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Serum concentrations (mean ± standard deviation) of (A) total IgG and (B-E) IgG subclasses following infusion with IVIG 10% in 30 patients on a 4-week schedule. The dotted lines indicate the normal physiological serum range of immunoglobulin (normal ranges as described here: http://www.globalrph.com/labs_i. htm).
Source publication
Intravenous immunoglobulin (IVIG) therapy is commonly used to treat patients with primary antibody deficiency. This prospective, open-label, non-randomised, multicentre, phase III trial investigated the pharmacokinetics of a new 10% liquid IVIG product (panzyga®; Octapharma) in 51 patients aged 2-75 years with common variable immunodeficiency (n =...
Contexts in source publication
Context 1
... serum concentrations of total IgG and IgG subclasses followed a similar pattern after an IVIG 10% infusion, with a steeper decline from their peaks just after the end of infusion followed by a slower terminal elimination phase ( Fig. 1). This profile was observed both for the 3-weekly and 4-weekly treatment schedules. As expected, IgG1 and IgG2 were present in much higher concentrations than the IgG3 and IgG4 subclasses (Fig. ...
Context 2
... after an IVIG 10% infusion, with a steeper decline from their peaks just after the end of infusion followed by a slower terminal elimination phase ( Fig. 1). This profile was observed both for the 3-weekly and 4-weekly treatment schedules. As expected, IgG1 and IgG2 were present in much higher concentrations than the IgG3 and IgG4 subclasses (Fig. ...
Similar publications
Genetic primary immunodeficiency diseases are increasingly recognized, with pathogenic mutations changing the composition of circulating leukocyte subsets measured by flow cytometry (FCM). Discerning changes in multiple subpopulations is challenging, and subtle trends might be missed if traditional reference ranges derived from a control population...
Citations
... Furthermore, immunoglobulin was added. Intravenous propionic immunoglobulin contains a high dose of anti-CMV IgG antibodies that specifically bind and kill CMV, and enhance immune persistence with a median half-life of 51.2 days (13). The role of immunoglobulin in preventing CMV infection is controversial. ...
Cytomegalovirus (CMV) infection is one of the most common infectious complications following hematopoietic stem cell transplantation (HSCT); however, cases involving multiple organs at the same time are rare. The present study describes a case of CMV pneumonia combined with CMV DNAemia and CMV cystitis after HSCT. A 33-year-old male patient with acute myeloid leukemia was treated with HSCT. The first month after HSCT, the patient developed a cough and shortness of breath. At 2 months post-HSCT, the patient developed hematuria. The CMV DNA levels in the blood and urine were elevated; bronchoalveolar lavage fluid (BALF) was also positive for CMV DNA. Heterotypic cells exhibiting a large nuclear morphology were observed in the BALF and bronchial brushes. Recurrent and progressive ground-glass opacities were evident on chest computed tomography. The patient was diagnosed with CMV pneumonia complicated by CMV DNAemia and CMV cystitis, and was treated with a combination of ganciclovir and foscarnet, along with immunoglobulin therapy. The patient was cured and discharged. It was determined that the CMV DNA in the blood was inconsistent with that in the BALF, which delayed the early diagnosis of CMV pneumonia. The association between T-cell immune function and the therapeutic efficacy for CMV multi-organ infection following HSCT is known to be significant. Moreover, the timely administration of ganciclovir and foscarnet in combination with immunoglobulin therapy demonstrated favorable clinical outcomes.
... Although there are no formal recommendations for timing of reevaluation of immune function after pausing IgG-RT, a period of 3 to 4 months is reasonable based on the fact that the half-life of IVIG is approximately 21 days, and it takes 4 to 5 half-lives to clear exogenous IgG from the system. [50][51][52][53] MEDICATIONS Many immunosuppressive medications have been associated with SHG, which can but does not always lead to secondary recurrent infections (Table II). Studies of clinical outcomes with SHG from medications, aside from BCTT and corticosteroids, are limited mostly to case reports, expert opinion, or reviews. ...
Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the HG is secondary or primary is important as this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential causal etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (e.g., discontinuation of an offending drug) or treatment of the underlying condition (e.g., management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy, although data are limited. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, post-transplant, protein-losing) associated with SHG and highlights key areas for future investigation.
... henselae IgG titers tested at six-week or 100-day intervals [21][22][23]. In contrast, IgG mean half-life of IVIG products ranges from three to five weeks, with big variability among studies, and leads to a rapid IgG decrease following IVIG administration as a function of immunoglobulin half-life [9,[24][25][26]. The rapid seroconversion from positive to negative in our patients, occurring within 30 days, strongly argues that the initial high anti-B. ...
Cat scratch disease (CSD), caused by Bartonella henselae, usually presents as regional lymphadenopathy/lymphadenitis, known as typical CSD or as atypical CSD, which includes, among others, neurological manifestations. Serology for anti–B. henselae IgG antibodies is the most commonly used diagnostic tests for CSD. Intravenous immunoglobulin (IVIG) is given for an increasing number of medical conditions and may cause interference with serological testing. We report six patients with neurological manifestations and two patients with Kawasaki disease mimicking typical CSD, mistakenly diagnosed as CSD due to false-positive serology following IVIG therapy. Bartonella IgG serology was positive one to six days after IVIG administration and reverted to negative in seven of eight patients or significantly decreased (1 patient) ≤30 days later. In patients with CSD, IgG titers remained essentially unchanged 15–78 days after the positive serum sample. An additional eight patients treated with IVIG for various conditions were evaluated prospectively. All were seronegative one day pre-IVIG infusion, five patients demonstrated an increase in the IgG titers one to three days after IVIG administration, one interpreted as positive and four as intermediate, whereas three patients remained seronegative, suggesting that false seropositivity after IVIG therapy may not occur in all patients. Treatment with IVIG can result in false-positive serology for B. henselae. Increased awareness to the misleading impact of IVIG is warranted to avoid misinterpretation. Repeat testing can distinguish between true and false serology. Preserving serum samples prior to IVIG administration is suggested.
... Lastly, we performed calculations based on previous pharmacokinetic profiles of IVIG [34] to obtain a first and preliminary insight into possibly achievable steady-state plasma levels of anti-SARS-CoV-2 IgG in patients regularly dosed with IVIG. ...
... Steady-state levels of SARS-CoV-2-neutralizing IgG on 4-weekly dosing were approximated by superposition principles using baseline-adjusted, dose-normalized reference profiles from a previously published clinical trial (EudraCT 2009-011434-10) that investigated the steady-state pharmacokinetics of IgG on 4-weekly repeated dosing of IVIG 10% in patients with PID [34]. The individual courses of total IgG were baseline-adjusted, assuming that the baseline levels were residuals from previous dosing whilst endogenous levels were negligible. ...
... Finally, we investigated how the currently measured final container potencies relate to steady-state plasma levels of anti-SARS-CoV-2 IgG in a patient receiving IVIG 10%. We 3) [34]. As detailed in the methods section, individual time courses of the untransformed IgG levels (Supp. ...
Introduction:
Patients with primary or secondary immunodeficiency (PID or SID) face increased insecurity and discomfort in the light of the COVID-19 pandemic, not knowing if and to what extent their comorbidities may impact the course of a potential SARS-CoV-2 infection. Furthermore, recently available vaccination options might not be amenable or effective for all patients in this heterogeneous population. Therefore, these patients often rely on passive immunization with plasma-derived, intravenous or subcutaneous immunoglobulin (IVIG/SCIG). Whether the ongoing COVID-19 pandemic and/or the progress in vaccination programs lead to increased and potentially protective titers in plasma-derived immunoglobulins (Ig) indicated (e.g., for humoral immunodeficiency) remains a pressing question for this patient population.
Purpose:
We investigated SARS-CoV-2 reactivity of US plasma-derived IVIG/SCIG products from the end of 2020 until June 2021 as well as in convalescent plasma (CP) from May 2020 to August 2020 to determine whether potentially neutralizing antibody titers may be present.
Methods:
Final containers of IVIG/SCIG and CP donations were analyzed by commercial ELISA for anti-SARS-CoV-2 S1-receptor binding domain (RBD) IgG as well as microneutralization assay using a patient-derived SARS-CoV-2 (D614G) isolate. Neutralization capacities of 313 single plasma donations and 119 plasma-derived IVIG/SCIG lots were determined. Results obtained from both analytical methods were normalized against the WHO International Standard. Finally, based on dense pharmacokinetic profiles of an IVIG preparation from previously published investigations, possible steady-state plasma levels of SARS-CoV-2 neutralization capacities were approximated based on currently measured anti-SARS-CoV-2 potencies in IVIG/SCIG preparations.
Results:
CP donations presented with high variability with regards to anti-SARS-CoV-2 reactivity in ELISA as well as in neutralization testing. While approximately 50% of convalescent donations were not/low neutralizing, approximately 10% were at or above 600 IU/mL. IVIG/SCIG lots derived from pre-pandemic plasma donations did not show neutralizing capacities for SARS-CoV-2. Lots produced between December 2020 and June 2021 entailing plasma donations after the emergence of SARS-CoV-2 showed a rapid and constant increase in anti-SARS-CoV-2 reactivity and neutralization capacity over time. While lot-to-lot variability was substantial, neutralization capacity increased from a mean of 21 IU/mL in December 2020 to 506 IU/mL in June 2021 with a maximum of 864 IU/mL for the most recent lots. Pharmacokinetic extrapolations, based on non-compartmental superposition principles using steady-state reference profiles from previously published pharmacokinetic investigations on IVIG in PID, yielded potential steady-state trough plasma levels of 16 IU/mL of neutralizing SARS-CoV-2 IgG based on the average final container concentration from May 2021 of 216 IU/mL. Maximum extrapolated trough levels could reach 64 IU/mL based on the latest maximal final container potency tested in June 2021.
Conclusions:
SARS-CoV-2 reactivity and neutralization capacity in IVIG/SCIG produced from US plasma rapidly and in part exponentially increased in the first half of 2021. The observed increase of final container potencies is likely trailing the serological status of the US donor population in terms of COVID-19 convalescence and vaccination by at least 5 months due to production lead times and should in principle continue at least until Fall 2021. In summary, the data support rapidly increasing levels of anti-SARS-CoV-2 antibodies in IVIG/SCIG products, implicating that a certain level of protection could be possible against COVID-19 for regularly substituted PID/SID patients. Nevertheless, more research is still needed to confirm which plasma levels are needed to provide protection against SARS-CoV-2 infection in immune-compromised patients.
... It allows to advance our understanding of B cell biology and antibody dynamics. Historically, general observations have been made about antibody half-lives using a single dose of labeled antibodies (Morell et al., 1970) or by determining the restoration of normal IgG levels following high-dose administrations of intravenous IgG (Melamed et al., 2018). Through the method presented here, we can monitor the longitudinal abundance of each single clone in the circulation and monitor how it responds to changes in the donor's physiology. ...
Although humans can produce billions of IgG1 variants through recombination and hypermutation, the diversity of IgG1 clones circulating in human blood plasma has largely eluded direct characterization. Here, we combined several mass-spectrometry-based approaches to reveal that the circulating IgG1 repertoire in human plasma is dominated by a limited number of clones in healthy donors and septic patients. We observe that each individual donor exhibits a unique serological IgG1 repertoire, which remains stable over time but can adapt rapidly to changes in physiology. We introduce an integrative protein- and peptide-centric approach to obtain and validate a full sequence of an individual plasma IgG1 clone de novo. This IgG1 clone emerged at the onset of a septic episode and exhibited a high mutation rate (13%) compared with the closest matching germline DNA sequence, highlighting the importance of de novo sequencing at the protein level. A record of this paper’s transparent peer review process is included in the supplemental information.
... In advanced illnesses, antibody clearance may be enhanced in inverse relationship to the serum albumin concentration which may be low due to the existing biological adversity [276]. The pharmacokinetics of intravenous immunoglobulin are mainly understood from distribution to healthy patients [277,278]. It is not known how the acute inflammation during COVID-19 may alter the latter. ...
In the absence of effective antiviral chemotherapy and still in the context of emerging vaccines for severe acute respiratory syndrome-CoV-2 infections, passive immunotherapy remains a key treatment and possible prevention strategy. What might initially be conceived as a simplified donor–recipient process, the intricacies of donor plasma, IV immunoglobulins, and monoclonal antibody modality applications are becoming more apparent. Key targets of such treatment have largely focused on virus neutralization and the specific viral components of the attachment Spike protein and its constituents (e.g., receptor binding domain, N-terminal domain). The cumulative laboratory and clinical experience suggests that beneficial protective and treatment outcomes are possible. Both a dose- and a time-dependency emerge. Lesser understood are the concepts of bioavailability and distribution. Apart from direct antigen binding from protective immunoglobulins, antibody effector functions have potential roles in outcome. In attempting to mimic the natural but variable response to infection or vaccination, a strong functional polyclonal approach attracts the potential benefits of attacking antigen diversity, high antibody avidity, antibody persistence, and protection against escape viral mutation. The availability and ease of administration for any passive immunotherapy product must be considered in the current climate of need. There is never a perfect product, but yet there is considerable room for improving patient outcomes. Given the variability of human genetics, immunity, and disease, and given the nuances of the virus and its potential for change, passive immunotherapy can be developed that will be effective for some but not all patients. An understanding of such patient variability and limitations is just as important as the understanding of the direct interactions between immunotherapy and virus.
... 2,3 Many clinical studies have reported various outcomes that resulted from a dose range of 200-900 mg kg −1 every 3-4 weeks. [17][18][19][20] Recent meta-regression analysis has found that the mean dose used across clinical studies was 387-560 mg kg −1 , and the mean immunoglobulin G (IgG) trough obtained ranged from 660 to 1280 mg d L −1 . 21 The dose selections of IVIG are weight-based. ...
... This assumption of initial estimate was obtained from previous non-compartmental PK studies. 17,28,[35][36][37][38][39] The patients' baseline endogenous IgG concentrations prior to treatment (i.e. treatment-naïve IgG level) were subtracted from the measured amount prior to analysis. ...
Aims
There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies.
Methods
Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed‐effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness‐of‐fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG.
Results
A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one‐compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness‐of‐fit plots indicated that the model fit the data adequately, with minor model mis‐specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3–4‐weekly dosing intervals were sufficient to maintain IgG levels of 5 g L⁻¹, with more frequent intervals needed to achieve higher trough levels.
Conclusions
Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.
... days), with similar values reported for IgG1, IgG2, and IgG4 (median, 30.7-38.0 days), and a lower value for IgG3 (26.7 days). For IgG3 and IgG4, there was a greater degree of variability in half-life among patients than for IgG1 and IgG2 [29]. ...
Background:
The most important infectious trigger of asthma is the virus and patients with immunoglobulin deficiencies are prone to recurrent respiratory infections.
Objective:
We investigated the relationship between immunoglobulin G subclass and recurrent respiratory symptom exacerbation and explored possible therapeutic effects of intravenous immunoglobulin administration.
Methods:
Twenty-eight infants less than 24 months old with 2 or more recurrent wheezing episodes (infantile wheezer group) and 29 asthmatic children aged 24 months to 15 years (bronchial asthma [B-asthma] group) visited our hospital from October 2010 to January 2018. Serum immunoglobulin G, A, M, E, G1, G2, G3, and G4 were measured in each group and compared. In both groups, serum immunoglobulin and symptoms were compared before and after intravenous immunoglobulin administration.
Results:
The 2 study groups exhibited several statistically significant differences when comparing respiratory virus infection rate (p < 0.001), coinfection rate (p < 0.0001), most commonly found viral infection (human bocavirus vs. human rhinovirus), and immunoglobulin A (p < 0.001), E (p = 0.008), G2 (p < 0.001), and G4 (p = 0.011) levels. In the infantile wheezer group, there was an inverse correlation between immunoglobulin G4 levels and wheezing numbers (R = -0.5538, P = 0.0022). Both groups showed significant changes in immunoglobulin levels and respiratory symptom exacerbations (recurrent wheezing, shortness of breath, chest tightness, cough, and fever) over 1 year after intravenous immunoglobulin administration.
Conclusion:
There was an association between recurrent wheezing and specific immunoglobulin G deficiencies. We suggest that intravenous immunoglobulin therapy significantly elevates specific immunoglobulin G levels though it lasts only for short term and might be associated with decreased respiratory symptoms. Therefore, low IgG4 levels among infants with recurrent wheezing may be indicative for intravenous immunoglobulin therapy.
... The difference in findings may be due to the inclusion of IgG levels before the commencement of IVIG therapy; hence, larger improvement was observed. Since then, many have aimed for higher IgG trough levels (above 1000 mg/dL) with the hope to minimize infection rates [47,48,53,58]. In a recent metaanalysis conducted by Shrestha et al. (2019), they found no significant association between the IVIG trough range and infection rate [24]. ...
PurposeWe conducted a systematic review and meta-regression analysis to evaluate the impact of increasing immunoglobulin G (IgG) trough levels on the clinical outcomes in patients with PID receiving intravenous immunoglobulin G (IVIG) treatment.Methods
Systematic search was conducted in PubMed and Cochrane. Other relevant articles were searched by reviewing the references of the reviewed article. All clinical trials with documented IgG trough levels and clinical outcome of interest in patients receiving IVIG treatment were eligible to be included in this review. Meta-regression analysis was conducted using Comprehensive Meta-analysis Software. Additional sensitivity analyses were undertaken to evaluate the robustness of the overall results.ResultsTwenty-eight clinical studies with 1218 patients reported from year 2001 to 2018 were included. The mean IVIG dose used ranges from 387 to 560 mg/kg every 3 to 4 weekly, and mean IgG trough obtained ranges from 660 to 1280 mg/dL. Random-effects meta-regression slope shows that IgG trough level increases significantly by 73 mg/dL with every increase of 100 mg/kg dose of IVIG (p < 0.05). Overall infection rates reduced significantly by 13% with every increment of 100 mg/dL of IgG trough up to 960 mg/dL (p < 0.05).Conclusion
This meta-analysis concludes that titrating the IgG trough levels up to 960 mg/dL progressively reduces the rate of infections, and there is less additional benefit beyond that. Further studies to validate this result are required before it can be used in clinical practice.
... Table 1 shows an example of pharmacokinetic (PK) characteristics for a commercially available IG (i.v.) product. 6 The short time of maximum plasma concentration (T max ) and long T1-2 suggest that a single infusion of H-IG may be sufficient for treatment in the acute disease settings. In upcoming studies, it is important to confirm that the PK of SARS-CoV-2 specific antibodies administered therapeutically in an active disease state is similar the PK of IG (i.v.). ...
Passive immunity against pathogens in epidemics has historical roots. Convalescent plasma (CP), plasma collected from individuals who have recovered from an infectious disease, has been used to confer therapeutic benefits in previous epidemics, including measles, mumps, and influenza, and remains the first line passive immunotherapy in emerging diseases, including the H1N1 influenza pandemic (2009) and now Covid‐19 (1). Over the last several decades, as technology has developed to purify and manufacture plasma‐derived immunoglobulin (IG) as a drug therapy, hyperimmune globulin (H‐IG) formulations have been used as the second line of passive immunotherapies against these diseases.
