Pure B-Cell Disorders Clinical Presentation

A history of recurrent infections is a common presenting feature. The onset of symptoms in childhood is suggestive of an inherited disorder.^[3] Patients with B-cell deficiencies begin having bacterial infections when aged 7-9 months, when the placental antibodies fall to undetectable levels. Patients with primary T-cell deficiency or SCID begin having infections 3-4 months after birth. Acquired B-cell disorders may start in persons of any age, depending on the underlying cause.

The site of infection may provide clues to the significance and the type of immune deficiency. Upper and lower respiratory infections, skin infections, meningitis, bacteremias, and abscesses are common in persons with B-cell disorders. Pneumonia with Pneumocystis carinii or cytomegalovirus (CMV), disseminated bacille Calmette-Guérin infection or atypical mycobacterial infection, and recurrent or persistent skin candidiasis are suggestive of T-cell disorders of SCID. Diarrhea with failure to thrive in children with SCID is usually related to viral infections (eg, rotaviruses, adenoviruses).

The type of microorganisms involved is also suggestive. Antibody deficiency is associated with recurrent infections with encapsulated bacteria. Giardia lamblia infection is very common in patients with CVID or IgA deficiency. Opportunistic infections with fungi, viruses, or intracellular bacteria are particularly common in patients with T-cell disorders or SCID.

An adverse reaction to transfused blood products or to vaccines should raise the possibility of an underlying immunodeficiency, particularly IgA deficiency.

A thorough family history is crucial in the evaluation of inherited disorders. Both XLA and hypogammaglobulinemia with hyper-IgM are X-linked disorders. CVID and IgA deficiency may be familial and are frequently associated with autoimmune disorders.^[4]

• X-linked agammaglobulinemia

  • The disorder affects boys only and is characterized by recurrent pyogenic infections during the second half of the first year of life.
  • Sinopulmonary infections are the most common (60% of patients), with chronic otitis media, sinusitis, and pneumonia. The other common infections, in decreasing order, are gastroenteritis (35%), pyoderma (25%), arthritis (20%), and meningitis/encephalitis (16%). Septicemia (10%), conjunctivitis (8%), and osteomyelitis (3%) are less common.
  • Diarrhea with monoarthritis or oligoarthritis of large joints with sterile effusion is occasionally observed.
  • Patients with XLA have an increased frequency of leukemia and lymphoma.
  • The encapsulated bacteria Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Staphylococcus aureus are the most common pathogens.
  • The frequency of viral and fungal infections and tuberculosis is not increased because cellular immunity is normal. However, live viral vaccines (eg, poliovirus vaccine) are not well tolerated and may result in viremia because of the lack of IgA. G lamblia and Rotavirus are frequently associated with the GI symptoms. Ureaplasma urealyticum is implicated in the pathogenesis of sterile arthritis; however, in many cases, the arthritis is related to direct bacterial infection.
• X-linked immunodeficiency with hyper-IgM

  • XHM affects only boys. The IgM level is elevated; the levels of all the other immunoglobulins are decreased. Recurrent infections of the upper and lower respiratory tracts beginning during the first 2 years of life are common. The susceptibility to P carinii and C parvum, both opportunistic infections controlled by cellular immunity, may be explained by the nature of the defect underlying this disease and involving T-cell CD40L.
  • These patients have a high incidence of liver disease, sclerosing cholangitis (approximately 20% of patients in a series reported by Levy et al^[5] ; 80% by age 20 y reported by others), and liver/GI malignancies.
  • Oral and rectal ulcers are common in patients with chronic neutropenia.
  • Autoimmune diseases such as arthritis, nephritis, and hematologic disorders have also been reported.
• Selective IgA deficiency

  • IgA deficiency may be primary or secondary (acquired), sporadic, or familial. Both serum and secretory IgA are lacking in most patients and, rarely, one or the other. Inheritance is either autosomal recessive or dominant. Administration of certain drugs, such as phenytoin, D-penicillamine, sulfasalazine, and hydroxychloroquine, has been incriminated in this entity. Cases of congenital noninherited IgA deficiency in association with rubella, CMV, and Toxoplasma gondii have been reported.
  • Although certain studies have reported recurrent infections in as many as 50% of IgA-deficient patients, most of these individuals are healthy. Some patients develop symptoms after an uneventful childhood and early adulthood. Recurrent or chronic upper and lower respiratory tract infections may result in bronchiectasis or cor pulmonale in insufficiently treated patients. G lamblia infection of the GI tract is common. Other GI diseases, such as spruelike syndrome, ulcerative colitis, and Crohn disease, have been reported.
  • The incidence of autoimmune and collagen vascular diseases is increased (up to 25% of patients in certain studies). Rheumatoid arthritis, systemic lupus erythematosus without renal disease, autoimmune hepatitis, hemolytic anemia, and endocrinopathies have been described.
  • Patients with undetectable levels of IgA antibodies may develop anti-IgA antibodies after receiving blood products. Once sensitized, these patients are at risk of anaphylactic reactions if they receive blood products containing even small amounts of IgA antibodies. Mounting an antibody response to cow milk protein is also common.
  • Several factors explain the variability of clinical expression of this disorder. Symptoms may be attenuated by the increased excretion of monomeric IgM in the secretions of these patients, compensating for the lack of IgA, or they may be worsened by the association of an IgG subclass deficiency such as IgG2/IgG4 or IgG3.
• Selective IgM deficiency:

  • This is a rare disorder associated with recurrent and life-threatening infections with encapsulated bacteria, particularly pneumococcal and meningococcal species.
  • IgG levels are usually normal, but the response to specific infections is reduced.
• IgG subclass deficiency

  • This is defined as a decrease of an IgG subclass greater than 2 standard deviations below the normal mean for age. One or more IgG subclasses may be involved. This deficiency may be isolated or associated with other immunodeficiencies. Unless a patient has an impaired response to tetanus, diphtheria, and pneumococcal vaccine, IgG deficiency is not considered clinically significant. IVIG should not be used in these patients until a thorough antibiotic trial has failed to control their infections.
  • IgG1 deficiency is rare. The more common IgG2 deficiency is associated with an inability to mount an antibody response to polysaccharides and to recurrent sinopulmonary infections with encapsulated bacteria such as H influenzae and S pneumoniae. Asymptomatic cases of IgG2 deficiency have been reported.
  • IgG3 is necessary to generate an antibody response to viral infections and Moraxella catarrhalis. Its deficiency is associated with recurrent sinopulmonary infections with these pathogens. IgG4 subclass deficiency is very common, affecting 10-15% of the general population. It may be isolated or associated with other IgG subclass deficiencies. The clinical significance of this disorder remains controversial.
• Transient hypogammaglobulinemia of infancy

  • THI is related to a delayed onset of immunoglobulin synthesis in infants. These patients recover a normal antibody response when aged 2-3 years.
  • During their first years, these patients have a high incidence of recurrent upper respiratory infections but not of pneumonias or life-threatening infections. These patients do not require IVIG therapy.
• Common variable immunodeficiency

  • CVID is the most common cause of hypogammaglobulinemia and affects both sexes equally. It encompasses a group of disorders that are heterogeneous in their mechanism and age of onset. Although a first manifestation in infancy and childhood is possible, symptoms typically become evident between the second and third decades of life.
  • Recurrent upper and lower respiratory infections, such as otitis media, sinusitis, pneumonia, and bronchitis, are the most common symptoms. Arthralgia and conjunctivitis are frequently reported. Pyoderma, urinary tract infection, osteomyelitis/arthritis, and meningitis/encephalitis are less common. Gastritis with achlorhydria and pernicious anemia may be observed. Diarrhea occurs in 60% of patients with CVID.
  • Encapsulated bacteria such as S pneumoniae, S pyogenes, and H influenzae are the most common pathogens. Bordetella pertussis plays an important role in respiratory infections. G lamblia and Campylobacter species are involved in GI manifestations.
  • Infections with fungi, mycobacteria, and P carinii are not usually encountered unless an associated deficiency of cellular immunity exists. Severe abnormalities of cell-mediated immunity are occasionally reported. In these patients, severe and prolonged primary varicella or zoster, herpes simplex, and CMV infections have been reported.
• Kappa/lambda light-chain deficiency: These are rare disorders that manifest clinically as upper respiratory tract infections, malabsorption syndrome with diarrhea, and pernicious anemia.
• Immunodeficiency with thymoma

  • Also known as Good syndrome, this disorder is typically described in adults aged 40-70 years. Thymoma of the benign spindle cell variety may be an incidental finding on images from a routine chest radiograph, but it is more often discovered during an evaluation for hypogammaglobulinemia. Of patients with thymoma, 3-6% have concomitant hypogammaglobulinemia or are found to have it upon follow-up examinations.
  • The decrease of immunoglobulins affects all isotypes and results in recurrent sinopulmonary infections and diarrhea, which may be ascribed to an infectious cause in only a third of cases. Pure red cell aplasia, agranulocytosis, and myasthenia gravis may be associated with this disorder and may improve after thymectomy, although the hypogammaglobulinemia does not. Half the patients have cell-mediated immunodeficiency and may present with mucocutaneous candidiasis, CMV, herpes zoster infection, or P carinii pneumonia.
• IgE hypogammaglobulinemia

  • Compared to controls, patients with decreased IgE levels have a higher incidence of autoimmune diseases (47% vs 15%), nonallergic reactive airway disease (73% vs 20%), and arthralgia and chronic fatigue.
  • The most common autoimmune diseases described with this entity are thyroid disease, rheumatoid arthritis, Sjögren syndrome, Raynaud syndrome, and systemic lupus erythematosus.
• Omenn syndrome^{[6, 7]}

  • This syndrome is characterized by high serum IgE levels, decreased levels of the other immunoglobulins, and hypereosinophilia. It manifests in early infancy as chronic diarrhea, failure to thrive, and an erythematous rash with desquamation. Hepatosplenomegaly is common.
  • Patients die in the first few months of life unless a successful allogeneic bone marrow transplantation is performed.
  • In a study of thymic maturation and organization in 9 infants in whom, owing to various genetic defects, T-cell development was partially or completely blocked, Poliani et al found evidence that severe defects in thymopoiesis adversely affect the homeostasis of thymocytes and thymic epithelial cells and "may affect deletional and nondeletional mechanisms of central tolerance."^[6] According to the authors, this would in turn favor the manifestation of immune dysreactivity, as occurs in Omenn syndrome.
• Hyperimmunoglobulin E syndrome

  • Also known as Job syndrome, hyperimmunoglobulin E (HIE) syndrome is also characterized by very high levels of serum IgE. However, the normal IgA, IgG, and IgM levels and the clinical presentation differentiate it from the previous disorder.
  • Beginning in early infancy, patients present with recurrent staphylococcal infections of the skin, joints, lungs, and other viscera. Grimbacher et al reported the results of their study of 30 patients with HIE syndrome. In addition to the previous symptoms, 72% of patients had delayed shedding of primary teeth, 57% had recurrent fractures, 76% had scoliosis and characteristic facial features, and 68% had hyperextensible joints.^[8] Atopiclike dermatitis may occur.
  • The inheritance in this disorder is autosomal dominant with variable expression.

• Growth and development: Early-onset recurrent infections cause growth retardation. However, normal growth does not exclude the presence of these disorders. Developmental abnormalities such as short-limbed dwarfism and hair abnormality are observed in cartilage-hair syndrome.
• Lymphoid tissue and organs: A paucity of tonsils, adenoids, and peripheral lymph nodes is observed in persons with XLA and in those with different forms of SCID. Diffuse lymphadenopathy is observed in persons with CVID, immunodeficiency with hyper-IgM, and Omenn syndrome; splenomegaly occurs in 25% of CVID patients with or without hypersplenism.
• Skin and mucous membranes: Permanent scars are observed following skin infections. An eczematous rash develops in persons with HIE syndrome, and a desquamating erythematous rash develops in those with Omenn syndrome. Livedo reticularis with muscle weakness or dermatomyositislike syndrome may be observed with XLA. A lupuslike rash may occur.
• Ear, nose, and throat: Evidence of past perforations, scarring, and dull tympanic membranes occur after recurrent episodes of otitis media. Purulent nasal discharge, a cobblestone pattern of pharyngeal mucosa, and postnasal exudate may be evident. The presence or absence of tonsillar tissue should be noted.
• Cardiovascular system: Signs such as a loud pulmonic heart sound, right ventricular heave, and tricuspid regurgitation murmur should be sought; if present, they support the diagnosis of pulmonary hypertension. Jugular venous distension, tender hepatomegaly, and lower-extremity edema suggest cor pulmonale.
• Pulmonary system: Rales, rhonchi, wheezing, and digital clubbing may be encountered.
• Neurologic system: Following vaccination, paralytic poliomyelitis may ensue in patients with antibody deficiency. Deep sensory loss with decreased vibratory sense and position of limb segments are observed in persons with pernicious anemia.

• Pure B-cell disorders

  • X-linked agammaglobulinemia
  • X-linked immunodeficiency with hyper-IgM
  • Selective IgA deficiency
  • Selective IgM deficiency
  • IgG subclass deficiency
  • Transient hypogammaglobulinemia of infancy
  • Common variable immunodeficiency
  • Kappa/lambda light-chain deficiency
  • Immunodeficiency with thymoma
  • IgE hypogammaglobulinemia
  • HIE syndrome
• Combined T- and B-cell deficiencies: These disorders combine symptoms related to both B- and T-cell deficiency (see Combined B-Cell and T-Cell Disorders).