Primary Immunodeficiencies with Predominantly Antibody Deficiency: Clinical Guidelines

List of Abbreviations

PID – Primary Immunodeficiency

IgG – immunoglobulin G

IgM – immunoglobulin M

IgA – immunoglobulin A

mg – milligram

dl – deciliter

IgD – immunoglobulin D

IgE – immunoglobulin E

CVID – Common Variable Immunodeficiency

ICD-10 – International Classification of Diseases, 10th Revision

IUIS - Union of Immunological Societies

GI – gastrointestinal tract

DM – diabetes mellitus

ILD – interstitial lung disease

CT – computed tomography

UC – ulcerative colitis

PCR — polymerase chain reaction

ESR – erythrocyte sedimentation rate

AST – alanine aminotransferase

ALT – aspartate aminotransferase

GGT – gamma-glutamyl transferase

LDH - lactate dehydrogenase

Ultrasound — ultrasound examination

LoE – level of evidence

LER — level of evidence and recommendation

WHO – World Health Organization

IVIG** – normal human immunoglobulin** for intravenous administration

SCIG** – normal human immunoglobulin** for subcutaneous administration

g – gram

kg – kilogram

l – liter

IMIG – normal human immunoglobulin for intramuscular administration

mL - milliliter

min – minute

cell – cell

mm – millimeter

sGCS – systemic glucocorticosteroids

AD – autosomal dominant inheritance

AR – autosomal recessive inheritance

LOF – loss-of-function

GOF – gain-of-function

IU – international unit

HIV - human immunodeficiency virus

TREC – T-cell receptor excision circles (DNA rings excised from T lymphocytes during their maturation)

KREC – kappa-deleting recombination excision circles (DNA rings excised during B-cell maturation from the locus encoding the kappa chain)

CP – clinical guidelines

AFP – alpha-fetoprotein

Terms and Definitions

Primary immunodeficiencies (PIDs) are a group of congenital diseases of the immune system comprising more than 450 nosologies associated with the loss, reduction, or improper functioning of one or more of its components.[1–5]

Hypogammaglobulinemia – a decrease in blood IgG (immunoglobulin G) levels below 2 standard deviations from the age-adjusted normal value in children and below 4.5 g/l (grams/liter) in adults. [5]

Agammaglobulinemia – a decrease in blood IgG levels below 1.0 g/l combined with a blood IgM (immunoglobulin M) level below 0.2 g/l and a blood IgA (immunoglobulin A) level below 0.1 g/l, with a peripheral CD19+ B-cell count below 2%.[5]

Pre-transfusion IgG level – the immunoglobulin G level measured on the day before the administration of normal human immunoglobulin (i.e., its lowest value during the month)**.

Class-switched memory B lymphocytes (CD19+CD27+IgD−) – B lymphocytes that do not express IgD (immunoglobulin D), express IgG, IgA, and IgE (immunoglobulin E), and serve as indicators of normal activation and development of B lymphocytes in the germinal centers of lymph nodes and other secondary lymphoid tissues.[6]

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

PIDs with predominant antibody synthesis deficiency are genetically determined diseases characterized by impaired antibody production in response to an infection or vaccination. This group includes a wide range of nosologies with variable changes in humoral and cellular immunity parameters: from a marked decrease in all classes of serum immunoglobulins (up to their complete absence) and absence of B lymphocytes to selective antibody deficiency.[6]

PIDs with predominant antibody deficiency are heterogeneous in their clinical manifestations, age of symptom onset, and alterations in humoral and cellular immunity parameters: CVID (Common Variable Immunodeficiency), X-linked agammaglobulinemia, autosomal recessive agammaglobulinemia, selective IgA deficiency, specific antibody deficiency, transient hypogammaglobulinemia of infancy, and IgG subclass deficiency.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The development of PIDs with predominant antibody synthesis impairment is based on abnormal B lymphocyte differentiation at various stages:

1. antigen-independent (in the bone marrow);

2. antigen-dependent (in the B-cell zones of peripheral lymphoid organs)

The final stage of B lymphocyte differentiation is the generation of memory B lymphocytes and plasma cells, which carry out antibody production.[6–8]

Mutations in genes involved in early B-cell development and differentiation lead to early-onset PID phenotypes. These are characterized by a marked decrease in all immunoglobulin classes, progressing to agammaglobulinemia with a substantial decrease or near-complete absence of B cells. About 90% of all hereditary agammaglobulinemia cases are represented by Bruton disease (X-linked agammaglobulinemia), while the remaining 10% are non-X-linked agammaglobulinemias [9]. X-linked agammaglobulinemia is caused by impaired synthesis of Btk tyrosine kinase (named after its discoverer, Bruton), which is involved in B-lymphocyte maturation in the bone marrow. This results in the virtual absence of B lymphocytes in the peripheral blood and peripheral lymphoid organs, alongside severe impairments in antibody production across all immunoglobulin isotypes. The Btk gene is located on the X chromosome (Xq21.3); therefore, this disease affects exclusively males, whereas females are asymptomatic carriers [6,7]. In other cases, agammaglobulinemia is caused by mutations in other genes, most of which are inherited in an autosomal recessive manner. Only one genetic form is inherited in an autosomal dominant manner (Appendix A3.2) [10].

CVID is the most frequent clinically significant form of PID with impaired antibody synthesis. In most cases, it is not possible to establish the genetic basis of the disease. Most likely, patients have a combination of certain gene polymorphisms with environmental factors.[6] However, thanks to the development of molecular genetics, causal mutations have been identified in a proportion of patients with CVID and a monogenic inheritance pattern has been established, which has led to the identification of separate nosological entities; some of these have been removed from the CVID diagnosis into other sections of the classification of inborn errors of immunity and no longer belong to PIDs with predominant antibody deficiency. Along with this, a number of polymorphisms have been described that predispose to the development of CVID but are not obligately pathogenic [5,11].

Selective IgA deficiency is the most widespread PID in the population, but is often clinically insignificant, characterized by a predominant impairment of antibody synthesis. The development mechanism and inheritance pattern of selective IgA deficiency are unknown. It is hypothesized that the development of the defect may be driven either by a failure in lymphocyte switching to IgA synthesis or by impaired maturation of IgA-producing lymphocytes. Meanwhile, the synthesis of other immunoglobulin classes remains normal. Members of the same family may include patients with CVID and selective IgA deficiency; furthermore, over the course of a patient's lifetime, selective IgA deficiency can transform into CVID [6].

The molecular-genetic basis for the development of IgG subclass deficiency is also unknown. The main clinical significance lies in IgG2 subclass deficiency. IgG1 deficiency is not considered in this group of PIDs because, constituting the bulk of total IgG, it leads to hypogammaglobulinemia. IgG3 deficiency generally matters when combined with deficiencies of other subclasses or IgA deficiency, whereas IgG4 deficiency is in most cases an incidental finding and runs an asymptomatic course. [6]

1.3 Epidemiology of the Disease or Condition

PIDs with predominant antibody synthesis impairment represent the most common form of PID (accounting for more than 50% of all patients suffering from PID) [7,14–16]. The Russian Patient Registry for PIDs records 782 patients with PIDs characterized by predominant antibody synthesis impairment, which accounts for 30% of the total number of PID patients.

The prevalence of various forms of PID with impaired antibody synthesis varies widely and depends on the specific PID form.

CVID is the most frequent diagnosis in cases where a clinically significant PID is identified in adults. The exact prevalence of this PID form is unknown; according to various estimates, it ranges from 1:10,000 to 1:50,000 [6,12]. Men and women are affected by the disease to an equal extent [13].

The prevalence of agammaglobulinemia ranges from 1:100,000 to 1:200,000. Since the majority of cases are X-linked inherited, clinical manifestations occur predominantly in male patients [6,8].

Selective IgA deficiency represents the most frequent form of PID with impaired antibody synthesis (with a prevalence ranging from 1:142 to 1:18,000); however, in the majority of patients, the disease is asymptomatic. The prevalence among males and females is equal [6,12].

The true prevalence of specific antibody deficiency and IgG subclass deficiency is unknown, since in a number of cases these alterations do not lead to clinically significant infections. Furthermore, in routine practice, the analysis of immunoglobulin subclasses and the testing of specific antibody titers are not always available [6,14].

To date, it is impossible to estimate the prevalence of other forms of PID with predominant antibody synthesis impairment [6].

1.4 Features of Coding the Disease or Condition

The classification of PIDs according to the International Classification of Diseases, 10th Revision (ICD-10) is outdated and does not reflect modern data. The most current classification of PIDs is based on the identifiable immunological defect (Appendix A3.2) [5,15].

D80 – Immunodeficiencies with predominant antibody defect

D80.0 Hereditary hypogammaglobulinemia

D80.1 Nonfamilial hypogammaglobulinemia

D80.2 Selective immunoglobulin A (IgA) deficiency

D80.3 Selective deficiency of immunoglobulin G (IgG) subclasses

D80.4 Selective immunoglobulin M (IgM) deficiency

D80.5 Immunodeficiency with increased immunoglobulin M [1]

D80.6 Antibody deficiency with near-normal immunoglobulin levels or with hyperimmunoglobulinemia

D80.7 Transient hypogammaglobulinemia of infancy

D80.8 Other immunodeficiencies with predominant antibody defect

D80.9 Immunodeficiency with predominant antibody defect, unspecified

D83 – Common variable immunodeficiency

D83.0 Common variable immunodeficiency with predominant abnormalities in B-cell number and function

D83.1 Common variable immunodeficiency with predominant abnormalities in immunoregulatory T-cells

D83.2 Common variable immunodeficiency with autoantibodies to B- or T-cells

D83.8 Other common variable immunodeficiencies

D83.9 Common variable immunodeficiency, unspecified [16]

[1] this category includes variants of hyper-IgM syndromes without defects in the cellular arm of the immune system; other forms are classified as combined PIDs).

1.5 Classification of the disease or condition

See Appendix A3.2.

1.6 Clinical presentation of the disease or condition

PIDs with predominant impairment of antibody synthesis represent a heterogeneous group of nosologies. Each form is characterized by its own unique spectrum of clinical manifestations and a different age of symptom onset. A unifying characteristic feature is the presence of recurrent infections, predominantly of the sinopulmonary tract, with an increased susceptibility to encapsulated bacteria.

Severe recurrent respiratory tract infections in patients with PID and predominant antibody synthesis impairment lead to the development of structural lung tissue changes: bronchiectasis, pneumosclerosis, and pneumofibrosis. [17–19]

The second most frequent infectious manifestation after sinopulmonary infections is infectious lesions of the gastrointestinal tract (GIT). Infectious enteropathy can be caused by small intestinal bacterial overgrowth syndrome or a specific pathogen. In the clinical presentation, these may be combined with skin infections, infectious arthritis, and other infectious manifestations.

A characteristic feature of infectious processes is (as in the case of other PID forms) torpidity to standard antibiotic therapy regimens, as well as the absence of predisposing factors for the development of severe infections (e.g., smoking, adverse working conditions) [8].

From a clinical perspective, the most relevant PIDs among those listed above in adults and children are:

· Agammaglobulinemia, including X-linked agammaglobulinemia (Bruton disease);

· Common variable immunodeficiency (CVID);

· Selective IgA deficiency;

· IgG subclass deficiency;

· Selective specific antibody deficiency;

· Transient hypogammaglobulinemia of infancy

X-Linked Agammaglobulinemia (Bruton Disease)

Characteristic features of this PID form, in addition to predisposition to infections, include:

· Symptoms of the disease typically appear between 6 months and 1 year of age, when transplacentally acquired maternal antibodies become depleted and the synthesis of the child's own antibodies is not yet adequate. However, in rarer cases, the disease may manifest after 1 year of age; [6,7,20]

· In some cases, growth retardation may be observed; [6]

· Underdevelopment of peripheral lymphoid organs (hypoplasia of tonsils, lymph nodes); [20]

· Chronic course of sinusitis with frequent exacerbations;

· Bronchiectasis as a consequence of repeated pneumonias;

· Sensorineural hearing loss as a consequence of purulent otitis media; [6]

· Joint deformity as a consequence of infectious and non-infectious arthritis; [6]

· Neutropenia at disease onset;

· To a lesser extent than other PID forms, Bruton disease is characterized by concomitant non-infectious complications, such as autoimmune manifestations and inflammatory bowel disease (IBD). Nevertheless, compared to the healthy population, the risk of these complications is significantly higher. For example, complications such as juvenile idiopathic arthritis, colorectal cancer, Crohn-like inflammatory bowel disease, and type 1 diabetes mellitus (DM) may develop. [7,8,20]

The clinical presentation of other forms of agammaglobulinemia (autosomal recessive and autosomal dominant) is similar to that of X-linked agammaglobulinemia. [5,8,14]

Common Variable Immunodeficiency (CVID)

· The first clinical symptoms of the disease can appear in both childhood and adulthood. Many authors identify two peaks of symptom onset characteristic of CVID: between 2 and 5 years, and between 18 and 25 years; [12,21]

· In addition to infectious manifestations of the disease (similar to those listed for Bruton disease), CVID is characterized by a wide spectrum of non-infectious manifestations associated with immune dysregulation:

· Pathological lymphoproliferation (lymphadenopathy, splenomegaly, etc.):

o Lymphadenopathy of various lymph node groups (approx. 40% of patients);

o Splenomegaly (up to 60% of patients);

o Hepatomegaly (up to 15% of patients). [22]

· One of the most severe non-infectious inflammatory complications affecting the bronchopulmonary system is interstitial lung disease (ILD). The prevalence of ILD is 240 times higher among patients with CVID than in the general population. [23] The clinical manifestations of ILD are highly variable. This term encompasses pathohistological entities such as lymphocytic interstitial pneumonia, follicular bronchiolitis, granulomatous lung disease, organizing pneumonia, granulomatous-lymphocytic lung disease, etc. [19,24]

· CVID is characterized by the formation of non-caseating granulomas in the lungs, lymph nodes, spleen, and less frequently in other organs. These granulomas share features similar to those seen in sarcoidosis. [6] When performing differential diagnosis between CVID and sarcoidosis, the characteristics of granulomas observed on chest computed tomography (CT) are of great importance. In CVID, the lower lung lobes are more frequently affected; nodules are prominent, large, and in most cases distributed randomly, with the presence of bronchiectasis being characteristic. In sarcoidosis, nodules are small, perilymphatically distributed, and hilar lymphadenopathy is typical. Since severe infections are not characteristic of sarcoidosis, bronchiectasis in the lungs is generally absent. [19,25]

· Non-infectious gastrointestinal (GI) tract involvement. Diarrheal syndrome (persistent or transient) is characteristic of more than 20% of patients. Intestinal involvement leads to malabsorption syndrome, hypoproteinemic edema, prominent electrolyte disturbances, and vitamin and trace element imbalances. Non-infectious forms of GI involvement in CVID patients include celiac-like small bowel disease, Crohn-like bowel disease, ulcerative colitis, nodular lymphoid hyperplasia of the intestine, and intestinal granuloma formation. Gastrointestinal symptoms are often the primary manifestation of CVID, which significantly complicates diagnosis. [6,26]

· Cytopenias (immune thrombocytopenia, autoimmune hemolytic anemia, less commonly neutropenia). Immune cytopenias are characteristic of 10–29% of CVID patients and are often the first clinical symptom of the disease. [6,8]

· Malignant neoplasms. Patients with CVID have an increased risk of developing malignancies, especially lymphomas. Furthermore, the risk of developing lymphoma increases significantly with the patient's age. Non-Hodgkin lymphomas are the most characteristic. [6]

Selective IgA deficiency

In almost two thirds of patients, selective IgA deficiency is asymptomatic. When symptomatic, the disease is characterized not so much by severe infections as by frequent ones. A more severe course is observed when IgA deficiency is combined with IgG subclass deficiency. Patients with selective IgA deficiency may also have comorbid gastrointestinal, autoimmune, and allergic diseases.

IgG subclass deficiency and specific antibody deficiency with normal immunoglobulin levels and a normal B-lymphocyte count

IgG subclass deficiency is more commonly characterized by sinusitis, otitis media, and bronchitis, whereas pneumonia and meningitis are less frequent. There is a tendency towards allergic diseases. [6,27]

Transient hypogammaglobulinemia of infancy.

The gap between the depletion of maternal antibodies and the onset of adequate endogenous synthesis in infants represents a physiological period of hypogammaglobulinemia, which typically lasts up to 3–6 months of age. The prolongation of this phase with a decrease in IgG levels is considered transient infantile hypogammaglobulinemia. The disease may be asymptomatic. In some cases, more frequent upper and lower respiratory tract infections are observed. [6,7]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Separate diagnostic criteria have been formulated for each form of PID with predominantly antibody synthesis deficiency. (Table 1, Appendix B1, Appendix B2). [28]

Table 1. ESID diagnostic criteria for various forms of PID with predominant antibody synthesis deficiency. [28]

• All patients with suspected PID with predominant antibody deficiency should undergo differential diagnosis with other forms of PID in order to select appropriate therapy. [3,6]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with decreased immunoglobulin levels should be evaluated to rule out secondary hypogammaglobulinemia to clarify the diagnosis. [3,31]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: secondary hypogammaglobulinemia is 30 times more common than PID with predominant antibody deficiency. Secondary hypogammaglobulinemia is not always accompanied by a propensity for severe chronic infectious processes and is often transient in nature. [31]

• All patients with hypogammaglobulinemia should be evaluated to rule out other diseases and/or conditions that can lead to an uncontrolled infectious process in order to clarify the diagnosis. [31]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

2.1 Complaints and Anamnesis

• To ensure timely diagnosis, screening for PID with predominant antibody deficiency is recommended for patients with the following clinical symptoms in their medical history:

o Family history burdened with immunological diseases;

o Severe chronic and/or recurrent infections refractory to standard treatment regimens (sinusitis, otitis media, bronchitis, pneumonia, arthritis, gastrointestinal infections, meningitis, sepsis, skin infections);

o Persistent diarrheal syndrome (including with the development of malabsorption syndrome);

o Symptoms of pathological lymphoproliferation (persistent lymphadenopathy involving multiple lymph node groups, splenomegaly, lymphocytic infiltration of the lungs and other organs, nodular hyperplasia of the gastrointestinal mucosa, etc.);

o Autoimmune manifestations (primarily cytopenias);

o Granulomatous inflammation in organs (primarily sarcoid-like changes in the lungs);

o Detection of bronchiectasis, especially in young patients;

o Malignancies of lymphoid tissue. [22,27,32,33]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: particular vigilance should be exercised regarding patients presenting with several of the above symptoms. [6]

• A thorough family history should be taken in all patients with suspected PID with predominant antibody deficiency for differential diagnosis purposes. [6,7,12,20]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: a burdened family history includes the death of a relative in infancy, the death of a relative from an infectious disease, the presence of one or more relatives with chronic or recurrent infections of a severe/atypical course, cytopenias, or other symptoms characteristic of PID. [3] Nearly half of patients with X-linked agammaglobulinemia have a positive family history. [20]

2.2 Physical Examination

• All patients with suspected PID with predominant antibody deficiency are recommended to undergo a complete physical examination to verify the diagnosis and assess the severity of the condition. [22,27,32,33]

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comments:

• General examination. Due to frequent past infections, children may experience growth retardation (more applicable to patients with X-linked agammaglobulinemia). Patients with severe enteropathy may exhibit weight loss;

• Palpation of peripheral lymph node groups. Evaluate the size, consistency, mobility, and tenderness of peripheral lymph nodes. Localized or generalized lymphadenopathy may be present (characteristic of patients with CVID). Hypoplasia of lymph nodes is characteristic of patients with agammaglobulinemia (including the absence of regional lymph node enlargement despite an active infectious process)

• Palpation of the liver and spleen: hepatomegaly and/or splenomegaly may be present (characteristic of patients with CVID, hyper-IgM syndrome).

• Hypoproteinemic edema is characteristic of patients with severe enteropathy or other conditions leading to protein loss.

• Presence of signs of chronic infectious processes: e.g., clubbing ("drumstick fingers") and watch-glass nails, increased anteroposterior chest diameter, etc.

• Deformities of large joints may occur as a consequence of non-infectious or past infectious arthritis.

• Examination of the skin — it is important to pay attention to the presence of skin rashes, boils, skin abscesses, as well as scars at the sites of their previous localization. [6]

2.3 Laboratory Diagnostics

2.3.1 Laboratory diagnostic tests to verify the diagnosis

• All patients with clinical signs characteristic of PID with predominant antibody deficiency are recommended to undergo a blood total protein test and determination of protein fraction ratios by electrophoresis to detect changes in gamma globulin levels. [34,35]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with clinical signs characteristic of PID with predominant antibody deficiency are recommended to undergo blood immunoglobulin A, G, and M testing to detect humoral immunity disorders (Table 1, Appendix B1). [28,33,36,37]

GCP CLOE 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: hypogammaglobulinemia is defined as a decrease in IgG levels below 2 standard deviations from the age-adjusted normal range in children and below 4.5 g/L in adults. Agammaglobulinemia is defined as an IgG concentration below 1.0 g/L, combined with IgM concentrations below 0.2 g/L and an IgA concentration below 0.1 g/L, with a peripheral CD19+ B-cell count below 2%. [5] Measurement must be confirmed by at least 2 tests. [29]

• Patients with hypogammaglobulinemia and agammaglobulinemia are recommended to undergo CD19+ lymphocyte testing to clarify the PID subtype (Table 1, Appendix B1). [3,6]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• Patients with suspected CVID are recommended to undergo one of the following tests to confirm the diagnosis (Table 1):

o blood isohemagglutinin level testing;

o CD19+CD27+IgD− lymphocyte testing (switched memory B cells);

o in case of borderline/normal quantitative blood immunoglobulin levels — determination of IgG antibody titers to two or more infectious agents before and after vaccination to assess the ability to mount a post-vaccination immune response (Appendix A3.3). [3,30]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: isoagglutinins are antibodies against blood group alloantigens (ABO blood group system antigens). [3]

To assess post-vaccination immunity, unvaccinated patients are recommended to be vaccinated with inactivated vaccines. Evaluation of the post-vaccination immune response using polysaccharide vaccines should be performed no earlier than the patient reaches 2 years of age. Assessment of post-vaccination immunity should be carried out before initiating replacement therapy with normal human immunoglobulin**. Clinically significant is the absence of a 2-4-fold titer increase 4-6 weeks after vaccination. In case of borderline values, dynamic monitoring is recommended in another 4 weeks. [38]

• Patients with suspected impaired synthesis of specific antibodies are recommended to have blood class G antibodies (to diphtheria toxoid, Clostridium tetani, Neisseria meningitidis, Haemophilus influenzae) determined before and after vaccination to assess the ability to form a post-vaccination immune response (Table 1, Appendix A3.3). [3,34]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• Patients with suspected IgG subclass deficiency (isolated or combined with IgA deficiency) are recommended to undergo a blood immunoglobulin G test to establish the diagnosis (Table 1). [27]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

• All patients with hypogammaglobulinemia and agammaglobulinemia are recommended to undergo CD3+, CD4+, CD8+, CD16+/56+ lymphocyte testing to rule out combined forms of PID (Table 1, Appendix B1, Appendix B2). [3,6,29]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

2.3.2 Molecular genetic diagnostics

• All male patients with agammaglobulinemia and a B-cell count reduced below 2% are recommended to undergo molecular genetic testing for mutations in the Btk gene in the blood to confirm the diagnosis of X-linked agammaglobulinemia (Table 1, Appendix B1). [3,6,20,39]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

• All female patients, as well as male patients without an identified mutation in the Btk gene who present with hypogammaglobulinemia and a B-cell count < 2%, are recommended to undergo molecular genetic testing for mutations in genes responsible for the development of other forms of agammaglobulinemia (Appendix A3.2) to confirm the diagnosis. [3,6,40–46]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

• All patients with agammaglobulinemia and other forms of PID with predominant antibody deficiency and an unidentified mutation are recommended to undergo molecular genetic testing using customized gene panels (next-generation sequencing (NGS) method) or whole-exome or whole-genome sequencing (Appendix A3.4) to clarify the PID subtype. [3,47,48].

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

2.3.3. Laboratory diagnostic tests in patients with an established diagnosis of PID with antibody synthesis disorders

• All patients with PID with predominant antibody deficiency are recommended to use the PCR (polymerase chain reaction) method to diagnose viral and other infections, since serological diagnostic methods are uninformative in this patient group. [7]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: the use of serological testing is associated with a high risk of obtaining unreliable results. [7]

• All patients with PID with predominant antibody deficiency are recommended to undergo regular laboratory tests at least once every 6 months for the timely detection and monitoring of complications:

o Complete blood count (CBC) with differential leukocyte count (leukogram) and ESR (erythrocyte sedimentation rate) determination;

o Urinalysis;

o General clinical blood chemistry panel (total protein, protein fractions, urea, creatinine, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase), LDH (lactate dehydrogenase), total bilirubin, glucose). [3,6,49,50]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with hypogammaglobulinemia and agammaglobulinemia receiving replacement therapy with normal human immunoglobulin** are recommended to have a monthly pre-infusion blood IgG level test until the target level is achieved to monitor treatment efficacy. [3]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with hypogammaglobulinemia and agammaglobulinemia receiving replacement therapy with normal human immunoglobulin** are recommended, after achieving the target IgG level, to undergo pre-infusion blood IgG testing at least once every 6 months to monitor treatment efficacy and adjust the dose.[3]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with PID with predominant antibody deficiency who develop infectious complications are recommended to verify the causative agent in order to select the optimal treatment strategy.[3,51]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

2.4 Instrumental Diagnostics

• All patients with PID with predominant antibody deficiency are recommended to undergo a chest CT scan at the time of diagnosis for the timely diagnosis of complications. [49,52,53]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: subsequently, the frequency of this examination is determined by clinical indications.

• All patients with CVID are recommended to undergo ultrasound examination (ultrasonography) of accessible lymph nodes and abdominal organs at the time of diagnosis and at least once a year for the timely detection of complications (pathological lymphoproliferation, malignancy) and monitoring of treatment efficacy. [13]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: these tests are necessary because patients with CVID are at risk for developing malignant lymphoproliferative disorders.

• All patients with CVID are recommended to undergo chest CT at least once a year for the timely diagnosis of complications.[ 3,49,52,53]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: Chest CT is the most sensitive method for detecting, evaluating, and characterizing lung involvement in patients with CVID, as not all pulmonary changes can be timely detected by radiography. The frequency of chest CT is determined individually for each patient, based on the CVID phenotype, disease severity, and therapy. It should be kept in mind that non-infectious manifestations of PID (ILD) can remain asymptomatic for a long time. Late detection and inadequate therapy of ILD can worsen the prognosis.

• All patients with CVID who present with pathologically altered lymph nodes are recommended to undergo excisional biopsy of these lymph nodes and subsequent histological and immunohistochemical examination of the biopsy (surgical) material of the lymph node for the timely diagnosis of malignancy and/or selection of targeted therapy. [12,21,49]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with CVID with suspected interstitial lung disease are recommended to undergo a lung biopsy with subsequent pathohistological and immunohistochemical examinations of the obtained biomaterial for the timely diagnosis of manifestations of immune dysregulation and malignant neoplasms and/or selection of targeted therapy. [12,21,49]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• Patients with gastrointestinal tract involvement and hypogammaglobulinemia are recommended to undergo a biopsy of the colon and/or small intestine using video endoscopic techniques and subsequent histological examination of the biopsy (surgical) material of the small intestine and/or colon using immunohistochemical methods for differential diagnosis between intestinal involvement in CVID and a number of GI diseases (celiac disease, ulcerative colitis, Crohn's disease). [54]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: CVID often occurs under the guise of various GI diseases (celiac disease, ulcerative colitis, Crohn's disease); the differential diagnosis is complicated by the similarity of the pathohistological picture in CVID with these diseases. A marker of CVID is the absence of CD20+ plasma cells in the lamina propria. [12,54]

2.5 Other Procedures

• All patients with PID with predominantly antibody deficiency are recommended to have consultations with an allergist-immunologist at least once a year to monitor the course of the disease, adjust therapy, and timely detect and control complications. [3,6,49]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All relatives of patients with PID with predominantly antibody deficiency with an established mutation are recommended an appointment (examination, consultation) with a geneticist to identify individuals in need of molecular genetic testing for the timely diagnosis of PID or detection of carrier status. [3]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All relatives of patients with PID with predominantly antibody deficiency with an established mutation are recommended an appointment (examination, consultation) with a geneticist for family planning. [3]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• All patients with PID with predominantly antibody deficiency are recommended to have consultations with multidisciplinary specialists for the timely diagnosis of complications and selection of therapy upon identification of relevant complaints and/or clinical manifestations, and/or changes during examination:

o gastroenterologist;

o pulmonologist;

o otorhinolaryngologist;

o dentist;

o hematologist;

o oncologist;

o rheumatologist;

o phthisiatrician. [3,21]

GCP CLOE 5Grade of Recommendation – C (Level of Evidence – 5)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The main areas in the treatment of patients with PID with predominantly antibody deficiency are:

o replacement therapy with normal human immunoglobulin** preparations for intravenous (IVIG**) and subcutaneous administration (SCIG**);

o prevention and/or therapy of infectious manifestations;

o therapy for manifestations of immune dysregulation. [35]

3.1 Replacement therapy with normal human immunoglobulin**

Replacement therapy with normal human immunoglobulin** is the basis of therapy for such forms of PID with predominantly antibody deficiency as CVID, agammaglobulinemia, and hyper-IgM syndrome with predominantly antibody deficiency. When severe and/or recurrent infections develop, the issue of prescribing this therapy can also be considered in other forms of PID with predominantly antibody deficiency. [3]

Placebo-controlled trials of normal human immunoglobulin preparations** for replacement therapy in patients with PID are considered ethically impossible and are not conducted. [55] Therefore, the LoE (level of evidence) and GoR (grade of recommendation) for this type of therapy are low. [56]

o agammaglobulinemia;

o CVID;

o hyper-IgM syndrome with predominantly antibody deficiency. [57–62]

GOR CLOE 4Grade of Recommendation – C (Level of Evidence - 4).

Comments: Normal human immunoglobulin** preparations are not generics, but the manufacturing process of normal human immunoglobulin** preparations is strictly regulated (Appendix A3.5). [55,63–66]

They are comparable in efficacy, but have differences due to the manufacturing process (different donor populations, IgG subclass distribution, IgA level, stabilizers, pH level, virus safety, and other characteristics). To achieve the best treatment result, the normal human immunoglobulin** preparation should be selected based on the individual characteristics of the patient. [60,67–69]

According to the route of administration, normal human immunoglobulin** preparations are divided into subcutaneous forms (SCIG**) and preparations for intravenous administration (IVIG**). The recommended IVIG** dose is 0.4–0.8 g/kg (grams/kilograms) of body weight once every 3–4 weeks. [3,57,58,60,68,70,71] The recommended total SCIG** dose for 1 month is 0.4–0.8 g/kg of body weight (in cases where a conversion factor exists, it is calculated in accordance with the instructions). The total dose is divided into several subcutaneous injections, which should be performed at equal intervals throughout the month. Administration of SCIG** preparations can be carried out using the rapid push method and with the help of a special administration device (pump). [71]

The dose of normal human immunoglobulin** and the frequency of administration should be selected individually for each patient, taking into account comorbidities (the presence of bronchiectasis, protein-losing enteropathy, etc.), metabolic characteristics, presence/absence of an infectious process exacerbation, etc. The target pre-infusion IgG value is not less than 7 g/L. The prescription of preparations in higher doses (0.6–0.8 g/kg of body weight) is recommended at the initiation of therapy, after replacement therapy interruptions of more than 3 months (loading therapy), as well as during clinically significant infectious episodes and/or complications leading to protein loss (enteropathy, nephrotic syndrome). In the presence of comorbid pathology (such as immune cytopenias), high-dose therapy with normal human immunoglobulin** may be performed in accordance with the clinical guidelines for this nosological entity. [71,72]

o Specific antibody deficiency with normal immunoglobulin levels and a normal B-cell count at a dose of 0.4 g/kg of body weight once every 4 weeks (adults and children); [73–75]

o Transient hypogammaglobulinemia of infancy at a dose of 0.4 g/kg of body weight monthly (children), usually for 2–3 months; [76,77]

o IgG subclass deficiency (with/without IgA deficiency) at a dose of 0.4 g/kg of body weight once every 4 weeks (adults and children). [78–82]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: the duration of replacement therapy is determined based on the clinical situation. [73–80,82]

• All patients with PID with predominantly antibody deficiency receiving replacement therapy with normal human immunoglobulin** are recommended to have their drug dose adjusted so that the pre-infusion IgG level is > 7 g/L to achieve control over infectious diseases. [83]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

• For all patients receiving replacement therapy with normal human immunoglobulin**, it is recommended to choose a preparation taking into account individual tolerability to reduce the risk of adverse events during replacement therapy. [84]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: the risk of adverse events increases at the initiation of therapy, as well as when switching between different normal human immunoglobulin** products during treatment. Isoosmolar products and ready-to-use solutions carry a lower risk of side effects compared to lyophilizates. When using multiple vials of a lyophilized product, the risk of adverse events increases. It should also be considered that patients may have hypersensitivity to certain components of the products. [84]

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin** products, to achieve effective control over infectious diseases, it is not recommended to use products containing less than 95% IgG (and/or not stating this in their instructions for use) (Appendix A3.5). [70,90,91]

GRC ALOE 2Level of Evidence – A (level of proof - 2).

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin** products, it is recommended to use products with an IgG subclass distribution close to physiological, which must be stated in the product instructions, in order to achieve control over the infectious process (Appendix A3.5). [63,68]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin**, it is not recommended to use products that do not undergo parvovirus B19 elimination steps during manufacturing and lack testing for its presence in donor plasma and the final product (or do not state this in their instructions) (Appendix A3.5). [87]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: parvovirus B19 can cause severe hematopoiesis disorders, which can become a life-threatening complication in patients with PID. [88–90] Since normal human immunoglobulin** is a blood product, its administration carries the risk of transmitting transfusion-transmitted infections; only a multi-step virus elimination process can minimize the possibility of such complications. [85].

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin**, it is not recommended to use products that do not indicate the IgA content, in order to reduce the risk of severe anaphylactic reactions (Appendix A3.5). [85,91]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID with predominant antibody deficiency, with a high risk of renal failure (age over 65 years, history of renal failure, sepsis, use of nephrotoxic drugs, dehydration, paraproteinemia) and/or cardiovascular diseases and/or an increased risk of thromboembolic diseases, who require replacement therapy with normal human immunoglobulin** products, it is recommended to use 10% IVIG** solutions (to reduce the infused fluid volume) or SCIG** to reduce the risk of adverse events. [92]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: in patients with pre-existing renal diseases, it is preferable to use IVIG** with a maltose stabilizer. [93]

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin** products, who have difficult venous access (especially children), it is recommended to use SCIG** to ensure the technical feasibility of regular therapy and reduce negative consequences for the patient. [71,94]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin** products, who have a history of systemic reactions during intravenous administration, it is recommended to switch the IVIG** product or use SCIG** to reduce the risk of severe systemic reactions. [95]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID with predominant antibody deficiency requiring replacement therapy with normal human immunoglobulin** products, who have a history of poor tolerance to IVIG** when switching the normal human immunoglobulin** product is impossible, the following rules are recommended to improve infusion tolerance:

o reduction of infusion rate (for IVIG** 5% and 10%): start at a rate of 0.01 mL/kg/min (0.5–1 mg/kg/min), gradually increasing (every 15–30 min) to 0.02 mL/kg/min, 0.04 mL/kg/min, 0.06 mL/kg/min, and up to 0.08 mL/kg/min (4–8 mg/kg/min),

o premedication using nonsteroidal anti-inflammatory and antirheumatic drugs, systemic antihistamines, systemic corticosteroids (sGCs),

o prehydration with #sodium chloride** 30 minutes prior to drug administration (500 mL for adults and 10–20 mL/kg of body weight for children). [71]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID with predominant antibody deficiency and concomitant diseases associated with protein loss (nephrotic syndrome, enteropathy) requiring replacement therapy with normal human immunoglobulin** products, it is recommended to use SCIG** to more effectively maintain the target IgG level.[73,97,98]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

• For patients with PID, the use of normal human immunoglobulin** for intramuscular (IMIG**) administration as replacement therapy is strictly discouraged.[98,99]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: IMIG** is ineffective due to the high rate of drug inactivation at the injection site and low systemic bioavailability. [68,98,99]

3.2 Prevention and/or treatment of infectious manifestations

For patients with PID with predominant antibody deficiency, antibiotic therapy may be prescribed in 3 regimens:

· As a course for treating an exacerbation;

· Intermittent prophylactic antibiotic therapy (short or long courses);

· Persistent prophylactic antibiotic therapy (lifelong intake of antibacterial drugs).

In patients with more severe forms of PID with predominant antibody deficiency (CVID, agammaglobulinemia, marked decrease in serum IgG and IgA with normal/elevated IgM and normal B-cell count (hyper-IgM)), antibacterial therapy is prescribed in addition to replacement therapy in the presence of chronic infection foci (in case of an uncontrolled infectious process, the issue of increasing the dose and/or frequency of administration of the normal human immunoglobulin product should be addressed). For patients with milder forms of PID with predominant antibody deficiency (transient hypogammaglobulinemia, selective IgA deficiency, IgG subclass deficiency, specific antibody deficiency with normal immunoglobulin levels and normal B-lymphocyte counts), antibacterial therapy is first-line therapy, and replacement therapy should only be considered in the event of an infectious process uncontrolled by antibacterial therapy (including in a persistent regimen). [3]

• For patients with PID with predominant antibody deficiency, early prescription and administration of combined and prolonged courses of antimicrobial, antiviral, and antifungal therapy are recommended to achieve effective control over infections (Table 2). [3,100]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: a course of antibacterial therapy of standard duration may be insufficient to eradicate the pathogen. [3,100]

• For patients with PID with predominant antibody deficiency with inadequate control of the infectious process, the prescription of prophylactic antibacterial therapy in long or short courses is recommended to control the infectious process (Table 2).[3,100]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Comments: in these forms of PID, intermittent prophylactic antibiotic therapy is usually sufficient (the drug, dosage, and duration of therapy are determined by the attending physician). If exacerbations of infectious diseases occur in a specific season, seasonal courses of antibiotic therapy are prescribed.

Table 2. Prophylactic antibiotic therapy.[3,100]

In case of ineffectiveness or poor tolerability of these regimens, any other systemic antibacterial drug may be chosen.

3.3 Treatment of manifestations of immune dysregulation

Methods of treating immune dysregulation have a limited evidence base (according to the LOE and GOR assessment scales) due to the lack of clinical studies dedicated to them. Despite this, they are necessary elements of the treatment strategy, as more effective and proven methods have not been developed at present. When choosing management and therapy tactics, it should be taken into account that the patient may have non-standard disease manifestations, as well as a combination of the disease with other pathologies, which may dictate the need for changes in the algorithm for choosing the optimal treatment strategy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Sanatorium-resort treatment for complications of the underlying disease profile. Psychological rehabilitation and social adaptation

5. Prevention and Dispensary Observation

The method of perinatal and early postnatal screening for hereditary agammaglobulinemias, transient hypogammaglobulinemia of infancy, certain forms of hyper-IgM syndromes, and early-onset CVID is the determination of TREC (T-cell receptor excision circles) and KREC (kappa-deleting recombination excision circles) in smear-imprints. This method allows screening patients for an in-depth immunological examination. [101–103]

• All patients with PID with predominant antibody deficiency are recommended to receive annual vaccination against influenza virus (with an inactivated vaccine), immunization with a vaccine for the prevention of pneumococcal infection and infections caused by Haemophilus influenzae type b to prevent infection with these pathogens. [104–107]

GOR CLOE 5Grade of recommendation — C (level of evidence - 5).

Comments: it is preferable to use conjugated and adjuvanted vaccines. [104–107]

• Patients with CVID, agammaglobulinemia, hyper-IgM syndrome are not recommended to use live vaccines to prevent the risk of developing a vaccine-associated infectious process or virus carriage. [104–108]

GOR CLOE 5Grade of recommendation — C (level of evidence - 5).

Comments: immunization with varicella vaccine, mumps vaccine, measles vaccine, and rubella vaccine is possible if the CD4+ count is > 500 cells/mm3 in adults, > 1000 cells/mm3 in children aged 1 to 6 years, and > 1500 cells/mm3 in children under 1 year of age.[ 104,108]

• All patients with immunoglobulin isotype deficiency or light chain deficiency with a normal number of B-lymphocytes are recommended to be vaccinated in accordance with the National Immunization Schedule for the prevention of infectious diseases. [104,105,108]

GOR CLOE 5Grade of recommendation — C (level of evidence - 5).

Comments: the vaccination plan for close contacts should include: routine vaccination according to the schedule (if not done previously), annual vaccination against influenza virus (with an inactivated vaccine), immunization for the prevention of pneumococcal infection and infections caused by Haemophilus influenzae type b. For the vaccination of close contacts of patients with PID with predominant antibody deficiency against influenza and polioviruses, the drugs of choice are vaccine preparations containing trivalent whole-inactivated poliovirus and whole-inactivated influenza virus. [104]

6. Organization of Medical Care

After diagnosis establishment:

· A patient with an established diagnosis of PID with antibody deficiency must be under dispensary observation by a local physician and attend follow-up visits to monitor therapy. The frequency of observation is determined based on the severity of the disease course.

· Patients receiving replacement therapy must undergo an examination at least once a year to monitor the development of complications.

· Patients with PID with antibody deficiency must be provided with baseline therapy drugs (normal human immunoglobulin** at the required dose and drugs to control symptoms of immune dysregulation).

6.1 Indications for planned hospitalization

• initial diagnosis establishment in the presence of symptoms characteristic of PID;

• hospitalization in specialized centers if therapy adjustment is necessary;

• any complications requiring inpatient treatment (autoimmune, malignancy, enteropathy, etc.).

6.2 Indications for emergency hospitalization

Life-threatening conditions requiring emergency medical care.

6.3 Indications for hospital discharge

· State stabilization;

· The duration of inpatient treatment is determined by the nature and severity of clinical manifestations of infectious and non-infectious PID complications.

7. Additional Information

A diagnosis of PID with predominant antibody deficiency is not a contraindication to pregnancy and childbirth. Rational preparation and monitoring of pregnancy are necessary, especially if the patient has a severe uncontrolled infectious process or serious complications. The choice of delivery method is based on obstetric indications.

• Pregnant women with PID with predominant antibody deficiency are recommended to have joint pregnancy management under the supervision of an allergist-immunologist and an obstetrician-gynecologist to reduce the risk of complications. [109]

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Pregnant women with PID with predominant antibody deficiency are recommended to carefully monitor the infectious process to reduce the risk of perinatal complications. [109]

• Pregnant patients with PID with predominant antibody deficiency are recommended to increase the dose of normal human immunoglobulin** for replacement therapy in order to prevent the development of infectious complications. [71,110–112]

GCR CLOC 4Level of recommendations grading — C (level of evidence certainty - 4).

Comments: the need to increase the dose is due to the patient's weight gain, hemodilution, and transplacental transfer of some immunoglobulins to the fetus. [113] The dose and administration interval are selected individually, taking into account the pre-infusion IgG concentration, the frequency of infectious processes, the presence of non-infectious complications, and the patient's weight. [71,110–112]

• Pregnant patients with PID with predominant antibody deficiency in the event of delivery by Caesarean section are recommended to undergo courses of antibacterial therapy lasting 2–3 times longer than the duration of standard antibacterial therapy in immunocompetent patients in order to prevent the development of infectious complications in the postoperative period. [109]

GCR CLOC 5Level of recommendations grading — C (level of evidence certainty - 5).

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Working Group Members:

1. Abramova Irina Nikolaevna – Allergist-Immunologist, Candidate of Medical Sciences, Department of Immunology, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health

2. Vakhlyarskaya Svetlana Sergeevna – Allergist-Immunologist, Candidate of Medical Sciences, Physician at the Department of Clinical Immunology and Rheumatology, Russian Children's Clinical Hospital of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Assistant Professor at the Department of Clinical Immunology, Faculty of Biomedical Engineering, Pirogov Russian National Research Medical University of the Russian Ministry of Health

3. Ilina Natalia Ivanovna – Vice-President of the Russian Association of Allergologists and Clinical Immunologists (RAACI), Doctor of Medical Sciences, Professor, Deputy Director for Clinical Work – Chief Physician, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia

4. Kondratenko Irina Vadimovna – Doctor of Medical Sciences, Professor, Head of the Department of Clinical Immunology and Rheumatology, Russian Children's Clinical Hospital of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Professor at the Department of Clinical Immunology, Faculty of Biomedical Engineering, Pirogov Russian National Research Medical University of the Russian Ministry of Health

5. Kuzmenko Natalia Borisovna – Head of the Department of Epidemiology and Immunodeficiency Monitoring, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health, Candidate of Medical Sciences, Allergist-Immunologist, Pediatrician

6. Latysheva Elena Aleksandrovna – Leading Researcher at the Department of Adult Immunopathology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia, Doctor of Medical Sciences, Associate Professor at the Department of Clinical Immunology, Faculty of Biomedical Engineering, Pirogov Russian State Medical University

7. Latysheva Tatiana Vasilievna – Doctor of Medical Sciences, Professor at the Department of Clinical Allergology and Immunology, Faculty of Postgraduate Professional Education of the Moscow State University of Medicine and Dentistry, Head of the Department of Adult Immunopathology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia

8. Manto Irina Aleksandrovna – Researcher at the Department of Adult Immunopathology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia

9. Pampura Alexander Nikolaevich – Head of the Department of Allergology and Clinical Immunology, Academician Yu.E. Veltischev Research and Clinical Institute of Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Doctor of Medical Sciences, Professor.

10. Prodeus Andrey Petrovich – Doctor of Medical Sciences, Professor, Chief Pediatrician of City Children's Hospital No. 9 named after G.N. Speransky. Head of the Department of Clinical Immunology, Non-State Educational Private Institution of Additional Professional Education "Higher Medical School", Chief Non-Staff Pediatric Allergist-Immunologist of the Ministry of Health of the Moscow Region.

11. Fomina Daria Sergeevna – Candidate of Medical Sciences, Associate Professor, Associate Professor at the Department of Clinical Immunology and Allergology, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Chief Specialist Allergist-Immunologist of the Moscow Healthcare Department, Head of the Moscow City Scientific and Practical Center of Allergology and Immunology, City Clinical Hospital No. 52 of the Moscow Healthcare Department

12. Shcherbina Anna Yurievna – Doctor of Medical Sciences, Professor, Deputy Director of the Institute of Hematology, Immunology and Cell Technologies, Head of the Department of Immunology, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health

13. Chuvirov Denis Gennadievich – Candidate of Medical Sciences, Head of the Department of Pediatric Immunopathology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia

14. Yartsev Mikhail Nikolaevich – Doctor of Medical Sciences, Professor at the Department of Clinical Allergology and Immunology, Faculty of Postgraduate Professional Education of the Moscow State University of Medicine and Dentistry, Leading Researcher at the Department of Pediatric Immunopathology, National Research Center Institute of Immunology of the Federal Medical-Biological Agency of Russia

Appendix A2. Methodology for Developing Clinical Guidelines

Appendix A2.1 Target audience for these clinical guidelines:

1. obstetrician-gynecologist;

2. allergist-immunologist;

3. gastroenterologist;

4. medical geneticist;

5. dermatovenereologist;

6. pediatric surgeon;

7. laboratory geneticist;

8. neonatologist;

9. general practitioner (family physician);

10. otorhinolaryngologist;

11. pediatrician;

12. municipal (district) pediatrician;

13. district pediatrician;

14. child and adolescent hygienist;

15. occupational health physician;

16. general hygienist;

17. admission department physician;

18. dentist;

19. pediatric dentist;

20. prosthetic dentist;

21. therapeutic dentist;

22. dental surgeon;

23. general physician (internist);

24. adolescent physician;

25. district general physician;

26. district occupational physician;

27. functional diagnostics physician;

28. surgeon;

29. maxillofacial surgeon;

Appendix A2.2 Methodology for developing clinical guidelines

2 members of the working group (Elena A. Latysheva and Irina A. Manto) independently performed a systematic search and selection of publications from 01.08.2019 to 23.09.2019. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), the EMBASE database (https://www.elsevier.com/solutions/embasebiomedicalresearch), as well as clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctrsearch/search. A total of 250 publications were found, and 118 publications were selected from them. In case of disagreements during the selection of publications, other members of the working group were involved. Based on the selected publications, both experts independently formulated recommendation theses, which were evaluated using scales for assessing the level of reliability of evidence for diagnostic methods, methods of prevention, treatment and rehabilitation (preventive, therapeutic, rehabilitation interventions), and levels of recommendation persuasiveness (LRP) for methods of prevention, diagnosis, treatment and rehabilitation (preventive, diagnostic, therapeutic, rehabilitation interventions). (Appendix 1, Appendix 2, Appendix 3) Subsequently, each recommendation thesis was thoroughly discussed at a general meeting of the working group, and consensus was reached on all cases of disagreement.

Appendix 1. Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Appendix 2. Scale for assessing levels of reliability of evidence (LRE) for methods of prevention, treatment and rehabilitation (preventive, therapeutic, rehabilitation interventions)

Appendix 3. Scale for assessing levels of recommendation persuasiveness (LRP) for methods of prevention, diagnosis, treatment and rehabilitation (preventive, diagnostic, therapeutic, rehabilitation interventions)

Appendix A2.3 Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Related documents

1. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n dated August 27, 2019 "On Classifications and Criteria Used in Medical and Social Expertise of Citizens by Federal State Institutions of Medical and Social Expertise" (entered into force on Jan. 1, 2020)

2. Federal Law No. 489-FZ dated December 25, 2018 "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Fundamentals of Protecting Citizens' Health in the Russian Federation' Regarding Clinical Guidelines".

3. Order of the Russian Ministry of Health No. 103n dated February 28, 2019 "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines and Requirements for Their Structure, Composition and Scientific Validity of Information Included in Clinical Guidelines".

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

5. Order of the Ministry of Health of the Russian Federation (Russian Ministry of Health) No. 1183n dated December 20, 2012, Moscow, "On Approval of the Nomenclature of Positions of Medical and Pharmaceutical Workers."

6. Order of the Ministry of Health and Social Development of the Russian Federation No. 366n dated April 16, 2012, "On Approval of the Procedure for Providing Pediatric Care."

7. Order of the Ministry of Health of the Russian Federation No. 917n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases."

8. State Register of Medicines: https://grls.rosminzdrav.ru

9. Decree of the Government of the Russian Federation No. 339 dated March 29, 2018, "On Amendments to the Rules for Recognizing a Person as Disabled."

Appendix A3.2. International Classification of PIDs (IUIS) Based on the Identified Genetic Defect. [10]

Appendix A3.3. Vaccines available in the Russian Federation for the diagnosis of PIDs with predominant antibody synthesis deficiency. [38,114]

Appendix A3.4 Example of a targeted NGS panel for the diagnosis of Primary Immunodeficiencies. [47,48]

ACP5, ACTB, ADA, ADAMTS13, ADAR, AGA, AICDA, AIRE, AK2, ALG13, AMN, ANK1, ANKRD26, AP3B1, APOL1, ATM, BLM, BLNK, BLOC1S3, BLOC1S6, BRCA2, BRIP1, BTK, C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C4A, C4B, C5, C6, C7, C8A, C8B, C9, CARD14, CARD9, CASP10, CASP8, CCDC103, CCDC39, CCDC40, CD19, CD247, CD27, CD3D, CD3E, CD3G, CD40, CD40LG, CD46, CD55, CD59, CD79A, CD79B, CD81, CD8A, CDAN1, CEBPA, CEBPE, CFB, CFD, CFH, CFHR1, CFHR3, CFHR5, CFI, CFP, CHD7, CIITA, CLEC7A, COLEC11, CORO1A, COX4I2, CR2, CREBBP, CSF3R, CTC1, CTSC, CUBN, CXCR4, CYBA, CYBB, CYCS, DCLRE1C, DHFR, DKC1, DNAAF1, DNAAF2, DNAAF3, DNAH11, DNAH5, DNAI1, DNAI2, DNAL1, DNM2, DNMT3B, DOCK8, DSG1, DTNBP1, EGLN1, ELANE, ENTPD1, EPAS1, EPB42, EPOR, ERCC2, ERCC3, F10, F11, F12, F13A1, F2, F5, F8, FADD, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FAS, FASLG, FCGR2B, FCGR3A, FCGR3B, FCN3, FERMT3, FGA, FGB, FGF10, FGFR2, FGG, FOXN1, FOXP3, G6PC, G6PC3, G6PD, GATA1, GATA2, GFI1, GIF, GJC2, GP1BA, GP1BB, GP9, GTF2H5, HAX1, HBA1, HBA2, HBB, HBD, HFE, HPS1, HPS3, HPS4, HPS5, HPS6, HYDIN, ICOS, IFNG, IFNGR1, IFNGR2, IGLL1, IKBKG, IL10, IL10RA, IL10RB, IL12B, IL12RB1, IL17F, IL17RA, IL1RN, IL2, IL21, IL21R, IL2RA, IL2RG, IL36RN, IL7R, INSR, IRAK4, IRF8, ITCH, ITGA2B, ITGB2, ITGB3, ITK, JAK2, JAK3, KLF1, KMT2D, KRAS, LAMTOR2, LIG1, LIG4, LPIN2, LRRC6, LRRC8A, LYST, MAGT1, MAN2B1, MANBA, MASP1, MASP2, MASTL, MBL2, MC2R, MCM4, MEFV, MLPH, MPL, MPO, MRE11A, MS4A1, MTHFD1, MVK, MYD88, MYH9, MYO5A, NBN, NCF1, NCF2, NCF4, NCSTN, NFKBIA, NHEJ1, NHP2, NKX2-5, NLRP12, NLRP3, NME8, NOD2, NOP10, NRAS, ORAI1, PALB2, PCCA, PCCB, PDGFRA, PEPD, PIGA, PIK3CD, PIK3R1, PLCG2, PLG, PMM2, PMS2, PNP, PRF1, PRKDC, PRPS1, PSENEN, PSMB8, PSTPIP1, PTPN11, PTPRC, PTRF, RAB27A, RAC2, RAD51C, RAG1, RAG2, RASGRP2, RBM8A, RECQL4, RFX5, RFXANK, RFXAP, RMRP, RNASEH2A, RNASEH2B, RNASEH2C, RNF168, RPL11, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS7, RSPH4A, RSPH9, RUNX1, RUNX2, SAMHD1, SBDS, SEC23B, SEMA3E, SERPINC1, SERPINE1, SERPING1, SH2B3, SH2D1A, SH3BP2, SKIV2L, SLC29A3, SLC35A1, SLC35C1, SLC37A4, SLC39A4, SLC46A1, SLC4A1, SLX4, SMARCAL1, SP110, SPINK5, SPTA1, SPTB, SRP72, STAT1, STAT3, STAT5B, STIM1, STK4, STX11, STXBP2, TAP1, TAP2, TAPBP, TAZ, TBK1, TBX1, TCF4, TCIRG1, TCN2, TERC, TERT, THBD, TICAM1, TINF2, TIRAP, TLR3, TMC6, TMC8, TNFRSF11A, TNFRSF13B, TNFRSF13C, TNFRSF1A, TNFRSF4, TRAF3, TRAF3IP2, TREX1, TTC37, TYK2, UNC119, UNC13D, UNC93B1, UNG, USB1, VHL, VPS13B, VWF, WAS, WIPF1, WRAP53, XIAP, ZAP70, ZBTB24

Appendix A3.5 Requirements of the World Health Organization, the European Pharmacopoeia, and the FDA for modern normal human immunoglobulin preparations.

Manufacturing process requirements:

· Antimicrobial preservatives must not be added to the production process of IVIG** either at the fractionation stage or at the final solution stage;

· The stability of IVIG** must be proven by appropriate studies during product development;

· The product must not exhibit thrombogenic (procoagulant) activity;

· The manufacturing method must include multiple steps for the removal and inactivation of known infectious agents to ensure the viral safety of the product;

· IVIG** must be manufactured from the plasma of more than 1,000 donors;

Product content requirements:

· The pH of the product must correspond to the declared value and be 4–7.4;

· Osmolality of at least 240 mOsm/kg;

· Gamma globulin level of at least 95%;

· The content of IgG dimers and monomers must be at least 90% of the total IgG content;

· The distribution of IVIG** IgG subclasses must be specified and correspond to the physiological distribution;

· Aggregate content must be no more than 3% of the total IgG content;

· Anti-A/B isohemagglutinin titer must be less than 1:64;

· IgA content must be specified and not exceed the declared value;

· Prekallikrein activator must be no more than 35 IU/mL;

· Anticomplementary activity: complement binding no more than 50% (1 CH50 hemolytic unit per 1 mg of immunoglobulin);

· The product must have a functionally intact Fc fragment;

· The product must contain at least 2 types of antibodies (against viruses and bacteria) for which international standards exist; the antibody concentration must be 3 times higher than that in the initial plasma pool;

· The product must not contain: HBsAg, antibodies to HIV (human immunodeficiency virus), antibodies to hepatitis C virus;

· Bacterial sterility;

· Antibodies to HBsAg – at least 0.5 IU per 1 g of immunoglobulin;

· Endotoxin levels must be no more than 5 IU/mL for 5% preparations, and no more than 10 IU/mL for preparations with a protein content of 5–10%. [55,63–66]

Appendix B. Physician Action Algorithms

Appendix B.1 Algorithm for the diagnosis of PID with humoral immunity defects

Appendix C. Patient Information

Primary immunodeficiency (PID) represents congenital disorders of the immune system. The disease leads to severe chronic infections, as well as autoimmune and inflammatory organ and tissue damage. To date, many different forms of PID have been identified; the most common form (especially among adults) is antibody deficiency disorders, among which common variable immunodeficiency (CVID) is of primary importance. These disorders are based on the immune system's inability to produce antibodies. Antibodies (or immunoglobulins) are special proteins produced by the body in response to contact with foreign agents (infections). A specific immunoglobulin is synthesized against each infectious agent a person encounters, hence their variety is extremely large.

There are 4 main types of immunoglobulins:

· Immunoglobulin G (IgG) is the most specific and has the highest affinity for infectious agents. This immunoglobulin constitutes the bulk of plasma antibodies in a healthy person. It is this immunoglobulin that plays the primary role in protecting the body against infectious agents.

· Immunoglobulin A (IgA) plays a key role in mucosal immunity. Found in blood, saliva, and tears.

· Immunoglobulin M (IgM) plays a primary role during the first encounter with an infection, being synthesized largely in the early stages of the immune response; it is less specific and less effective compared to IgG. It has a shorter half-life than IgG.

· Immunoglobulin E (IgE) plays a role in allergic reactions and protection against parasitic pathogens. Its normal level is very low.

In CVID patients, IgG and IgA levels are significantly reduced (sometimes down to complete absence), and IgM levels may also be reduced. This leads to an increased susceptibility to infections.

Causes of the disease.

In most cases, the cause of the disease cannot be identified. Only in a small number of patients can a mutation ("genetic defect") responsible for the disease be identified. Also, it is very rare for a family member to have CVID or other forms of PID. CVID affects men and women equally.

Symptoms of CVID

Contrary to popular belief, the first symptoms of CVID can appear not only in childhood, but also in adulthood and even old age.

Clinical manifestations of the disease are highly variable. The most typical clinical manifestations of CVID are upper and lower respiratory tract infections, as well as ENT infections: otitis media, tonsillitis, rhinitis, sinusitis, laryngitis, tracheitis, bronchitis, pneumonia. Gastrointestinal (GI) tract infections rank next in frequency. Skin infections, infectious arthritis, and other infectious manifestations may also be present in the clinical picture. Characteristic features of these infections are a protracted course, frequent relapses, and a lack of the expected effect from standard courses of antibiotics in the absence of predispositions for such conditions (e.g., smoking, difficult working conditions).

In addition to infections, non-infectious manifestations may also occur:

• Enlargement of lymph nodes, spleen, and liver;

• Non-infectious inflammation of lung tissue – interstitial lung disease (ILD);

• Non-caseating granulomas (non-infectious inflammatory nodules) in the lungs, lymph nodes, and spleen. These granulomas closely resemble those seen in sarcoidosis;

• Frequent loose stools – diarrhea, caused not only by infectious pathogens, but also by various non-infectious (inflammatory and autoimmune) processes;

• Decreased levels of one or more complete blood count parameters (red blood cells, platelets, neutrophils): immune thrombocytopenia, autoimmune hemolytic anemia, less commonly neutropenia;

• Malignancies. Patients with antibody deficiency PID have an increased risk of developing malignancies, especially lymphomas. Furthermore, the risk of developing lymphoma increases substantially with the patient's age.

Diagnosis

The diagnosis of antibody deficiency PID is established based on medical history, physical examination, and laboratory test results.

When antibody deficiency PID is suspected, IgA, IgG, and IgM levels are assessed first. The obtained values are compared with age-related norms. To make a diagnosis, a significant decrease in IgA and IgG must be detected on two separate measurements.

At the next stage, various causes that could lead to a decrease in these immunoglobulin classes are excluded (use of certain medications, presence of certain conditions including protein-losing enteropathies, oncological diseases, HIV). If all other causes are excluded, further examination is performed to definitively establish the diagnosis (its scope is determined by the attending physician).

Treatment

The treatment of CVID is based on normal human immunoglobulin (IG) replacement therapy, the main goal of which is to replenish the deficiency of the patient's own IgG. This therapy brings the patient's quality and life expectancy close to those of the healthy population.

IG is a blood product, predominantly consisting of IgG, obtained from the plasma of a large number of healthy donors. This ensures the diversity of IGs and protection against most infections potentially encountered in everyday life. Therefore, IG therapy prevents patients with PID from falling frequently and severely ill.

IGs can be intended for intravenous (IVIG) and subcutaneous (SCIG) administration. The dose of the drug is determined by the attending physician based on the patient's weight and the severity of clinical manifestations. The dose should not be less than 0.4 g/kg of body weight.

Immunoglobulins for intravenous administration are typically administered once every 3–4 weeks, and for subcutaneous administration, once every 1–2 weeks. Missing therapy and lengthening intervals between infusions are extremely undesirable, as the drug is eliminated from the body in an average of 21 days. If an infusion has been missed, an increase in the administered immunoglobulin dose should be discussed with the attending physician. The decision is made taking into account the duration of the break, the patient's condition, and the pre-infusion IgG level (IgG level prior to drug administration).

Much depends on the timeliness of initiating therapy (treatment should be started immediately after diagnosis). Years and even decades often pass from the onset of symptoms to diagnosis. Uncontrolled infections prior to the initiation of correct therapy lead to irreversible organ damage (for example, bronchiectasis — deformation of the bronchi resulting in dilated spaces where bacterial flora constantly resides, since it is practically impossible to completely clear sputum from these cavities).

Since the most frequent clinical manifestations of PID with impaired antibody synthesis are infectious diseases, the prescription of antibacterial drugs is quite frequently required. It should be taken into account that standard courses are usually insufficient, therefore antibiotics are prescribed for longer courses than usual. In some cases, the physician may prescribe long-term antibacterial therapy for months or even years.

Also, in the presence of inflammatory and/or autoimmune complications, immunosuppressive therapy may be prescribed. This type of treatment can only be carried out under the supervision of the attending physician and provided that adequate replacement therapy is continued (if necessary, the dose and/or frequency of immunoglobulin administration may be increased).

Vaccination

It is important to vaccinate the patient's close contacts to minimize potential contact with infections.

Forbidden. The use of live vaccines is contraindicated.

Physician Follow-up and Monitoring After Diagnosis

Patients receiving IVIG replacement immunotherapy visit the physician before the administration of replacement therapy, i.e., once every 21–28 days. Any changes in condition should be reported to the physician so as not to miss the development of disease complications requiring correction.

CVID and Family

· If the genetic defect that led to the development of PID is known, all relatives must be screened for the presence of this defect.

· It is important to vaccinate the close contacts of a patient with PID with impaired antibody synthesis in accordance with the National Immunization Schedule (inactivated vaccines are preferred for vaccination)

· CVID is inherited very rarely, so the risk of having an affected child is low.

· A diagnosis of CVID in women is not a contraindication to pregnancy. To minimize risks to the mother and fetus, it is necessary to:

o Ensure adequate replacement therapy (at a sufficient dose and with sufficient frequency).

o Monitor disease complications.

During pregnancy, the dose and frequency of drug administration should be adjusted by the attending physician based on the patient's needs and condition (weight gain).

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not developed