Hypogammaglobulinemia is a term describing insufficient levels of gamma globulins, which may occur from malignant, genetic or iatrogenic diseases. Recurrent infections of the respiratory tract and the ear are the main clinical manifestations and infections are one of the most important complications. The diagnosis is made through laboratory and imaging studies, whereas intravenous immunoglobulins coupled with long-term antibiotic prophylaxis are main therapeutic measures.
In patients with X-linked agammaglobulinemia, different clinical phenomena may be observed depending on age . In children between 6 months and 5 years, paralysis after oral polio immunization is considered as a hallmark, whereas deterioration of dermatomyositis and chronic echo-virus encephalitis are seen in in children older than 5 years . In the vast majority of patients, however, recurrent otitis is one of the most prevalent symptoms , while pneumonia, sinusitis and other types of infections are readily observed. Physicians may encounter decreased or even absent cervical lymph nodes or tonsils, suggesting hypoplasia of lymphoid tissue . Recurrent infections are clinical hallmarks of CVID as well .
Patient history may be one of the most important parts of the diagnostic workup, as signs and symptoms may provide important clues for further evaluation . Additionally, history of prolonged immunosuppression therapy, antiepileptics, sulfasalazine, or rituximab and other immunotherapeutics  , should prompt the physician to evaluate and iatrogenic etiology, as these two drug groups are known causes of reduced IgG levels . In all patients with suspected hypogammaglobulinemia, a complete blood count (CBC) with determination of lymphocyte subset numbers, as well as their distribution is necessary, most frequently through flow cytometry . In the setting of transient hypogammaglobulinemia, IgG levels below 2 standard deviations for appropriate age and normal B lymphocyte numbers are highly suggestive of the diagnosis . Because of possible renal loss of immunoglobulins, kidney function tests, including urinalysis for protein levels, urea and creatinine should be performed . CT of the chest, abdomen and pelvis is of significant benefit in evaluation of lymph nodes and viscera .
Antibody replacement therapy through administration of intravenous immunoglobulins (IVIG) is the mainstay of therapy in these patients . A starting dose of 400-600 mg/kg/per month is recommended, but in patients with severe hypogammaglobulinemia (< 2g/L), a loading dose of 1g/kg of body weight may be necessary . The administration of IVIG is carried out once weekly or once every two weeks when subcutaneous routes are used, whereas intravenous administration requires a regimen of once every three to four weeks . The use of IVIG is a topic of significant debate for transient hypogammaglobulineia of infancy, but its use has proved to be beneficial in severe forms of the disease . Antibiotic prophylaxis is considered to be equally important in long-term management of patients with hypogammaglobulinemia, primarily because infections are the most important causes of morbidity. Amoxicillin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, azithromycin or clarithromycin are used in various regimens and depending on the source of infection .
The prognosis depends on the underlying cause, but recurrent infections are present regardless of the disease and are established as most important complications . In addition, numerous diseases may appear in patients with hypogammaglobulinemia. 10% of patients suffering from CVID will develop gastric carcinoma or lymphoma, autoimmune diseases including SLE, Addison's disease, thyroiditis, rheumatoid arthritis and several other have shown increased rates in these patients  . Bronchiectasis, one of the forms of chronic obstructive pulmonary disease were also seen in higher rates in patients who suffer from hypogammaglobulinemia . Infections, however, are the most important causes of morbidity in these patient, the most important pathogens being Streptococcus pneumoniae and Haemophilus influenzae. . 20-years Survival rates for CVID are estimated at 64% and 67% for males and females, respectively, indicating that this form of immunodeficiency poses great risk, especially if not diagnosed on time. Transient hypogammaglobulinemia of infancy may spontaneously resolve within a few years.
Most important causes of hypogammaglobulinemia are:
Transient hypogammaglobulinemia of infancy is considered to be one of the most common forms of primary immunodeficiency and isolated epidemiological reports show a prevalence rate of 7 per 100,000 individuals . X-linked agammaglobulinemia, on the other hand, has an estimated prevalence rate of 1 per 190,000 male births in the United States . Age and onset of symptoms is an important factor in distinguishing between diseases that cause reduced IgG production. XLA is symptomatic in 90% of patients by the age of 5 ., whereas certain reports have determined that CVID is most commonly diagnosed at the end of third and the beginning of fourth decade of life . Moreover, Good's syndrome is almost exclusively seen in patients around 40 years .
In almost all diseases (except renal loss of gamma globulins), impaired B cell function is the main pathophysiological event, but various forms of B-cell damage have been established. The pathogenesis model for THI is incompletely formed, but most likely includes abnormal secretion of interleukin 10 (IL-10) and two tumor necrosis factors - TNF-α and TNF-β, leading to an excessive Th1-T cell subtype activation that causes abnormalities in B-cell development . Additionally, the role of CD19/CD21 co-receptor complex in regulating the B cell response has been well-documented and deficiencies of CD19 or CD21 were shown to be crucial in poor B cell response to antigens and low antibody production . In X-linked agammaglobulinemia, mutations of the tyrosine kinase BTK enzyme lead to inability of B cells to proliferate from the bone marrow ., whereas rituximab is known for its role of marked B-cell suppression . In hematologic diseases, a combination of immune-mediated mechanism triggered by malignant alteration and the effects of chemotherapy has been proposed as the pathogenic mechanism .
Certain studies have determined that 5-6 years pass from the onset of symptoms to the diagnosis ., suggesting that physicians need to consider this condition when evaluating patients with recurrent infections and other signs that may suggest an impaired immune function. Drug-induced hypogammaglobulinemia can be prevented in some patients through regular follow-ups and monitoring of B-cell function through various laboratory tests, whereas long-term management of the underlying cause (when possible) might be one of the most important preventive strategy.
Hypogammaglobulinemia a rare clinical condition defined as plasma levels of immunoglobulin G under 5g/L . Numerous diseases have been described as potential causes that either impair normal antibody production or provoke their loss from the body. Hematologic malignancies such as chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma and multiple myeloma, primary immune deficits including common variable immunodeficiency (CVID), renal diseases that trigger excretion of proteins (nephrotic syndrome and protein-losing enteropathy), but also various drugs (immunosuppessants, antiepileptics and immunotherapeutics) are all established causes of hypogammaglobulinemia . Additionally, this condition may appear in the setting of transient hypogammaglobulinemia of infancy (THI), where the physiological period of 3-6 months of age in which low IgG levels are normally observed is prolonged . The pathogenesis model significantly varies from one condition to another, but the end-result is insufficient production of gamma globulins from B cells. The diagnosis can be made in patients in patients of various ages and their respective clinical appearance should be taken into consideration in the differential diagnosis  . Clinical presentation invariably includes recurrent infections - pneumonia, otitis and sinusitis, most frequently caused by Streptococcus pneumoniae and Haemophilus influenzae ., which are the most significant complications seen in hypogammaglobulinemia. To make the diagnosis, it is necessary to obtain a thorough patient history and conduct a meticulous physical examination, while various laboratory and imaging findings may be used to support the obtained findings. A complete blood counts (CBC) with determination of lymphocyte numbers and their distribution, renal function tests and computed tomography (CT) of the chest, abdomen and pelvis are recommended  . Long-term antibiotic prophylaxis and replacement of antibodies through intravenous immunoglobulins (IVIG) are the two main forms of therapy that have shown marked success when administered carefully and appropriately . The prognosis of patients with hypogammaglobulinemia depend on several factors, such as the underlying cause and its management, level of long-term care and the promptness of the diagnosis, as studies have determined that several years may pass from the onset of the disease to its diagnosis . For these reasons, a high clinical suspicion is necessary in children and younger adults who report recurrent infectious without an identifiable cause.
Hypogammaglobulinemia is a rare clinical condition that is defined as reduced levels of a specific subset of antibodies (gamma globulins or IgG) in the circulation. Numerous conditions are described as potential causes:
In virtually all conditions, the end-result is impaired activity of B cells, except in the setting of renal diseases such as nephrotic syndrome and protein-losing enteropathy, in which increased excretion of proteins through urine consequently reduces the levels of gamma globulins in the circulation. The main clinical symptom (and the most important complication) is the presence of recurrent infections that occur due to the inability of the immune system to defend against various microorganisms, most important pathogens being Streptococcus pneumoniae and Haemophilus influenzae. Infections of the lungs (pneumonia), ear (otitis) and sinuses (sinusitis) are most frequently reported. Having in mind the age of onset and typical symptoms, the physician should carefully evaluate these patients through a detailed patient history and a proper physical examination, whereas laboratory and imaging studies should be used in order to confirm the diagnosis and the underlying cause. The focus of treatment is aimed at prevention of recurrent infections through long-term antibiotic prophylaxis together with administration of intravenous immunoglobulins (IVIG) to replace the depleted stores of IgG. In addition to recurrent infections, patients are exposed to numerous autoimmune diseases and malignancies (approximately 10% of patients develop gastric carcinoma or lymphoma), which is why high clinical suspicion and an early diagnosis is necessary in these patients.