**6. Indications of IVIG treatment**

96 Immunodeficiency

of co-stimulatory molecules like CD80 and CD86, both leading to lower self antigen processing and presentation [8]. Fc and F(ab′)2 fragments of IgG molecule are both able to suppress of DCs. Antibodies with the intrinsic capacity to recognize foreign antigens or common

At a lower dose, administered generally to patients with immunodeficiencies, however, IVIG exerts a contrasting effect. DCs of patients with common variable immune deficiency (CVID) differentiated in the presence of IVIG and presented with an up-regulated expression of CD1a and the co-stimulatory molecules CD80, CD86 and CD40 [38,39]. Defective functions of DCs have been associated with predisposition to several pathological conditions. CVID patients display high susceptibility to recurrent infections and

In recent years, manufactures aim to develop products that provide a high-yield, safe, well tolerated and stable concentrates of polyclonal IgG. Each new intravenous immunoglobulin product has to be tested for its biochemical characterization done by standart methods focusing on purity, integrity and functionality. Efficacy must be shown by opsonization, protein A affinity chromatography and mouse protection tests. Pharmacokinetics of the product, the influence of product on vital functions, acute toxicity, anaphylactoid potential, thrombogenicity should be evaluated in rats, dogs or a rabbit models. Development of new methods for fractionation, combining processes and integrating three dedicated virus clearance steps provided fulfilling the clinical requirements for intravenous administration

The US Food and Drug Administration (FDA) standardized clinical trials with IVIG in patients with primary immunodeficiencies. FDA has proposed to measure the rate of serious bacterial infections during regular infusions of investigational IVIG for 12 months to avoid seasonal variations. Serious bacterial infection term has to be well defined, thus bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia,

pathogen-specific IgG antibodies are replaced by those from the donor pool [35].

autoimmune diseases that could be due in part to impaired DC functions [38,39].

Unfortunately, there are also some disadvantages of IVIG administrations:

of second-generation intravenous immunoglobulins products (Table 2) [21].

and visceral abscess were defined as serious infections [8].

Advantages of IVIG administration are the following:

• Absence of proteolysis of the product

• Easy administration of large doses

• Requirement for a venous access • Long duration of the infusion

• Severe adverse reactions such as anaphlaxis

• Painless administration

• No sterile abscess • Rapid onset of action

• 5-15% adverse events

**5. IVIG preparations** 

• High cost

IVIG, has been licensed by FDA for only 6 clinical indications [8,22,23]:


IVIG therapy has been evaluated in a number of clinical conditions mentioned above and categorization of evidence, basis of recommendation and strength of recommendation have been established (Table 3 and Table 4) [16].


**Table 3.** Categorization of evidence and basis of recommendation and strength of recommendation [17]



Immunoglobulin Treatment of Immunodeficient Patients 99

**1. Antibody deficiencies**

Hyper IgM syndrome

**2. Combined immunodeficiencies**

Wiskott –Aldrich syndrome

**4. Diseases of immune dysregulation**

Di George Anomaly Primary CD4 deficiency

ICF syndrome

[17, 42-47].

X -linked Agammaglobulinemia(XLA) Common variable immunodeficiency(CVID)

Transient hypogammaglobulinemia of infancy(selected cases) IgG subclass deficiency± Selected IgA deficiency (selected cases)

All type of severe combined immunodeficiencies(SCID)

**3. Other well-defined immunodeficiency syndromes**

X-linked lymphoproliferative syndrome (XLP) **Table 5.** Primary Immunodeficiencies benefit IVIG treatment

IgG levels were above 800mg/dL [16,21,42,43].

Impaired specific sntibody production with normal plasma immunoglobulin evel

Evaluation of IVIG use in patients lacking immunoglobulin has demonstrated reduction of acute and chronic bacterial infections frequency, pneumonia, days of antibiotic usage, days of fever and hospital admission [16]. Retrospective studies in patients with XLA revealed that severity and number of infections are decreased depending on IVIG dose. Serious bacterial illnesses and enteroviral meningoancephalitis were prevented when maintained

Bars S et al. evaluated the efficacy of IVIG treatment (500 mg/kg every 3 weeks) in 29 children diagnosed with CVID. During therapy, median serum IgG levels increased from 410 to 900 mg/dL. The mean number of respiratory infections per patient per year decreased significantly from 10.2 to 2.5. The annual number and length of hospital stays decreased significantly from 1.36 to 0.21 and 16.35 to 6.33 days per patient, respectively. The mean annual number of antibiotics used decreased significantly from 8.27 to 2.50 per patient.

Intravenous immunoglobulin therapy has to be started without any delay in patients with CVID predisposed to chronic lung diseases. Appropriate replacement therapy in these patients, reduced the incidence of pneumonia and prevent progression of lung involvement

A 5-year multicenter prospective study on 201 patients with CVID and 101 patients with XLA was conducted to identify the effects of long-term immunoglobulin treatment and the IgG trough level to be maintained over time required to minimise infection risk. Overall, 21% of the patients with CVID and 24% of patients with XLA remained infection free during the study. Pneumonia episodes had been reduced. Patients with pneumonia did not have

Twelve patients had developed bronchiectasis before initiation of IVIG [44].

DNA repair defects; Ataxia-telangiectasia, Nijmegen breakage syndrome

**Table 4.** Recommendation of IVIG in primary and secondary immunodeficiencies [17]
