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Keywords:

  • chronic lymphocytic leukemia;
  • intravenous immunoglobulin;
  • recurrent infections;
  • secondary immunodeficiency

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

Secondary hypogammaglobulinemia is one of the factors responsible for the increased susceptibility to infection in patients with chronic lymphocytic leukemia (CLL). This study assessed the therapeutic results, concomitant medication and tolerance of administering 5% intravenous immunoglobulin, secondary immunodeficiency and recurrent serious bacterial infections. A single center, post-marketing, observational clinical study was performed on 10 patients with a variety of hematological malignancies (CLL, follicular non-Hodgkin lymphoma, IgM-secreting immunocytoma, IgA plasmacytoma and myelodysplastic syndrome/non-Hodgkin lymphoma) who had been infused with IVIG from June 1994 to May 2009. The clinical benefit of IVIG was assessed by comparing the incidence of bacterial infections before and after starting this therapy. Plasma immunoglobulin concentrations and relevant hematological variables were recorded. For safety assessment, adverse events were monitored. The standard IVIG dosage was approximately 0.35 g/kg body weight every 3–4 weeks. Most patients had normal IgG trough values of >600 mg/dL during the IVIG treatment period. The rate of bacterial infections was reduced from 2.4 per patient in the 3 months before IVIG to 0.7 (0–1.5) per patient per year during IVIG treatment. All patients received concomitant medication, mainly anticancer and anti-anemia therapy (100%). No serious adverse events related to IVIG were observed. The frequency of at least one minor adverse reaction was 1.44% (8/556 infusions). In conclusion, the investigated IVIG preparation was well tolerated and clinically beneficial in reducing the long term rate of serious bacterial infections in patients receiving concomitant treatment for malignant diseases.

List of Abbreviations
AE

adverse event

bw

body weight

CLL

chronic lymphocytic leukemia

EI

ear infection

GI

gastrointestinal infection

Hb

hemoglobin

HBsAg

surface antigen of the hepatitis B virus

HCV

hepatitis C virus

IgA

immunoglobulin A

IgG

immunoglobulin G

IgM

immunoglobulin M

IVIG

intravenous immunoglobulin G

LRTI

lower respiratory tract infection

OM

otitis media

SSTI

skin and soft tissue infection

URTI

upper respiratory tract infection

US FDA

United States Food and Drug Administration

Chronic lymphocytic leukemia, a hematological malignancy with a variable prognosis, is more prevalent in patients aged more than 50 years. Depending on the stage of the disease, current standard treatment ranges from watchful waiting to radiation therapy, chemotherapy (allogeneic), hematopoietic stem cell transplantation or targeted therapy with monoclonal antibodies [1-4].

In the past, the median survival for patients with advanced disease was less than 2 years [5]. This was due in part to the increased risk of infection associated with this disease. Secondary hypogammaglobulinemia has long been recognized to be one of the factors responsible for the increased susceptibility of CLL patients to infection; this is the rationale for the use of IVIG in these patients [6, 7].

According to the current version of the European Guidelines on Core Summary of Product Characteristics for IVIG [8], replacement therapy with IVIG is indicated in CLL patients with secondary hypogammaglobulinemia and recurrent bacterial infections in whom prophylactic antibiotics have failed. The recommended immunoglobulin dose is 0.2–0.4 g/kg every 3–4 weeks to obtain IgG trough levels of at least 5–6 g/L.

The first study assessing IVIG treatment in a small group of CLL patients, carried out in the mid-1980 s, suggested that IVIG has beneficial immunomodulating effects [9]. Later, in a double blind randomized clinical trial that compared IVIG treatment with placebo in 84 patients with CLL, a significantly reduced rate of bacterial infections was observed in the treatment group, whereas there was no difference in the incidence of non-bacterial infections [10]. In an open, uncontrolled multicenter study performed in 55 patients with primary immunodeficiency and secondary immunodeficiency caused by myeloablative chemotherapy, IVIG therapy resulted in increased mean plasma IgG concentrations and significantly reduced infection rates [11]. In addition to these studies, there have been a number of clinical trials demonstrating that bacterial infections in CLL are significantly less frequent with prophylactic treatment with IVIG [12-15]. However, there have been no recent publications regarding this indication for IVIG.

In this study we used an extremely pure IVIG solution that has been available since 1992 (Flebogamma, formerly marketed as Alphaglobin; Grifols Deutschland GmbH, Frankfurt, Germany). The manufacturing process of this product incorporates a combination of validated methods, including pasteurization, to eliminate pathogens. In this long-term study, we have documented the use of this product in patients with CLL and secondary immunodeficiency.

1 MATERIALS AND METHODS

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

1.1 Study design and objectives

This single center, post-marketing observational study was conducted at the Medical Care Center for Blood and Cancer Diseases, Community Practice in Potsdam, Germany, from April 1997 to November 2010. Its main objective was to obtain information about treatment of CLL patients with secondary immunodeficiency with IVIG, including therapeutic results, concomitant medication and tolerance. IVIG and concomitant therapies were administered according to the physician's medical criteria and normal clinical practice. The study was essentially prospective; however, some information about patients who had started IVIG treatment prior to the beginning of the study was retrieved from their medical records. All data for the study were recorded on Case Report Forms.

According to German Drug Law (Arzneimittelgesetz), the initiation of the study was communicated to the Paul-Ehrlich-Institut and the Kassenaerztliche Bundesvereinigung, as is required for non-interventional studies.

1.2 Patients and study product

The study cohort consisted of adult individuals whose indication for IVIG therapy was secondary immune deficiency with recurrent serious bacterial infections due to a variety of hematological malignancies (CLL, follicular non-Hodgkin lymphoma, IgM-secreting immunocytoma, IgA plasmacytoma and myelodysplastic syndrome/non-Hodgkin lymphoma). Patients were diagnosed and classified as described in published reports [16-18]. Patients, who were already receiving or to whom it was planned to administer IVIG therapy, were included in the study. Treatment and diagnostic procedures were performed according to the usual medical routines of the internist center.

The therapeutic IVIG preparation (Flebogamma, formerly Alphaglobin; Grifols) used throughout the study is an extremely pure, liquid, pasteurized 5% IVIG solution containing >99% therapeutically active IgG (95% monomers and dimmers) with fully represented IgG subclasses. The preparation contains minimal amounts of IgA (<0.05 mg/mL) and only traces of IgM (<0.002 mg/mL). It is stabilized with sorbitol [19].

1.3 Variables of interest and procedures

Initially, relevant clinical and medical data (date of birth, sex, height, weight, diagnosis, concomitant diseases, concomitant medication, and pathological findings at physical examination) were documented for every patient. Laboratory values prior to the first IVIG infusion (when available) and every 3 months during IVIG treatment were also documented. These included leukocyte counts, Hb, platelet counts and IgG, IgM and IgA plasma concentrations. The infection markers HBsAg, Anti-IgM HCV and Anti-IgG HCV were also recorded. Collected information on IVIG infusions included dates of infusion, lot number and total amount of preparation infused (g).

For clinical benefit assessment, information on bacterial infections (type, treatment administered and duration) was collected. The incidence of bacterial infections within the three months before starting IVIG therapy was compared with the incidence during the IVIG treatment period. Infections of non-bacterial origin during IVIG treatment were also recorded and analyzed.

For safety assessment, AEs from the first IVIG infusion to the end of the study were considered and rated by the physician according to anticipated pharmacological properties of the study product (expected or unexpected), intensity (mild, moderate or severe), seriousness (serious or non-serious), and cause and effect relationship (definite, probable, possible, conditional or doubtful) [20].

1.4 Statistical evaluation

Because the sample size for all variables was small and there was no control group, statistical analysis was descriptive. For quantitative variables, mean, median, standard deviation of the mean, minimum and maximum were used. For qualitative variables, absolute and relative frequency (percentage) is presented. For laboratory analysis comparison, normal values were taken from published reports [21, 22]. Software from Microsoft Excel 2003 SP3 spreadsheet and GraphPad Prism 5 v. 5.04 for Windows was used for calculations and charting.

2 RESULTS

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

2.1 Patient characteristics

Ten patients (seven men and three women) aged 38−73 years at the initiation of IVIG treatment for secondary immune deficiency caused by the variety of hematological malignancies listed in the Diagnosis section of Table 1 and with recurrent serious bacterial infections were studied. Relevant clinical variables of patients are shown in Table 1.

Table 1. Relevant clinical variables and IVIG treatment data of patients (n = 10)
  • Unless otherwise indicated, data are presented as median (range). Symbol # stands for patient's number identification.

  • , five patients: fludarabine, vincristine, bendamustin; four patients: chlorambucil; three patients: cyclophosphamide; one patient: daunorubicin, vindesine, trofosfamide, doxorubicin;

  • , seven patients: prednisolone; one patient: dexamethasone.

Sex (% male/female)70/30
Weight (kg)77 (57–100)
Age at start of treatment (years)63 (38–73)
Age at end of the study (years)68 (42–76)
IVIG treatment duration (months)54 (23–114)
Diagnosis (patients, n) 
Chronic lymphatic leukemia (#2, #3, #5, #8, #10)5
Follicular non-Hodgkin lymphoma (#6, #9)2
IgM-secreting immunocytoma (#1)1
IgA plasmocytoma (#4)1
Myelodysplasic syndrome/non-Hodgkin lymphoma (#7)1
Disease stage (patients, n) 
Binet A2
Binet B/Rai II/Ann Arbor II A3
Rai III/Ann Arbor IV A/Durie Salmon III B4
Not specified1
Medication at the start of IVIG treatment (patients, n) 
Anticancer therapy10
Chemotherapy/cytotoxic agents9
Monoclonal antibodies (rituximab)2
Corticosteroids7
Anti-anemia therapy6
Transfusions (erythrocyte, platelets)5
Hormonal (erythropoietin)3
Antibiotics9
Other medications (≤2 patients each)10

The first IVIG infusion was on 6 June 1994 and the last on 5 May 2009. Four patients started IVIG therapy before the launch of the study (April 1997); therefore, data from that period were collected retrospectively. The duration of immunoglobulin treatment documented in these patients ranged from 22.5 months to more than 9 years, during which time the underlying disease progressed. Individual treatment periods are plotted in Figure 1.

image

Figure 1. Intravenous immunoglobulin (IVIG) treatment periods in the 10 study patients. Patients #1, #2, #3 and #5 started IVIG therapy before the initiation of the study (April 1997).

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All 10 patients were receiving concomitant medication before starting IVIG therapy (Table 1). The average was nine medications per patient. The patients received a combined total of 56 drugs from 17 different product groups. All 10 patients received anticancer (chemotherapy, corticosteroids and monoclonal antibodies) or anti-anemia treatment (transfusions, erythropoietin) or both. Prednisolone was the most commonly prescribed corticosteroid (seven patients) and fludarabine, vincristine and bendamustin the most prescribed chemotherapy agents (five patients each). Of the two patients receiving rituximab, only one was simultaneously receiving chemotherapy (bendamustin). Further details on concomitant medication are shown in Table 1.

2.2 Infusions

During the study period, the patients received a combined total of 556 IVIG infusions, corresponding to 15,610 g of administered product. Details of infusions per patient are shown in Table 2. The number of infusions per patient ranged from 25 (patient #4, in a single course of treatment) to 116 (patient #1, in eight different courses). In total, 86 different lots of the product were used. The dose per infusion ranged from 20 to 40 g, the standard dosage being approximately 0.35 g/kg bw. IVIG treatment was administered at intervals of 3–4 weeks. In the 12 years that were documented, there was a trend toward a slightly lower dosage per treatment.

Table 2. Infusions performed on the 10 study patients according to intravenous immunoglobulin (IVIG) dosage. Values separated by hyphens mean an inclusive range
PatientCoursesDuration of course (months)Number of infusions per courseTotal dosage per course (g)Dose per infusion (g)Dose per patient (g/kg bw)
#181–301–3320–99025–300.35–0.53
#2160712130300.35
#3142431290300.49
#412225750300.35
#551–171–2030–40020–300.28–0.42
#6153691380200.35
#7157601800300.36
#833–293–3290–96020–300.25–0.37
#931–481–4630–184030–400.30–0.40
#1012730600200.30

2.3 Laboratory analysis

Most patients had normal IgG trough values (range: 600–1800 mg/dL) and low values of IgM and IgA (normal ranges: 50–150 and 80–320 mg/dL, respectively) over the course of treatment, as is summarized in Figure 2. Occasionally, IgG concentrations were transiently between 400 and 600 mg/dL after chemotherapy or anti-CD20 treatment (rituximab). Patient #4 was the only patient with low average IgG concentrations (317 mg/dL), and patient #7 the only one with normal IgM (99.6 mg/dL) and IgA (89.3 mg/dL) concentrations. Patients #1 and #6 had high mean IgM concentrations (1394 and 491 mg/dL, respectively) although with major fluctuations, whereas patients #4 and #10 had high IgA concentrations (1030 and 343 mg/dL, respectively).

image

Figure 2. Laboratory measurements assessed in patients during the overall intravenous immunoglobulin (IVIG) treatment time. Bars represent the number of patients showing low, normal or high values of the listed variables.

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Hemoglobin levels were maintained within the limits of the normality (7–12 mM) over the treatment time. Occasional Hb reduction due to the course of the underlying disease (patients #1, #4, #6 and #7) or treatment (i.e., chemotherapy in patient #2) necessitated erythropoietin or blood transfusion.

The average platelet count ranged from 96 to 236 × 106/µL. In six patients, the count was below the normal range (150–400 × 106/µL).

The leukocyte count and percentage of neutrophils were mostly within the normal range (4.5–14.5 × 106/µL and 30–85%, respectively). Low leukocyte counts were observed in patients #1 and #6 (3.3 and 2.4 × 106/µL, respectively), whereas in patient #3, the mean count was much higher than normal at 46.2 × 106/µL. The percentage of neutrophils was found to be low in two patients (#3 and #5) at 15.33% and 27.11%, respectively. These results are summarized in Figure 2. All instances of low leukocyte counts or percentage of neutrophils were parallel with chemotherapy.

There were no changes in viral infection markers (HBsAg, anti-IgM HCV and anti-IgG HCV) during the treatment period.

2.4 Clinical benefit assessments

All 10 patients had experienced severe bacterial infections within the 3 months before IVIG treatment; 24 infections in all and at least two infections each in seven of the patients. Indicatively extrapolated, this means an average of 9.6 infections per patient per year. The average incidence of bacterial infections was reduced during IVIG treatment to 0.7 infections per patient per year (range: 0–1.5). During the combined 528 months for all ten patients, 29 severe bacterial infections (predominantly respiratory infections, 17 of them bronchitis or pneumonia) were recorded, and 26 courses of antibiotics prescribed (one infection being rated as a minor infection). Three patients received treatments other than antibiotics. In addition, 30 infections that the physician did not consider to be caused by bacteria (4 fungal, 20 viral and 6 of unclear cause) were diagnosed. The overall incidence of infections (bacterial plus non-bacterial) averaged 1.4 per patient per year (range: 0.4–2.4). Detailed data of infections per patient before and after IVIG treatment are shown in Tables 3 and 4. URTIs and LRTIs were the most commonly observed type of infection. A variety of antibiotics were prescribed during the time over which IVIG was being administered (Table 4). Cefuroxime and roxithromycin were each taken by four patients and each of azithromycin, ceftriaxone and ciprofloxacin by two patients. The other antibiotics were each taken by one patient.

Table 3. Bacterial and non-bacterial infections per patient before (within the three previous months) and during intravenous immunoglobulin (IVIG) treatment
PatientBacterial infections before IVIG treatmentIVIG treatment
Length of treatment (months)Bacterial infectionsBacterial infections per yearNon-bacterial infectionsOverall infections per year
  1. n.s., not specified.

#13 URTI1141 URTI0.34 viral0.8
   2 LRTI 1 unclear 
#22 URTI601 URTI0.81 viral 
 1 sinusitis 1 LRTI 1 unclear1.2
   1 EI   
   1 SSTI   
#32 LRTI432 LRTI0.61 viral0.8
#43 n.s.2301 fungal0.5
#51 LRTI 1 URTI0.92 fungal1.5
 4 n.s.391 LRTI   
   1 GI   
#63 LRTI534 LRTI1.12 viral 
   1 EI 1 unclear1.8
#71 LRTI581 LRTI0.64 viral1.9
   2 n.s. 1 fungal 
     1 unclear 
#81 LRTI383 LRTI0.93 viral2.2
#92 LRTI563 URTI 3 viral 
   3 LRTI1.52 unclear2.4
#101 LRTI2801 viral0.4
Table 4. Details of infections during intravenous immunoglobulin (IVIG) treatment in all patients
Bacterial infectionsNTreatments
LRTI
Acute bronchitis13Azithromycin, roxithromycin, ceftriaxone, ciprofloxacin, cefuroxime, clarithromycin, carbacephem,
Bronchopulmonary3 
Pneumonia1 
URTI
Rhinitis2Doxycyclin, cefuroxime, roxithromycin, azithromycin, clarithromycin
Cough2 
n.s.2 
EI
Otitis media2Amoxicillin, ciprofloxacin
GI
Salmonellosis1Ciprofloxacin
SSTI
Sudoriparous abscess1Minocycline
n.s.
2Cefuroxime
Total29 
Non bacterial infectionsNCausative agent/disease
  1. n.s., not specified.

Viral
Skin rash5Herpes zoster
Rhinopharyngitis3Common cold
Pharyngitis3n.s.
Rhinitis2n.s.
Systemic symptoms2Influenza
GI n.s.2n.s.
n.s.2n.s.
Bronchitis1n.s.
URTI n.s.1n.s.
Fungal
Onychomycosis2Candida sp.
Thrush1Candida sp.
Pneumonia1Pneumocystis carinii
Unclear
Cough1
Cystitis1
Fever1
Gingivitis1
GI n.s.1
Total30 

2.5 Safety assessments

In all, eight AEs that the physician rated as possibly related to the study product occurred in five patients. Three patients developed shivering and fever (one with concomitant pruritus), one shivering, headache and nausea, whereas the fifth patient reported arthralgia after three infusions. None of these AEs were severe. The frequency of infusions associated with at least one AE was 1.44% (8/556 infusions). In addition, eight serious AEs occurred in six patients during the study period; the physician rated these as related to the underlying disease. One patient (#6) underwent splenectomy; one (#4) developed renal failure and six died during the study period, five due to progression of their malignant underlying disease (#1, #3, #4, #5 and #6), and one (#2) during coronary bypass surgery.

3 DISCUSSION

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

In this post-marketing observational study, IVIG treatment of a patient cohort with secondary immune deficiency and recurrent serious bacterial infections due to the variety of hematological malignancies listed in the diagnosis section of Table 1 was documented over more than 16 years. All patients received concomitant medications that could have had considerable effects on their immunity. Under the conditions of our study, the investigated IVIG preparation (marketed as Alphaglobin/Flebogamma; Grifols) was found to be clinically beneficial and safe.

Several limitations should be considered when interpreting the results. First, the study was partially retrospective. Second, patients were their own controls. Third, because the study cohort was small, results cannot be generalized to all individuals with the studied pathology. Lastly, the study was observational in nature and all interventions were performed as a component of normal clinical practice. The assumption of a cause and effect relationship between IVIG treatment and reduction in infection rate should be examined with caution. However, that there is clinical evidence that IVIG replacement therapy decreases the frequency of infections in patients with hypogammaglobulinemia [6-15] adds some weight to this assumption. Commercial IVIG preparations contain a range of antibody specificities and therefore neutralize a variety of antigens and pathogens. The pathogen-neutralizing mechanisms of action of IVIG are complex and can be divided into those mediated by the variable regions F(ab')2, and those mediated by the Fc fragment, including complement binding [23].

Overall, IVIG dosage in our study was 0.25–0.53 g/kg bw every 3–4 weeks, with a trend toward a slightly lower dosage over time. This dose is considered adequate for replacement therapy in myeloma or CLL with severe secondary hypogammaglobulinemia and recurrent infections [8].

The observed low average trough concentrations of IgM and IgA are consistent with those expected in immunodeficient patients. However, as a result of ongoing courses of IVIG treatment, average IgG trough concentrations remained in the normal range and consistently above 400 mg/dL. These results are comparable with what was found in another study of the same product (Flebogamma; 5% IgG; Grifols) in 13 patients with secondary immunodeficiency [24]. The instances of transient decreases in IgG concentrations can generally be explained by concomitant antineoplastic therapy; patient #4, who had consistently low average IgG concentrations, being the only exception. This patient had an IgA plasmocytoma (Stage III B), which accounts for the greatly increased IgA concentrations found in this case [17]. However, no bacterial infections occurred in this patient during the documented time and therefore no antibiotic treatment was necessary, suggesting that the IVIG dose administered (0.35 g/kg bw) was sufficient to maintain adequate immunity. No patient received rituximab and fludarabine simultaneously. This combination has been linked to more marked hypogammaglobulinemia and higher risk of bacterial infections [25].

In general, because they received erythropoietin and blood transfusions when required, no patients had sustained anemia. Of the patients with platelet counts below the normal range, none actually had thrombocytopenia (<50 × 106/µL). Finally, all abnormal values of leukocyte counts and percentages of neutrophils were considered expected consequences of the underlying disease or chemotherapy.

The clinical benefit of the IVIG therapy was evidenced by the low rate of infections achieved during the treatment period (decreased to 0.7 bacterial and 1.4 overall infections per patient-year). These results are in line with previous results reported for the same IVIG treatment in primary and secondary immunodeficiencies [11]. For example, the US FDA goal is ≤1.0 serious bacterial infection per patient per year [26]. Studies assessing other IVIG products have reported a range of 0.08 serious bacterial infections to 4.4 overall infections per subject per year [27].

During the overall 528 months documented for the ten study patients, 26 courses of antibiotics were prescribed for infections. This is much lower than the rate of antibiotic prescriptions previously reported for CLL patients receiving low-dose IVIG therapy (54 antibiotic prescriptions in 169 months of replacement therapy) [7]. This apparent discrepancy can be ascribed to fact that patients in the latter study were at more advanced stages of disease at the start of therapy. The types of antibiotics prescribed varied, particularly for LRTIs and URTIs. These antibiotics are normally used against the most common bacterial pathogens that cause these diseases, such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. Because diagnosis and treatment were performed during normal clinical practice, not all pathogens were identified.

None of the AEs rated by the physician to be possibly drug-related was severe, and all AEs were previously known to be possible adverse reactions to IVIG treatment. The good safety profile of the IVIG product we used (Flebogamma 5%; Grifols) in patients with immune deficiencies is supported by other published clinical reports [28]. Moreover, in our study, fewer infusions were associated with at least one adverse reaction than that observed in a clinical trial of patients with primary and secondary immunodeficiency treated with the same product (Flebogamma 5%; Grifols) [24].

In summary, IVIG was well-tolerated and clinically beneficial in the long-term, reducing the rate of serious bacterial infections in patients with secondary hypogammaglobulinemia receiving concomitant treatment for malignant diseases.

ACKNOWLEDGMENTS

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

This work was supported by Grifols (Grifols Deutschland GmbH, Frankfurt, Germany). Assistance in writing and preparation of this manuscript was provided under the direction of the authors by Anna Seriola and Dr Jordi Bozzo of Grifols.

4 DISCLOSURES

  1. Top of page
  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES

Dr Bettina Dreger is an employee of Grifols. The authors state that they have no other interests which might be perceived as posing a conflict or bias in relation to this paper.

REFERENCES

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  2. ABSTRACT
  3. 1 MATERIALS AND METHODS
  4. 2 RESULTS
  5. 3 DISCUSSION
  6. ACKNOWLEDGMENTS
  7. 4 DISCLOSURES
  8. REFERENCES
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