Agammaglobulinemia

INTRODUCTION — Immunoglobulins are produced by plasma cells, which themselves are the result of the development and differentiation of B cells. Any factor that impedes the development of the B cell lineage and/or the function of mature B cells may result in levels of serum immunoglobulins that are reduced (ie, hypogammaglobulinemia) or nearly absent (ie, agammaglobulinemia). Primary agammaglobulinemia is most commonly inherited as an X-linked trait, but autosomal recessive (AR) forms also exist. Only those inherited defects that are intrinsic to and limited to cells of the B cell lineage will be considered in this topic.

The following related issues are discussed separately:

●Other inborn errors of immunity (formerly primary immunodeficiencies) that have agammaglobulinemia or hypogammaglobulinemia associated with combined B and T cell defects and therefore are part of a broader immunodeficiency (see "Severe combined immunodeficiency (SCID): An overview" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Syndromic immunodeficiencies")

●The various causes of hypogammaglobulinemia (see "Primary humoral immunodeficiencies: An overview" and "Transient hypogammaglobulinemia of infancy" and "IgG subclass deficiency" and "Specific antibody deficiency" and "IgG subclasses: Physical properties, genetics, and biologic functions" and "Pathogenesis of common variable immunodeficiency")

●The development of B cells from hematopoietic stem cells, immunoglobulin genetics, and the generation of the humoral immune response (see "Normal B and T lymphocyte development" and "Immunoglobulin genetics" and "The adaptive humoral immune response")

X-LINKED AGAMMAGLOBULINEMIA — X-linked agammaglobulinemia (XLA; MIM 300755) is a primary humoral immunodeficiency characterized by severe hypogammaglobulinemia, antibody deficiency, and increased susceptibility to infection (table 1) [1-3]. Clinical symptoms (infections) are generally first noted in male infants between 3 and 18 months of age.

XLA is due to defects in a signal transduction molecule called Bruton tyrosine kinase (Btk) [4,5]. Patients who present because of clinical symptoms are usually initially identified by significant hypogammaglobulinemia/agammaglobulinemia and the near absence of CD19+ B cells. The diagnosis is then confirmed with molecular studies identifying a pathogenic variant in the BTK gene. The cornerstone of treatment for XLA is replacement therapy with immune globulin.

Epidemiology — An accurate estimate of the incidence or prevalence of XLA is difficult to obtain because the disease is uncommon and population screening has not been performed. However, results from a United States registry of patients with XLA provided a minimal estimate of approximately 1 in 379,000 live births (1 in 190,000 male births) [6].

Genetics — XLA is caused by pathogenic variants in the BTK gene, named in honor of the clinician who described the first case in 1952, located on the long arm of the X chromosome [1-5,7]. Approximately 40 percent of patients with XLA are born into a family with a previously affected family member [6]. This reiterates the importance of suspecting the diagnosis in patients with a phenotype consistent with XLA since approximately 60 percent of patients have a spontaneous variant.

Btk is a member of the Tec family of nonreceptor tyrosine kinases, which are signal transduction molecules. Btk is expressed in all stages of B cell lineage development, as well as in myeloid and erythroid cells [8,9]. Its major role appears to be in promoting pre-B cell expansion at the pre-B1 to pre-B2 stage.

Pathophysiology — As a consequence of the failure of B cell development, patients affected by a pathogenic variant in BTK have significantly reduced levels of B lymphocytes in their blood and tissues, fail to generate plasma cells, and have severely decreased production of all classes of immunoglobulins with markedly defective antibody responses [1-3,6,10,11]. (See "Normal B and T lymphocyte development" and "Immunoglobulin genetics".)

As a result of their deficient humoral immune response, patients with XLA have an increased susceptibility to infection by encapsulated bacteria and certain bloodborne viruses [1-3,6,10-13], reflecting the important role of antibody in opsonization of encapsulated bacteria and neutralization of bloodborne enteroviruses. (See "The adaptive humoral immune response".)

Impairment is also seen in T cell memory responses to mucosal-colonizing bacteria (eg, Neisseria meningitidis) but not to obligate respiratory pathogens (eg, influenza virus) [14]. The T cell repertoire is altered compared with that of persons without immunologic defects, showing restricted diversity [15].

Presentation — Most patients present with recurrent infection, although some are identified at an earlier stage due to a positive family history [6]. Unfortunately, two-thirds of patients even with a positive family history are not diagnosed at or soon after birth but rather are diagnosed after they have presented with clinical symptoms. A study of a cohort of patients in Italy found a similar age of diagnosis for sporadic and familial cases (67 months and 64 months, respectively) [16]. A World Allergy Organization (WAO) survey that included 783 patients with XLA from 40 centers worldwide revealed that more than one-third of centers reported a delay between symptoms and diagnosis >24 months [17].

The term newborn with XLA is protected by maternal immunoglobulin G (IgG) that is actively transported across the placenta during the last trimester of pregnancy. Hypogammaglobulinemia and an increased susceptibility to infection develop as the maternally acquired IgG is catabolized after birth and the infant is unable to make their own (figure 1). Thus, patients generally do not present with clinical symptoms until after three months of age [6]. Nearly 50 percent of patients develop clinical manifestations by one year of age, and well over 95 percent develop symptoms by five years of age [6].

Approximately 50 percent of patients are diagnosed by two years of age. There are rare reports of individual patients with well-documented XLA who did not have sufficient clinical symptoms to be diagnosed with agammaglobulinemia until well into adult life [18-23].

When to suspect XLA — A major problem for the clinician is when to suspect XLA or any other primary immunodeficiency. The disorder is relatively uncommon [6], but many of the clinical manifestations of the disease, such as infections, are relatively common in the general population.

It is important to obtain a detailed family history in any patient since a substantial minority of patients (41 percent) has had an affected male family member [6]. It is critical to ask specifically if there have been previous male relatives who were hospitalized as children, had significant illnesses as children, or died as children as these are important clues to the presence of significant inherited disorders. In patients with a positive family history, one may be able to make the diagnosis before the patient has had any infections.

The majority of patients with XLA, however, do not have a positive family history, and this is where the clinical skills of the clinician are critically important. There is no easy formula for the number of infections that should prompt a suspicion of an inborn error of immunity. However, there are clinical settings in which the diagnosis should be considered. Chief among them is when the clinician suspects that the patient has an increased susceptibility to infection as defined by recurrent infections (ie, otitis media), unusually severe infections such as pneumonia requiring hospitalization, or infections that are atypical in their presentation or their causative organism. (See "Approach to the child with recurrent infections".)

Clinical manifestations — There is only one characteristic physical finding of XLA and that is the absence or near absence of the B cell-rich tonsils and adenoids. Palpable lymphoid tissue is absent in some patients. However, peripheral lymph nodes can appear normal because of hypertrophy of the T cells areas. Recurrent bacterial respiratory tract infections are the most common manifestation of XLA.

Clinical signs and symptoms of recurrent and chronic sinopulmonary infections and their sequelae include chronic cough, chronic rhinitis and postnasal drainage, and digital clubbing. Growth charts should be examined for evidence of failure to thrive/growth delay.

Bacterial infections — Bacterial infections are the most common clinical manifestations of XLA both before and after diagnosis [1-3,6,10-13,24]. The infections are usually caused by encapsulated pyogenic bacteria, organisms for which opsonization by antibody is a primary host defense.

Several bacterial species account for the majority of episodes of sepsis, osteomyelitis, septic arthritis, and central nervous system (CNS) infections in patients with XLA [6,24]:

●Streptococcus pneumoniae

●Haemophilus influenzae type B

●Streptococcus pyogenes

●Pseudomonas species

●Staphylococcus aureus

The specific infectious etiology of lower respiratory tract infections is usually unknown. However, these same organisms are also the major causes of lower respiratory infections when an etiologic agent can be identified.

Salmonella and Campylobacter species can cause gastroenteritis. Organisms of the Helicobacter genus (including Flexispira) cause characteristic chronic bacteremia and/or lymphatic infections.

Before diagnosis, recurrent otitis media is the most common respiratory tract infection, with pneumonia and sinusitis following close behind [6,11,12]. In a report of 254 children with community-acquired pneumonia who were screened for immunodeficiency, 2 of 132 males in the series were found to have XLA [25]. After diagnosis, pneumonia and acute and chronic sinusitis are the most common of the respiratory tract infections, even after replacement therapy with immune globulin [6]. Bronchitis and pneumonia are of special significance since they can lead to chronic lung disease (bronchiectasis and airflow obstruction) and pulmonary insufficiency [6,10,11,13,26-28]. One publication analyzing patients with XLA in a US registry found that respiratory infections were most commonly reported, and the earlier patients were diagnosed, the less likely they were to develop lower respiratory tract infections [24]. (See "Pulmonary complications of primary immunodeficiencies", section on 'X-linked agammaglobulinemia'.)

Systemic bloodborne bacterial infections, such as bacteremia/sepsis, osteomyelitis, septic arthritis, and meningitis, were more common in the first few decades following the initial description of the disease by Bruton in 1952 [10,11]. In fact, the first patient described presented with recurrent episodes of sepsis [7]. Systemic bloodborne bacterial infections have become less frequent with the advent of adequate immune globulin replacement therapy, although these infections still occur [6,11].

Intravascular/lymphatic infection caused by organisms of the Helicobacteraceae family (including Helicobacter and Flexispira) has been described in XLA patients [29-32]. These infections are bloodborne and usually persistent and/or recurrent. A clue to their diagnosis is the presence of characteristic brawny, indurated, violaceous cutaneous and subcutaneous lesions on the extremities that are similar in appearance to pyoderma gangrenosum (picture 1).

Viral, fungal, and parasitic infections — Patients with XLA are also more susceptible to certain viral, fungal, and parasitic infections.

Chronic and unremitting systemic infections with enteroviruses such as ECHOvirus and coxsackievirus can occur [33,34]. Enteroviral infections occur more frequently in patients with XLA [35]. These chronic enteroviral infections were more common in the period before adequate treatment with immune globulin was available [6,10]. However, they still occur in some isolated cases, even in the face of adequate levels of IgG with replacement therapy. Enteroviral infections can take the form of chronic meningoencephalitis and/or chronic hepatitis, or they may masquerade as dermatomyositis with direct infection of muscle and skin [33-35]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention" and "Enterovirus and parechovirus infections: Epidemiology and pathogenesis".)

The earliest signs of enteroviral meningoencephalitis may be a change in behavior and/or developmental regression, which then progresses to full-blown neurologic impairment and coma over a period of months to years. The most common cause of neurologic deterioration in patients with XLA is an enteroviral infection [35]. A variety of therapies have been attempted for this difficult infection, including high-dose intravenous immune globulin (IVIG), intrathecal immune globulin, and antiviral drugs, such as pleconaril and pocapavir [33-35]. Unfortunately, none have provided reliable and consistent long-term improvement, although there are cases where each appeared to have some benefit. New enteroviral medications under study show promise in the treatment of life-threatening enteroviral infections in inborn errors of immunity [35]. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention".)

Other, less common viral, fungal, and parasitic infections also occur. Lower respiratory infections caused by Pneumocystis jirovecii (formerly P. carinii) are usually only seen in patients who are debilitated [36,37]. Mycoplasma/ureaplasma cause some cases of arthritis and/or osteomyelitis, most often in patients receiving inadequate immune globulin replacement therapy. Other examples include chronic rotavirus gastroenteritis, described in isolated cases, and Giardia lamblia gastrointestinal infection [1-3,6,11,38].

Patients with XLA are also prone to develop vaccine-related polio after receiving the live-attenuated poliovirus vaccine directly or, less commonly, after close contact with an individual who received the live-attenuated vaccine [6,39]. Vaccine-related poliomyelitis is characterized by a relatively long incubation period, a chronic encephalomyelitis, and a high mortality rate. This complication has not been seen in patients who live in countries that have replaced the live-attenuated vaccine with a killed vaccine.

Malignancy — The risk of malignancy is uncertain given the conflicting data. Epidemiologic studies are needed to determine if patients with XLA are at any increased risk for particular tumors and, if so, to what degree.

A variety of malignancies have been reported in patients with XLA [6,39-44]. These include lymphoreticular malignancies (eg, lymphoma) [6,40], gastric and colorectal adenocarcinoma [41-44], and squamous cell carcinoma of the lung [45]. In one report, colorectal cancer was found in 3 of 52 patients (6 percent) [42]. However, no malignancies were found in two other series of 73 and 44 patients, respectively [11,13]. In another report, adenomatous polyps were found at a relatively young age in two of four patients with XLA [46]. A single patient with XLA and precursor B cell acute lymphoblastic leukemia (ALL) was also reported. Due to the mild variant in BTK in this patient, however, it is not possible to conclude that the lack of BTK led to an increased risk of ALL [47,48]. Malignancy was reported in 3.7 percent of patients with XLA from an Italian primary immunodeficiency registry, with four involving the gastrointestinal system, one thyroid, and one CNS [16].

Autoimmunity and inflammatory disease — Inflammatory conditions are associated with XLA. Even though autoantibodies are not produced, up to 28 percent of patients in one report had complaints consistent with autoinflammation, and several had been diagnosed with arthralgias or arthritis, hypothyroidism, and inflammatory bowel disease (IBD) [49]. A retrospective review of patients with XLA reported that over one-third of patients had gastrointestinal manifestations, and 11 percent were diagnosed with IBD or enteritis [50]. Patients should thus be monitored for the development of autoimmune or gastrointestinal disease. The WAO survey described a broad range of autoimmune and inflammatory conditions, including IBD [17]. (See "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

Other — Patients also have been reported to suffer from a higher incidence of sensorineural hearing loss [51] and eczema [52].

Atypical XLA — The large majority of patients have classic XLA, with near absence of B cells and the typical clinical phenotype. However, "atypical" forms of XLA, characterized by low numbers of B cells, low-level antibody production, and less severe disease, have been described [53-56].

Some patients with atypical forms of XLA are initially incorrectly diagnosed with other causes of humoral immunodeficiency, including transient hypogammaglobulinemia of infancy [55], specific antibody deficiency [56], and common variable immunodeficiency (CVID) [22]. These patients develop more severe disease and laboratory abnormalities more characteristic of XLA later in life. Some patients with mild XLA have been diagnosed as late as 51 years of age [54].

Laboratory findings — Laboratory findings include hypogammaglobulinemia/agammaglobulinemia, deficient antibody responses to immunizations, and absent or markedly reduced B cells in the blood.

The hallmark of patients with XLA is a marked reduction in all classes and subclasses of serum immunoglobulins and B cells [1-3,6,10-13]. IgG, immunoglobulin A (IgA), and immunoglobulin M (IgM) levels are generally below 100 mg/dL and may be below the level of detection in clinical laboratories. However, IgG levels may be as high as 200 to 300 mg/dL in some patients [6].

Mature B cells (eg, immunoglobulin-bearing B cells, or CD19 or CD20-positive B cells) are markedly reduced and may be as low as 0.01 percent to below 2 percent CD19+ B cells [57] in both blood and tissues, such as lymphoid follicles and germinal centers of lymph nodes [1-3,6,10-13]. Similarly, plasma cells are absent in the lymphoid tissue, bone marrow, and the lamina propria of the rectal mucosa [1-3,6,10-13].

Serum levels of antibodies to ubiquitous antigens (eg, isohemagglutinins and Escherichia coli) or to immunizations (eg, polio, tetanus, diphtheria) are markedly reduced or undetectable [1-3,6,10-13]. While T cell number and function are normal, a report of 15 patients with XLA showed skewed and limited T cell repertoire [15].

Fifteen to 25 percent of patients may have neutropenia at some point, which can be severe [58-61]. Neutropenia is associated with the high bacterial burden seen with active infection, and it resolves with antimicrobial and immune globulin therapy.

The performance of tests such as a complete blood count, serum chemistries, and/or specific radiologic procedures can provide insight into whether the patient has an acute or chronic infection, as they can with any other patient. (See "Laboratory evaluation of the immune system".)

Diagnosis — The diagnosis of XLA is usually suspected based upon a combination of family history (if present), clinical history, and physical examination. The initial laboratory evaluation of a male patient with suspected XLA includes a complete blood count with differential, quantitative serum immunoglobulin levels (IgG, IgA, and IgM), and serum-specific antibody titers in response to immunization and/or infection (eg, tetanus, diphtheria, H. influenzae type B, and pneumococcus) (see 'Presentation' above and "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections"). The finding of low immunoglobulin levels indicates a need for further testing, including determination of lymphocyte subpopulations (T, B, and natural killer [NK] cell subsets) by flow cytometry to document markedly reduced to absent B cell numbers in the peripheral blood. Every effort should be made to document a variant in the BTK gene once significantly decreased immunoglobulin levels and B cell numbers have been found. Approximately 20 percent of patients with the phenotype of XLA will not have BTK defects, but rather pathogenic variants in autosomal genes. These rarer disorders can affect females as well as males. (See 'Autosomal recessive agammaglobulinemia' below.)

An international committee has established criteria for the diagnosis of XLA (table 2) [62]. A definitive diagnosis is made when a male patient has hypogammaglobulinemia or agammaglobulinemia, <2 percent CD19+ B cells, and either a male family member of maternal lineage who is documented to also have agammaglobulinemia and <2 percent CD19+ B cells or a confirmed (by deoxyribonucleic acid [DNA], messenger ribonucleic acid [mRNA], or protein analysis) defect in the BTK gene or Btk expression. A probable or possible diagnosis based upon clinical history, low quantitative serum immunoglobulin levels, and absent response to vaccines is made if these criteria are not met but other causes of agammaglobulinemia/hypogammaglobulinemia are ruled out.

Newborn screening — Research reports suggest that it is possible to screen for defects in B cell maturation such as agammaglobulinemia in newborns. Newborn screening would be of value in these disorders since early diagnosis and therapy would prevent some infections.

Immunoglobulin kappa-deleting recombination excision circles (KRECs) are formed in the process of B cell maturation during allelic exclusion. KRECs are not produced in patients with B cell maturation defects, such as XLA, that occur before this stage. (See "Normal B and T lymphocyte development" and "Immunoglobulin genetics", section on 'Allelic exclusion'.)

KRECs can be used to screen for early B cell maturation defects from dried blood spots on newborn screening cards using polymerase chain reaction (PCR), similar to using T cell receptor excision circles (TRECs) to screen for T cell defects [63]. Simultaneous screening for both T and B cell deficiencies using TRECs and KRECs is under study [64,65]. A study looking at KRECs over time in patients with XLA reported markedly low or decreased KRECs at birth that remained consistent over time. (See "Newborn screening for inborn errors of immunity".)

Carrier detection — There are three available techniques for determining the carrier status of female family members:

●Detection of the relevant variant in BTK

●Linkage analysis

●Detection of altered X-chromosome inactivation in B cells

Although all have been used in clinical practice, genomic DNA sequencing has become the most widely performed technique.

Identification of a variant in BTK is the most direct method of detecting a carrier female [66]. The detection of a heterozygous variant is particularly useful in a female family member of an affected patient with XLA in whom the BTK variant is known.

Linkage analysis depends upon the analysis of closely linked X-chromosome polymorphic DNA segments that flank the BTK gene and permit one to track the inheritance of a block of genomic DNA in a family with an affected member. A known BTK variant is not required for linkage analysis, and both coding and noncoding variants can be inferred from this method. A number of polymorphic loci that are closely linked to BTK have been used for this purpose [67-69].

Altered X-chromosome inactivation analysis has also been used for carrier detection and does not require either that the variant is known or that a previously affected family member is available. This technique depends upon the fact that noncarrier females have two populations of B cells in their blood, one in which the maternal X chromosome is active and one in which the paternal X chromosome is active (the inactivation of one or the other X chromosome in every cell is also called lyonization).

In contrast to non-B cell lineages, the active X chromosome in all of the B cells of XLA carrier females bears the normal BTK allele [70]. A number of tools/techniques are available for detecting nonrandom X-chromosome inactivation, but they are performed only in specialized laboratories. These techniques include analysis of methylation patterns of X-chromosome genes [71], examination of somatic cell hybrids that have selectively retained the active X chromosome [72], and flow cytometric analysis of intracellular Btk protein expression in monocytes or platelets [73].

Differential diagnosis — The differential diagnosis of XLA includes other causes of agammaglobulinemia and hypogammaglobulinemia:

●Transient hypogammaglobulinemia of infancy – The immune system of patients with transient hypogammaglobulinemia of infancy will also improve with time as opposed to patients with XLA, which is a lifelong agammaglobulinemia. Patients with transient hypogammaglobulinemia of infancy will produce specific antibodies, as opposed to XLA patients. (See "Transient hypogammaglobulinemia of infancy".)

●CVID – The age of presentation guides the clinician in differentiating CVID from agammaglobulinemia, as patients with agammaglobulinemia usually manifest earlier in life. Patients with XLA are males, whereas CVID patients may be males or females. (See "Pathogenesis of common variable immunodeficiency" and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Treatment and prognosis of common variable immunodeficiency".)

●Autosomal recessive agammaglobulinemia (ARA) – While the labs in patients with XLA and ARA may be similar, patients with XLA are males, in contrast to ARA patients, who may be males or females. The presentation also varies, depending on the genetic variant leading to the agammaglobulinemia. (See 'Autosomal recessive agammaglobulinemia' below.)

●Combined T and B cell immunodeficiencies with agammaglobulinemia – In patients with combined immunodeficiency, both T and B cell lymphocytes are affected, as opposed to XLA, which is primarily a B cell disorder. Patients with combined defects may be either male or female, as opposed to XLA patients, who are male. (See "Severe combined immunodeficiency (SCID): An overview" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis" and "Syndromic immunodeficiencies".)

The measurement of B and T lymphocytes, antibody levels in response to immunizations, and, ultimately, the identification of a pathogenic variant in BTK usually leads to an accurate diagnosis. B cell levels are generally normal with most other causes of agammaglobulinemia/hypogammaglobulinemia. The exceptions are some of the more uncommon forms of severe combined immunodeficiency (SCID; T-B-NK+ SCID) and ARA.

An accurate diagnosis of XLA is important not only for the patient, but also for the patient's female family members who may be carriers. For example, all of the female offspring of a patient with XLA will be carriers, and the carriers' sons will have a 50 percent chance of being affected. Similarly, if the mother is a carrier, then the sisters have a 50 percent chance of being carriers.

Indications for referral — If the patient's history and clinical presentation are consistent with a diagnosis of agammaglobulinemia, the workup should include serum immunoglobulins along with vaccine antibody titers and lymphocyte subsets. Clinical immunologists are an essential part of the medical team and can help interpret laboratory results, ensure appropriate treatment, and monitor the patient over time in order to assess for other comorbid conditions. (See 'Clinical manifestations' above and 'Diagnosis' above.)

Initial evaluation — High-resolution computed tomography (HRCT) of the chest, along with pulmonary function testing in children old enough to complete the study, should be performed as part of the initial evaluation to ascertain the presence/extent of bronchiectasis and to assess pulmonary functional status.

Management — Replacement of immunoglobulin is the cornerstone of treatment for XLA. General supportive care includes measures to avoid infection and immunization with killed vaccines. The general medical management of immunodeficiency is discussed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Immune globulin replacement therapy — Two forms of replacement immune globulin therapy are available: intravenous immune globulin G (IVIG) and subcutaneous immune globulin G (SCIG). The dose for each of these preparations is determined by a combination of the patient's weight, "trough" or preinfusion levels of IgG after treatment has commenced, and the clinical response and condition of the patient. (See "Immune globulin therapy in inborn errors of immunity", section on 'Administration and dosing'.)

The use of immune globulin therapy in patients with XLA has not been studied in randomized trials, and it is unlikely that a randomized trial will ever be performed. Clinical experience and observational studies in patients with XLA and other forms of agammaglobulinemia/hypogammaglobulinemia overwhelmingly indicate that immune globulin therapy lowers morbidity and mortality. (See "Treatment and prognosis of common variable immunodeficiency", section on 'Immune globulin replacement therapy' and "Immune globulin therapy in inborn errors of immunity", section on 'Indications' and "Immune globulin therapy in inborn errors of immunity", section on 'Efficacy'.)

Data from observational studies show that immune globulin therapy lowers the rate of infection and reduces hospitalization rates in patients with XLA [26,74]. Immune globulin therapy also helps prevent the development of long-term pulmonary insufficiency in most studies and lowers the risk for systemic enteroviral infections [26,74].

●In a series of 29 patients with XLA, a dose response to immune globulin replacement therapy was seen with regard to incidence of pneumonia and number of days hospitalized [74]. Bacterial meningitis, bronchiectasis, and chronic lung disease were not reported in patients who received IVIG, but they did occur in patients who received lower immune globulin doses intramuscularly. IVIG was most beneficial when it was started before five years of age.

●In another series of 31 patients with XLA, the incidence of bacterial infections requiring hospitalization also decreased after starting IVIG (from 0.4 to 0.06 per patient per year) [26].

However, replacement therapy has its limitations. The available preparations only replace IgG, but not IgM or IgA, which have some biologic functions unique from IgG. In addition, the commercially available preparations of immune globulin are isolated from pools consisting of thousands of donors. Thus, although they possess significant titers of antibodies against common pathogens, commercial preparations may not have significant titers against uncommon organisms that patients with XLA may encounter. It also may not protect against a novel virus. Finally, the passive immunity conferred by immune globulin replacement therapy does not replicate the normal increase in antibody production against an infecting microorganism that occurs in immunocompetent individuals with active immunity.

Antibiotics — In addition to immunoglobulin replacement therapy, patients with XLA require aggressive antibiotic therapy for any documented and/or suspected infection. In some instances, prolonged antibiotic therapy may be indicated as a treatment for ongoing pulmonary infections or chronic sinusitis or as prophylaxis against such infections. Antimicrobial therapy is reviewed in detail separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Prophylactic antimicrobial therapy' and "Inborn errors of immunity (primary immunodeficiencies): Overview of management", section on 'Infectious disease'.)

Measures to avoid infection — Other considerations in the care of patients with XLA include vaccinations and avoidance of infection. Patients with XLA will not generate significant antibody responses to prophylactic immunization. However, many clinicians still immunize these patients with killed viral (ie, yearly influenza vaccine) and bacterial vaccines in the hopes that they will generate T cell-mediated immune responses that may afford some additional protection beyond that obtained with immune globulin replacement therapy. Live-viral vaccines are contraindicated. Immunization against transmissible infectious agents is encouraged for close family members. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Passive protection against certain infections, such as tetanus and varicella, with hyperimmune globulin is usually not necessary in patients already receiving standard immune globulin replacement therapy. Commonsense approaches to lowering the patient's exposure to communicable infectious diseases, such as handwashing and avoidance of respiratory droplets, are advised. Finally, patients should avoid ingestion of untreated drinking water, if possible. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Monitoring of pulmonary status — Monitoring the patient for subclinical, but progressive, pulmonary damage is also important since a number of studies have shown that these patients can develop chronic pulmonary disease [6,10,11,13,26-28]. Such monitoring may take the form of routine pulmonary function tests. HRCT examinations of the chest may be of value in detecting early and progressive pulmonary structural damage, although the accumulated risk of radiation should be taken into account when performing these exams. Six XLA patients with bronchiectasis who underwent lung transplantation had poor long-term outcomes with a high incidence of pulmonary sepsis, chronic lung allograft dysfunction, and mortality in five patients within three years of transplant [75].

Hematopoietic cell transplantation and gene therapy for XLA — The risks of allogeneic hematopoietic cell transplantation (HCT) or gene therapy for XLA have long been felt to outweigh the benefits, particularly in view of the successful management with immune globulin replacement and antibiotics. However, the high cost of immune globulin, limited access to immune globulin in some countries and populations, and patient desire to be free of lifelong periodic infusions have spurred interest in these potential cures. Gene therapy and gene editing to correct autologous hematopoietic cells remains under investigation, although no clinical trials in humans have been undertaken to date [76,77]. Anecdotal reports of HCT indicate that it can be successful in patients with XLA [78-80]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Overview of gene therapy for inborn errors of immunity".)

Prognosis — The average age of diagnosis has dropped significantly since the initial description of XLA over 50 years ago [6]. In addition, immune globulin preparations have improved, allowing patients to maintain normal levels of IgG on replacement therapy. Most patients with XLA born in the last few decades and treated optimally (without HCT) can be expected to survive into adult life because of these improvements in initial diagnosis, immune globulin replacement therapy, and treatment of infections. In a 2006 report, over 40 percent of patients with XLA in a United States registry were adults. In the same series, only 3 of 80 patients followed prospectively over a four-year period died and, notably, two died of iatrogenic causes [6]. Reports from an Italian registry with a mean follow-up of over eight years per patient revealed an overall survival rate of almost 93 percent at 43 years of age [16]. Mortality was increased in those with chronic lung disease In a worldwide survey, 41 percent of deaths reported were due to acute or chronic lung disease [17]. In a US registry of patients with XLA, the reported cause of death was infection, particularly lower respiratory tract infections such as pneumonia, in almost three-quarters of patients [24].

For patients who survive into adulthood, the quality of life is generally good [27,81,82]. Adults with XLA miss more days of school/work, and they are hospitalized more frequently than males in the general population. Quality-of-life reports revealed that hospitalization was associated with decreased physical health quality of life, and two or more chronic conditions affected physical and mental quality of life. However, most lead productive and fulfilling lives despite these limitations.

AUTOSOMAL RECESSIVE AGAMMAGLOBULINEMIA — There are at least nine forms of genetically determined agammaglobulinemia that are caused by autosomal recessive (AR) pathogenic variants in genes contributing to the maturation and function of B cells (table 1) [83-96]. The discovery of variants in these genes in patients with agammaglobulinemia has provided important insights into the normal development of B cells. Each form of AR agammaglobulinemia (ARA) has only been described in a few families.

ARA should be suspected when the patient's family history is consistent with an AR pattern of inheritance, when the patient with agammaglobulinemia is female, or when a pathogenic variant in BTK cannot be identified in a male with agammaglobulinemia.

The clinical and laboratory features of these disorders resemble those of X-linked agammaglobulinemia (XLA), and the treatment is the same. However, it is important to try to discriminate between ARA and XLA since the patterns of inheritance and implications for genetic counseling are different.

AUTOSOMAL DOMINANT AGAMMAGLOBULINEMIA — There are three forms of agammaglobulinemia caused by autosomal dominant pathogenic variants (table 1) [96-99]. Patients present with recurrent infections and agammaglobulinemia. One patient with facial anomalies and agammaglobulinemia has also been described [97].

The importance of proper diagnosis cannot be overemphasized, as in patients with autosomal recessive agammaglobulinemia (ARA), since genetic counseling is essential.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●X-linked agammaglobulinemia – X-linked agammaglobulinemia (XLA; Bruton-type agammaglobulinemia) is a primary humoral immunodeficiency characterized by recurrent bacterial infections of the respiratory tract and increased susceptibility to enteroviral infection. (See 'X-linked agammaglobulinemia' above.)

•Age at presentation and diagnosis – Clinical symptoms of an increased susceptibility to infection are generally first noted between 6 to 18 months of age. The average age of diagnosis is 2.6 years in males with a positive family history and 5.4 years in males with a negative family history. Although uncommon, some patients have mild enough disease that they are not diagnosed until adult life. (See 'Epidemiology' above.)

•Clinical manifestations – The only characteristic physical finding of XLA is the absence, or near absence, of the tonsils and adenoids, although they may be present if T cell areas are hypertrophied. The respiratory tract is the most common site of bacterial infections in XLA. Bacteremia/sepsis, osteomyelitis, septic arthritis, meningitis, and intravascular/lymphatic infections can also occur. (See 'Clinical manifestations' above.)

•Common infections – Streptococcus pneumonia, Haemophilus influenzae type B, Streptococcus pyogenes, and Pseudomonas species cause most of the bacterial infections. Chronic and unremitting systemic infections with enteroviruses such as ECHOvirus and coxsackievirus can also occur. (See 'Bacterial infections' above and 'Viral, fungal, and parasitic infections' above.)

•Genetics and diagnosis – XLA is due to defects in a signal transduction molecule called Bruton tyrosine kinase (Btk). The diagnosis is suspected in a male patient with agammaglobulinemia/hypogammaglobulinemia, very low to absent CD19+ B cells, and a consistent clinical and/or family history. The diagnosis may be confirmed with a molecular study identifying a defect in the BTK gene or Btk protein expression. (See 'Pathophysiology' above and 'Laboratory findings' above and 'Diagnosis' above.)

•Treatment – We recommend replacement immune globulin therapy for patients with XLA (Grade 1A). (See 'Management' above and "Immune globulin therapy in inborn errors of immunity".)

●Autosomal recessive agammaglobulinemia – Autosomal-recessive agammaglobulinemia (ARA) should be suspected when the patient's family history is consistent with an autosomal recessive (AR) pattern of inheritance, when the patient with agammaglobulinemia is female, or when a pathogenic variant in BTK cannot be identified in a male with agammaglobulinemia. The clinical and laboratory features of these disorders resemble those of XLA, and the treatment is the same. (See 'Autosomal recessive agammaglobulinemia' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Jerry A Winkelstein, MD and E Richard Stiehm, MD, who contributed to earlier versions of this topic review as an author and a Section Editor, respectively.