Abnormalities of the Phagocytic System

Children with abnormalities of the phagocytic and neutrophil system have problems with bacteria as well as environmental fungi. Disease manifests as recurrent infections of the skin, mucous membranes, lungs, liver, and bones. Dysfunction of this arm of the immune system can be due to inadequate numbers, abnormal movement properties, or aberrant function of neutrophils (Chapter 124).

Neutropenia is defined as an absolute neutrophil count of <1,000 cells/mm³ and can be associated with significant risk for developing severe bacterial and fungal disease, particularly when the absolute count is <500 cells/mm³ (Chapter 125). Although acquired neutropenia secondary to bone marrow suppression from a virus or medication is common, genetic causes of neutropenia also exist. Primary congenital neutropenia most often manifests during the 1st year of life with cellulitis, perirectal abscesses, or stomatitis from Staphylococcus aureus or Pseudomonas aeruginosa. Episodes of severe disease, including bacteremia or meningitis, are also possible. Bone marrow evaluation shows a failure of maturation of myeloid precursors. Most forms of congenital neutropenia are autosomal dominant, but some, such as Kostmann syndrome (Chapter 125) and Shwachman-Diamond syndrome (Chapter 462) are due to autosomal-recessive mutations. Cyclic neutropenia can be associated with autosomal-dominant inheritance or de novo sporadic mutations and manifests as fixed cycles of severe neutropenia between periods of normal granulocyte numbers. Often the neutrophil count has normalized by the time the patient presents with symptoms thus hampering the diagnosis. The cycles classically occur every 21 days (range, 14-36 days), with neutropenia lasting 3-6 days. Most often the disease is characterized by recurrent aphthous ulcers and stomatitis during the periods of neutropenia. However, life-threatening necrotizing myositis or cellulitis and systemic disease can occur, especially with Clostridium septicum or Clostridium perfringens. Many of the neutropenic syndromes respond to colony-stimulating factor.

Leukocyte adhesion defects are caused by defects in the β chain of integrin (CD18), which is required for the normal process of neutrophil aggregation and attachment to endothelial surfaces (Chapter 124). In the most-severe form there is a total absence of CD18. Children with this defect can have a history of delayed cord separation and recurrent infections of the skin, oral mucosa, and genital tract beginning early in life. Ecthyma gangrenosum and pyoderma gangrenosum also occur. Because the defect involves leukocyte migration and adherence, the neutrophil count in the peripheral blood is usually extremely elevated and pus is not found at the site of infection. Survival is usually <10 yr in the absence of stem cell transplantation.

Chronic granulomatous disease is an inherited neutrophil dysfunction syndrome, which can be either X-linked or autosomal recessive (Chapter 124). Neutrophils and other myeloid cells have defects in their nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase function, rendering them incapable of generating superoxide and thereby impairing intracellular killing. Accordingly, microbes that destroy their own hydrogen peroxide (S. aureus, Serratia marcescens, Burkholderia cepacia, Nocardia spp, Aspergillus) cause recurrent infections in these children. Infections have a predilection to involve the lungs, liver, and bone in these children. Prophylaxis with trimethoprim-sulfamethoxazole, recombinant human interferon-γ (IFN-γ), and oral antifungal agents that have activity against Aspergillus spp such as itraconazole or newer azoles substantially reduce the incidence of severe infections. Patients with life-threatening infections have also been reported to benefit from aggressive treatment with white cell transfusions in addition to antimicrobial agents directed against the specific pathogen.

Defective Splenic Function, Opsonization, or Complement Activity

Children who have congenital asplenia or splenic dysfunction due to hemoglobinopathies such as sickle cell disease or have undergone splenectomy are at risk for serious infections from encapsulated bacteria and blood-borne protozoa such as Plasmodium and Babesia. Prophylaxis against bacterial infection with penicillin should be considered for these patients, particularly children <5 yr of age. The most common causative organisms include Streptococcus pneumoniae, Haemophilus influenzae type b, and Salmonella, which can cause sepsis, pneumonia, meningitis, and osteomyelitis. Defects in the early complement components, particularly C2 and C3, can also be associated with severe infection from these bacteria. Terminal complement defects (C5, C6, C7, C8, and C9) are associated with recurrent infections with Neisseria. Patients with complement deficiency also have an increased incidence of autoimmune disorders. Vaccines for S. pneumoniae, H. influenzae type b, and Neisseria meningitidis should be administered to all children with abnormalities in opsonization or complement pathways.

B-Cell Defects (Humoral Immunodeficiencies)

Antibody deficiencies account for the majority of primary immunodeficiencies among humans (Chapter 118). Patients with defects in the B-cell arm of the immune system fail to develop appropriate antibody responses, with abnormalities that range from complete agammaglobulinemia to isolated failure to produce antibody against a specific antigen or organism. Antibody deficiencies found in children with diseases such as X-linked agammaglobulinemia or common variable immunodeficiency predispose to infections with encapsulated organisms such as S. pneumoniae and H. influenzae type b. Other bacteria can also be problematic in these children (see Table 171-2). Even though most other classes of microbes do not cause problems for these patients, some notable exceptions exist. Rotavirus can lead to chronic diarrhea, and enteroviruses can disseminate and cause a chronic meningoencephalitis syndrome. Paralytic polio has developed after immunization with live polio vaccine. Protozoan infections such as giardiasis can be severe and persistent. Children with B-cell defects can develop bronchiectasis over time following chronic or recurrent pulmonary infections.

Children with antibody deficiencies are usually asymptomatic until 5-6 mo of age, when maternally derived antibody levels begin to wane. These children begin to develop recurrent episodes of otitis media, bronchitis, pneumonia, bacteremia, and meningitis. Many of these infections respond quickly to antibiotics, which can delay the recognition of antibody deficiency. Children who require myringotomy tube placement before 2 yr of age because of recurrent episodes of otitis media (≥3 episodes within 6 mo, or ≥4 episodes within 12 mo) should be considered for screening measurement of immunoglobulin levels.

The significance and impact of specific immunoglobulin G (IgG) subclass deficiencies is less well understood and remains controversial. Deficiencies of specific IgG subclasses were first noted in healthy adult blood donors in whom no increased susceptibility to infections was documented. However, others have identified specific IgG deficiencies to be associated with a predisposition to recurrent bacterial sinopulmonary infection, bacteremia, meningitis, osteomyelitis, and pyoderma. Deficiency of subclass IgG₂ has been associated with poor antibody production after exposure to polysaccharide antigens, either after vaccination or after infection with a polysaccharide-encapsulated organism such as S. pneumoniae and H. influenzae type b.

Selective IgA deficiency leads to a lack of production of secretory antibody at the mucosal membranes (Chapter 118). Even though most patients have no increased risk for infections, some have mild to moderate disease at sites of mucosal barriers. Accordingly, recurrent sinopulmonary infection and GI disease are the major clinical manifestations. These patients also have an increased incidence of allergies and autoimmune disorders compared with the normal population.

Hyper-IgM syndrome is caused by a defect in the CD40 ligand on the T cell and is associated with a deficiency in the production of IgG and IgA antibody (Chapter 118). In addition, recurrent neutropenia, hemolytic anemia, or aplastic anemia can be present. Similar to patients with agammaglobulinemia, these patients are at risk for bacterial sinopulmonary infections, Pneumocystis jiroveci pneumonia (PCP), and Cryptosporidium intestinal infection.

Replacement of antibody with intravenous immunoglobulin (IVIG) has been the mainstay of treatment for most of the primary IgG antibody deficiencies. More recently, a subcutaneous formulation of immunoglobulin that can be given at home on a weekly basis has been approved. Immunoglobulin replacement is not advocated for IgA deficiency, because it does not correct the defect. Prophylaxis with specific antibiotic regimens is controversial and should be individualized for patients who do not respond to immunoglobulin replacement.

T-Cell Defects (Cell-Mediated Immunodeficiencies)

Children with primary cell-mediated immunodeficiencies, either isolated or more commonly in combination with B-cell defects, present early in life and are susceptible to viral, fungal, and protozoan infections. Clinical manifestations include chronic diarrhea, mucocutaneous candidiasis, and recurrent pneumonia, rhinitis, and otitis media. In thymic hypoplasia (DiGeorge syndrome), hypoplasia or aplasia of the thymus and parathyroid glands occurs during fetal development in association with the presence of other congenital abnormalities (Chapter 119). Hypocalcemia and cardiac anomalies are usually the presenting features of DiGeorge syndrome, which should prompt evaluation of the T-cell system. Chronic mucocutaneous candidiasis is a rare immunodeficiency associated primarily with T-cell dysfunction. These patients might not demonstrate delayed hypersensitivity to skin tests for Candida antigen despite having chronic superficial infection with yeast, but they do not appear to be at increased risk for systemic yeast infections. Endocrinopathies are commonly associated with chronic mucocutaneous candidiasis.

Combined B-Cell and T-Cell Defects

Patients with defects in both the T-cell and B-cell components of the immune system have variable manifestations depending on the extent of the defect (Chapter 120). Complete immunodeficiency is found with severe combined immunodeficiency syndrome (SCID), whereas partial defects can be present in such states as ataxia-telangiectasia, Wiskott-Aldrich syndrome, hyper-IgE syndrome, and X-linked immunodeficiency syndrome. Children with SCID present in the 1st 6 mo of life with recurrent, severe infections caused by a variety of bacteria, fungi, and viruses. Failure to thrive, chronic diarrhea, mucocutaneous or systemic candidiasis, PCP, or cytomegalovirus (CMV) infections are common early in life. Passive maternal antibody is relatively protective against the bacterial pathogens during the 1st few months of life, but thereafter patients are susceptible to both gram-positive and gram-negative organisms. Exposure to live virus vaccines can also lead to disseminated disease. Without stem cell transplantation, most affected children succumb to opportunistic infections within the 1st year of life.

Children with ataxia-telangiectasia

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