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 develop late onset of 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, a 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 markedly 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.

Acquired Immunodeficiency from Infectious Agents

Infection with HIV, the causative agent of AIDS, is the most important infectious cause of acquired immunodeficiency (Chapter 268). Left untreated, HIV infection has profound effects on T-cell–mediated immunity that lead to susceptibility to the same types of infections as with primary T-cell immunodeficiencies (Table 171-3).

Table 171-3 DISEASES ESTABLISHED AS THE ETIOLOGY OF FEVER IN 70 CASES OF HIV-ASSOCIATED FEVER OF UNKNOWN ORIGIN

CMV, cytomegalovirus; DMAC, disseminated Mycobacterium avium complex; HIV, human immunodeficiency virus; PCP, Pneumocystis pneumonia.

* Includes hepatitis C, hepatitis B, adenovirus pneumonia, herpes simplex esophagitis, and varicella-zoster encephalitis (one case each).

^† Includes disseminated cryptococcosis and pulmonary aspergillosis (1 case each).

^‡ Includes cerebral toxoplasmosis and disseminated cryptosporidiosis (1 case each).

From Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 7, vol 1, Philadephia, 2010, Churchill Livingstone.

Other organisms can also lead to temporary alterations of the immune system. On rare occasions, transient neutropenia associated with community-acquired viruses can lead to significant disease with bacterial infections. Secondary infections can occur because of impaired immunity or disruption of normal mucosal immunity, as exemplified by the increased risk for S. pneumoniae pneumonia following influenza infection and group A streptococcus cellulitis and fasciitis following varicella.

Malignancies

The immune systems of children with malignancies are compromised by the therapies used to treat the cancer and, at times, by direct effects of the cancer itself. The type, duration, and intensity of anticancer therapy remain the major risk factors for infections in these children and often affect multiple arms of the immune system. The presence of mucous membrane abnormalities, indwelling catheters, malnutrition, prolonged exposure to antibiotics, and frequent hospitalizations add to the risk for infection in these children.

Even though several arms of the immune system can be affected, the major abnormality predisposing to infection in children with cancer is neutropenia. The degree and duration of neutropenia have long been relied upon as accurate predictors of the risk of infection in children being treated for cancer. Patients are at particular risk for bacterial infections if the absolute neutrophil count decreases to <500 cells/mm³. Counts of >500 cells/mm³ but <1,000 cells/mm³ incur some increased risk for infection but not nearly as great. The lack of neutrophils can lead to a loss of inflammatory response, and fever may be the only manifestation of infection. Accordingly, the absence of physical signs and symptoms is not always reliable, resulting in the need for empirical antibiotics (Fig. 171-1).

Figure 171-1 Guide to the initial management of the febrile neutropenic patient. Cefepime or meropenem may be as effective as ceftazidime or imipenem as monotherapy. *Aminoglycoside antibiotics should be avoided if the patient is also receiving nephrotoxic, ototoxic, or neuromuscular blocking agents; has renal or severe electrolyte dysfunction; or is suspected of having meningitis (because of poor blood-brain perfusion).

(Adapted from Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer, Clin Infect Dis 34:730–751, 2002.)

Because patients with fever and neutropenia might only have subtle signs and symptoms of infection, the presence of fever warrants a thorough physical examination with careful attention to the oropharynx (Table 171-4), lungs, perineum and anus, skin, nail beds, and intravascular catheter insertion sites. A comprehensive laboratory evaluation including a complete blood cell count, serum creatinine, blood urea nitrogen, and serum transaminases should be obtained. Blood cultures should be taken from each port of any central venous catheter. Consideration should also be given to obtaining a peripheral venous sample for blood culture, especially in children with ≥1 positive cultures from a central venous catheter, facilitating localization of the source of the infection. Other microbiologic studies should be done if there are associated clinical symptoms including nasal aspirate for viruses in patients with upper respiratory findings; stool for rotavirus in the winter months and for Clostridium difficile toxin in patients with diarrhea; urinalysis and culture in young children or in older patients with symptoms of urgency, frequency, dysuria, or hematuria; and biopsy and culture of cutaneous lesions. Chest radiographs should be obtained in any patient with lower respiratory tract symptoms, although pulmonary infiltrates may be absent in children with severe neutropenia. Sinus films should be obtained if rhinorrhea is prolonged. Abdominal CT scans should also be considered in children with profound neutropenia and abdominal pain to evaluate for the presence of typhlitis. Biopsies for cytology, Gram stain, and culture should be considered if abnormalities are found during endoscopic procedures or if lung nodules are identified radiographically.

Table 171-4 POSSIBLE CAUSES OF FEVER IN NEUTROPENIC PATIENTS NOT RESPONDING TO BROAD-SPECTRUM ANTIBIOTICS

From Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 7, vol 1, Philadephia, 2010, Churchill Livingstone.

Before the routine institution of empirical antimicrobial therapy for fever and neutropenia, 75% of children with fever and neutropenia were ultimately found to have a documented site of infection (see Table 171-4). Currently, gram-positive cocci are the most common pathogens; however, gram-negative organisms such as P. aeruginosa, E. coli, and Klebsiella can cause life-threatening infection and must be considered in the empirical treatment regimen. Other gram-negative pathogens such as Enterobacter and Acinetobacter are increasing in prevalence as well. While coagulase-negative staphylococci often cause infections in these children in association with central venous catheters, these infections are typically indolent, and a short delay in treatment usually does not lead to a detrimental outcome. Other gram-positive bacteria such as S. aureus and S. pneumoniae can cause more-fulminant disease and require prompt institution of therapy. Viridans streptococci are potential pathogens in patients with the oral mucositis that is often associated with use of cytarabine and in patients who experience selective pressure from treatment with certain antibiotics such as quinolones. Infection due to this organism can present as acute septic shock syndrome. Patients with prolonged neutropenia are at increased risk for opportunistic fungal infections, with Candida spp and Aspergillus spp being the most commonly identified fungi. Other fungi that can cause serious disease in these children include Mucor spp, Fusarium spp, and dematiaceous molds.

Fever and Neutropenia

The use of empiric antimicrobial treatment as part of the management of fever and neutropenia decreases the risk of progression to sepsis, septic shock, acute respiratory distress syndrome, organ dysfunction, and death. In 2002, the Infectious Diseases Society of America published comprehensive guidelines for the use of antimicrobial agents in neutropenic children and adults with cancer (see Fig. 171-1). First-line antimicrobial therapy should take into consideration the types of microbes anticipated and the local resistance patterns encountered at each institution. In addition, antibiotic choices may be limited by specific circumstances, such as the presence of drug allergy and renal or hepatic dysfunction. The empirical use of oral antibiotics is safe in some low-risk adults who have no evidence of bacterial focus or signs of significant illness (rigors, hypotension, mental status changes) and for whom a quick recovery of the bone marrow is anticipated. However, substantive data for this approach are lacking in children, and it is not currently recommended. The decision to use intravenous monotherapy versus an expanded regimen of antibiotics depends on the severity of illness of the patient, history of previous colonization with resistant organisms, and obvious presence of catheter-related infection. Vancomycin should be added to the empiric initial regimen if the patient has hypotension or other evidence of septic shock, an obvious catheter-related infection, or a history of colonization with methicillin-resistant S. aureus, or if the patient is at high risk for viridans streptococci (severe mucositis, acute myelogenous leukemia, or prior use of quinolone prophylaxis). Monotherapy with cefepime, ceftazidime, imipenem/cilastatin, meropenem, or piperacillin-tazobactam has been equally effective.

Regardless of the regimen chosen initially, it is critical to carefully and continually evaluate the patient for response to therapy, development of secondary infections, and adverse effects. Patients without an identified etiology who become afebrile within the 1st 3-5 days of therapy and who are clinically well with absolute neutrophil counts of >100 cells/mm³ can have antibiotics changed to an oral regimen (cefixime or amoxicillin-clavulanate) and should receive a minimum of 7 days of therapy. However, if symptoms persist or evolve, intravenous antibiotics should be continued. Continuation of antibiotics in children whose fever has abated but who continue to have depression of neutrophils is more controversial. Some experts advocate discontinuing antibiotics 5-7 days after the fever resolves, whereas others continue antibiotics in this circumstance to prevent recurrence of fever.

Patients without an identified etiology but with persistent fever should be reassessed after 3-5 days. Those remaining clinically well may continue on the same regimen, although consideration should be given to discontinuing vancomycin if it was included initially. Patients who remain febrile with clinical progression warrant the addition of vancomycin if it was not included initially and certain risk factors exist; clinicians should also consider changing the empirical antibacterial regimen. If fever persists for >5 days, the addition of an antifungal agent such as an amphotericin product, voriconazole, or caspofungin is generally warranted. Studies comparing caspofungin to liposomal amphotericin for children with malignancies and fever and neutropenia showed caspofungin to be noninferior. Because not all fevers are due to bacterial or fungal etiologies, patients with persistent fever without an identified cause and without complications may have therapy discontinued 4-5 days after the neutrophil count becomes >500 cells/mm³. In clinically stable patients without an identified etiology but with persistent neutropenia after 2 weeks of therapy, discontinuation of antibiotics may be considered if continued close observation can be assured.

The use of antiviral agents in fever and neutropenia is not warranted without specific evidence of viral disease. Active herpes simplex or varicella-zoster lesions merit treatment to decrease the time of healing; even if these lesions are not the source of fever, they are potential portals of entry for bacteria and fungi. CMV is a rare cause of fever in children with cancer and neutropenia. If CMV infection is suspected, assays to evaluate viremia and organ-specific infection should be obtained. Ganciclovir, foscarnet, or cidofovir may be considered while evaluation is pending, although ganciclovir can cause bone marrow suppression and foscarnet and cidofovir can be nephrotoxic (Chapter 247). If influenza is identified, specific treatment with antiviral agents should be administerd. Choice of treatment (oseltamivir, zanamivir, amantadine, or rimantadine) should be based on the anticipated susceptibility of the circulating influenza (Chapter 250).

The use of hematopoietic growth factors shortens the duration of neutropenia but has not been proved to reduce morbidity or mortality. Accordingly, the 2002 recommendations from the Infectious Diseases Society of America do not endorse the routine use of hematopoietic growth factors in patients with uncomplicated fever and neutropenia. Infections occur in children with cancer even without neutropenia. Most often these organisms are viral in etiology. However, P. jiroveci can cause pneumonia (PCP) regardless of the neutrophil count. Prophylaxis with trimethoprim-sulfamethoxazole against PCP is an effective preventive strategy and should be provided to all children undergoing active treatment for malignancy (Chapter 236). Environmental fungi such as Cryptococcus, Histoplasma, and Coccidioides can also cause disease. Toxoplasma gondii is an uncommon but occasional pathogen in children with cancer. Infections encountered in healthy children (S. pneumoniae, group A streptococcus) can cause disease in children with cancer regardless of the granulocyte count.

Transplantation

Transplantation of stem cells (bone marrow) and solid organs, including heart, liver, kidney, lungs, pancreas, and intestines, is increasingly used as therapy for a variety of disorders. Children with transplants are at risk for infections caused by many of the same microbial agents that cause disease in children with primary immunodeficiencies. Although the type and timing of infections after organ transplantation are similar in general among all recipients of these procedures, some differences exist between patients depending on the type of transplantation performed, the type and amount of immunosuppression given, and the child’s previous immunity to specific pathogens.