IMMUNOLOGY TEXTBOOK - Mercury Podillya 2013

CONGENITAL IMMUNE DEFICIENCY

Clinical Forms of Primary Immunodeficiencies

Humoral (B-Cell) immune deficiency. Accounts for 50-70% of all Primary immunodeficiencies (Tables 50-51).

Class="center">Hereditary hypogammaglobulinemia (HHG).

Bruton's disease (ICD-10 Code D80.0)

Specific defect. Absence of B Cells, low levels of all Ig. A defect in cytoplasmic Tyrosine kinase (Src family), which acts as a signal transducer to the B-Cell Nucleus for its activation and differentiation into a plasma cell.

Defect localization on chromosome: Xq 21.3 - 22(b+k). X-linked form.

Clinical Features. Characterized by recurrent purulent infections of the Lungs (Pneumonia, Chronic Bronchitis), Paranasal Sinuses (sinusitis), Middle ear (otitis), Central Nervous system (meningitis), intestines (enteritis, colitis), eyes (Conjunctivitis), Skin (Pyoderma), and Lymph Nodes (lymphadenitis) caused by Streptococcus, Haemophilus, Staphylococcus, Pseudomonas, etc. Resistance to viral infections is generally preserved, although cases of severe enteroviral polyradiculoneuropathy and vaccine-associated poliomyelitis do occur. Typical findings in patients with HHG include hypoplasia of the palatine Tonsils and peripheral lymph nodes, delayed physical development, Arthritis, and agranulocytosis. The disease typically manifests at 5-9 months of age, when maternal IgG ceases to protect the child's body.

The disease is rare (1:50,000) and exhibits an X-linked recessive inheritance pattern. Only males are affected; when taking a family history, it is crucial to ascertain whether similar conditions occurred on the maternal side of the family.

The clinical course is severe and prone to frequent relapses. An important diagnostic sign is that the lymph nodes, Spleen, and Liver do not show enlargement in response to the inflammatory process. Sluggish arthritis, allergic reactions to Antibiotics, slowly progressive neurological disorders, and malignant lymphoma may develop.

Table 50. Clinical manifestations of primary immunodeficiencies

Table 51. Characteristics of major immunological manifestations of primary immunodeficiencies

Immunological evaluation (performed at least twice) reveals:

1) very low levels of all Ig classes (G, M, A, D, and E) with serum IgG concentration < 200 mg/dL, and IgA, IgM < 20 mg/dL; 2) absence of circulating B lymphocytes (<1% by immunofluorescence using Monoclonal Antibodies against CD19-22 or CD72); 3) absence of germinal centers and plasma cells in lymph nodes; 4) absence or hypoplasia of tonsils; 5) preserved T-lymphocyte function.

In this disorder, pre-B cells are present, but they fail to differentiate into mature B lymphocytes due to a mutation in the tyrosine kinase Gene—a crucial protein involved in signal Transduction during B-cell maturation (Table 59).

Treatment. Patients with HHG require lifelong replacement therapy with antibody-containing preparations.

Loading dose replacement immunotherapy protocol:

✵ IVIG: twice weekly at a dose of 0.1 - 0.2 g/kg of the patient's body weight, up to a monthly total dose of 1.2 g/kg of body weight.

✵ Native plasma: twice weekly at a dose of 15 - 20 mL/kg of the patient's body weight, up to a monthly total dose of 120 mL/kg of body weight.

Maintenance replacement immunotherapy protocol:

✵ IVIG: once a month at a dose of 0.1 - 0.2 g/kg of the patient's body weight.

✵ Native plasma: once a month at a dose of 15 - 20 mL/kg of the patient's body weight.

✵ Efficacy control: IgG level of at least 3 g/L.

Antibacterial therapy. Episodes of bacterial infectious complications in congenital hypogammaglobulinemia require antibacterial therapy, which is typically parenteral.

As an example of the Immune Response in humoral (B-cell) immune deficiency, we present the case history of patient S., 12 years old, who suffers from congenital hypogammaglobulinemia (Bruton's syndrome) and is under observation at the City Pediatric Immunology Center (Table 52).

Patient S., 12 years old, has been suffering from congenital hypogammaglobulinemia (Bruton's syndrome) since early childhood and regularly receives intravenous immunoglobulin (IVIG).

The immunogram shows a sharp decrease in the level of B lymphocytes, lymphocyte blastogenesis transformation test (LBTT) reactions, a decrease in IgG and IgM, neutrophilic leukocytosis, and an increase in phagocytosis indices and phagocytic bactericidal properties.

Diagnosis: congenital hypogammaglobulinemia (Bruton's syndrome).

Treatment: maintenance replacement immunotherapy with pentaglobin 200 mL IV drip once a month or bioven 5% 50 mL IV drip once a month.

Table 52. Immunogram of patient S., 12 years old

Immunodeficiency with increased immunoglobulin M. Hyper-IgM syndrome (ICD-10 Code D80.5)

This code should be used when diagnosing a patient with agammaglobulinemia accompanied by elevated IgM levels.

Agammaglobulinemia with hyper-IgM (HIGM) is a primary immunodeficiency state manifesting in individuals of either sex with recurrent bacterial infections.

Patients with HIGM are characterized by a high frequency of chronic and recurrent purulent-inflammatory bacterial infections of various localizations. Resistance to viral infections is generally preserved, although cases of severe enteroviral polyradiculoneuritis and post-vaccine poliomyelitis do occur. Hyperplasia of the palatine tonsils and peripheral lymph nodes, hepatosplenomegaly, post-infection growth retardation, arthritis, and agranulocytosis are typical for patients with HIGM.

Immunological study: detection (at least twice) of a serum IgG concentration <200 mg/dL, IgA <5 mg/dL with an IgM level above 300 mg/dL (Table 51).

In some children, IgM levels may decrease below 300 mg/dL with age, followed by a drop below age-normal values; in such cases, the diagnosis should be revised to common variable hypogammaglobulinemia (code D80.0). The disease can occur at any age, although it most commonly manifests in early childhood.

In essence, HIGM is a variant of hereditary hypogammaglobulinemia (code D80.0) and requires the same complex of therapeutic and diagnostic measures as congenital hypogammaglobulinemia.

Common variable immune deficiency (CVID, common variable hypogammaglobulinemia) (ICD-10 Code D83.0)

CVID is a primary immunodeficiency state manifesting in individuals of either sex with recurrent bacterial infections, whose laboratory diagnosis is based on the detection (at least twice) of a total serum concentration of IgG, IgA, and IgM < 300 mg/dL. The disease can occur at any age, although in children it most commonly manifests in early childhood. In essence, CVID is a variant of hereditary hypogammaglobulinemia (D80.0) and requires the same complex of therapeutic and diagnostic measures as congenital hypogammaglobulinemia.

Specific defect: decreased levels of IgM, IgA, and IgG. The number of B lymphocytes is normal or slightly reduced. Impaired antibody production. T-lymphocyte function defects are frequently detected.

Defect localization on chromosome: 6p21.3.

Clinical features. The clinical picture closely resembles Bruton's hypogammaglobulinemia (recurrent pyogenic pulmonary infections); however, the main difference is that the disease begins not in infancy, but typically at 15–35 years of age. Stomach and intestinal disorders are observed. Resistance to viral infections is generally preserved, although cases of severe enteroviral polyradiculoneuritis and post-vaccine poliomyelitis occur. Arthritis and agranulocytosis are typical for patients with CVID.

Both sexes are affected.

Immuno-Laboratory examination reveals: 1) a normal or slightly decreased count of circulating B lymphocytes; 2) decreased synthesis and/or secretion of IMMUNOGLOBULINS, manifested by lowered serum Ig levels; 3) the T-cell Lineage is generally preserved, although in some cases a decrease in T-helper levels and an increase in T-suppressor levels are observed.

In 25–30% of cases, the following additional symptoms are noted: 1) malabsorption with frequent impairment of cyanocobalamin (Vitamin B12) absorption; 2) presence of giardiasis; 3) lactose intolerance; 4) abnormalities of the small intestinal villi (Table 50).

Patients with common variable hypoimmunoglobulinemia frequently develop autoimmune pathology.

Treatment. Patients with PID require lifelong replacement therapy with intravenous immunoglobulin (IVIG). If unavailable, native plasma can be used as an alternative.

Replacement therapy in a child with a newly diagnosed PID (or in those who have not previously received adequate immunoglobulin replacement therapy), as well as following any severe infectious episodes, should be administered in a loading dose regimen. Only after the child achieves IgG levels of at least 400-600 mg/dL and the infectious process is suppressed can they be transitioned to a maintenance prophylactic immunoglobulin therapy regimen.

Antibacterial therapy is prescribed depending on the severity of bacterial complications. There is evidence supporting the efficacy of myelopid.

Transient Hypogammaglobulinemia of Infancy (THI) (Delayed Immunological Onset) (ICD-10 Code: D80.7)

THI (synonyms: transient infantile hypogammaglobulinemia, transient hypogammaglobulinemia of early childhood) is an immunodeficiency state diagnosed in children aged 1 to 5 years when serum concentrations of one or more immunoglobulin isotypes fall below IgG < 500 mg/dL, IgA < 20 mg/dL, and IgM < 40 mg/dL, with other immunodeficiency states having been ruled out.

Specific defect: low Ig levels.

THI is a benign immunodeficiency condition and essentially represents a prolonged variant of the physiological hypogammaglobulinemia normally observed in infants aged 3-6 months, when transplacentally acquired maternal IgG stores are depleted and endogenous synthesis remains insufficient.

Such a "natural immunodeficiency state" occurs in 5-8% of infants and typically resolves by 1.5 to 4 years of age. Lymph nodes and tonsils are characteristically unchanged. THI may be discovered incidentally in ostensibly healthy children. However, children with THI may experience an increased frequency of respiratory infections, ENT infections, skin and mucosal infections, as well as urogenital and intestinal infections.

Clinical features: Recurrent purulent infections; family history often reveals immunodeficiency. Onset ranges from 3-5 months to 2-4 years of age. The condition is characterized by a previously healthy (most commonly 5-6-month-old) child suddenly and inexplicably developing recurrent pyogenic infections of the kidneys and respiratory tract (Table 50).

Treatment: THI is self-limiting by definition and does not require pathogenetic immunocorrection. Management is limited to treating occasional clinical manifestations of the disease, primarily infections. In some cases, symptomatic IVIG replacement therapy is indicated.

Selective Immunoglobulin Deficiencies (Dysgammaglobulinemia)

Specific defect: decreased Ig levels.

Clinical features: The condition is caused by a reduction in serum levels of one or two—but not all three—major Ig classes, with normal or elevated levels of the others. Selective IgA deficiency is the most common (1 in 500-700 individuals), whereas IgG and IgM deficiencies are rare.

The most severe clinical manifestations are observed when IgG2 levels are reduced. Adults may also be affected.

Selective Immunoglobulin A Deficiency (SIgAD)

(ICD-10 Code: D80.2)

Selective immunoglobulin A deficiency (SIgAD, synonym: selective IgA deficiency) is a primary immunodeficiency characterized by a serum IgA concentration of < 0.5 g/L in children older than 1 year, in the absence of other immunodeficiency disorders (e.g., ataxia-telangiectasia).

Selective immunoglobulin A deficiency may be detected as an incidental finding in outwardly healthy individuals. However, this immunodeficiency is associated with an increased incidence of respiratory, ENT, skin, mucosal, urogenital, and intestinal infections. In addition to heightened susceptibility to infections, SIgAD predisposes to allergies (atopic dermatitis and Bronchial Asthma) and is associated with an increased frequency of autoimmune diseases (scleroderma, rheumatoid arthritis, vitiligo, etc.).

Immunological evaluation reveals: 1) trace amounts of IgA with normal or decreased IgG levels; 2) normal or elevated serum IgM levels; 3) normal B-lymphocyte counts; 4) decreased T-helper and increased T-suppressor counts in some patients. The underlying cause of this immunodeficiency may be related to impaired isotype switching from IgG to IgA (Table 50).

Treatment: SIgAD is a primary immune defect that cannot be corrected. Therapeutic measures are limited to managing secondary infectious, allergic, or autoimmune complications, as well as supporting unaffected immune pathways to achieve compensation (bridging the IgA production defect). Such immunostimulation is administered on an indicator basis (primarily driven by clinical manifestations of reduced anti-infective resistance).

Recommended medications and courses of Immunomodulatory therapy:

Bronchomunal: 3.5 mg once daily in the morning on an empty stomach for 10-30 days. For the subsequent 3 months, 1 capsule daily for 10 days each month.

Ribomunyl: A single dose is 3 tablets or the granules from one sachet pre-dissolved in Water. The medication is taken once daily in the morning on an empty stomach. During the first 3 weeks of treatment, it is taken on the first 4 days of each week. For the subsequent 2-5 months, it is taken on the first 4 days of each month.

Likopid is prescribed for children aged 1 to 3 years:

✵ first course: one 1 mg tablet in the morning for 10 days, followed by a 2-week break;

✵ second course: 1 tablet of 1 mg each in the morning for 10 days, followed by a 2-week break;

✵ third course: 1 tablet of 1 mg each in the morning for 10 days.

- for children aged 3 to 12 years:

✵ first course: 5 mg in the morning for 10 days, followed by a 2-week break;

✵ second course: 5 mg in the morning for 10 days, followed by a 2-week break;

✵ third course: 5 mg in the morning for 10 days.

- for children over 12 years of age:

✵ first course: 10 mg in the morning for 10 days, followed by a 2-week break;

✵ second course: 10 mg in the morning for 10 days, followed by a 2-week break;

✵ third course: 10 mg in the morning for 10 days.

Sodium nucleinate, 0.2 g 3 times a day for 21 days.

As an example of the immune response in humoral (B-cell) Immunity deficiency, we present the case history of patient B., aged 14 (Table 53), who suffers from selective immunoglobulin A deficiency and is under observation at the municipal pediatric immunology center.

Since childhood, the patient has frequently suffered from pneumonia, Pyelonephritis, cystitis, and presented with oral candidiasis. In childhood, the patient was diagnosed with selective immunoglobulin A deficiency.

The immunogram revealed neutrophilic leukocytosis, a sharp decrease in IgA levels, an increase in IgM levels, a decrease in the immunoregulatory index due to a reduction in T-helpers, a slight increase in phagocytosis parameters, and decreased phagocytic activity.

Diagnosis: selective immunoglobulin A deficiency.

Treatment:

1) itraconazole (intrungar) 100 mg every other day for 4 months, then 2 times a week for up to another 1 month orally;

2) lysobact — a topical antiseptic, prescribed for resorption, 2 tablets 3–4 times/day for 8 days;

3) licopid 10 mg in the morning for 10 days, 2 weeks break, 3 courses;

4) polyoxidonium 12 mg (suppositories) 1 time every 3 days, no. 10;

Immunorehabilitation

5) respibron 1 tablet per day sublingually, course — 10 days, 20 days break, for 3 months;

6) thymalin 1 ml subcutaneously every other day, no. 10;

7) ribomunyl 3 tablets once in the morning 1 hour before meals 4 days a week, for 3 weeks.

Table 53. Immunogram of patient B., aged 14