Infectious Complications of Antibody Deficiency

Approach to the Patient With A Suspected Antibody Deficiency

A primary antibody deficiency should be considered in children with recurrent or chronic sinopulmonary infections, particularly in association with (1) poor growth, (2) unusual or unusually severe infections, (3) chronic or recurrent diarrhea, (4) a family history of recurrent and severe infections or of early childhood deaths, or (5) granulomatous or autoimmune disease. Physical features suggesting humoral immunodeficiency include absent or small lymph nodes and tonsils, chronic lymphadenopathy, a dermatomyositis-like rash, or hypertrophic osteoarthropathy.

Timely diagnosis of primary antibody deficiency and institution of immunoglobulin replacement therapy reduces the morbidity and mortality associated with these disorders. Quantitative serum immunoglobulin concentrations should be compared with normal values for age and reduced levels of IgG, IgM, or IgA (or normal levels in the presence of a clinical picture strongly suggestive of antibody deficiency) should prompt additional investigations ( Fig. 102.2 ). ^, B lymphocytes (CD19 ⁺ ) and other lymphocyte subsets are quantified by flow cytometry and should be compared with normal values for age. The ability to generate a specific antibody response is assessed by measuring serum isohemagglutinins (naturally occurring antibodies to ABO blood group antigens) and antigen-specific serum antibody concentrations before and after vaccination with protein (e.g., tetanus, diphtheria, pertussis) and polysaccharide antigens (e.g., pneumococcal polysaccharide vaccine in children >2 years). Quantifying IgG subclasses may be helpful in some cases, but the wide range of normal values and an inconsistent correlation between low serum concentrations and clinical disease complicate the interpretation of results, particularly in younger children. B lymphocyte and immunoglobulin levels obtained during acute severe illness should be interpreted with caution and abnormal results confirmed after recovery. Evidence of the decreased expression or function of a specific gene product may be useful, but these tests generally are available on a research basis only. A definitive diagnosis is possible for disorders caused by known genetic mutations. Carrier detection and prenatal diagnosis is also possible in some cases.

Patients with primary antibody deficiencies and severe symptoms should receive immunoglobulin replacement therapy, which reduces the rate and severity of infections. The half-life of IgG varies based on clinical status and is significantly shortened during severe illness. Ideally, trough serum IgG concentrations (immediately before the next administration of immunoglobulin) should be within the normal range of healthy persons. Increasing use has been made of rapid subcutaneous infusion and home or infusion center programs. Immunoglobulin replacement therapy does not prevent all infections, and signs and symptoms of infection should be evaluated promptly and breakthrough infections treated aggressively. Some patients, particularly those with frequent or chronic respiratory infections, may benefit from prophylactic antibacterial therapy. Patients with hyper-IgM syndrome (HIGM) caused by CD40L or CD40 deficiency have an increased susceptibility to Pneumocystis jirovecii infection and should receive trimethoprim-sulfamethoxazole or other effective prophylaxis. Vaccines composed of live-attenuated virus vaccines should not be administered to patients known or suspected of having a primary antibody deficiency.

Agammaglobulinemias: Severely Reduced IgG, IgA, and IgM With Absent B Lymphocytes

The prototype of antibody deficiency syndromes is X-linked agammaglobulinemia (XLA), which has an incidence of approximately 1 in 200,000 persons and accounts for about 85% of cases of agammaglobulinemia ( Box 102.1 ; Table 102.1 ,). ^, XLA is caused by mutations in the Bruton tyrosine kinase gene, Btk, which is required for the normal differentiation of pro-B cells to pre-B cells and mature B lymphocytes. ^, A family history of male relatives with recurrent infections is common, but about one half of patients represent new mutations. The severity of infectious complications can also differ among family members. Prenatal diagnosis and carrier detection are possible if the mutation is known. Rare autosomal recessive and autosomal dominant agammaglobulinemias result from mutations in other genes important to B cell development.

Serum IgG, IgA, and IgM levels are very low (>2 standard deviations [SD] below the mean value for age), and patients have poor or no specific antibody responses following infection or immunization. Circulating CD19 ⁺ B lymphocytes are absent or present in very low numbers (generally <2%). Plasma cells are absent from lymph nodes and bone marrow, and lymph nodes and tonsils are absent or small. T lymphocytes are normal in both number and function. Neutropenia can occur in association with acute infections.

Transplacentally acquired maternal IgG typically protects infants with agammaglobulinemia from infection in the first few months of life. Thereafter, affected children have recurrent bacterial infections, particularly otitis media, sinusitis, and pneumonia. More than one half of patients are symptomatic by 1 year of age and almost all by 5 years of age. Other invasive bacterial infections (septicemia, meningitis, osteoarticular infections) are also common. Encapsulated bacteria, particularly H. influenzae type b (Hib), S. pneumoniae, Staphylococcus aureus, and Pseudomonas spp. cause most infections. Up to 50% of patients experience chronic diarrhea, steatorrhea, or malabsorption, in some cases associated with chronic rotavirus and G. lamblia infections. ^, The incidence of enteritis due to Salmonella spp. and Campylobacter jejuni is higher in persons with agammaglobulinemia than the general population. Persistent Mycoplasma and Ureaplasma infections of the respiratory tract, joints, and urogenital tract also occur.

Although children with antibody deficiencies usually manifest greater susceptibility to bacterial than to viral infections, some children with agammaglobulinemia have severe and chronic enteroviral infections. In regions of the world where wild-type or live-vaccine-strain polioviruses circulate, paralytic disease in patients with agammaglobulinemia can occur. Meningitis caused by non-polio enteroviruses can have an insidious onset with ataxia, loss of cognitive skills, and paresthesias, or present more acutely with fever, headache, and seizures. Central nervous system (CNS) enterovirus infection can be the initial manifestation of XLA and can occur despite intravenous IgG (IGIV) replacement therapy. Cerebrospinal fluid (CSF) pleocytosis with a lymphocytic predominance, increased protein levels, and, frequently, decreased glucose levels is typical, although some children have normal or only mildly abnormal findings. CSF abnormalities tend to worsen with clinical exacerbations. Some individuals with chronic enteroviral infections develop a dermatomyositis-like syndrome characterized by muscle weakness, edema and woody induration of the skin, and a violaceous rash over the extensor surfaces of joints, often accompanied by hepatitis.

The prognosis of XLA has greatly improved with IGIV therapy, particularly when it is initiated at an early age. Aggressive and prolonged treatment of bacterial infections is critical. Patients with chronic enteroviral meningoencephalitis are treated with high doses of IgG (to maintain trough levels of >1000 mg/dL) or with plasma or immune serum known to have high antibody titers to the enterovirus causing the infection. Intrathecal IGIV has also been used. The most common causes of death among patients with agammaglobulinemia remain chronic enteroviral and pulmonary infections.

Common Variable Immunodeficiency Disorders: Severely Reduced IgG, IgA, and/or IgM With Normal or Low Numbers of B Lymphocytes

Common variable immunodeficiency disorder (CVID) represents a heterogeneous group of disorders characterized by low serum Ig concentrations, defective production of specific antibodies, and an increased susceptibility to respiratory and gastrointestinal tract infections ( Box 102.2 ). ^{, , , ,} CVID affects 1 in 30,000 persons and has an equal prevalence in males and females. Persons with CVID have serum total IgG concentration ≥2 SD below the mean for their age, a marked decrease in IgM and/or IgA, and impaired specific antibody responses. ^, Numbers of peripheral B lymphocytes may be normal, reduced, or increased; the clinical phenotype exhibited by an individual patient generally correlates with the numbers and subtypes of peripheral B lymphocytes. Current diagnostic criteria restrict the definitive diagnosis of CVID to persons >4 years of age, in part owing to the need to exclude other immunodeficiencies that manifest early in life. CVID can develop in persons who initially have clinical and laboratory findings suggestive of selective IgA or IgG subclass deficiencies. Immunodeficiency can be progressive, and patients must be followed longitudinally; up to 10% of patients develop opportunistic infections. ^,

Approximately 25% of cases of CVID are familial. While many mutations have been described, almost all are uncommon, and the genetic basis of most CVID is not known. Most have autosomal recessive inheritance; some forms have distinctive associated features. Other immunodeficiencies, including agammaglobulinemia, class switch recombination defects, X-linked lymphoproliferative disease, and “leaky” severe combined immunodeficiency syndromes may resemble CVID. Certain drugs, chromosomal abnormalities, infection, malignancy, protein losing states, and systemic illnesses are associated with secondary CVID ( Table 102.2 ).

Symptoms of CVID are unusual in children under 2 years of age. Bimodal peaks of incidence are recognized at 2–5 and 16–28 years of age. Patients most commonly have recurrent sinopulmonary infection, chiefly due to bacteria such as S. pneumoniae, H. influenzae, Moraxella catarrhalis, and M. pneumoniae. Recurrent pneumonia sometimes progresses to bronchiectasis. Invasive bacterial infections occur in 10%–25%. Enteric infections caused by Giardia, C. jejuni, and Salmonella spp. are frequent and can be more severe and prolonged than in immunocompetent persons. Chronic genitourinary tract, joint, and systemic infections caused by Mycoplasma spp. have been described. Although most viral infections are not complicated in patients with CVID, increased frequency and severity of hepatitis C virus, cytomegalovirus (CMV), measles, and varicella-zoster virus infection have been reported. ^, Complications of enteroviral infection, including chronic encephalomyelitis and dermatomyositis-like syndrome, occur but are less frequent than with the agammaglobulinemias.

Allergic disorders are found in over 30% of children and adolescents with CVID. Inflammatory or autoimmune diseases occur in 20%–35% of patients and can cause more serious morbidity than infections. Diffuse and pulmonary granulomatous disease, lymphocytic interstitial pneumonitis, and chronic lymphadenopathy are reported in 10%–20% of patients. Inflammatory bowel disease, lymphonodular hyperplasia, or nonspecific malabsorption affect up to 25% of patients; immune cytopenias and hematological disorders, such as autoimmune thrombocytopenia, hemolytic anemia, neutropenia, and pernicious anemia occur in 10%. About one fourth of patients have significantly reduced growth. The incidence of some cancers, particularly lymphomas and gastric carcinoma, is markedly elevated in patients with CVID, but onset is predominantly in adults.

Most patients with CVID require IG replacement therapy. Prophylactic antibiotics may benefit some patients, particularly those with recurrent respiratory infections and bronchiectasis. Patients require careful monitoring for autoimmune and lymphoproliferative complications.

Hyper-IgM Syndromes (Hims, Class Switch Recombination Defects): Reduced IgG and IgA With Normal or Elevated IgM and Normal Numbers of B Lymphocytes

Children with hyper-IgM syndromes (HIMS) have recurrent or serious infections in the first 5 years of life, absent or low levels of serum IgG, normal or elevated serum IgM, absent or poor specific immune responses, normal or elevated numbers of B lymphocytes, and normal numbers of T lymphocytes ( Box 102.3 ). ^{, , , ,} HIMS is rare, affecting about 1 in 300,000 persons. Approximately 65% of cases are inherited in an X-linked recessive fashion and are due to mutations of the gene encoding CD40L ( TNFSF5 ). ^{, ,} Rare mutations of CD40 ( TNFRSF5 ) cause a similar disorder with autosomal-recessive inheritance. Both CD40 and CD40L deficiency are associated with impaired humoral and cellular immunity. Mutations of AICDA are responsible for autosomal recessive and autosomal dominant forms of HIMS, and mutations in UNG , INO80, and MSH6 cause autosomal recessively inherited forms that are not associated with significant cellular immunodeficiency.