[Show abstract][Hide abstract] ABSTRACT: Combination antiretroviral therapy (cART) can alter HIV infection in children into a chronic condition. Studies investigating health-related quality of life (HRQoL) in HIV-infected children are scarce, and lacking from Western Europe. This study aimed to compare the HRQoL of clinically stable perinatally HIV-infected children to healthy, socioeconomically (SES)-matched controls as well as the Dutch norm population, and to explore associations between HIV and cART-related factors with HRQoL. HIV-infected and healthy children aged 8-18 years completed the Pediatric Quality of Life Inventory™ 4.0 (PedsQL™). We determined differences between groups on PedsQL™ mean scores, and the proportion of children with an impaired HRQoL per group (≥1 SD lower than the Dutch norm population). Logistic regression models were used to explore associations between disease-related factors and HRQoL impairment. In total, 33 HIV-infected and 37 healthy children were included. There were no differences in the mean PedsQL™ subscales between HIV-infected children and both control groups. The proportion of children with an impaired HRQoL was higher in the HIV-infected group (27%) as compared to the healthy control group (22%) and the Dutch norm (14%) on the school functioning subscale (HIV vs. Dutch norm: P = .045). Mean scores of HRQoL of perinatally HIV-infected children in the Netherlands were not different from a SES-matched control group, or from the Dutch norm population. However, the HIV-infected group did contain more children with HRQoL impairment, suggesting that HIV-infected children in the Netherlands are still more vulnerable to a compromised HRQoL.
AIDS Care 08/2015; DOI:10.1080/09540121.2015.1050986 · 1.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate enhancing synovial thickness upon contrast-enhanced magnetic resonance imaging (MRI) of the knee in children unaffected by clinical arthritis compared with clinically active juvenile idiopathic arthritis (JIA) patients. A secondary objective was optimization of the scoring method based on maximizing differences on MRI between these groups.
Twenty-five children without history of joint complaints nor any clinical signs of joint inflammation were age/sex-matched with 25 clinically active JIA patients with arthritis of at least one knee. Two trained radiologists, blinded for clinical status, independently evaluated location and extent of enhancing synovial thickness with the validated Juvenile Arthritis MRI Scoring system (JAMRIS) on contrast-enhanced axial fat-saturated T1-weighted MRI of the knee.
Enhancing synovium (≥2 mm) was present in 13 (52 %) unaffected children. Using the total JAMRIS score for synovial thickening, no significant difference was found between unaffected children and active JIA patients (p = 0.091). Additional weighting of synovial thickening at the JIA-specific locations enabled more sensitive discrimination (p = 0.011).
Mild synovial thickening is commonly present in the knee of children unaffected by clinical arthritis. The infrapatellar and cruciate ligament synovial involvement were specific for JIA, which-in a revised JAMRIS-increases the ability to discriminate between JIA and unaffected children.
• Synovial inflammation is the primary disease feature in juvenile idiopathic arthritis (JIA). • Appearance of the synovium on contrast-enhanced MRI in unaffected children is unknown. • Validation of existing scoring methods requires comparison between JIA and unaffected children. • Mild enhancing synovial thickening was detected in half of the unaffected children. • Location-weighting for JIA-specific locations increased discriminative value of the scoring methods (p = 0.011).
European Radiology 08/2015; DOI:10.1007/s00330-015-3912-z · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the feasibility of non-invasive diffusion-weighted imaging (DWI) of the knee of children with juvenile idiopathic arthritis (JIA) and, further, to analyze the apparent diffusion coefficient (ADC) levels to distinguish synovium from effusion.
Standard magnetic resonance imaging of the knee including post-contrast imaging was obtained in eight patients (mean age, 12 years 8 months, five females) using an open-bore magnetic resonance imaging system (1.0 T). In addition, axially acquired echo-planar DWI datasets (b-values 0, 50, and 600) were prospectively obtained and the diffusion images were post-processed into ADC50-600 maps. Two independent observers selected a region of interest (ROI) for both synovium and effusion using aligned post-contrast images as landmarks. Mann-Whitney U test was performed to compare ADC synovium and ADC effusion.
DWI was successfully obtained in all patients. When data of both observers was combined, ADC synovium was lower than ADC effusion in the ROI in seven out of eight patients (median, 1.92 × 10(-3) mm(2)/s vs. 2.40 × 10(-3) mm(2)/s, p = 0.006, respectively). Similar results were obtained when the two observers were analyzed separately (observer 1: p = 0.006, observer 2: p = 0.04).
In this pilot study, on a patient-friendly 1.0-T open-bore MRI, we demonstrated that DWI may potentially be a feasible non-invasive imaging technique in children with JIA. We could differentiate synovium from effusion in seven out of eight patients based on the ADC of synovium and effusion. However, to select synovium and effusion on DWI, post-contrast images were still a necessity.
[Show abstract][Hide abstract] ABSTRACT: Kawasaki disease (KD) is a systemic pediatric vasculitis. Its main complication is the development of coronary arterial aneurysms (CAA), causing an increased risk for ischemia and myocardial infarction. It is unclear whether KD patients, apart from the presence of CAA, have an increased cardiovascular disease (CVD) risk due to the previous systemic vasculitis. The aim of this study was to systematically review and meta-analyse the literature regarding surrogate markers for CVD risk in KD patients.
Medline and Embase were searched for articles comparing endothelial dysfunction (flow-mediated dilation, nitroglycerin-mediated dilation and peripheral arterial tonometry), vascular stiffness (stiffness index, pulse wave velocity) and carotid intima-media thickness (cIMT) between patients and controls. Two investigators assessed the articles for eligibility and evaluated quality.
Thirty studies were included. For all outcomes, moderate to high heterogeneity between studies was found. Most studies reported a decreased flow-mediated dilation in the whole KD- and CAA-positive group compared to controls, while data on CAA-negative patients were conflicting. The stiffness index was increased in the majority of studies evaluating the whole KD- and CAA-positive group, but not in most studies on CAA-negative patients. Mean cIMT was neither significantly increased in the whole KD-group nor in the CAA-positive group nor in most studies studying CAA-negative patients. Studies measuring maximum cIMT were conflicting.
Literature suggests that surrogate markers for CVD risk in KD patients are increased in CAA-positive but not in CAA-negative patients. This may indicate that CAA-positive patients should be monitored for CVD in later life. The results of this review have to be interpreted with care due to substantial heterogeneity between studies and methodological limitations, as well as the lack of long-term follow-up studies.
PLoS ONE 07/2015; 10(7):e0130913. DOI:10.1371/journal.pone.0130913 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The human FCGR2/3 locus contains highly homologous genes encoding the five major receptors for IgG (Fc-gamma receptors, FcγRs). In two prior GWAS on Kawasaki disease (KD), a SNP in FCGR2A (131H>R; rs1801274) was identified to be associated with disease susceptibility. However, the FCGR2/3 locus contains multiple single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), which were not covered by the detection platforms used in the GWAS. In this study we therefore focused on further fine-mapping of this locus to investigate the association of the different genetic variations with KD susceptibility. A highly accurate and validated multiplex ligation-dependent probe amplification (MLPA) assay was used to analyze all functionally relevant SNPs and CNVs within this locus. In a genetic association study involving case-control and family-based testing with 1028 patients with KD, the previous finding of FCGR2A-131H as a susceptibility marker for KD was confirmed (OR 1.16; 95%CI 1.08-1.32, meta-P = 0.01). In addition, we found a novel significant association of the FCGR2C-ORF haplotype with susceptibility to KD (OR 1.34; 95% confidence interval 1.11-1.62, meta-P = 0.003). FCGR2C-ORF leads to the expression of an extra, functionally activating FcγR (i.e. FcγRIIc) on myeloid cell types and NK cells. Being absent in Asian individuals, the FCGR2C-ORF haplotype only contributed to KD susceptibility in European subjects, independent of the established association with FCGR2A-H131R. We did not find any significant association of CNV of the locus with susceptibility to KD.
Our data point to an important role of the activating FcγRs in KD pathology. We hypothesize that the identified functional SNPs might alter the balance between the activating and inhibitory FcγRs leading to unbalanced inflammation and KD.
[Show abstract][Hide abstract] ABSTRACT: Longitudinal studies objectively evaluating changes in regional fat distribution of HIV-infected children assessed by whole body dual energy X-ray absorptiometry (DEXA) are scarce, whilst this long-term effect of HIV and antiretroviral therapy (cART) is an important issue in infected children in need for lifelong treatment.
We assessed regional fat distribution over time, measured with sequential DEXA-scans in HIV-infected children on cART in cohorts from South Africa (SA) and the Netherlands (NL), and in healthy controls (SA). Limb and trunk fat Z-scores were calculated with the lambda-mu-sigma (LMS) method. Multivariable linear regression models with mixed effects were used to investigate the effect of cART compounds on body fat distribution over time.
In total, 218 children underwent 445 DEXA assessments with a median follow-up of 3.5 years. Fat mass in all limbs was decreased in HIV-infected children compared to controls (arm fat Z-score: coefficient -0.4813; P = 0.006, leg fat Z-score: coefficient -0.4345; P = 0.013). In the HIV-infected group, stavudine treatment was associated with lower subcutaneous fat mass (arm fat Z-score: coefficient -0.5838; P = 0.001), with an additional cumulative exposure effect (arm fat Z-score: coefficient -0.0867; P = 0.003).
Our study shows that subcutaneous fat loss is still prevalent in HIV-infected children on cART, and is strongly associated with cumulative stavudine exposure. These results underline the need for early detection of subcutaneous fat loss and alternative treatment options for HIV-infected children globally.
PLoS ONE 07/2015; 10(7):e0120927. DOI:10.1371/journal.pone.0120927 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Signaling through the inhibitory receptor signal regulatory protein-alpha (SIRPα) controls effector functions in phagocytes. However, there are also indications that interactions between SIRPα and its ligand CD47 are involved in phagocyte transendothelial migration. We have investigated the involvement of SIRPα signaling in phagocyte migration in vitro and in vivo using mice that lack the SIRPα cytoplasmic tail. During thioglycolate-induced peritonitis in SIRPα mutant mice, both neutrophil and macrophage influx were found to occur, but to be significantly delayed. SIRPα signaling appeared to be essential for an optimal transendothelial migration and chemotaxis, and for the amoeboid type of phagocyte migration in 3-dimensional environments. These findings demonstrate, for the first time, that SIRPα signaling can directly control phagocyte migration, and this may contribute to the impaired inflammatory phenotype that has been observed in the absence of SIRPα signaling.
PLoS ONE 06/2015; 10(6):e0127178. DOI:10.1371/journal.pone.0127178 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Subtle structural and functional neuroretinal changes have been described in human immunodeficiency virus (HIV)-infected adults without retinitis treated with combination antiretroviral therapy (cART). However, studies on this subject in HIV-infected children are scarce. This study aimed to assess the presence of (neuro)retinal functional and structural differences between a group of perinatally HIV-infected children on cART and age-, sex-, ethnicity-, and socioeconomically matched healthy controls.
All participants underwent an extensive ophthalmological examination, including functional tests as well as optical coherence tomography, to measure individual retinal layer thicknesses. Multivariable mixed linear regression models were used to assess possible associations between HIV status (and other HIV-related parameters) and ocular parameters, while accounting for the inclusion of both eyes and several known confounders.
Thirty-three HIV-infected children (median age 13.7 years [interquartile range (IQR), 12.2-15.8], median CD4+ T-cell count 760 cells/mm3, 82% with an undetectable HIV viral load [VL]), and 36 controls (median age 12.1 years [IQR, 11.5-15.8]) were included. Contrast sensitivity (CS) was significantly lower in the HIV-infected group (1.74 vs. 1.76 logCS; P = 0.006). The patients had a significantly thinner foveal thickness (-11.2 μm, P = 0.012), which was associated with a higher peak HIV VL (-10.3 μm per log copy/mL, P = 0.016).
In this study, we found a decrease in foveal thickness in HIV-infected children, which was associated with a higher peak VL. Longitudinal studies are warranted to confirm our findings and to determine the course and clinical consequences of these foveal changes.
[Show abstract][Hide abstract] ABSTRACT: To determine whether clinical, laboratory or Magnetic Resonance Imaging (MRI) measures differentiate Juvenile Idiopathic Arthritis (JIA) from other forms of active childhood arthritis.
We prospectively collected data of 80 treatment-naïve patients clinically suspected of JIA with active non-infectious arthritis of (at least) one knee for <12 months duration. Upon presentation patients underwent clinical and laboratory assessments and contrast-enhanced MRI. MRI was not used as a diagnostic criterion.
Forty-four (55 %) patients were clinically diagnosed with JIA, whereas in 36 (45 %) patients the diagnosis of JIA was discarded on clinical or laboratory findings. MRI-based synovitis was present in 27 (61.4 %) JIA patients and in 7 (19.4 %) non-JIA patients (P < 0.001). Five factors (male gender, physician's global assessment of overall disease activity, joints with limited range of motion, HLA-B27, MRI-based synovitis) were associated with the onset of JIA. In multivariate analysis MRI-based synovitis proved to be independently associated with JIA (OR 6.58, 95 % CI 2.36-18.33). In patients with MRI-based synovitis, the RR of having JIA was 3.16 (95 % CI 1.6-6.4).
The presence of MRI-based synovitis is associated with the clinical onset of JIA. Physical examination could be supported by MRI, particularly to contribute in the early differentiation of different forms of non-infectious childhood arthritis.
• Juvenile Idiopathic Arthritis (JIA) is a diagnosis of exclusion. • Differentiating JIA and other forms of childhood arthritis can be difficult. • MRI-techniques have substantially improved evaluation of joint abnormalities in JIA patients. • MRI-based synovitis is significantly associated with the clinical onset of JIA. • MRI could support physical examination in the early differentiation of childhood arthritis.
European Radiology 05/2015; DOI:10.1007/s00330-015-3752-x · 4.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed and Candida albicans was the only pathogen identified by PCR and culture. Despite systemic antifungal multidrug therapy a prolonged course of 16 months of therapy was necessary to clear C. albicans from the cerebrospinal fluid (CSF). Molecular genetic analysis revealed a homozygous caspase recruitment domain 9 (CARD9) mutation (Q295X), which was reported to predispose to chronic mucocutaneous candidiasis. Immunologic workup excluded predisposing B- and T-cell defects. In addition, T cells producing IL-17 were repeatedly measured within the normal range. Analyses of neutrophils demonstrated normal NADPH oxidase activity in response to various stimuli including S. aureus and C. albicans. Additional neutrophilic functional testing, however, showed a decreased cytotoxicity to non-opsonized C. albicans, indicating an impaired killing mechanism against Candida spp. independent from the production of reactive oxygen species by the NADPH oxidase system. Since this defect was only demonstrated in the absence of opsonins, it might especially predispose to chronic C. albicans infections in the central nervous system (CNS) where opsonin concentrations are usually low. We therefore, that an additional neutrophil dependent defect CARD9 deficiency predisposes not only to chronic mucocutaneous candidiasis, but also to invasive chronic Candida infections, especially of the CNS.
Plastic and Reconstructive Surgery 04/2015; Publish Ahead of Print. DOI:10.1097/INF.0000000000000736 · 2.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe combined immune deficiency (SCID) is a fatal primary immunodeficiency usually presenting in the first months of life with (opportunistic) infections, diarrhea, and failure to thrive. Hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are curative treatment options. The objective of the study was to assess the morbidity, mortality, and diagnostic and therapeutic delay in children with SCID in the Netherlands in the last 15 years. These data may help to judge whether SCID should be considered to be included in our national neonatal screening program. In the period 1998-2013, 43 SCID patients were diagnosed in the Netherlands, 11 of whom were atypical SCID (presentation beyond the first year). The median interval between the first symptom and diagnosis was 2 months (range 0-1173 months). The total mortality was 42 %. In total, 32 patients were treated with HSCT of whom 8 were deceased. Nine patients died due to severe infectious complications before curative treatment could be initiated.
Because of a high mortality of patients with SCID before HSCT could be initiated, only a national newborn screening program and pre-emptive HSCT or GT will be able to improve survival of these patients. "What is known" • SCID is a fatal disease if a curative hematopoietic stem cell transplantation cannot be performed in time. • Newborn screening for SCID enables early diagnosis in the asymptomatic phase. "What is new" • Nine out of 43 SCID patients in the Netherlands died due to severe infectious complications before curative treatment could be initiated. • Only newborn screening and pre-emptive curative therapy will improve survival of children with SCID in the Netherlands.
European Journal of Pediatrics 04/2015; 174(9). DOI:10.1007/s00431-015-2518-4 · 1.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Therapy by human immunoglobulin G (IgG) concentrates is a success story ongoing for decades with an ever increasing demand for this plasma product. The success of IgG concentrates on a clinical level is documented by the slowly increasing number of registered indication and the more rapid increase of the off-label uses, a topic dealt with in another contribution to this special issue of Frontiers in Immunology. A part of the success is the adverse event (AE) profile of IgG concentrates which is, even at life-long need for therapy, excellent. Transmission of pathogens in the last decade could be entirely controlled through the antecedent introduction by authorities of a regulatory network and installing quality standards by the plasma fractionation industry. The cornerstone of the regulatory network is current good manufacturing practice. Non-infectious AEs occur rarely and mainly are mild to moderate. However, in recent times, the increase in frequency of hemolytic and thrombotic AEs raised worrying questions on the possible background for these AEs. Below, we review elements of non-infectious AEs, and particularly focus on hemolysis and thrombosis. We discuss how the introduction of plasma fractionation by ion-exchange chromatography and polishing by immunoaffinity chromatographic steps might alter repertoire of specificities and influence AE profiles and efficacy of IgG concentrates.
Frontiers in Immunology 02/2015; 6:11. DOI:10.3389/fimmu.2015.00011
[Show abstract][Hide abstract] ABSTRACT: The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro. In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.This article is protected by copyright. All rights reserved
European Journal of Immunology 02/2015; 45(2). DOI:10.1002/eji.201445070 · 4.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.
[Show abstract][Hide abstract] ABSTRACT: Background: Despite the declined incidence of severe neurological complications such as HIV‐encephalopathy, HIV‐infection in children is still associated with a range of cognitive problems. Studies comparing HIV‐infected children to socioeconomically (SES)‐matched controls are lacking, while most HIV‐infected children in industrialized countries are immigrants with a relatively low SES.
Methods: This cross‐sectional study included perinatally HIV‐infected children and controls matched for age, gender, ethnicity and SES, who completed a neuropsychological assessment (NPA) evaluating intelligence, information processing speed, attention, memory, executive‐ and visual‐motor functioning. Multivariate normative comparison (MNC) was used to assess the prevalence of cognitive impairment in the HIV‐infected group. Multivariable regression analyses were performed to identify HIV‐ and cART‐related factors associated with cognitive performance.
Results: In total, 35 perinatally HIV‐infected (median age: 13.8 years, median CD4+ T‐cells: 770*106/L, 83% with an undetectable HIV VL) and 37 healthy children (median age: 12.1 years) were included. HIV‐infected children scored lower than the healthy controls on all cognitive domains (e.g. intelligence quotient (IQ): 76 [SD 15.7] and 87.5 [SD 13.6] for HIV‐infected versus healthy children; P=0.002). Cognitive impairment was found in 6 HIV‐infected children (17%). The CDC clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC C: coefficient ‐22.98, P=0.010).
Conclusion: Our results show that cognitive performance of HIV‐infected children is poor as compared to SES‐matched healthy controls. Gaining insight in these cognitive deficits is essential as subtle impairments may progress to more pronounced complications, that will influence future intellectual performance, job opportunities and community participation of HIV‐infected children.
[Show abstract][Hide abstract] ABSTRACT: The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals and infusion rates are paving the way towards more individualized therapy regimens. In primary antibody deficiencies adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic ‘per kg’ dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents or biologics. This antibody failure, as shown by test immunisation, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings (e.g. ITP) selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review the developments in dosing of therapeutic immunoglobulins have been limited to high and
Frontiers in Immunology 12/2014; 5:629. DOI:10.3389/fimmu.2014.00629