Original Title: Guides et normes: Usage optimal des immunoglobulines en infectiologie

Authors' objectives: Non-specific human immunoglobulins (Igs) are stable products derived from human plasma. Their cost is high, their supply variable, and their use in Québec has been steadily increasing for many years in several areas of medicine, including infectious diseases. Providing a framework for the use of Igs is therefore one of the concerns of Québec’s Comité consultatif national de médecine transfusionnelle, which has called attention to the lack of recommendations regarding their use for most infectious disease indications. At the suggestion of the Comité consultatif national de médecine transfusionnelle, the Ministère de la Santé et des Services sociaux asked the Institut national d’excellence en santé et en services sociaux to develop clinical recommendations regarding the use of Igs in infectious diseases, in the form of an optimal use guide. On completion of this project, the Institut developed clinical recommendations for the optimal use of Igs in infectious diseases, specifically for the treatment of nine indications of interest.

Authors' results and conclusions: RESULTS: For the indications of interest, the results of the systematic reviews allow for the conclusion that IVIg is efficacious for treating toxic shock syndrome and pediatric viral cardiomyopathy, with a level of evidence considered to be low to moderate. Most of the clinical practice guidelines consulted also recommend the use of IVIg to treat toxic shock syndrome, especially if it is streptococcal in nature. On the other hand, clinical practice guidelines do not recommend the use of IVIg to treat viral cardiomyopathies. The final recommendations were formulated based on the clinical perspective of the consulted experts. Thus, it was determined that IVIg can be recommended as a treatment option for toxic shock syndrome and viral cardiomyopathy in children with severe acute viral myocarditis and reduced ejection fraction or significant cardiac dysfunction. The systematic literature reviews indicate that IVIg is ineffective for treating Clostridioides difficile enterocolitis (with a level of evidence considered to be low) and for treating Mycoplasma pneumoniae-induced rash and mucositis (with a level of evidence considered to be insufficient). In the case of Clostridioides difficile enterocolitis, clinical practice guidelines are divided on the subject, with half recommending IVIg as a treatment option or in exceptional situations. In the case of Mycoplasma pneumoniaeinduced rash and mucositis, clinical practice guidelines make no recommendations. Therefore, the recommendation that IVIg not be used for these two indications was based on clinician perspective (expert opinion). As with Stevens-Johnson syndrome, the advisory committee members confirm that IVIg can be considered on an exceptional basis for the treatment of severe Mycoplasma pneumoniae-induced rash and mucositis when all other treatment options have failed. Data from the systematic reviews indicate that IVIg has little or no efficacy compared to placebo or therapy without IVIg for five indications: sepsis (moderate level of evidence), adult viral cardiomyopathy (moderate level of evidence), infection prevention after trauma or surgery (moderate to low level of evidence), necrotizing fasciitis (low level of evidence), and COVID-19 (low to inadequate level of evidence). In addition, clinical practice guideline recommendations and the clinician opinion are in agreement in not recommending IVIg for the treatment of these five conditions. The experts consulted nonetheless agree that IVIg could be considered for fulminant myocarditis in cases of acute heart failure when an endomyocardial biopsy reveals the presence of significant lymphocytic infiltrate. For sepsis, the recommendation excludes the neonatal enterovirus type, which is considered as a separate indication in this guide. As for necrotizing fasciitis, further specifications must also be made. According to the clinical perspective of the experts consulted, IVIg could be used to treat pediatric necrotizing fasciitis. In the absence of scientific data and clinical practice guideline recommendations on this topic, the advisory committee members agreed to place pediatric necrotizing fasciitis in the ‟insufficient data” category and to add a note to the effect that IVIg can be considered for this condition. They also specify that IVIg is not recommended for adult necrotizing fasciitis when it is not accompanied by shock. These details have therefore been added. Since the clinical situation of an individual presenting with necrotizing fasciitis with shock can vary widely and could be similar to toxic shock syndrome, the advisory committee members believed it best not to add any further specifications for this indication. The systematic literature review conducted for multisystem inflammatory syndrome temporally associated with COVID-19 suggests that the efficacy of IVIg is similar to that of corticosteroids for this indication in children, with a low to insufficient level of evidence. Based on an analysis of all the available data, which include best clinical practice guideline recommendations, the advisory committee members agreed that IVIg can be considered a treatment option for multisystem inflammatory syndrome temporally associated with COVID-19 in children who meet established diagnostic criteria. Since no primary study nor clinical practice guideline dealing with the treatment of adult multisystem inflammatory syndrome temporally associated with COVID-19 was identified this indication was included in the ‟insufficient data” category. Based on the limited information available and the clinical experience of the experts consulted, the advisory committee members were of the opinion that IVIg could still be considered for this indication. Lastly, the efficacy of IVIg in treating neonatal enterovirus sepsis could not be demonstrated by the systematic literature review carried out for this indication. The level of evidence obtained was considered to be insufficient, with only one primary study and no clinical practice guidelines identified. The advisory committee members stated that the population concerned -- neonates -- and the seriousness of the condition make it difficult to conduct good-quality clinical trials. They also pointed out that in the absence of a recommended treatment for neonatal enterovirus sepsis, IVIg is often the only available option. Therefore, neonatal enterovirus sepsis was placed in the ‟insufficient data” category with a note specifying that the use of IVIg can be considered for this indication, on the basis of the clinical experience of the experts consulted. The scientific data on safety indicate that most of the transfusion reactions that occur after IVIg administration are not serious. However, various serious reactions have nonetheless been reported in the scientific literature or to Québec’s hemovigilance system, although these events remain rare. Two of them -- a thromboembolic event and a hemolytic reaction -- have been the subject of studies and of communications from Health Canada and the Food and Drug Administration in recent years. RESULTS: Evidence on the efficacy of Igs was available for most of the indications of interest, and the level of evidence was considered to be low or insufficient for four of the nine indications in question. Regarding COVID-19, its associated multisystem inflammatory syndrome, as well as Mycoplasma pneumoniae-induced rash and mucositis, were only recently defined, and the last two conditions are quite rare. An assessment of the scientific and contextual data and the clinician perspective led to the following conclusions: • the Institut national d’excellence en santé et en services sociaux recommends that IVIg be considered a treatment option, as second-line therapy or in special situations, for pediatric viral cardiomyopathy, toxic shock syndrome and multisystem inflammatory syndrome temporally associated with COVID-19 in children; 5 • the Institut national d’excellence en santé et en services sociaux does not recommend the use of IVIg for seven indications: adult viral cardiomyopathy, COVID-19 (without multisystem inflammatory syndrome), Clostridioides difficile enterocolitis, Mycoplasma pneumoniae-induced rash and mucositis, necrotizing fasciitis (without shock criteria), infection prevention after trauma or surgery, and sepsis (with the exception of neonatal enterovirus sepsis); • Due to the available scientific data being insufficient for pediatric necrotizing fasciitis, neonatal enterovirus sepsis and multisystem inflammatory syndrome temporally associated with COVID-19 in adults, the Institut national d’excellence en santé et en services sociaux could not make recommendations concerning these indications, but suggests discussions among medical experts take place with a view to achieving a consensus on the prescribing of IVIg, on a case-bycase basis, for these indications. The use of IVIg can be associated with transfusion reactions, which are usually not serious. Serious transfusion reactions, although rare, have nonetheless been reported. In conclusion, the recommendations presented in the optimal use guide for Igs in infectious diseases add to those in the previous guides for neurology, hematology, clinical immunology, dermatology and rheumatology, all of which are aimed at reducing inappropriate use of this resource.

Authors' methods: In response to the mandate from the Ministère de la Santé et des Services sociaux, the Institut national d’excellence en santé et en services sociaux used a collaborative approach known as ‟knowledge mobilization”. This approach consists of analyzing and assessing scientific and contextual data as well as the perspectives of clinicians. Scientific data To evaluate the efficacy and safety of Igs in children and adults for the ten infectious disease indications of interest, ten individual systematic reviews were conducted by searching several bibliographic databases from the date of their inception until February 2021 to identify all primary studies and systematic reviews with a meta-analysis published on these topics. The official product monographs for Health Canada-approved Igs, Health Canada and U.S. Food and Drug Administration advisories, and a transfusion accident and incident report published by the Institut national de santé publique du Québec were consulted to complete the search concerning safety. To document the conditions of Ig use, we conducted a systematic literature search to identify guidance documents, clinical practice guidelines and any other sources containing clinical recommendations published between January 2011 and February 2021 for the ten indications of interest. The grey literature and the official product monographs for Health Canada-approved immunoglobulins were consulted to complete the search on conditions of Ig use. For multisystem inflammatory syndrome temporally associated with COVID-19, the literature search was updated to find any new documents published between February and July 2021. Documents were selected according to predefined inclusion and exclusion criteria, and their quality was assessed using appropriate tools. These steps were carried out independently by two professional scientists. The data were then extracted by one scientist and validated by the other. The results are presented in tables and summarized in the form of an analytical narrative synthesis. The main efficacy results reported in the retained studies are expressed as brief statements of scientific evidence, and an overall level of scientific evidence has been assigned to each statement according to a four-level scale (high, moderate, low, insufficient). Lastly, to determine the main characteristics of the ten infectious disease indications of interest, the scientific literature, clinical practice guidelines and the Orphanet website were consulted. Contextual data and clinician perspectives The number of persons treated and the quantity (expressed in grams) of Igs administered in Québec in 2018 and 2019 were documented using a report on their use prepared by the Institut national de santé publique du Québec based on information extracted from the TraceLine™ system database. Health Canada’s website was consulted to check the approval status of intravenously administered immunoglobulins (IVIg). Recommendations were drawn up in collaboration with the advisory committee consisting of Québec experts. In general, information on contextual data and the perspectives of the consulted clinicians are presented in narrative form and summarized in tables. Process of constructing recommendations The analysis and synthesis of the scientific and contextual data as well as the clinician perspective enabled structuring of the arguments leading to the formulation of the recommendations. Only those recommendations for which there was a consensus among the experts were retained. The ten infectious disease indications were divided into four use categories, namely IVIg recommended, IVIg as a possible treatment option, IVIg not recommended, and insufficient data

Project Status: Completed

URL for project: https://www.inesss.qc.ca/en/publications/publications/publication/usage-optimal-des-immunoglobulines-en-infectiologie.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/en/publications/publications/publication/usage-optimal-des-immunoglobulines-en-infectiologie.html

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec