Infections in Immunocompromised Persons

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 a result of inadequate numbers, abnormal movement properties, or aberrant function of neutrophils (see Chapter 153 ).

Neutropenia is defined as an absolute neutrophil count (ANC) of <1,000 cells/mm ³ and can be associated with significant risk for developing severe bacterial and fungal disease, particularly when the ANC is <500 cells/mm ³ . 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 yr 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 (see Chapter 153 ) and Shwachman-Diamond syndrome, are caused by 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 ANC 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 (see Chapter 153 ). 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 also occurs. Because the defect involves leukocyte migration and adherence, the ANC in the peripheral blood is usually extremely elevated, but pus is not found at the site of infection. Survival is usually <10 yr in the absence of hematopoietic stem cell transplantation (HSCT) .

Chronic granulomatous disease (CGD) is an inherited neutrophil dysfunction syndrome, which can be either X-linked or autosomal recessive (see Chapter 156 ). In addition, CGD can develop in response to spontaneous mutations in the genes associated with heritable chronic granulomatous disease. Neutrophils and other myeloid cells have defects in their nicotinamide-adenine dinucleotide phosphate 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. Less common but considered pathognomonic are Granulibacter bethesdensis , Francisella philomiragia , Chromobacterium violaceum, and Paecilomyces infections. Infections have a predilection to involve the lungs, liver, and bone. Mulch pneumonitis can be seen in patients with known CGD but also can be a unique presenting feature in adults with autosomal recessive CGD. Mulch pneumonitis can resemble hypersensitivity pneumonitis, and bronchoscopy may yield aspergillus but often may not identify a clear organism. Treatment with antifungals and corticosteroids for the inflammation is recommended. S. aureus abscesses can occur in the liver despite prophylaxis. In addition, these children can present with recurrent abscesses affecting the skin or perirectal region or lymph nodes. Sepsis can occur but is more common with certain gram-negative organisms such as C. violaceum and F. philomiragia .

Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), recombinant human interferon-γ, and oral antifungal agents with activity against Aspergillus spp., such as itraconazole or newer azoles, substantially reduces the incidence of severe infections. Patients with life-threatening infections are also reported to benefit from aggressive treatment with white blood cell transfusions in addition to antimicrobial agents directed against the specific pathogen. It is important to remember that patients with CGD do not make pus, and thus drain placement for liver abscesses may not be effective. In addition, HSCT can be curative, and gene therapy trials are also a consideration.

Defective Splenic Function, Opsonization, or Complement Activity

Children who have congenital asplenia or splenic dysfunction associated with polysplenia or hemoglobinopathies, such as sickle cell disease, as well as those who have undergone splenectomy, are at risk for serious infections from encapsulated bacteria and bloodborne 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 S. pneumoniae, Haemophilus influenzae type b (Hib), and Salmonella , which can cause sepsis, pneumonia, meningitis, and osteomyelitis. Defects in the early complement components, particularly C2 and C3, may 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, Hib, and N. meningitidis should be administered to all children with abnormalities in opsonization or complement pathways (see Chapters 159 and 160 ).

B Cell Defects (Humoral Immunodeficiencies)

Antibody deficiencies account for the majority of primary immunodeficiencies among humans (see Chapters 149 and 150 ). 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 (XLA) 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 205.1 ). Patients with XLA can also have neutropenia, with one case series showing 12 of 13 patients with XLA having neutropenia as part of the initial presentation. Because of the neutropenia, patients with XLA can present with Pseudomonas septicemia. Viral infections can also occur, with rotavirus leading to chronic diarrhea. Enteroviruses can disseminate and cause a chronic meningoencephalitis syndrome in these patients. 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, delaying the recognition of antibody deficiency.

Selective IgA deficiency leads to a lack of production of secretory antibody at the mucosal membranes (see Chapter 150 ). 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 encompasses a group of genetic defects in immunoglobulin class switch recombination. The most common type is caused by a defect in the CD40 ligand on the T cell, leading to the inability of the B cell to class switch (see Chapter 150 ). Similar to other patients with humoral defects, these patients are at risk for bacterial sinopulmonary infections. However, unlike a true pure antibody defect, besides being important in T cell–B cell interactions, CD40 ligand is also important in the interaction between T cells and macrophages/monocytes, influencing opportunistic infections such as Pneumocystis jiroveci pneumonia (PCP) and Cryptosporidium intestinal infection.

T Cell Defects (Cell-Mediated Immunodeficiencies)

Children with primary cell-mediated immunodeficiencies, either isolated or more often 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. Hypocalcemia and cardiac anomalies are usually the presenting features of DiGeorge syndrome, which should prompt evaluation of the T cell system.

Chronic mucocutaneous candidiasis (CMC) is a group of immunodeficiencies leading to susceptibility to fungal infections of the skin, nails, oral cavity, and genitals. Most frequently caused by Candida spp., dermatophyte infections with Microsporum , Epidermophyton , and Trichophyton have also been described. Interestingly, patients with CMC do not have an increased risk for histoplasmosis, blastomycosis, or coccidioidomycosis. Despite chronic cutaneous and mucosal infection with Candida spp., these patients often lack a delayed hypersensitivity to skin tests for Candida antigen. Several gene defects make up this group of disorders, including STAT1 gain-of-function mutations, IL17R defects, CARD9 deficiency, and ACT1 deficiency. Although patients with CMC generally do not develop invasive candidiasis, this differs depending on the gene defect. Endocrinopathies and autoimmunity can also be seen in affected people, especially in individuals with STAT1 gain-of-function mutations.

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 (see Chapter 149, Chapter 150, Chapter 151, Chapter 152 ). Complete or almost complete immunodeficiency is found with severe combined immunodeficiency disorder (SCID) , whereas partial defects can be present in such states as ataxia-telangiectasia, Wiskott-Aldrich syndrome, hyper-IgE syndrome, and X-linked lymphoproliferative disorder. Rather than one disorder, it is now recognized that SCID represents a heterogeneous group of genetic defects that leave the infant globally immune deficient and present in the 1st 6 mo of life with recurrent and typically 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 mo 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; accordingly, the use of live vaccines (including rotavirus vaccine) is contraindicated in patients with suspected or proven SCID. Without stem cell transplantation or gene therapy, most affected children succumb to opportunistic infections within the 1st yr of life.

Children with ataxia-telangiectasia develop late-onset recurrent sinopulmonary infections from both bacteria and respiratory viruses. In addition, these children experience an increased incidence of malignancies. Wiskott-Aldrich syndrome is an X-linked recessive disease associated with eczema, thrombocytopenia, reduced number of CD3 lymphocytes, moderately suppressed mitogen responses, and impaired antibody response to polysaccharide antigens. Accordingly, infections with S. pneumoniae or H. influenzae type b and PCP are common. Children with hyper-IgE syndrome have greatly elevated levels of IgE and present with recurrent episodes of S. aureus abscesses of the skin, lungs, and musculoskeletal system. Although the antibody abnormality is notable, these patients also have marked eosinophilia and poor cell-mediated responses to neoantigens and are at increased risk for fungal infections.