Case Report
Safe Subcutaneous Immunoglobulin Replacement Therapy in the Treatment of X-Linked Agammaglobulinemia Patient: A Case Report
Patuzzo Giuseppe1*, Tinazzi Elisa1, Puccetti Antonio2 and Lunardi Claudio1
Department of Otolaryngology-Head & Neck Surgery, American University of Beirut Medical Center– Beirut-
Lebanon
*Corresponding author: Giuseppe Patuzzo, Department of Autoimmune Diseases, University of Verona, Policlinico G.B. Rossi, P.le Scuro, 1037134 Verona, Italy
Published: 14 Apr, 2017
Cite this article as: Giuseppe P, Elisa T, Antonio P, Claudio
L. Safe Subcutaneous Immunoglobulin
Replacement Therapy in the Treatment
of X-Linked Agammaglobulinemia
Patient: A Case Report. Ann Clin Case
Rep. 2017; 2: 1333.
Abstract
Bruton’s agammaglobulinemia is a rare X-linked humoral immunodeficiency (XLA) characterized by recurrent bacterial infections. The usual treatment of this primary immunodeficiency consists of life-long immunoglobulins (Igs) replacement, administered intravenously or subcutaneously. We report the case of an18-year-oldpatient affected by XLA, diagnosed during childhood. Over time, his subcutaneous Igs dose had been progressively reduced and the intervals between administrations prolonged. After three years of subcutaneous Igs administration, he was able to maintain an IgG level higher than 700 mg/dl, by taking 10.000 mg of subcutaneous Igs every 20 days. This dose regimen provided a continuous protection against infections, while no significant adverse event was observed. Patient adherence was guaranty by a home-based therapy; a regular follow-up and serum IgG level monitoring were also assured. Given the shortage of Ig available for the treatment of different primary immunodeficiencies, a therapy that, with a low Ig amount together with a reduced number of administrations, is able tosustaining a safe IgG level, is essential to preserve patient adherence.
Keywords: X-linked agammaglobulinemia; Bruton’s tyrosine kinase (Btk); Subcutaneous immunoglobulin (SCIG); Local tolerability; Serum IgG trough level
Introduction
X-linked agammaglobulinemia (XLA) or Bruton’s disease is a rare inherited disorder of the
immune system: XLA is a primary immunodeficiency, occurring in 1 of 190,000 male births in the
United States [1,2]. XLA represents nearly 85% of agammaglobulinemia cases, and is caused by a
defect in gene, located on the X chromosome, coding for Bruton’s tyrosine kinase (BTK). BTK
gene mutation causes a failure in B-lymphocytes maturation, associated with a failure of Ig heavy
chain rearrangement, leading to a decrease in antibody production [2]. XLA patients may present
recurrent bacterial infections as well as non-infectious complications, or exhibit heterogeneous
clinical phenotypes [3]. This complex clinical outline and the variable severity of symptoms entail
an early correct diagnosis to properly manage patients, with appropriate treatment [4]. Symptoms
appear during the first year of life, in half of patients, and, within the age of 5 years in in more than
90% of the subjects affected [5]. XLA is diagnosed in approximately 60% of individuals who develop
a severe, life-threatening infection [6].
The majority of the diagnosed patients show low level in serum Igs. IgG levels < 200 mg/dl, IgA
levels < 15 mg/dl, and IgM levels < 40 mg/dl [2], or serum IgG, IgM and IgA more than 2 SD below
the normal level for age [5], and a reduced B-cell number, i.e. < 2% of CD19- or CD20-positive
blood lymphocytes [2] are found. Therefore, early diagnosis and development of immunoglobulines
formulations, ensuring normal serum IgG concentrations, were the key factors in improving
prognosis of patients with XLA, during the last 25 years [2,5].
Case Presentation
An 18-year-old Caucasian man, who was the second-born child, had apparently normal
growth and development until he was 4-year-old. At this age, after he started kindergarten, the
patient suffered for frequent episodes of upper airway infections, high fever, cough and, in general,
sickness. Moreover, retrocardiac bronchopneumonia was diagnosed. After a second episode of bronchopneumonia, he was admitted to the hospital and severe
hypogammaglobulinemia was detected (IgG, 41 mg/dl; undetectable
IgA and IgM- Normal range, as measured in our laboratory, IgG 700-
1600 mg/dl; IgA 70-400 mg/dl; IgM 40-230 mg/dl ). Flow cytometric
evaluation of peripheral blood lymphocytes showed, at that time, a
considerably decreased number of CD19+ cells (4 cells/μl, 0.1% of
lymphocyte count. Normal range, in our hand, B lynphocites, 110-
393 cells/μl), while the other lymphocyte subsets were normal. No
remarkable signs were reported upon physical examination.
Given the hypogammaglobulinemia and the low B-cell count, the
diagnostic approach included a suspected primary immunodeficiency;
hence, a broad spectrum of clinical and laboratory investigations
were performed. BTK gene mutation (T592G in the exon 6) was
detected in the patient as in the mother, and diagnosis of XLA was
made according to diagnostic criteria [5]. A written informed consent
was obtained; the study was approved by the Local Ethics Committee.
At 4 years of age, the patient initiated intravenous immunoglobulin
substitution (IVIG) (0.4 g/kg every 4 weeks) with prompt positive
clinical response in terms of serum IgG level, reacting 750 mg/dl.
Lymphocyte typing highlighted a complete absence of B-cells, whereas
all other parameters were normal. After diagnosis, the patient did not
have any other severe infective episodes requiring hospitalization.
When the patient was 15-year-old, he started a weakly subcutaneous
immunoglobulin administration (SCIG)once a week, with the benefit
of a more comfortable home therapy. As per international guidelines,
the dosage of 0.4 g/kg/month was continued. Total monthly amount
of Igs was slightly increased, based on the patient’s growth and when
the patient was 17 to 18-year-old, the monthly dosage of 30 g (50 ml
contains 10 g of Ig) was divided in three administrations (10 g every 10
days). During this time, clinical and laboratory benefits were retained.
Then, since the patient refused to come to the University Hospital
Day Service, the intervals between administrations was progressively
delayed from 10 to 20 days in order to keep the adherence to the
therapy.
The frequency of SCIG administrations was reduced and the
current schedule is 15 g/month of SCIG (Hizentra®, IgPro 20, CSL
Behring GmbH, Berne, Switzerland) divided in two boluses, 10 g
each, one every 20 days, in order to maintain target serum IgG level
higher than 700 mg/dl, necessarily to maintain clinical benefits. Every
three months, serum Igs levels were monitored by blood test; followup
visits, including physical examination, were planned during the
intervals between administrations, based on clinical conditions
(in particular, lack of infections) and patient preference. Table 1
summarizes the patient’s main characteristics and immunological
parameters at diagnosis, after IVIG treatment and SCIG treatment.
Figure 1 shows dosages of Igs replacement, number of infusions per
month administered, and corresponding serum IgG levels over the
years.
The patient regularly undergoes hematological examinations
(full blood count), and instrumental examinations (abdominal
ultrasound, chest X-ray or high resolution TC; pulmonary functional
tests). Regarding safety features, neoplasia or autoimmune diseases
have not been observed during the follow-up. In the last 3 years, no
relevant infective episodes have been occurred, except for some colds
in the wintertime and one upper airway infection, rapidly resolved.
Discussion
Timely started, lifelong Igs replacement therapy demonstrated a significant reduction in mortality, prevention from morbidities,
improved quality of life of XLA patients [2,3], and is the gold
standard in the management of primary antibody deficiency [2,6].
The replacement therapy with IgG can be administered to patients
intravenously or subcutaneously. The intravenous route is the most
common, since it allows a larger and faster amount of Igs infused;
however, it may have side effects related to increased blood viscosity.
Thus, SCIG administration has become increasingly wide spread,
leading to a more stable serum IgG level, due to the use of lower and
more frequent doses and opening to the possibility of home-based
self-administration, improving life quality [6,7]. Currently, numerous
SCIG products are available; they differ mainly in IgG concentration
(16%, 16.5%, and 20%), and all of them are administered once a
week or more frequently according to the serum IgG level obtained
to minimize peak/trough variations [8]. The case reported describes
the experience of switching from IVIG to SCIG administration in a
15-year-old XLA patient. Administration route change had a positive
impact, improving the adherence of the patient to the therapy,
sustaining clinical benefits.
Between the ages of 15 and 17, the once-a-week SCIG was able
to guarantee clinical and serological benefits. The initial monthly
amount of SCIG, 30 g, was the same as previously given intravenously,
while the serum level of IgG was stable at nearly800 mg/dl. Serum
IgG level was identified as the more important parameter, instead the
infusion timing, given the optimal response to the SCIG t therapy,
at this dose. Dosage reduction and infusion schedule, SCIG from 30
g to 10 g, every 20 days (15 g/month), was carried out strictly along
with monitoring of plasmatic IgG levels. This infusion plan assured
that the serum IgG level was higher than 700 mg/dl; not relevant
local or systemic infections were observed. The benefits of Igs therapy
in primary immunodeficiencies are not only related to antibody
replacement but also to immune response modulation [9,10]. These
hallmarks have been observed when Igs is administered intravenous;
however, we can hypothesize that a similar outcome may also be
found after subcutaneous administration. Such observations may
lead to a therapy with reduced amount of monthly Igs, achieving
positive effects on infections prevention.
Pharmacokinetic studies have highlighted the equivalent bioavailable
features of IVIG and SCIG administrations [7]. The SC
administration is featured by a progressive release of IgG into the
circulation, with a stable serum IgG level achieved. As described by
in the results of a multicenter European study, SCIgs increase serum
IgG levels of 17.7% compared to IV Igs, when equivalent doses of
Ig were used, in patients who switched from the IV to the SC route
[11]. Moreover, retrospective and prospective cohort studies have
demonstrated that SCIG reach similar levels and efficacy to IVIG
administration, with a lower incidence of side effects and improved
quality of life [12]. Home-based SCIG has been shown to be safe and
effective both for pediatric [13] and elderly patients [14].
Among the different commercially availableSCIG preparations,
Hizentra® hasthe highest concentration of Ig (20% human Ig), and it
has been shown to achieve sustained IgG level sat equivalent doses
of IVIG [15,16]. The high concentration of Ig of Hizentra® allow time
infusion and number administrations reduction [6,17]. The choice,
among various SGIG formulations, should be perform to minimize
number of infusions and to keep the steady state target of IgG levels
[17]. With the view to a treat-to-target strategy of replacement
therapy, reduction in the risk of infections is the primary goal. Each patient has his own “biological IgG level” that needs to be identified
[18]. In our clinical case, the “biological IgG level” was maintained
with a 20-day interval regimen, and the patient stayed substantially
infection-free.
Different administration intervals of SCIG that maintain serum
IgG levels with flexible dose regimens, may further address the
patients’ adherence needs and quality of life [19]. Given the shortage
of Ig supply and the wide spectrum of diseases in which Ig are used, the
possibility of reducing the amount of Igs infused and the number of
injections is important to obtain better adherence to XLA replacement
therapy. The objective of Igs replacement therapy management in
XLA patients, which is to maintain appropriate protection against
infections, is based on regular follow-ups and monitoring of serum
IgG levels. The availability of manageable Igs replacement therapies
may offer a tailored dose regimen and personalized treatment for
each single patient. Moreover, an effective home-based SCIG therapy
may facilitate patients’ adherence to the replacement therapy.
Acknowledgement
Editorial assistance for the editing the manuscript was provided by Content Ed Net with the helpful assistance of Dr Rossella Ferrari, and funded by CSL Behring Sp A, Milano Italy.
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