Hypogammaglobulinemia: what is it, causes, symptoms, treatment, prognosis

What is hypogammaglobulinemia?

Hypogammaglobulinemia Is a disease caused by low levels of serum immunoglobulin or antibodies. Immunoglobulins are the main components of the humoral immune system and are capable of recognizing antigens, triggering a biological response, and eliminating the source of infection. Hypogammaglobulinemia is the most common primary immunodeficiency disorder that affects most immunocompromised patients. The disorder can be diagnosed during childhood or adulthood. The beginning usually falls on the second or third decade of life; however, clinical signs of primary hypogammaglobulinemia can occur at any age. Clinical manifestations are rare, but have been reported in patients over 50 years of age.

The condition predisposes children and adults to recurrent infections, allergies, neoplasms, and autoimmune diseases. Previous clinical evidence suggested that these disorders develop during childhood, but they are now increasingly seen in adults. Common variable immunodeficiency (CVID) is often the cause of hypogammaglobulinemia in adults, and X-linked

agammaglobulinemia (CSA) is the most common in the pediatric population.

Symptoms and Signs

Hypogammaglobulinemia is usually characterized by a history of recurrent, chronic, or atypical infections. These infections include, but are not limited to: bronchitis, ear infections (otitis), meningitis, pneumonia, sinus infections (sinusitis) and skin infections. Such infections can potentially damage organs, leading to serious complications. Other symptoms of hypogammaglobulinemia include chronic diarrhea and complications after receiving live vaccines. Some of the symptoms of chronic damage may be associated with recurrent infection. For example, dyspnea, chronic cough and sputum production may indicate the presence of bronchiectasis. Sinus pain, nasal discharge, and postnasal discharge may indicate the presence of chronic sinusitis. Diarrhea and steatorrhea may indicate malabsorption.

In infants with transient neonatal hypogammaglobulinemia (THN), symptoms usually manifest through 6-12 months after birth, with symptoms usually including frequent ear infections, sinus infections, and lungs. Other symptoms include respiratory tract infections, food allergies, dermatitis, urinary tract infections and infections of the gastrointestinal tract.

Causes and risk factors

Hypogammaglobulinemia can be primary or secondary. Primary immunodeficiencies result from genetic disorders and / or chromosomal abnormalities during the development of the immune system. Secondary causes are usually caused by an external or acquired factor, such as taking corticosteroids or immunosuppressants, nutritional disorders, infections, chemotherapy, malignant neoplasms, nephrotic syndrome, other metabolic diseases and hazardous environmental conditions. It is important to distinguish between primary and secondary causes of hypogammaglobulinemia in order to ensure appropriate treatment.

Categories of primary humoral immunodeficiencies include X-linked agammaglobulinemia, OVID, syndrome hyper-IgM, selective / isolated deficiency of immunoglobulin (Ig) and transient hypogammaglobulinemia early age.

- X-linked agammaglobulinemia (CSA) or Bruton's agammaglobulinemia.

This is the first primary immunodeficiency disease with an identified genetic cause. A mutation noted in the Bruton tyrosine kinase (TKB) gene is an important component of pre-B cell maturation. This leads to a lack of plasma cells with low Ig levels and, therefore, a lack of a humoral response. Primary inheritance agammaglobulinemia is X-linked, with most mutations being familial with several autosomal recessive forms.

- General variable immunodeficiency (OVID, variable pan-hypogammaglobulinemia).

OVID is defined by immune dysfunction of B cells, T cells and dendritic cells due to impaired ability of B cells to differentiate into plasma cells, reducing the secretion of immunoglobulins. Approximately 25 to 50% of patients with AVID have a single gene defect that can lead to molecular deficiencies, epigenetic changes affecting gene expression, immune cell abnormalities such as gain apoptosis B cells and disruption of antibody production. Genetic defects include mutations in the nucleus, cytoplasm, or cell surface and can be autosomal dominant or recessive. An intrinsic B cell defect may play a role by involving mutations in CD19 at 16p11.2, resulting in CD19 deficiency. Another identified gene is a transmembrane activator, a calcium modulator, and a cyclophilin ligand interactor that affects B cell maturation. OVID deficient in the cyclophilin interactor ligand including the gene TACI at 17p11.2, is another well-known mutation. Defects in the tumor necrosis factor (TNF) receptor gene have been studied and are also involved. Other T cell defects with mutations in ICOS, 2q33 (ICOS-deficient OVID), SH2DIA (responsible for X-linked lymphoproliferative syndromes), CD19, CD20, CD21, CD81, BAFF-R (B-cell activating factor of the tumor necrosis factor receptor family) and 2 genes encoding DNA methyltransferase (DNMT3B and ZBTB24). Patients with OVID and IgA deficiency have a common genetic basis. OVID is common in patients with a 1st degree IgA-deficient relative, and some IgA-deficient patients may later develop panhypogammaglobulinemia.

- Transient hypogammaglobulinemia of newborns (TGN).

The disorder is characterized by hypogammaglobulinemia with an adequate antibody response. It is observed during the first three to six months of life due to the prolongation of the physiological lower level of immunoglobulins. Ig levels return to normal by 3 years of age in most children (age range 2-6 years). The cause is unknown, but several theories have been proposed, including the inability of T cells to stimulate B cell synthesis and antibodies, suppression of maternal IgG IgG production, low levels of critical cytokines, and hereditary genetic mutations.

- Selective deficiency of immunoglobulin A (IgA).

Decreased levels or complete absence of IgA in both serum and secretory form (IgA <10 mg / dL). B cells are phenotypically normal. Selective IgA deficiency has an autosomal dominant inheritance with variable expression. It has been reported that chromosomal abnormalities and mutations in JAK3, TACI, RAG1, RAG2, STAT1 are a potential cause of selective IgA deficiency. Secondary IgA deficiency was found in patients treated with drugs such as phenytoin, D-penicillamine, who developed OVID. It is also seen in conditions such as ataxia-telangiectasia. Infections such as cytomegalovirus infection, Epstein-Barr virus, rubella and toxoplasmosiscan also cause transient IgA deficiency.

- Syndrome of hyper-IgM.

It is a rare primary immunodeficiency disorder characterized by normal or elevated IgM levels with decreased levels of IgG, IgA and IgE, caused by mutations in genes on the X chromosome and autosomal chromosomes that are responsible for switching the class of B cells from IgM to other classes antibodies. On the X chromosome, the genes of the ligand CD40 (type 1 hyper-IgM syndrome) and NEMO (the main modulator of NF-κB, X-linked hyper-IgM immunodeficiency with ectodermal dysplasia) play an active role. Autosomal chromosomal damage is observed with 3 genes, including the activation-induced cytidine deaminase gene (AID, hyper-IgM 2 type) on chromosome 12, the uracil-DNA glycosylase gene (UNG, type 5 hyper-IgM) on chromosome 12 and the CD40 gene (type 3 hyper-IgM) on chromosome 20.

Epidemiology

The prevalence of X-linked agammaglobulinemia is approximately 1 in 379,000 live births (1 in 190,000 male newborns) registered in the United States registry. There is no data for Russia.

Of primary immunodeficiencies, the most common after selective IgA deficiency is the common variable immunodeficiency, which is noted to have a high prevalence of 1 in every 10,000–50,000 live births. OVID affects 1 in 25,000 people, with some evidence of a higher prevalence in northern Europeans. OVID in children's age groups is manifested mainly after puberty, but in all patients with OVID, about 25% have the disease in childhood or adolescence, with a peak age of diagnosis of 8 years. The male to female ratio is approximately 5: 3.

Transient neonatal hypogammaglobulinemia is usually diagnosed retrospectively and predominates in men with a male to female ratio of 2: 1. The reason is unknown.

Pathophysiology

The immune system has the potential to produce several types of antibodies to remove many different antigens. Immunoglobulins (Ig / Ig) are glycoproteins produced by plasma cells, known as antibodies, that are present in the extracellular fluid and serum. There are different classes of Ig such as IgG with subtypes 1-4, immunoglobulin A (IgA) with subtypes 1-2, IgM, IgD and IgE. The functions and lifespan of subclasses vary, with some living for weeks and others for hours. Anti-infective immunity is primarily regulated by IgG, IgA and IgM.

Ig heavy chain class switching occurs rapidly after activation of mature naive B cells. This leads to a switch from IgM and IgD expression to IgG, IgA or IgE. This switching of the antibody isotype then enhances the immune response by adequately removing the pathogen that originally elicited the humoral response. There are various mechanisms of anti-infectious immunity, such as antigen neutralization, activation classical complement pathway with bactericidal effect, antibody-dependent cellular cytotoxicity and opsonization with phagocytosis. During electrophoresis of serum proteins, Ig moves mainly in the area of ​​gamma globulins, and normal values ​​are determined based on the person's age. The different categories and their pathophysiology are described below.

- X-linked agammaglobulinemia (CSA) or Bruton's disease.

The Bruton tyrosine kinase gene (TKB / Btk gene) is required for the development of mature B cells. Mutations in the gene cause low levels of plasma cells and immunoglobulins, resulting in little or no humoral response. This can cause a deficiency of immunoglobulins (hypogammaglobulinemia) or a complete absence of immunoglobulins (agammaglobulinemia).

- General variable immunodeficiency (OVID).

Defective B cells result in low plasma cell levels and therefore low immunoglobulin levels. Defects in T cells and dendritic cells are present, causing both humoral and cell-mediated impairment of the immune response. OVID is determined on the basis of age-related levels of serum IG, response to immunization (poor or absent), absence of deep T-cell immunodeficiency and any other conditions immunodeficiency.

- Transient hypogammaglobulinemia of newborns (TGN).

Occurs after 3-6 months of life with low levels of immunoglobulins due to the presence of maternal antibodies that cross the placenta. This indirectly induces immunosuppression in the infant. In addition to IgG, IgM and IgA can also be suppressed at this stage. In most children, Ig levels return to normal by age 3. Patients with TGN may have recurrent infections or no symptoms. The diagnosis can be accidental, while other causes are diagnosed.

- Selective deficiency of immunoglobulin A (IgA).

The main defect is the switching of the class of immunoglobulins. IgA-carrying B-lymphocytes cannot be converted to plasma cells secreting IgA. Helper T-cell deficiencies, impaired B-cell signaling, and cytokine abnormalities may play a role in the production of defective antibodies. Infectious etiology and drug deficiency, among others, are secondary causes.

- Syndrome of hyper-IgM.

It is a rare primary immunodeficiency disorder with normal or elevated M immunoglobulins and decreased G, A, and E immunoglobulins.

Diagnostics

The diagnostic criteria for hypogammaglobulinemia established by the European Society for the Study of Immunodeficiencies require a significant decrease in the concentration of IgG, determined at least two standard deviations below the average for age groups. The range for healthy adults is 8 to 12 g / L. In this group, hypogammaglobulinemia is diagnosed 2 standard deviations below the mean with levels less than 5 g / L.

Decreased IgA and IgM isotypes are also often seen with low IgG levels. IgM is the main immunoglobulin, which is abundant during the primary immune response, but it is contained in the intravascular compartment. IgG is most abundant in both the vascular and extravascular regions and interacts with various Fc fragments on immune cells to activate the complement pathway. IgG measurement is key in the diagnosis of hypogammaglobulinemia.

Treatment

Treatment includes:

1. ​Avoiding infections practicing hand hygiene by drinking purified water and providing adequate respiratory protection.
2. Intravenous immunoglobulins(IVIG). Replacement therapy with intravenous immunoglobulin has limitations, since it replaces only IgG, but not IgM or IgA. Immunoglobulin levels should be monitored every 6 months and the dose should be adjusted based on IgG production and patient weight. Immunoglobulin therapy is not indicated for THN or conditions with normal B cells but with abnormal specific antibodies. Patients with high IgG levels and mildly impaired vaccination response can be closely monitored. Side effects of IVIG administration can range from inflammatory reactions to rare anaphylaxis. You may also experience a headache, acute renal failure, hemolytic anemia and neutropenia. Patients receiving IVIG should be screened for IgA antibodies to prevent anaphylactic reactions caused by the patient's IgE antibodies to IgA in IVIG preparation in patients with AVID or IgA deficiency. Patients with IgA deficiency develop IgG antibodies normally and therefore do not need IVIG with> 99% IgG. IVIG administration to patients with IgA deficiency can cause anaphylaxis.
3. Antibiotics for active infections or prevention and monitoring of chronic lung diseasescaused by recurrent pneumonia.
4. Systemic glucocorticoids can be used in cytopenia, high doses of IVIG and rituximab as a steroid-sparing adjuvant have also been shown to be beneficial.
5. Hematopoietic Stem Cell Transplantk can also be done when assessing the cost and availability of IVIG. If there is no response to the above treatment, splenectomy may be considered.
6. Vaccination recommendations: seasonal influenza vaccine for high-risk patients. Recommendations vary depending on the degree of antibody deficiency. For severe deficiencies, live attenuated vaccines are not recommended, but routine vaccination with inactivated vaccines such as flu, HPV, anthrax and rabies. The vaccination schedule for inactivated or subunit vaccines is the same as for the general population with mild deficiency of antibodies, but it is important to weigh the benefits and possible harm from the introduction of live attenuated vaccines of this population.
7. Children with ongoing synopulmonary symptoms need allergy test. They may need allergy testing to rule out asthma or allergic triggers that contribute to these symptoms.
8. Repeated ear infections can lead to sensorineural hearing loss and require audiological screening hearing problems or poor school performance.

Forecast

The prognosis is mainly determined by pulmonary complications and malignant neoplasms. Antibiotic use and IVIG therapy have reduced mortality from bacterial infections. Early intervention can delay or prevent complications, but the range of IgG replacement to prevent complications is not clear.

THN patients with low IgM and IgA levels were found to recover slowly, while children who were breastfed for a longer period of time recovered faster. In patients with hyper-IgM syndrome, mortality is secondary to opportunistic infections, malignant neoplasms, and liver diseases/ biliary tract.

Complications

Pulmonary complications can lead to a reduction in life expectancy even with early detection of hypogammaglobulinemia. The main complication is the development of bronchiectasis, which occurs in about 20% of patients with a history of recurrent infections. This can cause worsening respiratory symptoms with increased bronchospasm, manifesting as obstructive and / or restrictive lung disease.

Periodic high-resolution computed tomography is recommended to monitor lung health. Another long-term complication is malignant neoplasm, which usually occurs in the fourth to fifth decade of life, for which close observation is recommended. The administration of high doses of intravenous immunoglobulins at an early stage of the disease may promote a healthier outcome and reduce pulmonary complications.