XLA is caused by defects in Btk (gene) encoding Bruton Tyrosine Kinase (Btk) and accounts for 85% of cases of congenital agammaglobulinemia.10,19,20 The estimated incidence ranges from 1:100,000 to 1:200,000 live births.8–10 BTK is expressed in all lineages of hematopoietic cells except for T cells and plasma cells.9,10 The BTK mutational consequences affect the expression of hundreds of genes, proteins, and molecular regulators.23–25

The first case reported by Ogden Bruton (1952)26 was an 8-year-old boy who had suffered recurrent invasive pneumococcal infections from the age of 4.5 years and in whom agammaglobulinemia was confirmed by using electrophoresis.26,27 Bruton not only realized that there was a connection between the clinical and absence of the gammaglobulin fraction, but also successfully treated this boy with replacement immunoglobulin therapy.26 Subsequent cases revealed an X-linked pedigree27,28 with family history in 40% of the affected individuals.7,8 Nearly 927 mutations have been associated with the disease in 1757 patients.29 Our group has been the first to publish the molecular diagnosis of XLA in Brazilian patients.30,31 Although it has not been possible to correlate the genetic defect with the severity of the clinical phenotype,7,10,16 it is possible that the nonsense mutations directing to RNA decay may affect BTK expression with its hypoexpression.32

Diagnosing relies first on detailed family history and infection history, with age of onset, frequency and duration of treatments, and if known, organisms that might suggest a primary B-cell defect or a combined B and T-cell immune defect. XLA diagnosis accounts for male patients with onset of recurrent infections most often during the first year of life, when transferred maternal IgG has been catabolized and the mother stops breastfeeding.33 Before the age of 5 years, the child required one or more hospitalizations. In a large study with 783 XLA patients,8 they reported vaccine-associated paralytic poliomyelitis in countries with attenuated live polio vaccination; acute and chronic lung diseases accounted for 41% of the deaths; inflammatory bowel disease and enteroviral meningoencephalitis were more prevalent in South American patients; large granular lymphocyte disease, among others, was enumerated in 20.3% of patients.

Initial laboratory tests include a complete blood count, quantitative serum levels of IgM IgG, IgA, IgE and antibody titers in response to vaccines (tetanus and diphtheria toxoids, Haemophilus influenzae, measles, mumps, rubella, varicella, pneumococcus, hepatitis A or B, influenza virus) to fully validate the immune defect.5,7,8,10,33 The next step is a lymphocyte phenotyping using flow cytometry, which documents normal T-cell numbers but <1–2% B cells. To confirm the diagnosis, genetic testing to look for variants in Btk gene can be performed. A confirmed family history of XLA can serve as a surrogate for genetic testing.[7,33]

Sepsis, meningitis, or cellulitis due to H. influenzae and S. pneumoniae in a vaccinated child should elicit an evaluation for PAD.5,7,8,18 After the onset of IRT, serious infections decrease, but they continue to have otitis, sinusitis, and or conjunctivitis.7,18Pseudomonas or Staphylococcal sepsis may occur in infants with neutropenia.34Non sporulating gram negative rod campylobacter jejuni infections cause sepsis, gastrointestinal disease, erysipelas-like skin lesions, pericarditis, and recurrent fever.18 Chronic diarrhea is caused by C. jejuni. Pneumocystis jirovecii pneumonia is rare.18 Fastidious organisms related to C. jejuni or Flexispira rapini have been reported in patients on Ig therapy.18 Systemic Ureaplasma urealyticum or Mycoplasma species are frequent in the respiratory tract, joints and urogenital tract.18

A report of two XLA patients with SARS-CoV-2 infection, aged 34 and 26 years, who developed interstitial pneumonia and lymphopenia, fever, cough, and anorexia, elevation of CRP and ferritin, but never required oxygen ventilation or intensive care.35 Two other adults, XLA and ARA, both with COVID-19, presented with mild symptoms, short duration, no need for drugs, and had a favorable outcome.36 Apart from that, the COVID-19 course was severe in 5 patients affected with CVID, requiring drug treatment and mechanical ventilation.36 It is speculated that the absence of BTK could advantage XLA patients.35 Other three XLA patients (10 y.o., 24 y.o., and 40 y.o.) with COVID-19 displayed strong pro-inflammatory responses in the absence of B cell, failed supportive treatment but recovered after receiving convalescent plasma.37 Therefore, more observational studies are necessary to extend these experiences to other patients with similar genetic immune defects.

XLA patients are susceptible to norovirus and severe enterovirus infections such as Echo virus and vaccine-associated paralytic poliomyelitis (VAPP) from live-attenuated oral poliovirus vaccine (OPV) and Rhinovirus.8,10,24,38 They are possibly also suscetible to arbovirus. However, they are not susceptible to herpes family, cytomegalovirus, varicella, or Epstein Barr virus, and H1N1 virus.24 The use of IRT has decreased the incidence of enteroviral infections manifesting as chronic meningoencephalitis, hepatitis, or dermatomyositis-like infections.21 Early literature on XLA found 15% to 20% of patients infected by enteroviral meningoencephalitis even in the presence of Ig therapy.22 Brain biopsy is recommended as soon as a neurological complication is suspected. Gait disturbances, progressive spastic tetraparesis, intellectual and speech deterioration, no infectious agent identified, periventricular demyelinating and cortical atrophy associated with stereotactic brain biopsy are all signs of progressive multifocal leukoencephalopathy (PML) in agammaglobulinemia.39

Impaired humoral immunity and intestinal abnormalities (Table 1) have been observed in XLA, ARA, CVID, IgAD and other genetic defects. Causes of chronic or recurrent diarrhea in XLA and ARA have included Giardia lamblia, rotavirus, Campylobacter fetus, enterovirus, Salmonella, and cryptosporidia.5,10,18 Since gastrointestinal manifestations are present in up to 35% of XLA patients, with IBD/enteritis diagnosed in up to 10% of patients, a close monitoring is necessary.[40]

Rates of malignancy in XLA are reported to be between 1.5 and 6%, with patients most likely to develop lymphoproliferative disorders (B or T-cell lymphoma, Hodgkin's lymphoma, myelodysplastic syndrome, leukemia, carcinoma; and, rarely, melanoma, medulloblastoma, neuroblastoma, or gastric cancer and colorectal cancer) (Table 2).7,8,41

Arthritis, inflammatory bowel disease (IBD) or other inflammatory conditions have been showed to be prevalent in these patients.5,7,8,10,42 Data from the USIDNET registry showed 12% of XLA patients reporting arthralgia or joint swelling, with 16% having a diagnosis of arthritis, which frequently responds to IRT. Because of lack of immunoglobulins, autoantibody analysis is of no value, and ESR is normal.

ARA corresponds to 15% of all patients with a B-lymphocyte differentiation arrest, caused by defects of the BCR structure itself, including the μ heavy chain gene mutations (IGHM OMIM 147020), surrogate light chains VpreB and λ5 (IGLL1 OMIM 146770), Igα (CD79A OMIM 112205), Igβ (CD79B OMIM 147245), B-cell linker (BLNK MIM 604515), p110δ (PIK3CD OMIM 602839), p85 (PIK3R1 615214), E47 transcription factor (TCF3 OMIM AD 616941; OMIM AR 147141), SLC39A7(ZIP7) SLC39A7 OMIM 601416), Hoffman syndrome/TOP2B (TOP2B OMIM 126431).1,10,18 Clinically, μ heavy chain gene mutations (IGHM OMIM 147020) is a more severe phenotype, with higher incidence of enteroviral infections, Pseudomonas sepsis, and neutropenia than patients with mutations in BTK. Gene defects of Igα and Igβ are very rare, and the patients have recurrent sinopulmonary infections, chronic diarrhea with malabsorption and dermatomyositis-like manifestations, and sometimes neutropenia. E47 Transcription Factor/TCF3 deficiency autosomal recessive (OMIM: 147141) includes severe, recurrent bacterial infections and failure to thrive, agammaglobulinemia and B-cells have increased expression of CD19+ but absence of a BCR.[1,5,10,18]

Autosomal dominant agammaglobulinemia was reported as a result of mutations in the LRRC8A gene on chromosome 9q34 in a 17-year-old girl (OMIM: 613506) and TCF3 gene on 19p13.3 (OMIM: 616941).8,18

The measures to prevent infections are frequent handwashing, good respiratory hygiene, and only ingesting drinking water. IRT has reduced the rate of infections and hospitalizations. However, a few uncommon pathogens to which the donor pool has not been exposed are not precluded. An emerging route of administration is via subcutaneous injections (SCIG); only IgG is replaced. In addition to IVIG, treatment with antibiotics for active infections should be done.7,8,10,18 Regular monitoring is recommended for recurrent pneumonia, bronchiectasis, chronic sinusitis, and chronic bronchitis using imaging studies. Hematopoietic stem cell transplantation (HSCT) is an alternative. The risks of allogeneic HSCT, such as rejection and graft-versus-host-disease, make the treatment option less safe.7 However, gene therapy is emerging as a promising possibility of lifetime cure for these patients, foregoing the need for long-term immunoglobulin therapy, eliminating the risks brought on by recurrent infections, restoring B-lymphocyte functions and potentially ensuring adequate BTK expression on other immune cells.[7]

Pneumonia caused by H. influenzae and S. pneumoniae may lead to pleurisy, empyema, and bronchospasm, which lead to chronic lung disease, as reported in 28.5% of 473 patients with CVID.6,10,17,44 The survival was significantly reduced compared to those without chronic lung disease. Early prophylactic antibiotics and immunoglobulin replacement therapy (IRT) can reduce respiratory infections and decrease morbidity and mortality from pulmonary disease in PADs.6,10,17,44 Chronic lung disease progresses in many patients, in part by immune dysregulation occurring independent of infection and also due to mucosal IgM and IgA responses’ deficiencies. Chest imaging and pulmonary function testing (PFT) form the basis of the diagnostic work-up of chronic lung disease, with lung tissue biopsy when indicated.44

Asthma and chronic obstructive pulmonary disease (COPD) has been reported in IgAD, 15% to 50% of those with CVID and 5% of patients with XLA. The etiologies must be considered in PADs to prevent it from being misdiagnosed as asthma.6,17,44

Bronchiectasis is associated with a history of pneumonia, older age, chronic cough with purulent sputum, occasional hemoptysis, and dyspnea, as well as reduced levels of CD4+ T cells and lower levels of IgA and/or IgM. Airflow obstruction is often evident on PFT, and diagnosis is made by CT.17,44

Interstitial lung disease (ILD) occurs in 10–20% of patients with CVID, but 64% of patients with respiratory symptoms have images of ground glass opacity and/or numerous pulmonary nodules in the CT. ILD is more common in CVID associated with autoimmunity and T-cell deficiency than in XLA, and in IgAD patients with autoimmunity and IgG subclass deficiency. ILD pathology in patients with PAD consists in forms of benign pulmonary lymphoproliferation, usually follicular bronchiolitis (benign hyperplasia of lymphoid follicles), lymphocytic interstitial pneumonia (LIP), or nodular lymphoid hyperplasia.6,17,44

Granulomatous inflammation and organizing pneumonia may also be found in the lungs of patients with PAD together with one of the lymphoproliferative pathologies, and the term granulomatous and lymphocytic interstitial lung disease (GLILD) is frequently used to describe the ILD associated with PAD.6,17,44 The role of B cells in determining lung inflammatory disorders is also demonstrated by the observation that GLILD occurs in 10% of patients with CVID and can be treated with B-cell-depleting drugs.44

Meningitis is the most common neurologic manifestation of CVID. The rare neurological diseases in CVID include axonal sensory-motor polyneuropathy as autoimmune involvements, transverse myelitis, progressive neurodegeneration, cerebral vasculitis causing recurrent occipital headaches, brain granulomatous lesions, free radical mediated neuronal damage due to vitamin E deficiency, including sensory loss, ataxia, retinitis pigmentosa, subacute combined degeneration of the cord secondary to vitamin B12 deficiency, peroneal muscular atrophy, Guillain-Barré syndrome and myasthenia gravis.6,10,11,17,45

“Hyper-IgM syndromes (HIGM)” are rare, characterized by impaired production of switched immunoglobulin isotypes (IgG, IgA, IgE) and normal or elevated IgM levels. Some deficiencies are caused by defects in CSR machinery and are intrinsic B-cell defects, due to variants in AID and UNG.5,10,46 In contrast, CD40 ligand (CD40L) and CD40 deficiencies are combined immune defects with impaired interaction between activated CD4+ T cells expressing CD40L and cell types expressing CD40, which include B cells, dendritic cells, monocytes/macrophages, platelets, and activated endothelial/epithelial cells.5,10,46 CD40L on activated T cells and cognate interactions with CD40 on B cells result in B-cell proliferation, adhesion, and finally, differentiation.5,10 CD40L deficiency is inherited as an X-linked trait and is the most common form of HIGM; its estimated frequency is 2:1,000,000 males.10 CD40L deficiency often presents in infancy with recurrent sinopulmonary infections, caused by Streptococcus pneumoniae and Haemophilus influenzae, and higher risk of opportunistic infections by Pneumocystis, Cryptosporidium, and Histoplasma organisms. Patients can often have chronic and recurrent diarrhea due to infection with Cryptosporidium parvum, with increased risk of biliary tract diseases such as sclerosing cholangitis and cholangiocarcinoma.5,10,46 Chronic viral hepatitis, CMV infections, Cryptococcus and Toxoplasma infections, JC virus-related enteroviral meningoencephalitis and progressive multifocal leukoencephalopathy (PML)5,10,46 have been reported. Recurrent oral ulcers and proctitis, often associated with chronic or cyclic neutropenia are common in half of the patients.10 Autoimmune complications include thrombocytopenia and autoimmune hemolytic anemia.5,10 Patients with CD40L deficiency also have an increased risk of malignancies of hepatobiliary origin including hepatocellular carcinoma, cholangiocarcinoma, peripheral neuroectodermal tumors of the gastrointestinal tract and with a lesser incidence of lymphoma.5,10 CD40 recessive mutations in the B-cell surface receptor CD40 (OMIM: 109535) are very rare, and the patients have similar clinical features as CD40L deficiency.10

A disease first described in 1956,47 the patients with THI have low IgG levels (2 SD below the mean for age-match controls) with possible involvement of IgA and, less frequently, IgM that spontaneously return to normal, usually within 2–3 years of age, although it often varies.5,10 Most subjects with THI remain asymptomatic; however, in some patients it can be associated with a higher rate of recurrent infections.5,10,47 A prospective study of infants with THI showed that those with a low number of memory B cells and inability to produce IgG in vitro were associated with persistence of hypogammaglobulinemia and an increased risk of infection beyond 2 years of age.10 The evaluation of THI should include specific antibody responses to age-appropriate vaccines and immunophenotyping by flow cytometry to exclude other immune defects.5,10 Vaccines’ antibody responses are often intact.5,10 THI is self-limited, and patients should be monitored over time until levels have normalized.5,10 However, the defect may be a harbinger of a more permanent immune defect.[10]