin in human disease: a review of evidence by..., Orange [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of..., Bichuetti-Silva [/bib_ref] [bib_ref] Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective..., Ramirez [/bib_ref] The exact pathophysiology of adverse events is still unknown. Some possibilities have been raised over the years, such as formation of IgG aggregates, interaction between the infused IgG and microbial antigens circulating in patients leading to formation of immune complexes, and reaction to vasoactive plasma components, contaminants, or other ingredients used during processing. [bib_ref] On the dark side of therapies with immunoglobulin concentrates: the adverse events, Spath [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Safety of IGIV therapy and infusion-related adverse events, Ballow [/bib_ref] Anaphylactic-type reactions mostly do not involve IgE. They usually evolve with hypertension instead of hypotension, and are less severe in subsequent infusions. [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] IgE-mediated anaphylaxis is a very rare event in patients with absence of IgA and preserved IgE production. [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] In these cases, the use of low-IgA intravenous preparations or subcutaneous Ig infusions is indicated. [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] The role of anti-IgA antibodies in causing adverse reactions to gamma globulin..., Rachid [/bib_ref] However, there is no need to assess the presence of anti-IgA antibodies before starting Ig therapy. [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] The role of anti-IgA antibodies in causing adverse reactions to gamma globulin..., Rachid [/bib_ref] Although rare, there are descriptions of neurological, respiratory, cardiovascular, gastrointestinal, renal, skin and blood abnormalities including headaches, aseptic meningitis, dyspnea, bronchospasm, transfusionrelated acute lung injury (TRALI), hypotension or hypertension, arrhythmias, nausea, vomiting, diarrhea, renal failure, hives, skin rash, pruritic dermatosis, hemolytic anemia and thromboembolic events (Chart 3). [bib_ref] Use of intravenous immunoglobulin in human disease: a review of evidence by..., Orange [/bib_ref] [bib_ref] On the dark side of therapies with immunoglobulin concentrates: the adverse events, Spath [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Safety of IGIV therapy and infusion-related adverse events, Ballow [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] [bib_ref] Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective..., Ramirez [/bib_ref] [bib_ref] Intravenous immune globulin in autoimmune and inflammatory diseases, Gelfand [/bib_ref] Some factors are associated with a higher risk of adverse effects and are listed in chart 4. [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Safety of intravenous immunoglobulin (IVIG) therapy, Katz [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] [bib_ref] Immediate infusion-related adverse reactions to intravenous immunoglobulin in a prospective cohort of..., Bichuetti-Silva [/bib_ref] [bib_ref] Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective..., Ramirez [/bib_ref] [bib_ref] Intravenous immune globulin in autoimmune and inflammatory diseases, Gelfand [/bib_ref] [bib_ref] Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis, Bonilla [/bib_ref] It is worth noting that the presence of adverse events varies between different Most adverse effects can be resolved by reducing the rate or briefly stopping the infusion, and by giving analgesics and/or anti-histamines. [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] Some patients may require corticosteroids. [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Safety of IGIV therapy and infusion-related adverse events, Ballow [/bib_ref] [bib_ref] A prospective study of the immediate and delayed adverse events following intravenous..., Singh-Grewal [/bib_ref] In case of adverse reactions during intravenous administration, proper measures must be taken for future infusions (Chart 6). [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] Chart 3. Types and frequency of adverse effects associated with administration of intravenous immunoglobulin

## Symptoms and signs frequency
Related to infusion rate products, or even between different batches of the same product. Some patients have adverse effects with one or more Ig products, but not all of them. [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] Considering the predisposing factors presented, proper measures must be taken to prevent adverse effects resulting from intravenous Ig infusions (Chart 5). [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Safety of intravenous immunoglobulin (IVIG) therapy, Katz [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] 

## Chart 6. measures for secondary prevention of adverse reactions to intravenous immunoglobulin

## Slower rate of infusion in patients with prior reaction
Pre-medication with analgesics and/or nonsteroidal anti-inflammatory drugs, H1 (and anti H2) antihistamines, and corticosteroids Pre-hydration with 0.9% saline solution Switch product or consider subcutaneous Ig in case of major reactions with no response to symptomatic drugs Ig: immunoglobulin. Special attention is needed for patients with comorbidities, such as heart diseases, kidney diseases, liver diseases, coagulation disorders (thrombophilia), and diabetes mellitus. In these situations, some product characteristics, such as the presence of sugars, osmolality, sodium, among others, must be assessed. Chart 7 describes the most relevant factors according to the associated morbidity, and chart 8 lists the products available to facilitate this choice. [bib_ref] Immunoglobulin replacement therapy: a twentyyear review and current update, Saeedian [/bib_ref] [bib_ref] Management of adverse events in the treatment of patients with immunoglobulin therapy:..., Cherin [/bib_ref] Subcutaneous administration is rarely associated with systemic adverse effects, which occur in less than 1% of infusions. [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency, Berger [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] Heart failure present with any grade of edema and hyperemia at the administration site which, however, usually resolve within 24 to 48 hours and tend to disappear in later infusions, without impairing treatment continuity using this route. [bib_ref] The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin..., Chapel [/bib_ref] [bib_ref] Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route, Gardulf [/bib_ref] [bib_ref] Subcutaneous administration of IgG, Berger [/bib_ref] [bib_ref] Subcutaneous IgG Study Group. Safety and efficacy of self-administered subcutaneous immunoglobulin in..., Ochs [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] [bib_ref] Intravenous immunoglobulin: adverse reactions and management, Bonilla [/bib_ref] [bib_ref] Adverse effects of IgG therapy, Berger [/bib_ref] [bib_ref] Subcutaneous immunoglobulins: product characteristics and their role in primary immunodeficiency disease, Melamed [/bib_ref] [bib_ref] Use of subcutaneous immunoglobulin in primary immune deficiencies, Aydner [/bib_ref] Therefore, there is no need for pre-medications or medical supervision during infusions after proper training of patients/ caregivers. [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] It is important to report the adverse effects of Ig administration observed by physicians as well as patients and their caregivers, at the website NOTIVISA -Health Surveillance Reporting System: http://www.anvisa. gov.br/hotsite/notivisa/index.htm. The manufacturers, according to Decree 6523, of 31 July 2008, by the Chief of Staff, must have a customer service call center (SAC) with lines readily available. And physicians and patients must be able to use this call center to report signs and symptoms related with the use of different human Ig presentations commercially available.
[formula] x x x - x Glycine x - Renal failure x x x x Sucrose-glucose - - - Anti-IgA antibodies - - - - - - x Thromboembolic risk x x x - - - - Diabetes mellitus - - - x Glucose-maltose - - - Hyperprolinemia - - - - x L-proline - - Hereditary fructose intolerance - - - x Sorbitol - - - Corn allergy - - - x Maltose - - - Seniors x x x x Glucose - - - Newborn/children x x x - - x - Source [/formula]

## Choosing between intravenous and subcutaneous administration
Treatment of patients with PID as well as other patients, particularly those with chronic diseases, must always be individualized to achieve good control of the disease and its manifestations, as well as good quality of life, and must be as adjusted as possible to patient characteristics and preferences. [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Comparison of American and European practices in the management of patients with..., Hernandez-Trujillo [/bib_ref] Each of the routes, intravenous or subcutaneous, has interesting features (Chart 9) depending on factors related to the disease, the patient and their family, as well as their socioeconomic level. What can be described as a disadvantage for a certain patient can be quite beneficial in other situations. For example, monthly intravenous application in a hospital could be interesting for patients with more severe disease, whose family does not adhere to the treatment, in which case close clinical monitoring is critical. The intravenous route allows for faster achievement of higher IgG concentrations, has documented efficacy and accommodates longer administration intervals. In addition, by infusing at the hospital, it is possible to have patients under stricter supervision by the healthcare staff. However, it is necessary to secure venous access, which can be difficult in many patients, and the procedure must be preferably performed at a hospital, requiring monthly visits. There is also systemic adverse effects, even if not frequent. The serum IgG concentrations obtained are unstable, with significant reduction 15 to 20 days after administration, sometimes associated with symptoms such as fatigue and malaise (wear-off effects). [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] [bib_ref] Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG..., Berger [/bib_ref] With subcutaneous use, serum IgG concentrations are more stable, allowing for easier application, without the need for venous access. In some countries, there is no need to visit the healthcare facility, offering greater independence to patients and caregivers. [bib_ref] Immunoglobulin replacement therapy for primary immunodeficiencies, Peter [/bib_ref] [bib_ref] Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody..., Abolhassani [/bib_ref] Other countries have vast experience with the subcutaneous route, with proven efficacy and safety, [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Kobrynski [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency in routine clinical..., Vultaggio [/bib_ref] [bib_ref] Use of subcutaneous immunoglobulin in primary immune deficiencies, Aydner [/bib_ref] [bib_ref] Self-infusion programmes for immunoglobulin replacement at home: feasibility, safety and efficacy, Bhole [/bib_ref] including fewer systemic adverse effects. [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route, Gardulf [/bib_ref] [bib_ref] Choices in IgG replacement therapy for primary immune deficiency diseases: subcutaneous IgG..., Berger [/bib_ref] [bib_ref] Headache and nausea after treatment with high-dose subcutaneous versus intravenous immunoglobulin, Markvardsen [/bib_ref] Furthermore, there are many studies demonstrating improved quality of life with subcutaneous Ig replacement. [bib_ref] Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases, Kobrynski [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] [bib_ref] Children and adults with primary antibody deficiencies gain quality of life by..., Gardulf [/bib_ref] [bib_ref] Healthrelated quality of life and treatment satisfaction in North American patients with..., Nicolay [/bib_ref] Serum IgG concentrations rise more slowly, which could be considered a disadvantage in cases of very low initial IgG levels, but is an advantage in patients with hypersplenism or high renal/gastrointestinal loss. [bib_ref] Improved outcomes on subcutaneous IgG in patients with humoral immunodeficiency and co-morbid..., Shah [/bib_ref] There is a need for training and engagement of patients and/or caregivers, which is usually possible to be achieved over 4 to 6 weeks, and close monitoring of the infusion technique must be maintained subsequently. [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy in patients with primary immunodeficiency in routine clinical..., Vultaggio [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20% SCIG preparation: a..., Jolles [/bib_ref] [bib_ref] Self-infusion programmes for immunoglobulin replacement at home: feasibility, safety and efficacy, Bhole [/bib_ref] There are several studies, [bib_ref] Rapid subcutaneous IgG replacement therapy is effective and safe in children and..., Gardulf [/bib_ref] [bib_ref] Pharmacoeconomic evaluation of immunoglobulin treatment in patients with antibody deficiencies from the..., Hogy [/bib_ref] [bib_ref] French PID study group CEREDIH. Economic evaluation of immunoglobulin replacement in patients..., Beaute [/bib_ref] [bib_ref] Pharmacoeconomic advantages of subcutaneous versus intravenous immunoglobulin treatment in a Canadian pediatric..., Ducruet [/bib_ref] [bib_ref] Economic benefits of subcutaneous rapid push versus intravenous immunoglobulin infusion therapy in..., Martin [/bib_ref] [bib_ref] Implications to payers of switch from hospital-based intravenous immunoglobulin to home-based subcutaneous..., Gerth [/bib_ref] including national studies, [bib_ref] Socioeconomic impact of immunoglobulin replacement therapy for primary immunodeficiency patients on the..., Carmo [/bib_ref] pointing to a considerable cost reduction associated with subcutaneous administration, particularly when performed at home.

## Chart 9. comparison between intravenous and subcutaneous immunoglobulin
Intravenous Ig is effective, safe, leads to a rapid rise in IgG concentrations, and can be obtained via the public healthcare system in Brazil (SUS -Sistema Unico de Saude) as well as the private system. Subcutaneous Ig has been offered only by the private healthcare system. The classic indications for subcutaneous Ig are problems with intravenous infusion: inadequate IgG concentrations, poor clinical control, wear-off, systemic adverse effects, difficulty securing venous access, or difficult access to healthcare facilities. [bib_ref] A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients..., Shabaninejad [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Why I use subcutaneous immunoglobulin (SCIG), Shapiro [/bib_ref] Individual aspects which can improve the quality of life of patients must also be considered when this choice is made, as well as reduction of treatment costs. [bib_ref] Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and..., Wasserman [/bib_ref] [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] The use of immunoglobulin therapy for patients with primary immune deficiency: an..., Shehata [/bib_ref] [bib_ref] Intravenous and subcutaneous immunoglobulin replacement: a two-way road. Optimizing healthcare quality in..., Soler-Palacin [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Why I use subcutaneous immunoglobulin (SCIG), Shapiro [/bib_ref] MONITORING Clinical and laboratory monitoring of patients must be performed to ensure good disease control and watch for complications and potential side effects of the therapy. It is critical to record the product brand, the lot number and the expiration date of every infusion. [bib_ref] Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary..., Yong [/bib_ref] Regular clinical evaluations must be performed at variable intervals, depending on the severity of the PID, as well as personal, familial and social characteristics of the patient. It is important to observe the number, type and severity of infections, use of antibiotics, need for hospitalizations, attendance of every day activities (school or work), new complaints and symptoms, and presence of comorbidities, in addition to performing a complete physical examination. [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement..., Orange [/bib_ref] The following tests are recommended before the start of infusions: Ig levels (A, M, G and E), evaluation of vaccine response and lymphocyte count (T, B and NK), complete blood count, direct Coombs, kidney and liver function, and PCR for infectious agents (because these patients have impaired antibody production, serologic tests for infectious agents are not indicated). [bib_ref] Guidelines for the use of human immunoglobulin therapy in patients with primary..., Condino-Neto [/bib_ref] [bib_ref] The use of immunoglobulin therapy for patients with primary immune deficiency: an..., Shehata [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] Laboratory control must be carried out every 3 to 6 months in the first year, and then every 6 to 12 months depending on the clinical condition. It must include [bib_ref] Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency, Berger [/bib_ref] [bib_ref] Immunoglobulin Replacement Therapy for Primary Immunodeficiency, Sriaroon [/bib_ref] serum IgG, and also IgA and IgM, particularly in very young patients, in order to detect recovery in patients with unspecified hypogammaglobulinemia; complete blood count; sedimentation rate; C-reactive protein; direct Coombs; and kidney and liver function tests.

## Approved products
The products approved for sales in Brazil are presented in chart 8. (LME); medical report with rationale for use, clinical condition and diagnosis; results of auxiliary tests and two copies of the prescription; informed consent form. All information can be found on the websites of State Health Departments in Brazil.
The use of subcutaneous or intravenous Ig at home is not yet approved in our country, despite it being common in other countries, [bib_ref] Subcutaneous immunoglobulin replacement therapy: the European experience, Chapel [/bib_ref] [bib_ref] The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin..., Chapel [/bib_ref] [bib_ref] Comparative study of subcutaneous versus intravenous IgG replacement therapy in pediatric patients..., Bezrodnik [/bib_ref] [bib_ref] Illustrative cases on individualizing immunoglobulin therapy in primary immunodeficiency disease, Bonagura [/bib_ref] [bib_ref] Oksenhendler E; DEFI study group. Efficiency of immunoglobulin G replacement therapy in..., Gouilleux-Gruart [/bib_ref] [bib_ref] Clinical ambiguities--ongoing questions, Torgerson [/bib_ref] [bib_ref] Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody..., Abolhassani [/bib_ref] as well as demonstratedly effective and safe. [bib_ref] Immunoglobulin replacement therapy by selfinfusion at home, Chapel [/bib_ref] [bib_ref] Subcutaneous IgG Study Group. Safety and efficacy of self-administered subcutaneous immunoglobulin in..., Ochs [/bib_ref] [bib_ref] Safety and efficacy of subcutaneous human immunoglobulin in children with primary immunodeficiency, Fasth [/bib_ref] [bib_ref] Self-infusion programmes for immunoglobulin replacement at home: feasibility, safety and efficacy, Bhole [/bib_ref] [bib_ref] Selfinfusion of intravenous immunoglobulin by immunodeficient patients at home, Ochs [/bib_ref] A recent survey conducted by the International Patient Organisation for Primary Immunodeficiencies (IPOPI), in 20 countries, showed that among 300 patients, 53% received intravenous Ig and 45%, subcutaneous Ig, and that 14% of patients on intravenous Ig and 94% of patients on subcutaneous Ig received infusions at home.CONCLUSION Ever since the 1 st Brazilian Consensus on the Use of Human Immunoglobulin in Patients with Primary Immunodeficiencies, published in 2010, several new primary immunodeficiencies have been described. Since then, new human immunoglobulin products have been made available in our country, with different compositions and administration routes. Therefore, the recommendations for the use of immunoglobulin in our country need to be updated.
This work provides new knowledge on the products available, their indications, mode of use and monitoring information.
The indication of each product depends on clinical and laboratory characteristics of patients, and treatment individualization and patient monitoring are critical, irrespective of the brand or route of administration of the product.

## Obtaining human immunoglobulin for therapeutic use in brazil
Treatment with human Ig can be obtained via the private healthcare system (regulated by the National Health Agency -ANVISA) or the public system.
To obtain from the private healthcare system, the assisting physician must write a report with the rationale for use, clinical condition, results of diagnostic and auxiliary tests, containing the ICD-10 and the prescription of the product with the proposed dose and frequency, informing where infusions will be performed. Products for intravenous or subcutaneous use can be administered at infusion centers, hospitals, day-hospitals or at home for patients on home care.
Requests to the public healthcare system must be submitted to State health departments. Patients or caregivers must go to the address informed on the website of the competent health department with the original and copies of their National Health Card, identity card, taxpayer ID and proof of residence; application report, evaluation and authorization for specialized pharmaceutical assistance components
[fig] Figure 1: Post-infusion serum concentration of immunoglobulin G in patients on regular use of human immunoglobulin. Comparison of intravenous and subcutaneous immunoglobulin [/fig]