Infectious outcomes of a standardized subcutaneous immunoglobulin dose reduction strategy in primary immune deficiencies amid global shortage

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During the COVID-19 pandemic, a global shortage of SCIg prompted our unit to reduce SCIg doses or maintain the same dose intravenously. This study evaluates the impact of a standardized SCIg dose reduction on infection rates and clinical outcomes in patients with PID. Adult PID patients on SCIg for at least 6 months, with IgG trough levels ≥ 700 mg/dL (or ≥ 900 mg/dL under specific conditions), and no significant infections in the past 6 months were eligible. A dose reduction of 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL above 700 mg/dL (or 900 mg/dL) was proposed. Clinical and laboratory data, and infectious events at 6- and 12-month follow-ups, were analyzed. Thirty-one patients with PID were included: common variable immunodeficiency (54.83%), IgG subclass deficiency (9.67%), and other PIDs (35.48%). The average SCIg dose was initially reduced from 7.82 g/week to 5.72 g/week and adjusted to 6.94 g/week at 12 months. There was no significant change in severe or recurrent infections before and at 6- and 12-months post-dose adjustment. The dose reduction saved an average of 5,550 euros per patient annually, totaling 172,050 euros annually for our cohort. Thus, optimizing SCIg doses in selected PIDs is feasible without increasing infection rates, conserving this plasma-derived product during shortages. Larger prospective studies are needed to confirm this strategy's utility and its application to other Ig formulations. Immunoglobulin replacement therapy humoral primary immune deficiencies subcutaneous immunoglobulin infections cost-effectiveness resource shortage Figures Figure 1 Figure 2 1. Introduction Primary immunodeficiencies (PID) represent a heterogeneous group of diseases characterized by abnormalities in one or more components of the immune system. Humoral immunodeficiencies are the most frequent PID, constituting around 30–70% of the total PIDs with specific defects involving a dysfunction or absence of B cell lymphocytes, with a consequently decrease in the production of immunoglobulins (Ig) that recognize specific antigens, facilitating their elimination [1] These patients mainly suffer from severe or recurrent infections [2], and some may suffer autoimmune and neoplastic complications due to immune dysregulation [3] which constitute, nowadays, constitutes its main cause of morbidity and mortality [4, 5]. Immunoglobulin replacement therapy (IgRT), administered either intravenously (IVIg) or subcutaneously (SCIg), is essential in managing humoral PIDs. It has been shown to reduce infection frequency and severity, decrease organ damage rates, and lower patient mortality [6, 7]. Both IVIg and SCIg have demonstrated similar efficacy levels, although SCIg is associated with fewer systemic adverse events, improved quality of life, and reduced costs [8, 9]. The correlation between IgG trough levels and reduced infection rates is well stablished [10–12]. Current clinical guidelines recommend an initial IgRT dose of 400–600 mg/kg/month to achieve steady-state trough IgG levels of 600–800 mg/dL [11, 13–15]. However, there are no defined protocols to adjust subsequent dosing and defining the ideal IgRT dose for each patient remains a challenge, as individual biological thresholds vary [11, 16–18]. In this regard, patients with bronchiectasis, interstitial lung disease (ILD), autoimmune cytopenias, and enteropathy, may require higher IgG trough levels [11, 16]. This necessitates careful dose optimization to avoid undertreatment, which increases infection risk, or overtreatment, especially regarding increasingly scarce availability of plasma-derived products, specifically Igs. Taking advantage of the global shortage of Ig during the COVID-19 pandemic, the objective of this study was to retrospectively evaluate the impact of a standardized reduction in SCIg doses on infection rates and clinical outcomes in patients with PID who have maintained stable high IgG trough levels and have not experienced serious or recurrent infections. We aim to provide evidence in individualized dosing strategies that enhance patient care while addressing the challenges posed by the limited availability of plasma-derived products. 2. Material and methods 2.1. Study design and inclusion criteria In 2021, coinciding with a severe global shortage of Ig due to the COVID-19 pandemic, hospitals across Spain experienced a drastic reduction in their stock of SCIg. To address this exceptional situation, the Unit for Primary Immunodeficiencies from the University and Polytechnic Hospital La Fe, implemented a contingency plan from a clinical perspective, which consisted of (1) a thorough revision of the clinical indications for IgRT for each patient, and (2) a dose adjustment in the dose of SCIg in patients with PID who had stable clinical and analytical conditions. Thus, patients over 18 years who were receiving SCIg for at least 6 months, maintained IgG trough levels of 700 mg/dL or higher (or more than 900 mg/dL in those patients who had ILD, enteropathy with or without malabsorption, use of immunosuppressants in the last 6 months or presence of bronchiectasis), and had no significant infections in the past 6 months (defined as infections requiring hospitalization or three or more outpatient mild infections requiring antibiotics) were eligible for dose adjustment. All patients who met the dose adjustment criteria were given the option to either reduce their SCIg dose as previously mentioned or switch to IVIg at the same dose they were receiving subcutaneously (Fig. 1 ). All patients were evaluated for these criteria in May 2021. Those who were eligible were proposed to reduce their SCIg regimen by 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL that their IgG trough levels exceeded 700 mg/dL (or 900 mg/dL in the mentioned cases) (Fig. 1 ). For example, a 70 kg patient showing IgG trough levels of 1000 mg/dL and without relevant infections in the past 6 months, would have their dose reduced by 2 g per week or 8 g per month. One year after completing this clinical contingency plan, data were retrospectively collected to conduct the scientific study. 2.2. Data collection and variables Clinical data were obtained retrospectively from electronic medical records and recorded in a database. The demographic characteristics of each patient were documented, encompassing age, sex, age at onset of immunodeficiency symptoms, age at diagnosis, and specific PID diagnosis. The presence and type of infections prior to dose adjustment were recorded, categorizing them into major bacterial infections (pneumonia, meningitis, osteomyelitis, intra-abdominal infections, cellulitis or soft tissue infections, sepsis, or opportunistic infections) and recurrent infections (upper respiratory tract infections, lower respiratory tract infections, gastrointestinal infections, urinary tract infections, and soft tissue infections). Additionally, the average number of emergency visits and hospitalizations per year was documented. Non-infectious comorbidities including autoimmune cytopenias, lymphadenopathies, splenomegaly, hepatomegaly, and clinical or imaging findings of portal hypertension, systemic autoimmune disorders, lung, gastrointestinal, cutaneous, and neurological involvement, as well as malignancy (both solid and hematological neoplasia) were documented. The infectious processes that the patient suffered at 6 and 12 months after the dose adjustment were documented, including bacterial major and recurrent infections. Laboratory variables including IgG trough levels (mg/dL), IgM (mg/dL), IgA (mg/dL), total number of leukocytes (cell/µL), neutrophils (cell/µL), CD3 cell count (cell/µL), CD4 cell count (cell/µL), CD8 cell count (cell/µL), CD4/CD8 ratio, CD19 cell count (cell/µL), and natural killers (NK) cell count (cell/µL) prior to dose adjustment, and at 6 and 12 months of follow-up were recorded. Regarding the treatment, the type of SCIg preparation (conventional ScIg 20% or hyaluronidase-facilitated ScIg 10%) and their brand, the SCIg dosage the patient received prior to adjustment, and the subsequent dosage after 6 and 12 months of follow-up were documented, as well as the immunosuppressant received therapy, if any. 2.3. Statistical analysis The statistical analysis was conducted using the statistical software R, version 4.0.1. Continuous variables were described by their mean and standard deviation. Discrete variables were presented through the distribution of frequencies and percentages. Normality was assessed by quantile-quantile QQ plots and the Shapiro-Wilk test. Comparisons between the parameters prior to the dose adjustment and after a 6- and 12-months follow-up period were made using the Cochran Q test for categorical variables and the Friedman test for quantitative variables. Statistical significance was defined as p < 0.05. 2.4. Ethics From an exclusively healthcare perspective, this dosage adjustment was conducted in a homogeneous and standardized manner at our Unit, following strict criteria established by a committee of experts, which consisted of an internist, a clinical immunologist, and a nurse with extensive experience in treating PID patients. All patients who met the dose adjustment criteria were given the option to either reduce their SCIg dose as previously mentioned or switch to IVIg at the same dose they were receiving subcutaneously. This study was approved by the University and Polytechnic Hospital La Fe Ethical Committee with the code “SUBDOSAGE”. The study was conducted in accordance with the Declaration of Helsinki and adhered to the STROBE guidelines. Anonymity and data confidentiality for all included patients were maintained in compliance with Spanish regulations governing observational studies. 3. Results 3.1. Study population Thirty-one patients with PID were included in the study. The mean age was 47.51 years (SD 15.47) with a near equal gender distribution: 16 females (51.61%) and 15 males (48.38%). Among the types of PID observed, 3 patients (9.67%) had IgG subclass deficiency, common variable immunodeficiency (CVID) was identified in 17 patients (54.83%), and 11 patients (35.48%) had other PID with hypogammaglobulinemia. More details are represented in Table 1 . Table 1 Clinical characteristics of the included patients Variable N (%) – Mean (SD) Age 47.51 (15.47) Sex Female 16 (51.61) Male 15 (48.38) Humoral primary immunodeficiency IgG subclass deficiency Common variable immunodeficiency 3 (9.67) 17 (54.83) Wiskott-Aldrich syndrome Chronic mucocutaneous candidiasis IgA and IgG subclass deficiency Good syndrome Di George syndrome Bloom syndrome Not well defined hypogammaglobulinemia 1 1 1 1 1 1 5 Comorbidities Cytopenias 6 (19.35) Lymphadenopathies 5 (16.12) Splenomegaly 1 (3.22) Interstitial lung disease 1 (3.22) Bronchiectasis 12 (38.70) Enteropathy 6 (19.35) Neurological affectation 1 (3.22) Autoimmune systemic disease 7 (22.58) Solid malignancy 2 (6.45) Hematological malignancy 3 (9.67) Regarding their clinical comorbidity, cytopenias were noted in 6 patients (19.35%), lymphadenopathies were present in 5 patients (16.12%), and splenomegaly in 1 patient (3.22%). ILD and neurological affectation were each observed in 1 patient (3.22%). Bronchiectasis was a common comorbidity, affecting 12 patients (38.70%), and 6 patients (19.35%) showed enteropathy. Additionally, 7 patients (22.58%) had autoimmune systemic diseases, and 5 patients of the study had a diagnose of neoplasia: 2 patients (6.45%) had solid malignancies, and 3 patients (9.67%) had haematological malignancies (Table 1 ). Patients were screened for the use of immunosuppressants before and after the dose adjustment. At baseline, 5 patients were receiving corticosteroids, 1 patient was receiving tacrolimus, and 1 patient was receiving rituximab. At 12 months follow-up, corticosteroid use increased to 6 patients, rituximab and tacrolimus remained unchanged to 1 patient each, and 1 patient started receiving azathioprine. Additionally, 9 patients (29%) were receiving prophylactic antibiotics at baseline, which non-significantly increased to 10 patients (32.3%) at both the 6-month and 12-month follow-ups (p = 0.82). Among these patients, 3 who were not previously on prophylactic antibiotics initiated the regimen, while 2 patients who had been on treatment for the prior 6 months discontinued it (Table 2 ). None of the patients who initiated had presented major bacterial infections. Table 2 Prophylactic antibiotic treatment of our cohort Before dose adjustment 6-month follow-up 12-month follow-up Azithromycin 4 4 5 Cotrimoxazole 3 3 3 Azithromycin, cotrimoxazole and inhaled colistin 1 1 1 Rifaximin 1 1 0 Ciprofloxacin 0 1 1 3.2. Dose adjustment The mean dose of SCIg before the dose adjustment was 7.82 g/week (SD 2.29). The mean dose reduction was 2.10 g/week (SD 1.18). Consequently, the new mean dose at time 0 was 5.72 g/week (SD 1.71). In addition, at 12 months, several dose-adjustments were made: 4 dose escalations (including the patient whose dose was reduced at 6 months) and 1 dose reduction. As so, at 12 months of follow-up, the average SCIg dose was 6.94 g/week (SD 1.91). Specifically, these dose adjustments were made as follows: one patient with CVID had their dose reduced from 8.3 g/week to 5 g/week, further reduced to 3.75 g/week at 6 months, and then increased to 6.7 g/week at 12 months due to two minor infections. Another CVID patient with renal transplantation had their dose reduced from 8 g/week to 5 g/week, then increased to 8.3 g/week at 12 months due to an increase in BK virus load. A CVID patient with multiple myeloma had her dose reduced from 8 g/week to 7 g/week, then increased back to 8 g/week at 12 months due to a minor infection. A patient with primary non-defined hypogammaglobulinemia and severe asthma had their dose reduced from 7 g/week to 5 g/week, then increased to 6.7 g/week at 12 months due to the development of a pneumonia. Finally, one patient had an initial dose reduction from 10 g/week to 6.7 g/week, further reduced to 5 g/week at 12 months, without any subsequent infections. The data on the type of SCIg and the administration frequency at time 0, as well as the changes in the type of SCIg and administration frequency after the dose adjustment, are detailed in Table 3 . Table 3 Data on the type of SCIg and administration frequency at time 0, and changes after dose adjustment Variable N Frequency (%) Type of ScIg ScIg 20% 19 61.29 Hyaluronidase-facilitated ScIg 10% 12 38.71 Frequency of administration Every 2 weeks 5 16.13 Every 3 weeks 7 22.58 Every 4 weeks 5 16.13 Weekly 14 45.16 Change in the type of ScIg No 30 96.77 Yes 1 (changed to Hyaluronidase-facilitated ScIg 10%) 3.23 Change in the frequency of administration No 25 80.65 Yes 6 19.35 3.3. Presence of infections before and after dose adjustment There was no significant difference in the mean number of severe major infections and recurrent infections before dose adjustment, at 6-months follow-up and at 12 months follow-up (p = 0.220 and p = 0.107, respectively). However, regarding major infections, there were none in the 6 months prior to dose adjustment, 2 in the 6 months after dose-adjustment, and 1 between 6- and 12-months follow-up in the whole cohort. All of these were community-acquired pneumonias, and at 12 months, the dose was increased for the patient who had experienced 2 pneumonias within 12 months follow-up. The percentage of patients who suffered severe infections at the three time points was also not statistically significant (p = 0.223). There were no cases of other major infections such as meningitis, osteomyelitis, cellulitis, sepsis, UTIs requiring hospitalization, opportunistic infections. No patient experienced more than 3 mild infections in any 6-month follow-up period. Additionally, the percentage of patients who suffered mild infections at the 6-month and 12-month follow-ups after dose adjustment was not statistically significant (p = 0.109). Regarding these mild infections, during before the dose adjustment, 3 patients experienced 1 mild infection, and 1 patient experienced 2 mild infections. In the first 6 months post-adjustment, 6 patients had 1 mild infection, and 3 patients had 2 mild infections. Between 6- and 12-months post-adjustment, 10 patients had 1 mild infection, and 1 patient had 2 mild infections. No patient experienced 3 or more mild infections (i.e., recurrent infections) in any 6-month period. Among these mild infections, one patient had a mild gastrointestinal infection at each time point. For lower respiratory tract infections, there was only 1 case before the dose adjustment, compared to 2 cases at 6 months and another 2 cases between 6 and 12 months. There were several cases of mild skin and soft tissue infections: 1 case before the dose adjustment, 3 cases at 6 months, and 2 cases between 6- and 12-months follow-up. Two episodes of mild upper respiratory tract infections were recorded: none in the pre-adjustment period, with 1 case each at 6 months and between 6 and 12 months. There was only 1 case of a mild urinary tract infection, which occurred in a patient during the 6 months post-adjustment period. No cases of mild parasitic infections were observed (Table 4 ). Table 4 Mean and standard deviation of all infections recorded before dose adjustment, and at 6 months and 12 months follow-up Variable Before dose adjustment (Mean ± SD) 6 months follow-up (Mean ± SD) 6–12 months follow-up (Mean ± SD) Major infection 0 0.065 ± 0.250 0.032 ± 0.180 Pneumonia 0 0.067 ± 0.254 0.033 ± 0.183 Meningitis 0 0 0 Osteomyelitis 0 0 0 Severe abdominal infection 0 0 0 Severe skin and soft tissue infection 0 0 0 Sepsis 0 0 0 Severe urinary tract infection 0 0 0 Opportunistic infection 0 0 0 Recurrent infection (more than 3) 0 0 0 Non-severe infection 0.161 ± 0.454 0.387 ± 0.667 0.387 ± 0.558 Mild upper respiratory tract infection 0.065 ± 0.250 0.200 ± 0.484 0.233 ± 0.504 Mild lower respiratory tract infection 0.032 ± 0.180 0.067 ± 0.254 0.067 ± 0.254 Mild gastrointestinal infection 0.032 ± 0.180 0.033 ± 0.183 0.033 ± 0.183 Mild urinary tract infection 0 0.033 ± 0.183 0 Parasitosis 0 0 0 Mild skin and soft tissue infection 0.032 ± 0.180 0.100 ± 0.305 0.067 ± 0.254 3.4. Analysis of immunological parameters After the dose adjustment, a statistically but not clinically significant difference was observed in the trough levels of IgG across the different time points in follow-up: 1,138.48 (SD 294.25) at baseline, 947.35 (SD 306.69) 6-months post-adjustment, and 983.28 (SD 310.51) at 12-months post-adjustment (p = 0.002), with the lowest IgG trough levels recorded at 6 months (Fig. 2 ). This implies a mean reduction of 15.21% of the previous IgG trough levels. However, this difference was not clinically relevant in the number of severe and recurrent infections. Mean total leukocyte counts were 6288.71 (SD 1752.84), 7037.24 (SD 1887.27), and 6662.50 (SD 2171.55) cells/µL at baseline, 6 months, and 12 months, respectively. Baseline mean CD4, CD8, and NK cell counts were 846.72 (SD 490.69), 510.03 (SD 292.55), and 245.10 (SD 201.99) cells/µL, respectively. 3.5. Pharmacoeconomic analysis In our study, a standardized dose reduction of Igs was implemented for a total of 31 patients with PID, maintained for at least one year. The average dose reduction was 2.09 g/week (SD 1.17) resulting in an average annual savings of 100.3 g per patient. For the entire cohort of 31 patients, this equated to an annual savings of approximately 3109.3 g. From a pharmacoeconomic perspective, using the reference price of 55.5 euros/g as established by the Spanish Ministry of Health, this translates to an average savings of 5,550 euros per patient per year, and a total annual savings of 172,050 euros for our cohort [19]. 4. Discussion The main findings of this study can be summarized as follows: (i) The implementation of a careful, clinically tailored and standardized dose reduction SCIg therapy in patients with PIDs was successfully maintained over an extended period without an increase in severe or recurrent infections, and (ii) individualized SCIg dose reduction could be a safe and cost-effective approach to managing PIDs, especially in contexts where plasma-derived products are scarce. These results highlight the potential of personalized dosing strategies to optimize patient care and resource utilization effectively. IgRT is essential for managing PIDs with hypogammaglobulinemia, as it significantly reduces the frequency and severity of infections, mitigates organ damage, and decreases mortality [7, 11]. It is well established that higher doses of immunoglobulins correlate with increased serum IgG levels and reduced infection rates, regardless of the administration route [11, 16]. However, there is no universally defined protective IgG level. Most practice guidelines recommend maintaining trough IgG levels between 600 and 800 mg/dL, achieved by administering 400 mg/kg every 3 to 4 weeks [6, 14, 15]. This recommendation is largely based on expert opinions and systematic reviews of limited data. Consequently, dose optimization is usually guided by the so-called "minimum biological trough levels," which represent the specific IgG concentration required to prevent infections in each patient [17, 18]. The variability in individual IgG thresholds implies that some patients might be under-treated, increasing their risk of infections, while others could be over-treated, leading to inefficient use of IgRT. The British Society for Immunology and the UK Primary Immunodeficiency Network (UKPIN) recommend initial trough IgG levels above 800 mg/dL for PID patients, with potential optimization to 1000 mg/dL for those with X-linked agammaglobulinemia, established organ damage, or persistent infections [20]. Nevertheless, this recommendation lacks a dose reduction protocol. In this regard, Elhaj et al. reduced IgRT doses for 61 patients, 48 of whom had humoral PID, during the COVID-19 Ig shortage. This reduction was applied to patients with IgG trough levels above 800 mg/dL, provided their condition was clinically stable [21]. In this study, the dose reduction group had significantly higher baseline trough levels compared to controls (1050 mg/dL vs. 820 mg/dL). After dose reduction, trough IgG levels in the reduction group decreased to 860 mg/dL, comparable to the control group (890 mg/dL). In our study, baseline trough levels were higher (1130 mg/dL), decreasing to 940 mg/dL at six months and 980 mg/dL at twelve months. The reduction magnitude was similar to the British study (-190 mg/dL vs. -150 mg/dL). However, in their study, breakthrough infections and the need for antibiotics occurred 1.55 times more frequently in the reduced dose group compared to controls, with a significant increase in antibiotic use post-IgRT dose reduction. In contrast, our study found no significant differences in infection rates before and after dose reduction, regardless of prophylactic antibiotic use. This discrepancy could be attributed to our patients having higher absolute trough IgG levels and the strict inclusion of PID patients. Contrarily, the study by Elhaj et al. included secondary immunodeficiency patients, who may have additional immunosuppressive factors necessitating prophylactic antibiotic use for infection prevention. Additionally, dose reduction was not individualized based on clinical factors (e.g., organ damage, comorbidities), but rather applied uniformly. This approach may have led to inappropriate patient selection and inadequate dose reductions, either by including patients who were not properly adjusted or by reducing doses excessively in particularly vulnerable patients. IgRT has complex production processes and relies on plasma donations, making it a scarce and valuable resource. Spain, in particular, faces vulnerability with low plasma self-sufficiency (34%) and heavy reliance on importation [22]. Recent measures, such as use optimization plans and plasma donation campaigns, have shown limited effectiveness. In our study, we carefully selected candidates for Ig dose reduction, including only PID patients with IgG trough levels ≥ 700 mg/dL and no significant infections in the past six months. For patients with GLILD, inflammatory enteropathy, recent immunosuppressant use, or bronchiectasis, trough levels ≥ 900 mg/dL were required, with decisions made by a clinical expert committee. Our study demonstrates that standardized Ig dose reduction in well-controlled PID patients can conserve Ig resources without compromising patient safety. This approach could significantly improve resource management and offer a potential solution to the Ig supply challenge. The total annual savings in our experience amounted to 172,050 euros for the Spanish National Health System, substantially exceeding the estimated direct costs of inpatient and outpatient breakthrough infections such as pneumonia, which are estimated at 3,955 euros for hospital admission and 511 euros for outpatient management in our setting [23]. However, this study is not exempt from limitations. Firstly, this is a retrospective observational study based on data analysis following the implementation of a contingency plan, designed from a primarily clinical perspective during the exceptional context of the 2021 Ig shortage crisis among COVID-19 pandemic. Secondly, the study included only patients with PIDs, making it difficult to extrapolate the results to patients with secondary immunodeficiencies, as these conditions involve additional iatrogenic non-humoral factors that could significantly influence infection rates. Additionally, the sample size was small, and the study lacks a control group, as all patients offered dose reduction accepted it. Finally, the analysis included only patients receiving SCIg, making it difficult to extrapolate the results to patients receiving IVIg, showing different pharmacokinetic profiles that could lead to different outcomes in IgG trough levels and infection rates following dose reduction. 5. Conclusion This study suggests that dose optimization of SCIg in patients with PIDs requiring IgRT is feasible without increasing the rate of severe or recurrent infections, provided certain clinical conditions are met: specifically, a meticulous selection of candidate patients and a standardized, proportional reduction of doses based on IgG trough levels. Candidates for dose reduction should have maintained stable IgG trough levels of at least 700 mg/dL, or 900 mg/dL for those with GLILD, inflammatory enteropathy, recent use of immunosuppressants, or bronchiectasis, and should not have experienced severe or recurrent infections in the past six months. Once selected, the dose reduction should be standardized, reducing 60 mg/kg/month (15 mg/kg/week) for every 150 mg/dL above the target trough levels of 700 mg/dL or 900 mg/dL. This approach appears effective for optimizing SCIg dosing in PID patients, significantly contributing to the preservation of this scarce and valuable resource. Prospective studies with a higher number of patients are needed to confirm the utility of this reduction strategy, not only in PID patients but also in secondary immunodeficiency patients, and to evaluate different formulations and routes of administration. Declarations Acknowledgements We would like to thank the European Society for Immunodeficiencies (ESID) for their support to the corresponding author. Authorship contributions PMM conceived the original idea for the manuscript. VGB performed the statistical analysis. MDCN and VGB contributed significantly to the drafting of the manuscript. PLL, HBM, SMM, and AM all played crucial roles in the review of the manuscript and the literature. VGS supervised the work. All authors reviewed the manuscript and provided substantial contributions to the literature review. Funding declaration No funding has been required for the development of this work. Disclosure of Conflicts of Interest The authors declare no conflicts of interest. 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Shehata N, Palda V, Bowen T, Haddad E, Issekutz TB, Mazer B, Schellenberg R, Warrington R, Easton D, Anderson D, Hume H. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev. 2010 Jan;24 Suppl 1:S28-50. doi: 10.1016/j.tmrv.2009.09.011. Chapel HM. Consensus on diagnosis and management of primary antibody deficiencies. Consensus Panel for the Diagnosis and Management of Primary Antibody Deficiencies. BMJ. 1994 Feb 26;308(6928):581-5. doi: 10.1136/bmj.308.6928.581. Erratum in: BMJ 1994 Apr 2;308(6933):913. Orange JS, Belohradsky BH, Berger M, Borte M, Hagan J, Jolles S, Wasserman RL, Baggish JS, Saunders R, Grimbacher B. Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy. Clin Exp Immunol. 2012 Aug;169(2):172 − 81. doi: 10.1111/j.1365-2249.2012.04594.x. Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008 Jul;122(1):210-2. doi: 10.1016/j.jaci.2008.04.044. Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010 Jun;125(6):1354–1360.e4. doi: 10.1016/j.jaci.2010.02.040. Spanish Ministry of Health, 2. Proyecto OPR 2024. Spanish Ministry of Health; 2024. Accessed 18th July 2024. Available from: https://sede.administracion.gob.es/pagSedeFront/servicios/consultaCSV.htm Grigoriadou S, Clubbe R, Garcez T, Huissoon A, Grosse-Kreul D, Jolles S, Henderson K, Edmonds J, Lowe D, Bethune C. British Society for Immunology and United Kingdom Primary Immunodeficiency Network (UKPIN) consensus guideline for the management of immunoglobulin replacement therapy. Clin Exp Immunol. 2022 Oct 21;210(1):1–13. doi: 10.1093/cei/uxac070. Elhaj MO, Richter AG, Goddard S, Shields AM. Dose reductions in immunoglobulin replacement are associated with increased antibiotic usage in patients with antibody deficiency. Br J Haematol. 2023 Aug;202(4):900–903. doi: 10.1111/bjh.18910. Spanish Ministry of Health, 1. Sistema Nacional para la Seguridad Transfusional. Informe 2019. Madrid: Ministerio de Sanidad; 2019. p. 3–15. Accessed 18th July 2024. Available from: https://www.sanidad.gob.es/profesionales/saludPublica/medicinaTransfusional/indicadores/docs/Informe_Actividad2019.pdf. Accessed on 16/07/2024. Rejas J, Sicras-Mainar A, Sicras-Navarro A, Lwoff N, Méndez C. All-cause community acquired pneumonia cost by age and risk in real-world conditions of care in Spain. Expert Rev Pharmacoecon Outcomes Res. 2022 Jul;22(5):853–867. doi: 10.1080/14737167.2022.2020649. Epub 2022 Jan 17. PMID: 34949148. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4800520","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":343268329,"identity":"896a6cff-49c2-4d0c-995e-f165966eb4b3","order_by":0,"name":"Pedro Moral Moral","email":"","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"Moral","lastName":"Moral","suffix":""},{"id":343268330,"identity":"d731bcec-eb23-4d99-85ef-0544f5dcb00a","order_by":1,"name":"Marta Dafne Cabanero-Navalon","email":"data:image/png;base64,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","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":true,"prefix":"","firstName":"Marta","middleName":"Dafne","lastName":"Cabanero-Navalon","suffix":""},{"id":343268331,"identity":"7b6d36f2-b53c-42f1-ae39-e4345f59a3e7","order_by":2,"name":"Paula López León","email":"","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Paula","middleName":"López","lastName":"León","suffix":""},{"id":343268333,"identity":"ee8cb012-88b5-4337-8a9c-fa241f269bcd","order_by":3,"name":"Héctor Balastegui-Martín","email":"","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Héctor","middleName":"","lastName":"Balastegui-Martín","suffix":""},{"id":343268334,"identity":"d5bcc7e1-85ec-48bb-97b8-c9c7a87bdcf2","order_by":4,"name":"Sandra Martínez Mercader","email":"","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Sandra","middleName":"Martínez","lastName":"Mercader","suffix":""},{"id":343268335,"identity":"22c4b50c-44f7-481d-b6a4-ca4152ce146d","order_by":5,"name":"Amparo Mir","email":"","orcid":"","institution":"University of Valencia","correspondingAuthor":false,"prefix":"","firstName":"Amparo","middleName":"","lastName":"Mir","suffix":""},{"id":343268336,"identity":"259c736d-f510-4498-adef-3c8825626c9c","order_by":6,"name":"Victor Garcia-Bustos","email":"","orcid":"","institution":"University and Polytechnic Hospital La Fe","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"","lastName":"Garcia-Bustos","suffix":""}],"badges":[],"createdAt":"2024-07-25 09:09:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4800520/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4800520/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63807247,"identity":"3b5f06bb-260a-4866-8c7b-e04174ce5717","added_by":"auto","created_at":"2024-09-02 13:41:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102878,"visible":true,"origin":"","legend":"\u003cp\u003eContingency plan for SCIg dose adjustment in PID patients during the COVID-19 pandemic in the Unit for Primary Immunodeficiencies from the University and Polytechnic Hospital La Fe\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4800520/v1/4b3b094c0791bcce5fe65466.jpg"},{"id":63807246,"identity":"c99e2107-bb06-40dc-86b7-70ebc7d1e50d","added_by":"auto","created_at":"2024-09-02 13:41:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24673,"visible":true,"origin":"","legend":"\u003cp\u003eIgG trough levels at baseline, 6- and 12-months follow up.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4800520/v1/ddf1f657a4af25633889cd38.jpg"},{"id":68392230,"identity":"3ca8f4af-87a5-456c-858c-af4d9ef97a58","added_by":"auto","created_at":"2024-11-06 20:01:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":665708,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4800520/v1/0e1dfc63-81d4-4ac3-8ac3-63aa5d4c2e15.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Infectious outcomes of a standardized subcutaneous immunoglobulin dose reduction strategy in primary immune deficiencies amid global shortage","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePrimary immunodeficiencies (PID) represent a heterogeneous group of diseases characterized by abnormalities in one or more components of the immune system. Humoral immunodeficiencies are the most frequent PID, constituting around 30\u0026ndash;70% of the total PIDs with specific defects involving a dysfunction or absence of B cell lymphocytes, with a consequently decrease in the production of immunoglobulins (Ig) that recognize specific antigens, facilitating their elimination [1] These patients mainly suffer from severe or recurrent infections [2], and some may suffer autoimmune and neoplastic complications due to immune dysregulation [3] which constitute, nowadays, constitutes its main cause of morbidity and mortality [4, 5].\u003c/p\u003e \u003cp\u003eImmunoglobulin replacement therapy (IgRT), administered either intravenously (IVIg) or subcutaneously (SCIg), is essential in managing humoral PIDs. It has been shown to reduce infection frequency and severity, decrease organ damage rates, and lower patient mortality [6, 7]. Both IVIg and SCIg have demonstrated similar efficacy levels, although SCIg is associated with fewer systemic adverse events, improved quality of life, and reduced costs [8, 9].\u003c/p\u003e \u003cp\u003eThe correlation between IgG trough levels and reduced infection rates is well stablished [10\u0026ndash;12]. Current clinical guidelines recommend an initial IgRT dose of 400\u0026ndash;600 mg/kg/month to achieve steady-state trough IgG levels of 600\u0026ndash;800 mg/dL [11, 13\u0026ndash;15]. However, there are no defined protocols to adjust subsequent dosing and defining the ideal IgRT dose for each patient remains a challenge, as individual biological thresholds vary [11, 16\u0026ndash;18]. In this regard, patients with bronchiectasis, interstitial lung disease (ILD), autoimmune cytopenias, and enteropathy, may require higher IgG trough levels [11, 16]. This necessitates careful dose optimization to avoid undertreatment, which increases infection risk, or overtreatment, especially regarding increasingly scarce availability of plasma-derived products, specifically Igs.\u003c/p\u003e \u003cp\u003eTaking advantage of the global shortage of Ig during the COVID-19 pandemic, the objective of this study was to retrospectively evaluate the impact of a standardized reduction in SCIg doses on infection rates and clinical outcomes in patients with PID who have maintained stable high IgG trough levels and have not experienced serious or recurrent infections. We aim to provide evidence in individualized dosing strategies that enhance patient care while addressing the challenges posed by the limited availability of plasma-derived products.\u003c/p\u003e"},{"header":"2. Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study design and inclusion criteria\u003c/h2\u003e \u003cp\u003eIn 2021, coinciding with a severe global shortage of Ig due to the COVID-19 pandemic, hospitals across Spain experienced a drastic reduction in their stock of SCIg. To address this exceptional situation, the Unit for Primary Immunodeficiencies from the University and Polytechnic Hospital La Fe, implemented a contingency plan from a clinical perspective, which consisted of (1) a thorough revision of the clinical indications for IgRT for each patient, and (2) a dose adjustment in the dose of SCIg in patients with PID who had stable clinical and analytical conditions. Thus, patients over 18 years who were receiving SCIg for at least 6 months, maintained IgG trough levels of 700 mg/dL or higher (or more than 900 mg/dL in those patients who had ILD, enteropathy with or without malabsorption, use of immunosuppressants in the last 6 months or presence of bronchiectasis), and had no significant infections in the past 6 months (defined as infections requiring hospitalization or three or more outpatient mild infections requiring antibiotics) were eligible for dose adjustment. All patients who met the dose adjustment criteria were given the option to either reduce their SCIg dose as previously mentioned or switch to IVIg at the same dose they were receiving subcutaneously (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAll patients were evaluated for these criteria in May 2021. Those who were eligible were proposed to reduce their SCIg regimen by 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL that their IgG trough levels exceeded 700 mg/dL (or 900 mg/dL in the mentioned cases) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For example, a 70 kg patient showing IgG trough levels of 1000 mg/dL and without relevant infections in the past 6 months, would have their dose reduced by 2 g per week or 8 g per month. One year after completing this clinical contingency plan, data were retrospectively collected to conduct the scientific study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Data collection and variables\u003c/h2\u003e \u003cp\u003eClinical data were obtained retrospectively from electronic medical records and recorded in a database. The demographic characteristics of each patient were documented, encompassing age, sex, age at onset of immunodeficiency symptoms, age at diagnosis, and specific PID diagnosis. The presence and type of infections prior to dose adjustment were recorded, categorizing them into major bacterial infections (pneumonia, meningitis, osteomyelitis, intra-abdominal infections, cellulitis or soft tissue infections, sepsis, or opportunistic infections) and recurrent infections (upper respiratory tract infections, lower respiratory tract infections, gastrointestinal infections, urinary tract infections, and soft tissue infections). Additionally, the average number of emergency visits and hospitalizations per year was documented. Non-infectious comorbidities including autoimmune cytopenias, lymphadenopathies, splenomegaly, hepatomegaly, and clinical or imaging findings of portal hypertension, systemic autoimmune disorders, lung, gastrointestinal, cutaneous, and neurological involvement, as well as malignancy (both solid and hematological neoplasia) were documented. The infectious processes that the patient suffered at 6 and 12 months after the dose adjustment were documented, including bacterial major and recurrent infections.\u003c/p\u003e \u003cp\u003eLaboratory variables including IgG trough levels (mg/dL), IgM (mg/dL), IgA (mg/dL), total number of leukocytes (cell/\u0026micro;L), neutrophils (cell/\u0026micro;L), CD3 cell count (cell/\u0026micro;L), CD4 cell count (cell/\u0026micro;L), CD8 cell count (cell/\u0026micro;L), CD4/CD8 ratio, CD19 cell count (cell/\u0026micro;L), and natural killers (NK) cell count (cell/\u0026micro;L) prior to dose adjustment, and at 6 and 12 months of follow-up were recorded. Regarding the treatment, the type of SCIg preparation (conventional ScIg 20% or hyaluronidase-facilitated ScIg 10%) and their brand, the SCIg dosage the patient received prior to adjustment, and the subsequent dosage after 6 and 12 months of follow-up were documented, as well as the immunosuppressant received therapy, if any.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis was conducted using the statistical software R, version 4.0.1. Continuous variables were described by their mean and standard deviation. Discrete variables were presented through the distribution of frequencies and percentages.\u003c/p\u003e \u003cp\u003eNormality was assessed by quantile-quantile QQ plots and the Shapiro-Wilk test. Comparisons between the parameters prior to the dose adjustment and after a 6- and 12-months follow-up period were made using the Cochran Q test for categorical variables and the Friedman test for quantitative variables. Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Ethics\u003c/h2\u003e \u003cp\u003e From an exclusively healthcare perspective, this dosage adjustment was conducted in a homogeneous and standardized manner at our Unit, following strict criteria established by a committee of experts, which consisted of an internist, a clinical immunologist, and a nurse with extensive experience in treating PID patients. All patients who met the dose adjustment criteria were given the option to either reduce their SCIg dose as previously mentioned or switch to IVIg at the same dose they were receiving subcutaneously. This study was approved by the University and Polytechnic Hospital La Fe Ethical Committee with the code \u0026ldquo;SUBDOSAGE\u0026rdquo;. The study was conducted in accordance with the Declaration of Helsinki and adhered to the STROBE guidelines. Anonymity and data confidentiality for all included patients were maintained in compliance with Spanish regulations governing observational studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Study population\u003c/h2\u003e \u003cp\u003eThirty-one patients with PID were included in the study. The mean age was 47.51 years (SD 15.47) with a near equal gender distribution: 16 females (51.61%) and 15 males (48.38%). Among the types of PID observed, 3 patients (9.67%) had IgG subclass deficiency, common variable immunodeficiency (CVID) was identified in 17 patients (54.83%), and 11 patients (35.48%) had other PID with hypogammaglobulinemia. More details are represented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of the included patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN (%) \u0026ndash; Mean (SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47.51 (15.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (51.61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (48.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHumoral primary immunodeficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIgG subclass deficiency\u003c/p\u003e \u003cp\u003eCommon variable immunodeficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.67)\u003c/p\u003e \u003cp\u003e17 (54.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWiskott-Aldrich syndrome\u003c/p\u003e \u003cp\u003eChronic mucocutaneous candidiasis\u003c/p\u003e \u003cp\u003eIgA and IgG subclass deficiency\u003c/p\u003e \u003cp\u003eGood syndrome\u003c/p\u003e \u003cp\u003eDi George syndrome\u003c/p\u003e \u003cp\u003eBloom syndrome\u003c/p\u003e \u003cp\u003eNot well defined hypogammaglobulinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytopenias\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (19.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLymphadenopathies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSplenomegaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInterstitial lung disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (38.70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEnteropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (19.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeurological affectation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (3.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAutoimmune systemic disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (22.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSolid malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6.45)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHematological malignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding their clinical comorbidity, cytopenias were noted in 6 patients (19.35%), lymphadenopathies were present in 5 patients (16.12%), and splenomegaly in 1 patient (3.22%). ILD and neurological affectation were each observed in 1 patient (3.22%). Bronchiectasis was a common comorbidity, affecting 12 patients (38.70%), and 6 patients (19.35%) showed enteropathy. Additionally, 7 patients (22.58%) had autoimmune systemic diseases, and 5 patients of the study had a diagnose of neoplasia: 2 patients (6.45%) had solid malignancies, and 3 patients (9.67%) had haematological malignancies (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients were screened for the use of immunosuppressants before and after the dose adjustment. At baseline, 5 patients were receiving corticosteroids, 1 patient was receiving tacrolimus, and 1 patient was receiving rituximab. At 12 months follow-up, corticosteroid use increased to 6 patients, rituximab and tacrolimus remained unchanged to 1 patient each, and 1 patient started receiving azathioprine.\u003c/p\u003e \u003cp\u003eAdditionally, 9 patients (29%) were receiving prophylactic antibiotics at baseline, which non-significantly increased to 10 patients (32.3%) at both the 6-month and 12-month follow-ups (p\u0026thinsp;=\u0026thinsp;0.82). Among these patients, 3 who were not previously on prophylactic antibiotics initiated the regimen, while 2 patients who had been on treatment for the prior 6 months discontinued it (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). None of the patients who initiated had presented major bacterial infections.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eProphylactic antibiotic treatment of our cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore dose adjustment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6-month follow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12-month follow-up\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzithromycin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCotrimoxazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAzithromycin, cotrimoxazole and inhaled colistin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRifaximin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCiprofloxacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Dose adjustment\u003c/h2\u003e \u003cp\u003eThe mean dose of SCIg before the dose adjustment was 7.82 g/week (SD 2.29). The mean dose reduction was 2.10 g/week (SD 1.18). Consequently, the new mean dose at time 0 was 5.72 g/week (SD 1.71). In addition, at 12 months, several dose-adjustments were made: 4 dose escalations (including the patient whose dose was reduced at 6 months) and 1 dose reduction. As so, at 12 months of follow-up, the average SCIg dose was 6.94 g/week (SD 1.91).\u003c/p\u003e \u003cp\u003eSpecifically, these dose adjustments were made as follows: one patient with CVID had their dose reduced from 8.3 g/week to 5 g/week, further reduced to 3.75 g/week at 6 months, and then increased to 6.7 g/week at 12 months due to two minor infections. Another CVID patient with renal transplantation had their dose reduced from 8 g/week to 5 g/week, then increased to 8.3 g/week at 12 months due to an increase in BK virus load. A CVID patient with multiple myeloma had her dose reduced from 8 g/week to 7 g/week, then increased back to 8 g/week at 12 months due to a minor infection. A patient with primary non-defined hypogammaglobulinemia and severe asthma had their dose reduced from 7 g/week to 5 g/week, then increased to 6.7 g/week at 12 months due to the development of a pneumonia. Finally, one patient had an initial dose reduction from 10 g/week to 6.7 g/week, further reduced to 5 g/week at 12 months, without any subsequent infections.\u003c/p\u003e \u003cp\u003eThe data on the type of SCIg and the administration frequency at time 0, as well as the changes in the type of SCIg and administration frequency after the dose adjustment, are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData on the type of SCIg and administration frequency at time 0, and changes after dose adjustment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFrequency (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of ScIg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScIg 20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e61.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHyaluronidase-facilitated ScIg 10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrequency of administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 2 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 3 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEvery 4 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeekly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e45.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange in the type of ScIg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96.77\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (changed to Hyaluronidase-facilitated ScIg 10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange in the frequency of administration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e80.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Presence of infections before and after dose adjustment\u003c/h2\u003e \u003cp\u003eThere was no significant difference in the mean number of severe major infections and recurrent infections before dose adjustment, at 6-months follow-up and at 12 months follow-up (p\u0026thinsp;=\u0026thinsp;0.220 and p\u0026thinsp;=\u0026thinsp;0.107, respectively).\u003c/p\u003e \u003cp\u003eHowever, regarding major infections, there were none in the 6 months prior to dose adjustment, 2 in the 6 months after dose-adjustment, and 1 between 6- and 12-months follow-up in the whole cohort. All of these were community-acquired pneumonias, and at 12 months, the dose was increased for the patient who had experienced 2 pneumonias within 12 months follow-up. The percentage of patients who suffered severe infections at the three time points was also not statistically significant (p\u0026thinsp;=\u0026thinsp;0.223). There were no cases of other major infections such as meningitis, osteomyelitis, cellulitis, sepsis, UTIs requiring hospitalization, opportunistic infections.\u003c/p\u003e \u003cp\u003eNo patient experienced more than 3 mild infections in any 6-month follow-up period. Additionally, the percentage of patients who suffered mild infections at the 6-month and 12-month follow-ups after dose adjustment was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.109). Regarding these mild infections, during before the dose adjustment, 3 patients experienced 1 mild infection, and 1 patient experienced 2 mild infections. In the first 6 months post-adjustment, 6 patients had 1 mild infection, and 3 patients had 2 mild infections. Between 6- and 12-months post-adjustment, 10 patients had 1 mild infection, and 1 patient had 2 mild infections. No patient experienced 3 or more mild infections (i.e., recurrent infections) in any 6-month period.\u003c/p\u003e \u003cp\u003eAmong these mild infections, one patient had a mild gastrointestinal infection at each time point. For lower respiratory tract infections, there was only 1 case before the dose adjustment, compared to 2 cases at 6 months and another 2 cases between 6 and 12 months. There were several cases of mild skin and soft tissue infections: 1 case before the dose adjustment, 3 cases at 6 months, and 2 cases between 6- and 12-months follow-up. Two episodes of mild upper respiratory tract infections were recorded: none in the pre-adjustment period, with 1 case each at 6 months and between 6 and 12 months. There was only 1 case of a mild urinary tract infection, which occurred in a patient during the 6 months post-adjustment period. No cases of mild parasitic infections were observed (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean and standard deviation of all infections recorded before dose adjustment, and at 6 months and 12 months follow-up\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore dose adjustment (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 months follow-up (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6\u0026ndash;12 months follow-up (Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.065\u0026thinsp;\u0026plusmn;\u0026thinsp;0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.032\u0026thinsp;\u0026plusmn;\u0026thinsp;0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.067\u0026thinsp;\u0026plusmn;\u0026thinsp;0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeningitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsteomyelitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere abdominal infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere skin and soft tissue infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere urinary tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpportunistic infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrent infection (more than 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-severe infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.161\u0026thinsp;\u0026plusmn;\u0026thinsp;0.454\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.387\u0026thinsp;\u0026plusmn;\u0026thinsp;0.667\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.387\u0026thinsp;\u0026plusmn;\u0026thinsp;0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild upper respiratory tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.065\u0026thinsp;\u0026plusmn;\u0026thinsp;0.250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.200\u0026thinsp;\u0026plusmn;\u0026thinsp;0.484\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.233\u0026thinsp;\u0026plusmn;\u0026thinsp;0.504\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild lower respiratory tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.032\u0026thinsp;\u0026plusmn;\u0026thinsp;0.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.067\u0026thinsp;\u0026plusmn;\u0026thinsp;0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.067\u0026thinsp;\u0026plusmn;\u0026thinsp;0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild gastrointestinal infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.032\u0026thinsp;\u0026plusmn;\u0026thinsp;0.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild urinary tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParasitosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild skin and soft tissue infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.032\u0026thinsp;\u0026plusmn;\u0026thinsp;0.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.100\u0026thinsp;\u0026plusmn;\u0026thinsp;0.305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.067\u0026thinsp;\u0026plusmn;\u0026thinsp;0.254\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Analysis of immunological parameters\u003c/h2\u003e \u003cp\u003eAfter the dose adjustment, a statistically but not clinically significant difference was observed in the trough levels of IgG across the different time points in follow-up: 1,138.48 (SD 294.25) at baseline, 947.35 (SD 306.69) 6-months post-adjustment, and 983.28 (SD 310.51) at 12-months post-adjustment (p\u0026thinsp;=\u0026thinsp;0.002), with the lowest IgG trough levels recorded at 6 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This implies a mean reduction of 15.21% of the previous IgG trough levels. However, this difference was not clinically relevant in the number of severe and recurrent infections. Mean total leukocyte counts were 6288.71 (SD 1752.84), 7037.24 (SD 1887.27), and 6662.50 (SD 2171.55) cells/\u0026micro;L at baseline, 6 months, and 12 months, respectively. Baseline mean CD4, CD8, and NK cell counts were 846.72 (SD 490.69), 510.03 (SD 292.55), and 245.10 (SD 201.99) cells/\u0026micro;L, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Pharmacoeconomic analysis\u003c/h2\u003e \u003cp\u003eIn our study, a standardized dose reduction of Igs was implemented for a total of 31 patients with PID, maintained for at least one year. The average dose reduction was 2.09 g/week (SD 1.17) resulting in an average annual savings of 100.3 g per patient. For the entire cohort of 31 patients, this equated to an annual savings of approximately 3109.3 g. From a pharmacoeconomic perspective, using the reference price of 55.5 euros/g as established by the Spanish Ministry of Health, this translates to an average savings of 5,550 euros per patient per year, and a total annual savings of 172,050 euros for our cohort [19].\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe main findings of this study can be summarized as follows: (i) The implementation of a careful, clinically tailored and standardized dose reduction SCIg therapy in patients with PIDs was successfully maintained over an extended period without an increase in severe or recurrent infections, and (ii) individualized SCIg dose reduction could be a safe and cost-effective approach to managing PIDs, especially in contexts where plasma-derived products are scarce. These results highlight the potential of personalized dosing strategies to optimize patient care and resource utilization effectively.\u003c/p\u003e \u003cp\u003eIgRT is essential for managing PIDs with hypogammaglobulinemia, as it significantly reduces the frequency and severity of infections, mitigates organ damage, and decreases mortality [7, 11]. It is well established that higher doses of immunoglobulins correlate with increased serum IgG levels and reduced infection rates, regardless of the administration route [11, 16]. However, there is no universally defined protective IgG level. Most practice guidelines recommend maintaining trough IgG levels between 600 and 800 mg/dL, achieved by administering 400 mg/kg every 3 to 4 weeks [6, 14, 15]. This recommendation is largely based on expert opinions and systematic reviews of limited data. Consequently, dose optimization is usually guided by the so-called \"minimum biological trough levels,\" which represent the specific IgG concentration required to prevent infections in each patient [17, 18]. The variability in individual IgG thresholds implies that some patients might be under-treated, increasing their risk of infections, while others could be over-treated, leading to inefficient use of IgRT.\u003c/p\u003e \u003cp\u003eThe British Society for Immunology and the UK Primary Immunodeficiency Network (UKPIN) recommend initial trough IgG levels above 800 mg/dL for PID patients, with potential optimization to 1000 mg/dL for those with X-linked agammaglobulinemia, established organ damage, or persistent infections [20]. Nevertheless, this recommendation lacks a dose reduction protocol.\u003c/p\u003e \u003cp\u003eIn this regard, Elhaj et al. reduced IgRT doses for 61 patients, 48 of whom had humoral PID, during the COVID-19 Ig shortage. This reduction was applied to patients with IgG trough levels above 800 mg/dL, provided their condition was clinically stable [21]. In this study, the dose reduction group had significantly higher baseline trough levels compared to controls (1050 mg/dL vs. 820 mg/dL). After dose reduction, trough IgG levels in the reduction group decreased to 860 mg/dL, comparable to the control group (890 mg/dL). In our study, baseline trough levels were higher (1130 mg/dL), decreasing to 940 mg/dL at six months and 980 mg/dL at twelve months. The reduction magnitude was similar to the British study (-190 mg/dL vs. -150 mg/dL). However, in their study, breakthrough infections and the need for antibiotics occurred 1.55 times more frequently in the reduced dose group compared to controls, with a significant increase in antibiotic use post-IgRT dose reduction. In contrast, our study found no significant differences in infection rates before and after dose reduction, regardless of prophylactic antibiotic use.\u003c/p\u003e \u003cp\u003eThis discrepancy could be attributed to our patients having higher absolute trough IgG levels and the strict inclusion of PID patients. Contrarily, the study by Elhaj et al. included secondary immunodeficiency patients, who may have additional immunosuppressive factors necessitating prophylactic antibiotic use for infection prevention. Additionally, dose reduction was not individualized based on clinical factors (e.g., organ damage, comorbidities), but rather applied uniformly. This approach may have led to inappropriate patient selection and inadequate dose reductions, either by including patients who were not properly adjusted or by reducing doses excessively in particularly vulnerable patients.\u003c/p\u003e \u003cp\u003eIgRT has complex production processes and relies on plasma donations, making it a scarce and valuable resource. Spain, in particular, faces vulnerability with low plasma self-sufficiency (34%) and heavy reliance on importation [22]. Recent measures, such as use optimization plans and plasma donation campaigns, have shown limited effectiveness. In our study, we carefully selected candidates for Ig dose reduction, including only PID patients with IgG trough levels\u0026thinsp;\u0026ge;\u0026thinsp;700 mg/dL and no significant infections in the past six months. For patients with GLILD, inflammatory enteropathy, recent immunosuppressant use, or bronchiectasis, trough levels\u0026thinsp;\u0026ge;\u0026thinsp;900 mg/dL were required, with decisions made by a clinical expert committee. Our study demonstrates that standardized Ig dose reduction in well-controlled PID patients can conserve Ig resources without compromising patient safety. This approach could significantly improve resource management and offer a potential solution to the Ig supply challenge. The total annual savings in our experience amounted to 172,050 euros for the Spanish National Health System, substantially exceeding the estimated direct costs of inpatient and outpatient breakthrough infections such as pneumonia, which are estimated at 3,955 euros for hospital admission and 511 euros for outpatient management in our setting [23].\u003c/p\u003e \u003cp\u003eHowever, this study is not exempt from limitations. Firstly, this is a retrospective observational study based on data analysis following the implementation of a contingency plan, designed from a primarily clinical perspective during the exceptional context of the 2021 Ig shortage crisis among COVID-19 pandemic. Secondly, the study included only patients with PIDs, making it difficult to extrapolate the results to patients with secondary immunodeficiencies, as these conditions involve additional iatrogenic non-humoral factors that could significantly influence infection rates. Additionally, the sample size was small, and the study lacks a control group, as all patients offered dose reduction accepted it. Finally, the analysis included only patients receiving SCIg, making it difficult to extrapolate the results to patients receiving IVIg, showing different pharmacokinetic profiles that could lead to different outcomes in IgG trough levels and infection rates following dose reduction.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study suggests that dose optimization of SCIg in patients with PIDs requiring IgRT is feasible without increasing the rate of severe or recurrent infections, provided certain clinical conditions are met: specifically, a meticulous selection of candidate patients and a standardized, proportional reduction of doses based on IgG trough levels. Candidates for dose reduction should have maintained stable IgG trough levels of at least 700 mg/dL, or 900 mg/dL for those with GLILD, inflammatory enteropathy, recent use of immunosuppressants, or bronchiectasis, and should not have experienced severe or recurrent infections in the past six months. Once selected, the dose reduction should be standardized, reducing 60 mg/kg/month (15 mg/kg/week) for every 150 mg/dL above the target trough levels of 700 mg/dL or 900 mg/dL. This approach appears effective for optimizing SCIg dosing in PID patients, significantly contributing to the preservation of this scarce and valuable resource. Prospective studies with a higher number of patients are needed to confirm the utility of this reduction strategy, not only in PID patients but also in secondary immunodeficiency patients, and to evaluate different formulations and routes of administration.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the European Society for Immunodeficiencies (ESID) for their support to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePMM conceived the original idea for the manuscript. VGB performed the statistical analysis. MDCN and VGB contributed significantly to the drafting of the manuscript. PLL, HBM, SMM, and AM all played crucial roles in the review of the manuscript and the literature. VGS supervised the work. All authors reviewed the manuscript and provided substantial contributions to the literature review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding has been required for the development of this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of Conflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eCunningham-Rundles C. Human B cell defects in perspective. Immunol Res. 2012 Dec;54(1\u0026ndash;3):227\u0026thinsp;\u0026minus;\u0026thinsp;32. doi: 10.1007/s12026-012-8318-2.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eArkwright PD, Gennery AR. 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PMID: 34949148.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immunoglobulin replacement therapy, humoral primary immune deficiencies, subcutaneous immunoglobulin, infections, cost-effectiveness, resource shortage","lastPublishedDoi":"10.21203/rs.3.rs-4800520/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4800520/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eImmunoglobulin replacement therapy (IgRT), either intravenous (IVIg) or subcutaneous (SCIg), is crucial for managing primary immune deficiencies (PIDs) with hypogammaglobulinemia by reducing infection rates and mortality. During the COVID-19 pandemic, a global shortage of SCIg prompted our unit to reduce SCIg doses or maintain the same dose intravenously. This study evaluates the impact of a standardized SCIg dose reduction on infection rates and clinical outcomes in patients with PID. Adult PID patients on SCIg for at least 6 months, with IgG trough levels\u0026thinsp;\u0026ge;\u0026thinsp;700 mg/dL (or \u0026ge;\u0026thinsp;900 mg/dL under specific conditions), and no significant infections in the past 6 months were eligible. A dose reduction of 15 mg/kg/week (60 mg/kg/month) for every 150 mg/dL above 700 mg/dL (or 900 mg/dL) was proposed. Clinical and laboratory data, and infectious events at 6- and 12-month follow-ups, were analyzed. Thirty-one patients with PID were included: common variable immunodeficiency (54.83%), IgG subclass deficiency (9.67%), and other PIDs (35.48%). The average SCIg dose was initially reduced from 7.82 g/week to 5.72 g/week and adjusted to 6.94 g/week at 12 months. There was no significant change in severe or recurrent infections before and at 6- and 12-months post-dose adjustment. The dose reduction saved an average of 5,550 euros per patient annually, totaling 172,050 euros annually for our cohort. Thus, optimizing SCIg doses in selected PIDs is feasible without increasing infection rates, conserving this plasma-derived product during shortages. Larger prospective studies are needed to confirm this strategy's utility and its application to other Ig formulations.\u003c/p\u003e","manuscriptTitle":"Infectious outcomes of a standardized subcutaneous immunoglobulin dose reduction strategy in primary immune deficiencies amid global shortage","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-02 13:41:30","doi":"10.21203/rs.3.rs-4800520/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4342bcfe-4918-43fb-94cd-f3cceb1f8665","owner":[],"postedDate":"September 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-06T19:53:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-02 13:41:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4800520","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4800520","identity":"rs-4800520","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}