**12. Differential diagnosis**

Differential diagnosis should be done by other disorder with hypogammaglobulinemia such as CVID, X-linked hyper IgM syndrome, and X-linked lymphoproliferative disease.

It had been known for several years that there were girls who had an immunodeficiency that looked just like XLA, and immunologists had suggested that there were forms of agamma‐ globulinemia with autosomal recessive inheritance (ARA). Since 1996, several genes (µ heavy chain deficiency, λ5 deficiency, Igα deficiency, Igβ deficiency, BLNK deficiency, PI3 kinase deficiency, and E47 transcription deficiency) that can cause ARA have been identified. All of these genes code for proteins that work with BTK to support the maturation of pro-B cells into pre-B cells. Patients with mutations in any of these genes have clinical and laboratory findings that are very similar to those seen in patients with mutations in Btk (Table 3) [35–39].



**Table 3.** Diseases with absent or decreased B cells and markedly reduced in serum immunoglobulin isotypes (Al-Herz et al., *Front Immunol*, 2014)

#### **13. Treatment**

*Possible diagnosis*—males with less than 2% CD19+ B cells in whom other causes of hypogam‐

*Chest X-ray or CT scan* of patients with XLA reveals bronchiectasis most commonly distributed in the middle or lower lobes, atelectasis, and bronchial wall thickening. CT scan of sinuses may

*Prenatal diagnosis—*this may be achieved by using mutation analysis in amniotic fluid cells and

Kappa-deleting recombination excision circles (KRECs) are chosen as markers for B lympho‐ penia at birth, indicative of X-linked agammaglobulinemia. The measurement of KRECs in

Differential diagnosis should be done by other disorder with hypogammaglobulinemia such

It had been known for several years that there were girls who had an immunodeficiency that looked just like XLA, and immunologists had suggested that there were forms of agamma‐ globulinemia with autosomal recessive inheritance (ARA). Since 1996, several genes (µ heavy chain deficiency, λ5 deficiency, Igα deficiency, Igβ deficiency, BLNK deficiency, PI3 kinase deficiency, and E47 transcription deficiency) that can cause ARA have been identified. All of these genes code for proteins that work with BTK to support the maturation of pro-B cells into pre-B cells. Patients with mutations in any of these genes have clinical and laboratory findings

as CVID, X-linked hyper IgM syndrome, and X-linked lymphoproliferative disease.

that are very similar to those seen in patients with mutations in Btk (Table 3) [35–39].

**Disease Genetic defect Inheritance Serum Ig Associated features**

XL All isotypes

decreased

Severe bacterial infections: normal numbers of pro-B cells

maglobulinemia have been excluded and who has at least one of the following:

**•** Onset of recurrent bacterial infections in the first 5 years of life

**•** Serum IgG, IgM, and IgA more than 2 SD below normal for age

Btk protein expression on cord blood cells by flow cytometry.

newborn would help the early diagnosis of XLA patients [87].

**•** Absent isohemagglutinins

230 Immunopathology and Immunomodulation

**11. Newborn screening**

**12. Differential diagnosis**

Btk deficiency Mutation in Btk, a cytoplasmic

tyrosine kinase activated by cross-linking the BCR

suggest the presence of chronic sinusitis.

There is no curative treatment for XLA. Therapeutic measures consist of intravenous immu‐ noglobulins (400–600 mg/kg monthly in order to maintain the IgG levels at 500–800 mg/dL), specific treatment of bacterial infections with antibiotics, and bronchodilators. The mainstay of treatment consists of immunoglobulin replacement therapy and prolonged antibiotic treatment of suspected bacterial infections. Immunoglobulin replacement therapy is essential for the XLA patients who are unable to produce sufficient antibodies against antigens. IgG is purified from thousand of human plasma and contains a wide range of antibodies against so many infections. Thus, it is life saving for XLA patients, and they have to continue to receive to survive. The aim of immunoglobulin treatment given by intravenous (IVIG) or subcutane‐ ous (SCIG) infusions is to avoid acute infections, to decrease the number of bacterial infections, to improve quality of life, and to increase life expectancy of patients [8, 9, 47, 88–92].

IVIG infusions have to be done at hospital or home by professionally educated staff if possible. The common recommended dose of IVIG treatment for antibody replacement is between 0.3 and 0.6 g/kg, administered every 2 to 4 weeks via the intravenous route. The first IVIG infusion must be given slowly starting with a rate of 0.5 to 1.0 mg/kg per minute. Patient should be monitored closely for any adverse reactions during infusion. If the patient tolerates well, the infusion rate may be increased to 1.5 to 2.5 mg/kg per minute after 15 to 30 minutes. The maximal infusion rate is 4 mg/kg per minute, and infusion of an IVIG product should last 2 to 4 hours. The aim of IVIG therapy in patients with PID is to maintain serum IgG levels between 350 and 500 mg/ dL. Since there is a large variation in individual IgG elimination rates, the periodic measurement of serum IgG concentration is critical to monitor the adequacy of replacement during therapy. Retrospective studies in patients with XLA revealed that the severity and the number of infections especially pulmonary diseases are decreased depending on IVIG dose [88]. Serious bacterial illnesses and enteroviral meningoencephalitis were prevented when maintained IgG levels were above 800 mg/dL [89–95].

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 minimize infection risk. Overall, 24% of patients with XLA remained infection free during the study. In addition, in XLA, the comor‐ bidity risk factor identified for pneumonia was the presence of bronchiectasis [96].

Infusion-related adverse effects and transmission of blood-borne viruses are adverse effects of immunoglobulin replacement therapy [97]. Reduced adverse reactions are reported with improved and new IVIG products. The subcutaneous IG (SCIG) therapy was reported to be effective, safe, and well tolerated in children and adults. High treatment satisfaction (TS) scores and health-related quality of life (HRQOL) were advantages of SCIG. Subcutaneous infusions are recommended to patients who are small children, reactive to IVIG, or have problem with vascular access. SCIG is given as a parent-managed or a self-managed treatment. Norway, Sweden, United Kingdom, and Belgium are the countries in which SCIG is often applied to children [98, 89]. Clinical records of 1151 XLA patients identified from ESID were included in ESID registry. According to ESID registry, 305 XLA patients were treated with IVIG (73%) and 114 patients were treated with SCIG (27%) [98, 99].

Bacterial infections treated with a high dose of selected antibiotics or antibiotics sensitive to yielded pathogens for prolonged periods.

Six young patients with XLA treated with cord blood or bone marrow transplants were reported. No one benefited from transplantation, and expected increase in serum IgM or blood B-cell number was not observed [100].
