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Background and importance Intravenous immunoglobulin (IVIG) is a blood product used for replacement therapy and immunomodulation in various conditions. Its use is usually restricted to situations with clinical benefit and established evidence, due to the drug’s production method and high economic value. Recently, the Portuguese National Pharmacy and Therapeutics Committee (NPTC) released guidance for a more evidence based IVIG use approach.¹ Aim and objectives To characterise the IVIG prescription profile in our institution; to assess if IVIG is prescribed and used in accordance with guidance No 8, May 2020, from NPTC and the National Medicines Formulary (NMF); and to evaluate the impact of IVIG consumption on the hospital’s financial budget. Material and methods All IVIG prescriptions from January 2018 to May 2020 were analysed. Indications, doses, infusion rates (IR) and adverse reactions (AR) were registered in an Excel spreadsheet. The indications were classified as either on or off-label, regarding their inclusion in the aforementioned guidance and as per the NMF. The economic impact was calculated from the average price, using SGICM-GLINTT pharmacy software. Results The study included 131 prescriptions, of which 92.4% conformed to the NMF: 60.3% were replacement therapy, 31.2% immunomodulation cases and the remaining 8.5% were off-label (of these, 64% had probable benefit). The most prevalent indications were chronic inflammatory demyelinating polyradiculopathy (39%) and MyD88 deficiency (31%). Doses and IR were as indicated. There were recorded AR. IVIG accounted for 1.21% of the institution’s total medication expenses. Conclusion and relevance IVIG was mostly used for approved indications. Doses and IR were within the recommended range and no AR were reported, suggesting that the administrations was well tolerated. Off-label use, although characterised by limited expression and for indications with probable benefit, included indications not mentioned in the guidance. In this study, hospital prescriptions showed a low level of compliance with the NPTC guidance; therefore, an institutional protocol should be developed for a more evidence based approach to IVIG use. Locally, the annual expenses for IVIG (1.21%), a value way below the national average (2.83%), may be due to the smaller size and complexity of the hospital and slight off-label use. References and/or acknowledgements Comissao Nacional de Farmacia/Terapeutica. (2020). Recomendacao sobre utilizacao de IgHN. Orientacoes Comissao Nacional Farmacia/Terapeutica. Conflict of interest No conflict of interest

Primary immunodeficiencies are genetic defects of the innate or adaptive immune system, resulting in a propensity to infections. The innate immune system is the first line of defense against pathogens and is critical to recognize microbes and start the inflammatory cascade. Sensing of microbes occurs by a number of pathogen-recognition receptors, resulting in the activation of inflammatory signal transduction pathways, such as the activation of NF-κB. Herein, we describe a case of IRAK4 deficiency, a key signal transduction molecule of toll-like and IL-1 receptors. We highlight the complexities in diagnosis of these disorders and review genetic defects of the NF-κB pathway.

Primary immune deficiencies are genetic defects of the innate or adaptive immune system resulting in a propensity to infections. The innate immune system is the first line of defense against pathogens, and is critical to recognize microbes and start the inflammatory cascade. Sensing of microbes occurs by a number of pathogen recognition receptors, resulting in the activation of inflammatory signal transduction pathways, such as the activation of NF-B. Herein we describe a case of IRAK4 deficiency, a key signal transduction molecule of toll-like and IL-1 receptors. We highlight the complexities in diagnosis of these disorders, and review genetic defects of the NFB pathway.

International audience; The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.

Yersiniosis is a food-borne illness, usually self-limited. Severe clinical courses may occur in chronic conditions, particularly in immunocompromised individuals.1 Here, we report on the case of a 2-year-old girl born to consanguineous parents of Roma descent (a traditionally itinerant ethnic group living mostly in Europe and the Americas, who originate from Northern India), with chronic yersiniosis, recurrent granulomatous lymphadenitis, and episodicneutropenia. Using a targeted next-generation sequencing panel for immunodeficiency genes, a homozygous in-frame deletion in the MYD88 gene was found. MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs).2 MYD88 deficiency has been associated with life-threatening and recurrent pyogenic bacterial infections, including invasive pneumococcal disease.

C Picard, H von Bernuth, P Ghandil. Medicine (Baltimore). 2010;89(6):403–425 To describe the clinical features and outcomes of patients with autosomal recessive defects in the interleukin 1 receptor-associated kinase 4 (IRAK-4) and the myeloid differentiation factor 88 (MyD88). The authors provided the cumulative data of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency from 37 kindreds in 15 countries. The data for this report were collected on the basis of a detailed questionnaire filled out by the physician who cared for the enrolled patient. The leading threat to these patients was invasive pneumococcal disease, which was seen …

von Bernuth H, Picard C, Jin Z, et al. Science . 2008;321(5889):691–696 PURPOSE OF THE STUDY. Myeloid differentiation protein 88 (MyD88) is a key downstream adapter for receptors of the innate immune system, including most Toll-like receptors (TLRs) and interleukin 1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens, and the goal of this study was to determine whether there are children with recurrent infections who have a deficiency in MyD88. STUDY POPULATION. Nine children with MyD88 deficiency were identified from those evaluated for …