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Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged ≥ 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged ≥ 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5-11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer ≥ 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

Background: Personalized medicine requires the assessment of the impact of health care interventions on Health-Related Quality of Life. Research design and methods: We run an observational study of HRQoL in 140 CVID patients with biannual assessments over 8 years using a disease-specific tool, the CVID_QoL, and the GHQ questionnaires. Factors influencing changes in HRQoL scores were identified using multiple linear regression models with a stepwise procedure. Results: Infections frequency, female gender, and chronic enteropathy were associated with worse global CVID_QoL scores. The presence of permanent organ damage and older age contributed to the perception of being at risk of health deterioration, while chronic enteropathy was associated with fatigue. The presence of permanent organ damage was also associated with perceived difficulties in usual activities. The frequency of infections was the main risk factor for difficulties in long-term planning and perceptions of vulnerability. Before COVID-19, improved HRQoL scores were associated with reduced respiratory infections and changes in immunoglobulin replacement route and setting. The COVID-19 pandemic caused a sudden deterioration in all HRQoL dimensions, and a further deterioration in the emotional dimension was observed during the pandemic period. Patients who died during the study had worse CVID_QoL scores at all time points, confirming that HRQoL performance is strongly related to patient outcome. Conclusions: Periodic HRQoL assessments are needed to capture relevant issues that change over time in patients affected by long-term chronic conditions such CVID, possibly identifying areas of intervention. [ABSTRACT FROM AUTHOR]

Purpose: The COVID-19 pandemic has impacted on how health services deliver care and the mental health of the population. Due to their clinical vulnerability, to reduce in-hospital attendances during the COVID-19 pandemic, modifications in immunoglobulin treatment regimens were made for patients with antibody deficiency. These patients were also likely to experience social isolation due to shielding measure that were advised. We aimed to investigate the impact of modifying immunoglobulin treatment regimen on infection and mental health burden during shielding restrictions. Method: Patients on immunoglobulin replacement therapy (IGRT) responded to a standardised questionnaire examining self-reported infection frequency, anxiety (GAD-7), depression (PHQ-8), fatigue (FACIT), and quality of life during the pandemic. Infection frequency and immunoglobulin trough levels were compared to pre-pandemic levels. Results: Patients who did not change treatment modality or those who received immunoglobulin replacement at home during the pandemic reported fewer infections. In patients who received less frequent hospital infusions, there was no significant increase in infections whilst immunoglobulin trough levels remained stable. There was no significant difference in anxiety, or depression scores between the treatment modality groups. Patients reported higher fatigue scores compared to the pre-COVID general population and in those discharged following hospitalisation for COVID. Conclusion: Changing immunoglobulin treatment regimen did not negatively impact infection rates or psychological wellbeing. However, psychological welfare should be prioritised for this group particularly given uncertainties around COVID-19 vaccination responsiveness and continued social isolation for many. [ABSTRACT FROM AUTHOR]

Abstract Secondary immunodeficiency (SID), manifesting as increased susceptibility to infection, is an emergent clinical problem in haematoncology. Management of SID includes vaccination, prophylactic antibiotics (pAbx) and immunoglobulin replacement therapy (IgRT). We report clinical and laboratory parameters of 75 individuals, treated for haematological malignancy, who were referred for immunological assessment due to recurrent infections. Forty‐five were managed with pAbx while thirty required IgRT after failing to improve on pAbx. Individuals requiring IgRT had significantly more bacterial, viral and fungal infections resulting in hospitalization at least 5 years after their original haemato‐oncological diagnosis. Following immunological assessment and intervention, a 4.39‐fold reduction in the frequency of hospital admissions to treat infection was observed in the IgRT cohort and a 2.30‐fold reduction in the pAbx cohort. Significant reductions in outpatient antibiotic use were also observed in both cohorts following immunology input. Patients requiring IgRT were more hypogammaglobulinaemic and had lower titres of pathogen‐specific antibodies and smaller memory B cell populations than those requiring pAbx. Test vaccination with pneumococcal conjugate vaccine discriminated poorly between the two groups. Patients requiring IgRT could be distinguished by combining wider pathogen‐specific serology with a frequency of hospital admissions for infection. If validated in larger cohorts, this approach may circumvent the need for test vaccination and enhance patient selection for IgRT.

Acquired hypogammaglobulinemia or secondary immunodeficiency (SID) occurs commonly in hematological malignancies with increasing incidence and complexity in the era of modern therapies. Despite current practice of immunoglobulin replacement (IgRT) in SID, the evidence is lacking, especially for newer treatments. We discuss the current evidence for IgRT in various disease groups including issues, such as actual or ideal body weight (IBW)-based dosing, length of treatment, antibiotic prophylaxis, and vaccination. Incidence of SID with newer treatment is lacking. While there is a trend toward decreased respiratory infections and hospitalizations with IgRT, this is not consistent across all disease course or treatment groups. Dosing and indications for cessation of IgRT are also inadequately characterized. Further randomized controlled trials (RCTs) and observational studies are required to assess the optimal indications, timing, and duration of IgRT to improve the efficacy, safety, and cost-effectiveness. Assessment of alternative and adjunctive therapies, such as vaccination and antibiotic prophylaxis could also improve the outcomes and costs. [ABSTRACT FROM AUTHOR]

Abstract Introduction In patients with common variable immunodeficiency (CVID), immunological response is compromised. Knowledge about COVID‐19 in CVID patients is sparse. We, here, synthesize current research addressing the level of threat COVID‐19 poses to CVID patients and the best‐known treatments. Method Review of 14 publications. Results The number of CVID patients with moderate to severe (~29%) and critical infection courses (~10%), and the number of fatal cases (~13%), are increased compared to the general picture of COVID‐19 infection. However, this might be an overestimate. Systematic cohort‐wide studies are lacking, and asymptomatic or mild cases among CVID patients occur that can easily remain unnoticed. Regular immunoglobulin replacement therapy was administered in almost all patients, potentially explaining why the numbers of critical and fatal cases were not higher. In addition, the application of convalescent plasma was demonstrated to have positive effects. Conclusions COVID‐19 poses an elevated threat to CVID patients. However, only systematic studies can provide robust information on the extent of this threat. Regular immunoglobulin replacement therapy is beneficial to combat COVID‐19 in CVID patients, and best treatment after infection includes the use of convalescent plasma in addition to common medication.

Inborn errors of immunity occur in 1 in 1000 to 1 in 5000 individuals and are characterized by immune deficiency and immune dysregulation. The primary care provider (PCP) should be familiar with key features of these diagnoses including recurrent and/or severe infections, hyperinflammation, malignancy, and autoimmunity and have a low threshold to refer for evaluation. The PCP can begin a laboratory evaluation before referral by sending a complete blood count (CBC) with differential, antibody levels, vaccine titers, and possibly other tests. Management approaches vary from antibiotic prophylaxis to hematopoietic stem cell transplantation depending on the specific diagnosis., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Although antibody deficiency (AD) is a well-known cause of recurrent respiratory infections, there are few data on its impact in adults with asthma. The objective of the present study was to assess outcomes in adults with severe asthma and AD after treatment with either azithromycin or subcutaneous immunoglobulins (SCIg). We performed a 5-year, prospective, observational, two-centre study of adults with severe asthma and AD in France. Bronchiectasis was ruled out by high-resolution computed tomography. Patients were treated for one year with either azithromycin (250 mg every other day) or SCIg (0.4–0.6 g/kg/months, weekly). All patients were evaluated for exacerbations, asthma control and lung function at baseline and then one year after treatment initiation. Thirty-nine patients with severe asthma were included in the study: 14 had been treated with azithromycin and 25 had been treated with SCIg. Before the initiation of treatment for AD, all patients had an Asthma Control Questionnaire (ACQ-7) score > 1.5 (mean ± SD: 2.71 ± 0.53) despite treatment at GINA step 4 or 5, and had a high exacerbation rate requiring oral corticosteroids and/or rescue antibiotics (∼7.2 ± 2.1/patient/year). One year after treatment initiation, we observed a significantly higher FEV1 (mean: 0.18 ± 0.22 L) and ACQ-7 score (1.26 ± 0.68), and a significantly lower exacerbation rate (1.63 ± 1.24/patient/year). Treatment of AD dramatically improved asthma outcomes - suggesting that adults with severe asthma and recurrent respiratory infections should be screened and (if appropriate) treated for AD. Image 1 [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T cell therapy targeting CD-19 has revolutionized the treatment of refractory B-cell malignancies. However, patients undergoing this therapy face an increased risk of infections due to compromised immune function, lymphodepleting chemotherapy, hospitalization, and therapy-related complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Patients with systemic corticosteroid use, low immunoglobulin levels, and severe CRS, are at higher risk of infection. This review article highlights the spectrum of infections encountered in CAR T cell therapy, including bacterial, viral, and fungal infections. Following consensus guidelines for vaccination and immunoglobulin replacement is recommended. Clear criteria for antibiotic usage and vaccinating household members against respiratory viruses are crucial. Understanding the risk factors, spectrum of infections, and implementing appropriate prophylactic measures are essential to optimize outcomes in patients undergoing CAR T cell therapy. By prioritizing infection prevention strategies, healthcare professionals can effectively improve patient care. [ABSTRACT FROM AUTHOR]

Introduction: In patients with common variable immunodeficiency (CVID), immunological response is compromised. Knowledge about COVID‐19 in CVID patients is sparse. We, here, synthesize current research addressing the level of threat COVID‐19 poses to CVID patients and the best‐known treatments. Method: Review of 14 publications. Results: The number of CVID patients with moderate to severe (~29%) and critical infection courses (~10%), and the number of fatal cases (~13%), are increased compared to the general picture of COVID‐19 infection. However, this might be an overestimate. Systematic cohort‐wide studies are lacking, and asymptomatic or mild cases among CVID patients occur that can easily remain unnoticed. Regular immunoglobulin replacement therapy was administered in almost all patients, potentially explaining why the numbers of critical and fatal cases were not higher. In addition, the application of convalescent plasma was demonstrated to have positive effects. Conclusions: COVID‐19 poses an elevated threat to CVID patients. However, only systematic studies can provide robust information on the extent of this threat. Regular immunoglobulin replacement therapy is beneficial to combat COVID‐19 in CVID patients, and best treatment after infection includes the use of convalescent plasma in addition to common medication. [ABSTRACT FROM AUTHOR]

Background: Acquired hypogammaglobulinaemia secondary to haematological malignancies is associated with increased infection risk. Immunoglobulin (Ig) replacement reduces major infections but not mortality, and is costly. No prospective randomised trials have compared Ig replacement with prophylactic antibiotics. Aims: To identify variation in current practice regarding management of secondary hypogammaglobulinaemia in Australia and New Zealand, to identify barriers to best practice, and to inform the development of a clinical trial assessing antibiotic prophylaxis in secondary hypogammaglobulinaemia. Methods: We conducted an online survey of current clinical practice regarding management of secondary hypogammaglobulinaemia among haematologists in Australia and New Zealand. Results: Seventy‐two haematologists responded; 89% of whom reported commencing Ig replacement for secondary hypogammaglobulinaemia in the setting of recurrent or severe infection. Most monitored trough immunoglobulin G levels, most often 3 monthly. Criteria for stopping Ig replacement varied. Most respondents recommended influenza and pneumococcal vaccination, while only 21% reported using antibiotic prophylaxis. Few respondents (3%) reported prescribing prophylactic antibiotics before commencing Ig replacement. Most reported an interest in recruiting patients to a clinical trial comparing Ig replacement with prophylactic antibiotics. Conclusion: In comparison to limited international data, this survey finds variation in practice, which may be due to differences in local policies governing access to Ig. These findings highlight the need for research into the indications for Ig commencement and cessation, and will inform design of prospective trials of infection prevention in secondary hypogammaglobulinaemia. [ABSTRACT FROM AUTHOR]

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach ( Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT). [ABSTRACT FROM AUTHOR]

Background: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled.Methods: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers.Results: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 μg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months.Conclusions: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin (Ig) replacement therapy is used for treating a variety of primary immunodeficiency diseases (PIDs). Ig replacement therapy is the most important therapy for these diseases, since it protects the body against infections and reduces autoimmune disease symptoms. The purpose of this research was to estimate the cost of subcutaneous and intravenous Ig therapy in Iran. Methods: This study is carried out from the perspective of Iran’s healthcare system and all the medical costs are calculated. Cost variables include personnel, equipment, and supplies. The data required for cost estimation are obtained from the records of children’s Medical center of Tehran for 2015. Personnel and medical treatment costs are calculated based on relative value units. For SCIg, cost items are extracted from the literature. Results: The total cost of IVIg and SCIg for the health system in the first year of treatment is $1370 and $121 respectively. The results indicate that SCIg reduces costs and is the preferred treatment for PID patients. Conclusions: SCIg therapy significantly reduces the costs of the healthcare system compared to IVIg therapy, and this is enough economic justification for introduction of this treatment in the Iranian healthcare system. SCIg is also critical in reducing the direct costs of patients. [ABSTRACT FROM AUTHOR]

Purpose: The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG-specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA. Methods: We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls ( n = 22), patients previously diagnosed with a primary immunodeficiency ( n = 30), and patients referred for possible humoral immune deficiency ( n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy. Results: Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients ( n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin. Conclusion: This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity occur in 1 in 1000 to 1 in 5000 individuals and are characterized by immune deficiency and immune dysregulation. The primary care provider (PCP) should be familiar with key features of these diagnoses including recurrent and/or severe infections, hyperinflammation, malignancy, and autoimmunity and have a low threshold to refer for evaluation. The PCP can begin a laboratory evaluation before referral by sending a complete blood count (CBC) with differential, antibody levels, vaccine titers, and possibly other tests. Management approaches vary from antibiotic prophylaxis to hematopoietic stem cell transplantation depending on the specific diagnosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: In primary immunodeficiency (PID), immunoglobulin replacement therapy (IgRT) for infection prevention is well-established and supported by a wealth of clinical data. On the contrary, very little evidence-based data is available on the challenges surrounding the use of IgRT in secondary immune deficiencies (SID), and most published guidelines are mere extrapolations from the experience in PID. Areas covered: In this article, four European experts provide their consolidated opinion on open questions surrounding the prophylactic use of IgRT in SID, based on their clinical experience. The main topics are IgRT initiation, route of administration, dose optimization, and therapy discontinuation. The authors hope this discussion will be of assistance to practicing physicians in their daily decision-making. Expert commentary: Although growing experience indicates that IgRT could play an important role in the management of SID, very little robust evidence is available to guide clinical practice. The authors stress the urgent need for new studies in the field and discuss points they find of importance to design them adequately. [ABSTRACT FROM PUBLISHER]

The number of patients with secondary immune deficiencies (SID) is on the rise, mostly since the arrival on the market of novel targeted therapies that have increased the survival rates of patients with hematological malignancies. The recent changes in the SID landscape have brought with them new and diverse medical needs that treatments for SID management should strive to meet. In this special report, we study the opportunities provided by facilitated subcutaneous immunoglobulin administration (fSCIg) to treat patients for whom the conventional routes (intravenous and subcutaneous) are sub-optimal. Experts in the treatment of SID describe real-life cases from their daily practice, in which fSCIg has led to reducing the burden of treatment and increasing the treatment satisfaction. [ABSTRACT FROM PUBLISHER]

Chronic rhinosinusitis (CRS) is estimated to affect over 35 million people. However, not all patients with the diagnosis respond to standard medical and surgical treatments. Although there are a variety of reasons a patient may be refractory to therapy, one possible etiology is the presence of an underlying immunodeficiency. This review will focus on the description, recognition, and treatment of several antibody deficiencies associated with CRS, including common variable immunodeficiency (CVID), selective IgA deficiency, IgG subclass deficiency, and specific antibody deficiency (SAD). The diagnosis of antibody deficiency in patients with CRS is important because of the large clinical implications it can have on sinus disease management. CVID is treated with immunoglobulin replacement, whereas SAD may be managed symptomatically and sometimes with prophylactic antibiotics and/or immunoglobulin replacement. [ABSTRACT FROM AUTHOR]

Background: Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and iymphoproliferative disorders. Objective: This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe. Methods: Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively. Results: Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections. Conclusion: Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome. [ABSTRACT FROM AUTHOR]

This Current perspectives article will review and highlight the importance of accurate diagnosis of patients who have failed to produce specific antibodies to naturally encountered foreign proteins or polysaccharides or after vaccination and the appropriate institution of immunoglobulin replacement therapy. The field of primary immunodeficiency disease (PIDD) has expanded remarkably since the early descriptions 6 decades ago. With greater recognition and advanced cellular and molecular diagnostic technology, new entities and single-gene defects in patients with PIDD are rapidly being defined. This, combined with treatment advances and newborn screening for severe combined immunodeficiency, has resulted in improved outcomes and survival and even permanent cures. Awareness of PIDD has also increased, but the guidelines for recognition remain to be validated. The zeal for registering and enrolling patients has potentially created a large body of “patients” treated with immunoglobulin replacement unnecessarily. The complexity, diversity, and availability of laboratory testing have brought awareness of PIDD to the forefront, but because of an absence of standardization of certain assays, concerns about the correct diagnosis and appropriate treatment have increased. We hope to refocus the discussion on identifying clear laboratory and clinical guidelines for the establishment of an accurate diagnosis of antibody deficiency, its rationale, and, where indicated, institution of safe treatment. [Copyright &y& Elsevier]

Abstract: Primary Immunodeficiencies (PID) although rare are serious; diagnosis is often delayed due to their non-specific presentation. Heightened clinical suspicion leads to earlier diagnosis and improved outcome. Historically fatal in early childhood recent advances in diagnosis and management mean much improved mortality and morbidity. Antimicrobial prophylaxis and Immunoglobulin substitution intravenously, or increasingly subcutaneously offer excellent improvement in quality of life. Haematopoietic Stem Cell Transplant is now the definitive curative treatment for a wide range of severe PIDs. The success of these treatments, allows more focus on improving longterm quality of life. Gene therapy has had early success but significant complications and remains an ongoing area of research with considerable potential. [Copyright &y& Elsevier]

Chronic lymphocytic leukemia (CLL) patients are at high risk for infections. The pathogenesis of infection in patients with this leukemia is complex and multifactorial. Patients with CLL have a number of immune system defects, including disordered B-cell function with decreased production of normal B-cells and abnormal production of immunoglobulins, suppressed T-cell function and neutropenia. Other immune abnormalities present in CLL patients include neutrophil dysfunction, and complement deficiencies. In addition, further perturbations in immune function are related to the antileukemic therapies. Immune disturbance might be common prior to CLL diagnosis and infectious agents could trigger CLL development. Current chemotherapy-based regimens are not curative and often worsen this immune suppression. The introduction of new effective therapeutic agents such as the purine analogues and monoclonal antibodies has influenced the spectrum of infections diagnosed in CLL patients. Some conditions increase the risk for the development of infections including advanced age, decreased levels of immunoglobulins, advanced Binet stage, neutropenia and treatment with more than one line of chemotherapy. Until now it is debatable whether and when antibacterial prophylaxis could be useful in CLL patients. The prevention of infection includes antimicrobial prophylaxis, as well as immunoglobulin replacement and vaccination. Antibacterial prophylaxis should be given to CLL patients with previous severe and/or relapsing bacterial infections. This article reviews the immune defects in CLL and discusses strategies aimed at prophylaxis and treatment of infections in patients with CLL [ABSTRACT FROM AUTHOR]

5-years multicenter prospective study on 201 patients with common variable immunodeficiencies and 101 patients with X-linked agammaglobulinemia over a cumulative follow-up period of 1,365 patient-years was conducted to identify prognostic markers and risk factors for associated clinical co-morbidities, the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with common variable immunodeficiencies and 24% of patients with X-linked agammaglobulinemia remained infection free during the study. A reduction of pneumonia episodes has been observed after initiation of Ig replacement. During the observation time, pneumonia incidence remained low and constant over time. Patients with pneumonia did not have significant lower IgG trough levels than patients without pneumonia, with the exception of patients whose IgG trough levels were persistently <400 mg/dL. In X-linked agammaglobulinemia, the only co-morbidity risk factor identified for pneumonia by the final multivariable model was the presence of bronchiectasis. In common variable immunodeficiencies, our data allowed us to identify a clinical phenotype characterised by a high pneumonia risk: patients with low IgG and IgA levels at diagnosis; patients who had IgA level <7 mg/dL and who had bronchiectasis. The effect of therapy with immunoglobulins at replacement dosage for non-infectious co-morbidities (autoimmunity, lymphocytic hyperplasia and enteropathy) remains to be established. A unique general protective trough IgG level in antibody deficiency patients will remain undefined because of the major role played by the progression of lung disease in X-linked agammaglobulinemia and in a subset of patients with common variable immunodeficiencies. [ABSTRACT FROM AUTHOR]

Lifelong immunoglobulin replacement is the standard, expensive therapy for severe primary antibody deficiencies. This treatment can be administrated either by intravenous immunoglobulin (IVIG) or subcutaneous infusions (SCIG) and delivered at home or in an out-patient setting. This study aims to determine whether SCIG is cost-effective compared with IVIG from a French social insurance perspective. Because both methods of administration provide similar efficacies, a cost-minimization analysis was performed. First, costs were calculated through a simulation testing different hypothesis on costs drivers. Secondly, costs were estimated on the basis of field data collected by a questionnaire completed by a population of patients suffering from agammaglobulinaemia and hyper-immunoglobulin (Ig)M syndrome. Patients' satisfaction was also documented. Results of the simulation showed that direct medical costs ranged from &U20AC;19 484 for home-based IVIG to &U20AC;25 583 for hospital-based IVIG, with home-based SCIG in between at &U20AC;24 952 per year. Estimations made from field data were found to be different, with significantly higher costs for IVIG. This result was explained mainly by a higher immunoglobulin mean dose prescribed for IVIG. While the theoretical model showed very little difference between SCIG and hospital-based IVIG costs, SCIG appears to be 25% less expensive with field data because of lower doses used in SCIG patients. The reality of the dose difference between both routes of administration needs to be confirmed by further and more specific studies. [ABSTRACT FROM AUTHOR]

Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/ or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy. [ABSTRACT FROM AUTHOR]

Abstract: We assessed the immediate effect of intravenous immunoglobulins (IVIG) on the biochemical, immunological and hematological profiles in patients with hypogammaglobulinemia. Over a period of three months, patients with antibody deficiencies, who had been established on stable IVIG treatment as replacement therapy in our hospital, were enrolled in the study. Participants underwent pre-therapy determinations of their biochemical, immunological and hematological profiles. Laboratory determinations were repeated after completion of IVIG infusions. Over the study period, fourteen patients were enrolled and a total of 34 pre- and post-IVIG infusion determinations were performed and results compared. We found that low-dose IVIG treatment in patients with hypogammaglobulinemia results in post-infusion biochemical and hematological changes, as follows: an increase in total protein concentration and a reduction in albumin, total cholesterol, sodium and alkaline phosphatase concentrations as well as lymphocyte and platelet counts. All these biochemical and cellular changes seems to be transient, since they were not observed in the subsequent pre-infusion determination. However, in other patient populations, some of these changes might differ, depending on the dose of IVIG administered and the baseline condition and immunological status of the patient. [Copyright &y& Elsevier]

Antibody or humoral immunodeficiencies comprise the largest group of primary immunodeficiency diseases. Since the first description of patients with low gammaglobulin levels more than four decades ago, a great wealth of information has been accumulated. Especially in the last several years, the application of molecular and genetic techniques has unraveled many of these disorders, identifying disorders of B cell development, failure of class switch recombination and abnormalities of specific antibody production. Regardless of the underlying defect, the mainstay of therapy has been and remains immunoglobulin (Ig) replacement therapy, currently by intravenous infusion or subcutaneous injection. With advances in manufacturing, a number of products are not only safe for intravenous administration but doses can be increased to provide even more effective infection prophylaxis. However, manufacturing processes, methods of viral inactivation and removal and final composition differ widely among the available preparations. How these variables impact clinical outcome is not clear, but they have the potential to do so. As a result, careful selection of an intravenous immunoglobulin (IVIG), matching patient needs and risks to those risks associated with a specific IVIG, is necessary to optimize outcomes and maximize the success of Ig replacement therapy. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The development of safe and effective intravenous preparations of immune globulin (IVIG) represents a major advance in the treatment of patients with severe antibody deficiencies. Such therapy is expensive, few trials have been performed to compare one type of IVIG preparation with another under equivalent conditions, and published studies have been of relatively short duration. The overall consensus is that high-dose IVIG (at least 400/mg/kg/month) is superior to lower doses and most clinicians aim to maintain trough IgG levels above an arbitrary level of 5 g/l. Adverse reactions, usually mild, are common in antibody-deficient patients during the first few infusions, but severe, anaphylactoid reactions are extremely rare other than in patients with antibodies to IgA. IVIG is not associated with transmission of human immunodeficiency virus or hepatitis B. but there remains a small but definite risk of transmission of non-A, non-B hepatitis, including hepatitis C. Self-infusion of IVIG in the patients home is a realistic alternative to hospitalization. In the UK, guidelines for home therapy have been approved by professional medical bodies and by the Department of Health. Home therapy has proven to be both safe and cost-effective. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a dynamic therapy of engineered T cells targeting neoplastic cells, which offers impressive long-term remissions for aggressive relapsed/refractory hematologic malignancies. However, side effects including severe infections can be life-threatening. Multiple factors, including cytokine release syndrome, B-cell aplasia, and hypogammaglobulinemia, contribute to infection risk. B-cell aplasia is an expected on-target, off-tumor effect of CD19 + -targeted CAR T cells and leads to hypogammaglobulinemia. We review hypogammaglobulinemia observed in the 5 currently Food and Drug Administration-approved CAR T-cell therapies and other CAR T-cell products evaluated in clinical trials, and discuss hypogammaglobulinemia onset, duration, and immune recovery. We review associations between hypogammaglobulinemia and infections, with a discussion informed by other known B-cell-depleting contexts. Differences in hypogammaglobulinemia between children and adults are identified. We integrate management strategies for evaluation and immunoglobulin replacement from clinical studies, expert recommendations, and organizational guidelines. Notably, our review also highlights newer CAR T-cell products targeting different B-cell antigens, including B-cell maturation antigen, signaling lymphocytic activation molecule, and κ light chains. Finally, we identify key areas for future study to mitigate and treat hypogammaglobulinemia resulting from this transformative therapy., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Common variable immunodeficiency (CVID) is the most common clinically significant primary antibody deficiency diagnosed in adults. The early symptoms are not specific. They include common infections, mainly of the respiratory tract, caused by typical microorganisms, so cases can be missed in primary care. In the majority of patients increased susceptibility to infections coexists with signs or symptoms of autoimmunity, inflammation or polyclonal lymphoproliferation, which can divert diagnosis from immune deficiency. The overall incidence of malignancy is increased in CVID and certain cancers are significantly more common. Lymphomas and gastric carcinoma are the most frequently reported malignancies in CVID, so a high index of suspicion is recommended. Diagnostic delay in CVID is seen worldwide. The main goal of this paper is to increase the awareness about CVID among health care professionals. We aim to present features which can be helpful in CVID diagnosis in order to shorten the "latency" of proper management of CVID patients. We review clinical symptoms, complications and laboratory abnormalities of CVID. Immunoglobulin replacement therapy is regarded as the cornerstone of pharmacological intervention. New modes of Ig application, mainly subcutaneously and via the hyaluronidase-facilitated subcutaneous route, help to adjust therapy to patients' needs and preferences. Still there remain unmet needs. It remains to be seen whether CVID complications can be avoided by earlier diagnosis, treatment and thorough monitoring in the context of increased risk of malignancy. Development of patient tailored protocols depending on the clinical phenotype and risk factors might be more appropriate. The most important consideration is to diagnose suspected cases and stratify patients in a precise and timely way. Work is needed to define features predictive of unfavorable prognosis., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The importance of registries is vital for almost every human disease but crucial for rare disorders, where the centralized collection, organization, and quality check of data create a platform from where multiple analyses and scientific advances are possible. In this article, the authors review the creation of the United States Immunodeficiency Network registry, its role, and the numerous scientific achievements generated from the collective effort of many., Competing Interests: Disclosure This work was supported by the National Institutes of Health, AI-101093, AI-086037, AI-48693, and the David S Gottesman Immunology Chair., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Refractory rhinosinusitis can be related to comorbid medical conditions, including primary immunodeficiency. Given the prevalence of immunodeficiency, clinicians should have a low threshold to consider these diagnoses. This article reviews primary immunodeficiencies contributing to chronic rhinosinusitis, including a proposed diagnostic work-up and the evidence for treatment in this unique population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Twenty-eight patients were maintained on subcutaneous immunoglobulin replacement for persistent B-cell aplasia and agammaglobulinemia following CD19-targeted chimeric antigen receptor T-cell therapy for B-cell lymphoblastic leukemia. Patients were transitioned from intravenous to subcutaneous immunoglobulin replacement at a median of 11.5 months (range, 4-20). Increasing serum IgG level was significantly associated with a lower rate of sinopulmonary infection (P = 0.0072). The median serum IgG level during infection-free periods was 1000 mg/dL (range, 720-1430), which was significantly higher than IgG levels in patients with sinopulmonary infections. As such, we recommend maintaining a goal IgG level > 1000 mg/dL to provide optimal protection., (© 2019 Wiley Periodicals, Inc.)

B-cell targeted therapies (BCTT) are now widely used in autoimmune rheumatic diseases, including SLE, antineutrophil cytoplasmic antibody-associated vasculitis and rheumatoid arthritis. Early studies suggested that rituximab did not influence serum immunoglobulins. However, subsequently, with increased patient numbers, longer follow-up duration and many patients having received multiple BCTT courses, multiple subsequent studies have identified hypogammaglobulinaemia as a potential side effect. Patients developing hypogammaglobulinaemia appear to fit into two principal categories: the majority who develop transient, often mild reduction in immunoglobulins without increased infection and a much smaller but clinically significant group with a more sustained antibody deficiency, who display increased risk of infection. Monitoring immunoglobulin levels represents an opportunity for the early detection of hypogammaglobulinaemia, and the prevention of avoidable morbidity. In the two major studies, approximately 4%-5% of BCTT-treated patients required immunoglobulin replacement due to recurrent infections in the context of hypogammaglobulinaemia. Despite this, monitoring of immunoglobulins is suboptimal, and there remains a lack of awareness of hypogammaglobulinaemia as an important side effect., Competing Interests: Competing interests: DJ has received research grants from Roche/Genentech. From August 2017 to February 2018, SW was a Clinical Research Fellow supported by an unrestricted grant from Roche Products (UK) to undertake a Systematic Literature Review on hypogammaglobulinaemia after B-cell targeted therapies. MYK, CM and DJ were co-applicants on that grant (grant number GDRC-FEB-001-2017).