A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Deficiency
A Multicentre Study on the Efficacy, Safety and Pharmacokinetics of IqYmune®, a Highly Purified 10% Liquid Intravenous Immunoglobulin, in Patients with Primary Immune Def iciency
Gergely Krivan 1 2 3 4 5 6 7 8 9
Ludmila Chernyshova 1 2 3 4 5 6 7 8 9
Larysa Kostyuchenko 0 1 2 3 4 5 6 7 8 9
Andrzej Lange 1 2 3 4 5 6 7 8 9
Zoltan Nyul 1 2 3 4 5 6 7 8 9
Beata Derfalvi 1 2 3 4 5 6 7 8 9
Jacek Musial 1 2 3 4 5 6 7 8 9
Anne Bellon 1 2 3 4 5 6 7 8 9
Martin Kappler 1 2 3 4 5 6 7 8 9
Alain Sadoun 1 2 3 4 5 6 7 8 9
Ewa Bernatowska 1 2 3 4 5 6 7 8 9
0 avenue des Tropiques , Les Ulis 91958, Courtaboeuf Cedex , France
1 West Ukrainian Specialized Children's Medical Centre , Lviv , Ukraine
2 Department of Paediatric Infectious Diseases and Clinical Immunology, P.L. Shupyk National Medical Academy for Post-graduate Education , Kiev , Ukraine
3 Paediatric Haematology and Stem Cell Transplantation Department, Szent Laszlo Hospital , Budapest , Hungary
4 Statalpha , Baziège , France
5 Clinical Development Department , LFB Biotechnologies, BP 40305
6 Alergiczno Internistyczny All-Med Specjalistyczny Osrodek , Krakow , Poland
7 2nd Department of Paediatrics, Semmelweis University , Budapest , Hungary
8 Children's Department, University of Pécs , Pécs , Hungary
9 Lower Silesian Center for Cellular Transplantation/Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Wroclaw , Poland
This multicentre, open-label, prospective, singlearm study was designed to evaluate the efficacy, pharmacokinetics, and safety of IqYmune®, a highly purified 10% polyvalent immunoglobulin preparation for intravenous administration in patients with primary immunodeficiency. IqYmune® was administered to 62 patients (aged 2-61 years) with X-linked agammaglobulinemia or common variable immune deficiency at a dose from 0.22 to 0.97 g/kg every 3 to 4 weeks for 12 months with an infusion rate up to 8 mL/kg/h. A pharmacokinetic study was performed at steady state between the 8th and the 9th infusion. A single case of serious bacterial infection was observed, leading to an annualized rate of serious bacterial infections/patient (primary endpoint) of 0.017 (98% CI: 0.000, 0.115). Overall, 228 infections were reported, most frequently bronchitis, chronic sinusitis, nasopharyngitis and upper respiratory tract infection. The mean annualized rate of infections was 3.79/patient. A lower risk of infections was associated with an IgG trough level > 8 g/L (p = 0.01). The mean annualized durations of absence from work or school and of hospitalization due to infections were 1.01 and 0.89 days/patient, respectively. The mean serum IgG trough level before the 6th infusion was 7.73 g/L after a mean dose of IqYmune® of 0.57 g/kg. The pharmacokinetic profile of IqYmune® was consistent with that of other intravenous immunoglobulins. Overall, 15.5% of infusions were associated with an adverse event occurring within 72 h post infusion. Headache was the most common adverse event. In conclusion, IqYmune® was shown to be effective and well tolerated in patients with primary immunodeficiency.
IVIg; Immunoglobulins; Clinical trials
Primary immunodeficiencies (PIDs) are a heterogeneous
group of inherited diseases predisposing individuals to
10 Immunology Clinic Department, Children’s Memorial Health
Institute, Warsaw, Poland
increased risk of infection. To date, more than 200 types of
PIDs have been reported in the literature, but less than 10 of
them account for more than 60% of all PID cases [
types of PIDs are associated with a hypogammaglobulinemia
due to impaired antibody production. Chronic or recurrent
upper and lower respiratory tract infections, sinusitis, and
otitis media are the most common infections, while severe
bacterial infections (SBIs) such as sepsis, meningitis, septic
arthritis, and osteomyelitis can also occur [
]. In the absence
of early diagnosis and appropriate therapy, recurrent
respiratory infections eventually lead to the development of
bronchiectases and other chronic pulmonary diseases [
Immunoglobulin (Ig) replacement is the mainstay of
therapy for PID patients with hypo- or agammaglobulinemia. Its
efficacy in preventing severe infections is widely
]. X-linked agammaglobulinemia (XLA) and common
variable immune deficiency (CVID) are the most common
forms of PIDs requiring Ig replacement therapy [
Treatment with intravenous immunoglobulin (IVIg) is
generally well tolerated. Headache, chills, fever, and myalgia are
the most common adverse reactions, usually mild in intensity
]. Severe complications are rare and include acute renal
failure, mainly associated with sucrose when used as a
], haemolysis caused by the presence of red blood cell
IgG alloantibodies in Ig preparations [
events mainly due to the increased blood viscosity early after
Ig administration and/or the presence of pro-coagulant
contaminants in Ig preparations [
], and severe allergic
reactions, particularly in IgA-deficient patients [
IqYmune® is a highly purified 10% liquid preparation of
human normal immunoglobulin for intravenous
administration obtained from thousands of healthy donors. The
manufacturing process consists of cold ethanol and caprylic
acid fractionation steps followed by purification steps
including an anion exchange chromatography for IgA and IgM
clearance and an affinity chromatography ensuring a low
anti-A and anti-B haemaglutinin content. The inactivation/
removal process of potential blood-borne pathogens is mainly
based on a solvent/detergent treatment followed by a 20-nm
The present study investigated the efficacy,
pharmacokinetics, and safety of IqYmune® in paediatric and adult patients
with XLA or CVID.
Clinical Study Methods
An open-label, prospective, single-arm study designed
according to the European Medical Agency (EMA) guidelines
] was conducted in 18 centres in five countries in Europe
(France, Hungary, Poland, Serbia and Ukraine) from August
2011 to March 2013. Approvals were obtained from the
respective national and institutional ethics committees. Written
informed consent and/or assent as appropriate were signed by
all patients and/or their legal representatives/witnesses.
Patients aged from 2 to 65 years with XLA or CVID
dia gno sed ac cor ding to th e Euro pe an Soc iety for
Immunodeficiencies (ESID) criteria, either Ig-naïve or
previously treated with Ig replacement therapy, were recruited.
Previously treated patients were to be administered with a
stable dose of Ig and to have at least three IgG trough levels
≥4 g/L within the last 6 months prior to study entry.
The main exclusion criteria were history of allergy or
serious adverse reaction to Ig therapy, anti-IgA antibodies,
glomerular filtration rate (GFR) <80 mL/min/1.73 m2 according
to MDRD formula in adults or creatinine clearance <60 mL/
min/1.73 m2 according to Schwartz formula in paediatric
patients, alanine aminotransferase (ALT), or aspartate
aminotransferase (AST) >3 times upper limit of normal, total
bilirubin >2 times upper limit of normal, protein-losing enteropathy
or nephrotic syndrome, history of thrombosis within the past
12 months, pregnancy, and breastfeeding.
IqYmune® is a ready-to-use liquid IVIg preparation
containing at least 95% of IgG. The IgA content is ≤28 μg/mL, and
the osmolality of 300 ± 30 mOsm/kg is in the physiological
range. The sodium chloride concentration is <0.02 mmol/L,
making the product appropriate for patients with
sodiumrestricted diet. No procoagulant activity is detected.
IqYmune® is stabilized with glycine and polysorbate 80 at a
pH of 4.8 ± 0.2 and can be stored at room temperature (25 °C).
IqYmune® was to be administered intravenously every 3 or
4 weeks (±3 days) for 12 months, at a stable dose between 0.2
and 0.8 g/kg/month. Dose adjustment was allowed in case of
IgG trough level < 6 g/L and/or recurrent infections.
The initial infusion rate was 1 mL/kg/h for 30 min, to be
increased up to 4 mL/kg/h for the first three administrations
and 8 mL/kg/h for the subsequent infusions.
No premedication was allowed, unless the patient
experienced an adverse reaction on two consecutive infusions that
could be prevented by acetaminophen, antihistamines,
hydroxyzin, non-steroidal anti-inflammatory drugs, or
antiemetic agents. Prophylactic antibiotics were forbidden.
Serum IgG trough levels were assessed in all patients before
each IqYmune® infusion throughout the study period.
In addition, a subset of 28 adult patients (four on a 3-week
and 24 on a 4-week dosing schedule) were enrolled in a formal
pharmacokinetic (PK) study. Blood samples were drawn
shortly before and immediately at the end of the 8th infusion,
then 30 min, 6 h, 12 h, 24 h, 3 days, 7 days, 14 days, 21 days
and 28 days (if applicable) after the end of infusion. Serum
IgG level were measured in a central laboratory using a
PK parameters were estimated from a population PK model
using Phoenix NLME version 1.2. A supportive
noncompartmental analysis (NCA) was performed using
Phoenix WinNonlin version 6.3 (Pharsight, Cary, NC,
USA). The PK parameters assessed were the maximum serum
IgG concentration (Cmax), the time to reach the maximum
serum IgG concentration (Tmax), the half-life (t1/2), the
elimination rate constant (Kel), the clearance (Cl), the volume of
distribution (Vd), and the area under the concentration-time
curve at infinite (AUC0-∞).
Evaluation of Efficacy
The primary efficacy endpoint was the rate of SBIs per patient
per year. SBIs included bacterial pneumonia, bacteraemia or
sepsis, osteomyelitis, septic arthritis, visceral abscess, and
bacterial meningitis as defined in the Food and Drug
Administration (FDA) guidance [
The secondary efficacy endpoints were the annualized rate
of all infections and number of days of infection-related
parameters (absence from school/work, hospitalization, fever
episode, and antibiotic therapy).
Evaluation of Safety
Patients were monitored for adverse events (AEs) and serious
adverse events (SAEs). Treatment-emergent AEs (TEAEs)
were defined as AEs occurring from the time of the first
IqYmune® infusion to the date of the end-of-study/early
termination (EoS/ET) visit. Temporally associated adverse
events (TAAEs) were defined as AEs occurring from the start
of infusion up to 72 h after end of infusion.
Vital signs were monitored during and 30 min after the end
of each infusion. Biochemistry (AST, ALT, GGT, alkaline
phosphatase, total bilirubin, albumin, creatinine, and
haptoglobin) and haematology (complete blood count with
differential and platelet count) parameters were recorded at
baseline, within 30 min after end of each infusion and at the EoS/
ET. Direct antiglobulin test (DAT) was analysed at the same
time points except EoS/ET.
The patients or parents/guardians had to record on diary cards
the following information: AEs, infectious episodes and
related events (school/work days missed, hospitalisations, and
fever), and concomitant medications.
The statistical analysis was performed on the total treated set
(TTS) which consisted of all patients who received at least one
IqYmune® administration. All efficacy and safety analyses
were performed using SAS® Software version 9.1.3.
Sixty patients were planned to be enrolled in the study to
ensure a power of at least 80% to reject a null hypothesis of ≥1
SBI/patient/year, the threshold below which Ig replacement
therapy can be considered effective [
]. Assuming that the
number of SBIs is following a Poisson distribution, an exact
one-sided one-sample Poisson test at a type I error of 0.01 was
The rate of infusions with at least one TAAE was
calculated, and the upper one-sided 95% confidence interval (CI) limit
was compared to the threshold of 0.40 specified in the FDA
A total of 62 patients were enrolled in the study, 36 (58.1%)
adults and 26 (41.9%) paediatric patients. Baseline
characteristics of the patients are presented in Table 1. Among them, 58
(93.5%) patients were previously on Ig replacement therapy,
while four (6.5%) patients were naïve to Ig therapy. Seven
(11.3%) patients had a medical history of bronchiectasis.
Mean interval from diagnosis of PID to study entry was
Nine of the 62 (14.5%) patients, all adults, discontinued
prematurely the study. Reasons for and times of
discontinuations are summarized in Table 2.
All enrolled patients were treated with IqYmune®: 57 patients
were on a 4-week and five on a 3-week dosing schedule.
Patients received a mean number of 12.4 ± 3.2 infusions
(range 1–17) leading to a total of 766 infusions over a mean
period of 44.5 ± 11.6 weeks (range 0.1–54.4) at a mean dose
of 0.56 ± 0.17 g/kg (range 0.22–0.97, excluding one patient
who received 0.01 g/kg due to an infusion-related reaction
leading to premature study drug discontinuation).
The mean maximum infusion rate per infusion was
4.88 ± 1.89 mL/kg/h, increasing with the visit number as
shown in Fig. 1. The mean maximum infusion rate per patient
was 6.10 ± 2.03 mL/kg/h. The maximum infusion rate was
≤4 mL/kg/h for 439 (57.3%) infusions, >4 to 6 mL/kg/h for
162 (21.1%) infusions, and >6 to 8 mL/kg/h for 165 (21.5%)
infusions. A total of 27 (43.5%) patients had at least one
infusion with a maximum flow rate equal to 8 mL/kg/h. Mean
infusion duration was 2.28 ± 0.64 h when the maximum
infusion rate was ≤4 mL/kg/h and 1.70 ± 0.40 h when the
maximum infusion rate was >4 mL/kg/h.
The mean serum IgG trough level in the total population
increased from 5.79 ± 2.03 g/L at baseline (range 0.45–9.99) to
7.73 ± 2.36 g/L before the 6th infusion and 7.96 ± 1.53 g/L
before the 13th infusion visit (last infusion for patients on a
4week dosing schedule). In parallel, the mean dose of
IqYmune® was 0.48 ± 0.15 g/kg at the 1st infusion,
0.57 ± 0.17 g/kg at the 5th infusion, and 0.60 ± 0.17 g/kg at
the 12th infusion. The mean ratio of IgG trough levels over
dose by infusion was stable over time and was comparable to
that obtained at baseline with the IVIgs administered prior to
the first IqYmune® infusion.
The primary PK parameters derived from the population
PK model were 4.9 mL/h for clearance and 3.5 L for the
volume of distribution in the central compartment. Derived
secondary PK parameter estimates were a half-life of 33.6 days
and an AUC0-∞ of 383 day × g/L. The Cmax, calculated using
the NCA instead of NLME model to take into account a
heterogeneity in infusion durations, was 18.1 g/L. The median
Tmax was approximately 2 h after the onset of infusion.
One SBI was reported during the total study period of 57.74
patient-years, leading to a rate of 0.017 SBI per patient per
year significantly lower than the predefined threshold of 1.0
(p < 0.001, 98% CI [0.00, 0.115]) as required by the EMA
Reason for discontinuation
Gastrointestinal disorders and ascitesd
Withdrawal of consent
Late identification of an exclusion criterion
Omission of the last study visit
TTS total treated set
a Consisting of a transient episode of dyspnoea, oropharyngeal pain, and chest pain
c Five minutes after the start of the infusion
d Not drug-related
Time of discontinuation
(after infusion number)
7 and 8
Fig. 1 Mean (±SD) maximum
infusion rate per infusion over
time (TTS, N = 62). SD standard
deviation, TTS total treated set.
Infusions beyond the 13th are not
reported as only five to eight
patients were concerned
The only SBI observed was an acinetobacter bacteraemia
diagnosed in a 24-year-old male CVID patient just before the
6th IVIg administration. The patient had a serum IgG trough
level of 2.47 g/L at the time of the onset of the SBI due to a
chronic protein-losing enteropathy gone unnoticed at study
entry. Resolution of the infection was complete after
intravenous antibiotic therapy.
Overall, a total of 228 infections were experienced by 51 of
the 62 patients (82.3%). The mean annualized rate of
infections per patient was 3.79 ± 3.62 (range 0.0–14.9) in the total
population, 3.01 ± 3.24 (range 0.0–14.0) in adults, and
4.88 ± 3.88 (range 1.0–14.9) in paediatric patients. Most of
infections involved the upper respiratory tract. Their
distribution is presented in Table 3. Infections were assessed to be
mild in severity in 192 cases (84.2%), moderate in 33 cases
(14.5%), and severe in 3 cases (1.3%). The severe infections
were a gastrointestinal candidiasis and a gastroenteritis
cryptosporidial infection in one adult patient and an
exacerbation of a chronic sinusitis in one paediatric patient. In all cases,
the infections resolved without sequelae.
The relationship between infections and IgG trough level
(assessed just before the infusion preceding the infection) was
analysed. The rate of infusions associated with at least one
infection was 26.3 and 18.6% in trough level categories of
≤8 and >8 g/L, respectively (p = 0.01).
Other infection-related parameters results (absence from
work or school, hospitalization, fever episode, and antibiotics
use) are summarized in Table 4.
Adverse events are summarized in Table 5. Fifty-one of
the 62 (82.3%) patients experienced a total of 343
TEAEs of mild (79%), moderate (20%), or severe
(1%) intensity. Severe TEAEs consisted of one case of
anaemia secondary to both inflammation and vitamin
B12 deficiency and one case of testicular torsion, and
were not related to the study drug.
Thirty-three (53.2%) patients presented a total of 148
drugrelated TEAEs, most commonly headache (16.1% of
patients), chills (14.5%), neutropenia (11.3%), pyrexia (9.7%),
back pain (6.5%), and hypertension (6.5%).
Thirty-nine (62.9%) patients experienced a total of 170
Out of the 766 infusions, 119 were associated with at least
one TAAE, resulting in a proportion of 15.5% (95% CI: 13.0;
18.3). As shown in Fig. 2, the percentage of infusions with at
least one TAAE was maximal after the first administration and
decreased over time. Taking into account the maximum rate of
each infusion, 77/439 (17.5%) infusions ≤4 mL/kg/h, 19/162
(11.7%) infusions from >4 to 6 mL/kg/h and 23/165 (13.9%)
infusions >6 mL/kg/h were associated with at least one TAAE.
Four (6.5%) patients discontinued the study drug due to a
TEAE, including two patients with drug-related TEAEs (see
Table 2). One of them presented with a hypersensitivity
reaction consisted of an acute infusion-related reaction of
moderate intensity with transient dyspnea and oropharyngeal and
chest pain. Temporary interruptions and/or flow rate decreases
or limitations of an infusion due to a TAAE occurred in 2% of
the total infusions, mostly at the first or second administration.
Twenty SAEs were reported in 15 (24.2%) patients
including four drug-related SAEs consisting of asymptomatic
transient and spontaneously reversible episodes of neutropenia.
A total of 12 (21.1%) of 57 evaluable patients had positive
DAT at baseline, whereas 25 (55.6%) of the 45 DAT negative
patients converted to positivity during the study period. No
patients exhibited biological signs of IVIg-induced
haemolysis defined as simultaneous reduction of Hb
level ≥ 1 g/dL within 10 days post-infusion and positive DAT
associated with low haptoglobin or increased bilirubin serum
levels. Regardless of the other parameters associated with
hemolysis, no patients presented with a clinically significant low
haptoglobin level throughout the study period.
Seven (11.3%) patients were reported with a drug-related
neutropenia. Three (3) of them had individual factors potentially
contributing to neutropenia, i.e., low neutrophil count at baseline,
medical history of bicytopenia, or diagnosis of Hodgkin’s disease
during the study period. Return to normal or baseline values was
spontaneous at the next pre-infusion analysis in all patients. One
neutropenia episode with a nadir <0.5 × 109/L was reported in
four of these seven patients. No infections occurred in two of
them, while the other two patients presented with mild cystitis
and common cold, respectively.
In the whole study population, the mean post-infusion
neutrophil count was approximately 1 × 109/L lower than the mean count
before the first IqYmune® administration with a greater relative
decrease in those patients who had a higher baseline value (data
not shown). The ratio of the number of infections over the number
of periods with neutrophil count in each categories (<0.5 × 109/L,
0.5 to 1.0 × 109/L, 1.0 to 1.5 × 109/L, and ≥1.5 × 109/L) was
similar, ranging between 19.1 and 29.7%. All three severe
infections reported in the study were associated with a neutrophil count
≥1.5 × 109/L.
Table 4 Infection-related
endpoints (TTS, N = 62)
Number of patients
(% of total patients)
Number of infections
(% of total infections)
≤4 (1.8) each
All episodes of hypertension occurred in adults were of
mild severity and did not require any medications.
No thromboembolic events, renal failure, or anaphylactic
reactions were reported. Analysis of vital signs and laboratory
parameters did not show any other safety signals.
The study met its primary efficacy endpoint with an
annualized SBI rate of 0.017 per patient significantly lower than the
EMA/FDA requirement of less than one SBI/patient/year [
] and in line with SBI rates published in similar studies
ranging from 0.0 to 0.12/patient/year [
]. The only SBI
occurred in a context of a very low IgG trough level due to an
aggravation of a chronic enteropathy with protein loss. The
annual rate of all infections of 3.79 per patient and their types
were in line with those reported for other IVIg products
]. The study treatment duration of 1 year for a single
patient was scheduled in order to prevent a seasonal bias due
Annualized number of days with
Mean (SD) [95% CI]
CI confidence interval, SD standard deviation, TTS total treated set
Table 5 Summary of adverse
events (TTS, N = 62)
Patients (n %) (N = 62)
Infusions (n %) (N = 766)
AEs Total (per infusion)
≤4 mL/kg/h (439 infusions)
>4 to ≤6 mL/kg/h (162 infusions)
>6 mL/kg/h (165 infusions)
Discontinuation of study drug due to AE
Interruption of study drug due to AE
Flow rate decrease or no increase due to AE
AE adverse event, SAE serious adverse event, TAAE temporally associated adverse event, TEAE
treatmentemergent adverse event, TTS total treated set
to a greater rate of infections in the winter months. The higher
rate of infections in paediatric patients as compared to adults
was expected, due to the exposure to not previously
encountered pathogens (mainly viruses) easily transmissible in the
childhood environment (child care centres and kindergarten),
as well as anatomical ENT characteristics and hypotrophy of
mucosal lymphoid tissues.
The number of days of work/school missed due to
infections (1.0 day/patient/year) and with curative antibiotic
therapy (19.5 days/patient/year) compared favourably with the
ranges of 2.28 to 13 days and 32.1 to 55.7 days/patient/year,
respectively, reported in the literature while the rate of days of
hospitalization (0.9 day/patient/year) was within the range of
0.21 to 2.31 days/patient/year reported with other IVIg
At baseline, the majority of patients (36/62) had IgG trough
levels <6 g/L which can be explained by lower Ig doses used
in some countries and the inclusion of four Ig-naïve patients.
Therefore, doses were increased during the study in order to
reach an IgG trough level ≥ 6 g/L and to prevent recurrent
infections. Dose increases were associated with proportional
increases in IgG trough levels. A satisfactory mean IgG trough
level of 7.73 ± 2.36 g/L was achieved before the 6th infusion.
As reported in other studies, fewer infections were observed
when trough IgG levels were >8 g/L [
7, 9, 21, 22
]. The mean
IgG half-life of 33.6 days was within the range of those
reported with other IVIgs [
IqYmune® was well tolerated. The observed types,
severity, and frequency of TEAEs did not differ from
those commonly reported with other IVIg preparations
]. Approximately 99% of the TEAEs were
assessed as mild or moderate in severity and the three
severe TEAEs were judged as not related to the study
drug. As reported in recent studies, both in adults and
children, the most frequent TEAE was headache [
]. The rate of infusions with TAAEs of 15.5% was
significantly below the safety threshold of 40% required
by the FDA [
] and compares favourably with the
range of 20.1 to 27.7% recently reported with other
IVIg products [
]. Due to the initiation of the IVIg
treatment or the switch to a new IVIg preparation, the
first infusion was associated with more TAAEs than the
Fig. 2 Proportion of infusions
with TAAEs over time (TTS,
N = 62). TTS total treated set.
Infusions beyond the 13th are not
reported as only five to eight
patients were concerned
Number of pa ents
subsequent ones [
]. The rate of infusions with at
least one TAAE then decreased even though a rebound
was observed at the time of the 4th infusion, when
maximal infusion rate up to 8 mL/kg/h was first
allowed. For the whole study period, the maximum
infusion rate was not correlated with the risk of TAAEs
(17.5, 11.7, and 13.9% of the infusions with a
maximum flow rate of ≤4, 4–6, and >6 mL/kg/h,
respectively), showing a good adaptation of the patients to high
Nonspecific positive DAT after IVIg infusions have been
reported with an incidence ranging from 8.5 to 47% [
finding is likely to be favoured by the immediate post-infusion
sampling and is deemed to be related to the nonspecific
binding of IgG to red blood cells [
A decrease in neutrophil count is frequently observed
with IVIgs. This decrease is of short duration, with a
nadir occurring usually within 4 days and a return to
baseline within 1 to 2 weeks [
]. Neutrophil count
after IVIg depends on the sampling time and blood
sampling shortly after the end of each infusion in this
study may have favoured the report of neutropenia.
Asymptomatic, transient, and spontaneously reversible
neutropenia has been reported after IVIg administration
in up to 58% of patients, including in patients with PID
without an increased risk of infection [
pathophysiology of the neutropenia is unclear and
several mechanisms have been hypothesised including
aggregation of neutrophils , adhesion on endothelial
cells with rapid migration to tissues [
presence of alloantibodies to neutrophil membrane
components in the IVIg preparation . IqYmune® tested
negative for anti-human neutrophil antigen antibodies.
No IgG aggregate or polymer levels were detected that
could have activated neutrophils or increase their
adhesion to endothelial cells. In addition, no signal of
neutrophil activation or degranulation was observed when
both the expression of CD11b and lactoferrin were
measured ex vivo in a whole blood assay. The absence of
severe infections in patients with neutrophil count
<0.5 × 109/L is consistent with the assumption that a
pool of functionally active blood neutrophils can be
mobilized to combat infections.
In summary, IqYmune® is effective in preventing
infections and well tolerated as replacement therapy in
patients with PID, including at high infusion rates.
Acknowledgements Study investigators: Margit Zeher (Debrecen) and
Gábor Sütö (Pécs) in Hungary; Bożena Mikołuć (Białystok) in Poland;
Goran Marjanovic (Nis) in Serbia; and Jean-François Viallard (Pessac),
Jean-Louis Pasquali (Strasbourg), Marianne Debré (Paris), Yves Perel
(Bordeaux), Caroline Thomas (Nantes), and Dr. Cyrille Hoarau (Tours)
LFB Biotechnologies employees: Nehza Chambron (medical writing)
and Rosanna Rende-Fournier (clinical project management).
Compliance with Ethical Standards
Conflicts of Interest A. Bellon and A. Sadoun are LFB
Biotechnologies employees. M. Kappler is the consultant for LFB
Biotechnologies. All other co-authors were the study investigators and
received investigator honoraria or funds for research from LFB
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