Infections in Immunocompromised Persons
Marian G. Michaels, Hey Jin Chong, Michael Green
Infection and disease develop when the host immune system fails to protect adequately against potential pathogens. In individuals with an intact immune system, infection occurs in the setting of naïveté to the microbe and absence of or inadequate preexisting microbe-specific immunity, or when protective barriers of the body such as the skin have been breached. Healthy children are able to meet the challenge of most infectious agents with an immunologic armamentarium capable of preventing significant disease. Once an infection begins to develop, an array of immune responses is set into action to control the disease and prevent it from reappearing. In contrast, immunocompromised children might not have this same capability. Depending on the level and type of immune defect, the affected child might not be able to contain the pathogen or develop an appropriate immune response to prevent recurrence.
General practitioners are likely to see children with an abnormal immune system in their practice because increasing numbers of children survive with primary immunodeficiencies or receive immunosuppressive therapy for treatment of malignancy, autoimmune disorders, or transplantation.
Primary immunodeficiencies are compromised states that result from genetic defects affecting one or more arms of the immune system. Acquired, or secondary, immunodeficiencies may result from infection (e.g., infection with HIV), from malignancy, or as an adverse effect of immunomodulating or immunosuppressing medications. The latter include medications that affect T cells (corticosteroids, calcineurin inhibitors, tumor necrosis factor [TNF] inhibitors, chemotherapy), neutrophils (myelosuppressive agents, idiosyncratic or immune-mediated neutropenia), specific immunoregulatory cells (TNF blockers, interleukin-2 inhibitors), or all immune cells (chemotherapy). Perturbations of the mucosal and skin barriers or the normal microbial flora can also be characterized as secondary immunodeficiencies, predisposing the host to infections, if only temporarily.
The major pathogens causing infections among immunocompetent hosts are also the main pathogens responsible for infections among children with immunodeficiencies. In addition, less virulent organisms, including normal skin flora, commensal bacteria of the oropharynx or gastrointestinal (GI) tract, environmental fungi, and common community viruses of low-level pathogenicity, can cause severe, life-threatening illnesses in immunocompromised patients (Table 205.1 ). For this reason, close communication with the diagnostic laboratory is critical to ensure that the laboratory does not disregard normal flora and organisms normally considered contaminants as being unimportant.
Table 205.1
Most Common Causes of Infections in Immunocompromised Children
|
BACTERIA, AEROBIC BACTERIA, ANAEROBIC FUNGI VIRUSES PROTOZOA |
Infections Occurring With Primary Immunodeficiencies
Marian G. Michaels, Hey Jin Chong, Michael Green
Currently, more than 300 genes involving inborn errors of immunity have been identified, accounting for a wide array of diseases presenting with susceptibility to infection, allergy, autoimmunity, and autoinflammation, as well as malignancy.
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/mm3 and can be associated with significant risk for developing severe bacterial and fungal disease, particularly when the ANC is <500 cells/mm3 . 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 Chapters 149-152 ). 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.
Bibliography
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Infections Occurring With Acquired Immunodeficiencies
Marian G. Michaels, Hey Jin Chong, Michael Green
Immunodeficiencies can be secondarily acquired as a result of infections or other underlying disorders, such as malignancy, cystic fibrosis, diabetes mellitus, sickle cell disease, or malnutrition. Immunosuppressive medications used to prevent rejection after organ transplantation, to prevent graft-versus-host disease (GVHD) after stem cell transplantation, or to treat malignancies may also leave the host vulnerable to infections. Similarly, medications used to control rheumatologic or other autoimmune diseases may be associated with an increased risk for developing infection. Surgical removal of the spleen likewise puts a person at increased risk for infections. Further, any process that disrupts the normal mucosal and skin barriers (e.g., burns, surgery, indwelling catheters) may lead to an increased risk for infection.
Acquired Immunodeficiency From Infectious Agents
Infection with HIV, the causative agent of AIDS, remains globally an important infectious cause of acquired immunodeficiency (see Chapter 302 ). Left untreated, HIV infection has profound effects on many parts of the immune system but in particular T cell–mediated immunity that leads to susceptibility to the same types of infections as with primary T cell immunodeficiencies.
Other organisms can also lead to temporary alterations of the immune system. Very rarely, 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 pneumonia from S. pneumoniae or S. aureus following influenza infection and group A streptococcal 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 adds 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 depth and duration of neutropenia are the primary predictors of the risk of infection in children being treated for cancer. Patients are at particular risk for bacterial and fungal infections if the ANC decreases to <500 cells/mm3 , and the risk is highest in those with counts <100 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 diminution of inflammatory response, limiting the ability to localize sites of infection and potentially leaving fever as the only manifestation of infection. Accordingly, the absence of physical signs and symptoms does not reliably exclude the presence of infection, resulting in the need for empirical antibiotics (Fig. 205.1 ). Because patients with fever and neutropenia might only have subtle signs and symptoms of infection, the presence of fever warrants an intensive investigation, including a thorough physical examination with careful attention to the oropharynx, lungs, perineum and anus, skin, nail beds, and intravascular catheter insertion sites (Table 205.2 ).
Table 205.2
Host Defense Defects and Common Pathogens by Time After Bone Marrow or Hematopoietic Stem Cell Transplantation
| TIME PERIOD | HOST DEFENSE DEFECTS | CAUSES | COMMON PATHOGENS |
|---|---|---|---|
| Pretransplant |
Neutropenia Abnormal anatomic barriers |
Underlying disease Prior chemotherapy |
Aerobic gram-negative bacilli |
| Preengraftment |
Neutropenia Abnormal anatomic barriers |
Chemotherapy Radiation Indwelling catheters |
Aerobic gram-positive cocci Aerobic gram-negative bacilli Candida Aspergillus Herpes simplex virus (in previously infected patients) Community-acquired viral pathogens |
| Postengraftment |
Abnormal cell-mediated immunity Abnormal anatomic barriers |
Chemotherapy Immunosuppressive medications Radiation Indwelling catheters Unrelated cord blood donor |
Gram-positive cocci Aerobic gram-negative bacilli Cytomegalovirus Adenoviruses Community-acquired viral pathogens Pneumocystis jiroveci |
| Late posttransplant | Delayed recovery of immune function (cell-mediated, humoral, and abnormal anatomic barriers) |
Time required to develop donor-related immune function Graft-versus-host disease |
Varicella-zoster virus Streptococcus pneumoniae |
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 (CVC) and from a peripheral vein. Although the latter sampling is often omitted with continued fevers and neutropenia, it should be obtained before the initial antibiotic administration and reconsidered in children with 1 or more positive cultures from a CVC, facilitating localization of the source of the infection. Other microbiologic studies should be done if there are associated clinical symptoms, including a nasal aspirate for viruses in patients with upper respiratory findings; stool for viruses such as rotavirus or norovirus 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 for children >2 yr of age 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. Chest CT scan and fungal biomarkers (e.g., galactomannan, β-D -glucan) testing should be considered for children not responding to broad-spectrum antibiotics who have continued fever and neutropenia for >96 hr. Biopsies for cytology, Gram stain, and culture should be considered if abnormalities are found during endoscopic procedures or if lung nodules are identified radiographically.
Classic studies by Pizzo and colleagues demonstrated that 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, suggesting that most children with fever and neutropenia will have an underlying infection (see Table 205.2 ). Currently, gram-positive cocci are the most common pathogens identified in these patients; however, gram-negative organisms such as Pseudomonas aeruginosa, Escherichia coli , and Klebsiella can cause life-threatening infection and must be considered in the empirical treatment regimen. Other multidrug-resistant Enterobacteriaceae are increasingly recovered in these children. Although coagulase-negative staphylococci often cause infections in these children in association with CVCs, 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 particularly important 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 caused by this group of organisms can present as acute septic shock syndrome. Also, patients with prolonged neutropenia are at increased risk for opportunistic fungal infections, with Candida and Aspergillus spp. being the most commonly identified fungi. Other fungi that can cause serious disease in these children include Mucor and Fusarium spp. and dematiaceous molds.
Fever and Neutropenia
The use of empirical 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 2010 the Infectious Diseases Society of America (IDSA) updated a comprehensive guideline for the use of antimicrobial agents in neutropenic children and adults with cancer (see Fig. 205.1 ).
First-line antimicrobial therapy should take into consideration the types of microbes anticipated and the local resistance patterns encountered at each institution as well as the level of risk for severe infection associated with a given patient. 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 has been shown to be 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. Guidelines for the management of fever and neutropenia in children with cancer and/or undergoing HSCT (2012) conclude that the use of oral antimicrobial therapy as either initial or stepdown therapy can be considered in low-risk children who can tolerate oral antibiotics and in whom careful monitoring can be ensured. However, the guideline emphasizes that oral medication use may present major challenges in children, including availability of liquid formulations of appropriate antibiotics, cooperation of young children, and presence of mucositis potentially interfering with absorption. Accordingly, decisions to implement this approach should be reserved for a select subset of these children presenting with fever and neutropenia.
The decision to initially use intravenous (IV) monotherapy vs 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 initial empirical 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). Otherwise, use of monotherapy with an antibiotic such as cefepime or piperacillin-tazobactam can be considered. Ceftazidime should not be used as monotherapy if concern exists for gram-positive organisms or resistant gram-negative bacteria. Carbapenems such as imipenem/cilastin and meropenem should not be first line, aiming to prevent pressure on carbapenem-resistant Enterobacteriaceae. The addition of a 2nd anti–gram-negative bacterial agent (e.g., aminoglycoside) for empirical therapy can be considered in patients who are clinically unstable when multidrug-resistant organisms are suspected.
Regardless of the regimen chosen initially, it is critical to evaluate the patient carefully and continually for response to therapy, development of secondary infections, and adverse effects. Management recommendations for these children are evolving. Based on the 2012 guidelines, patients who have negative blood cultures at 48 hr, who have been afebrile for at least 24 hr, and who have evidence of bone marrow recovery (ANC >100 cells/mm3 ) can have antibiotics discontinued. However, if symptoms persist or evolve, IV antibiotics should be continued. Continuation of antibiotics in children whose fever has abated and who are clinically well but continue to have depression of neutrophils is more controversial. The 2012 pediatric guidelines advocate for discontinuing antibiotics in low-risk patients at 72 hr for children who have negative blood cultures and who have been afebrile for at least 24 hr regardless of bone marrow recovery, as long as careful follow-up is ensured. In contrast, others continue to advocate for continuing antibiotics in this circumstance to prevent recurrence of fever.
Patients without an identified etiology but with persistent fever should be reassessed daily. At day 3-5 of persistent fever and neutropenia, those remaining clinically well may continue on the same regimen, although consideration should be given to discontinuing vancomycin or double gram-negative bacterial coverage if they were included initially. Patients who remain febrile with clinical progression warrant the addition of vancomycin if it was not included initially and risk factors exist; clinicians should also consider changing the empirical antibacterial regimen to cover for potential antimicrobial resistance in these children. If fever persists for >96 hr, the addition of an antifungal agent with antimold activity should be considered, particularly for those at high risk for invasive fungal infection (those with acute myelogenous leukemia or relapsed acute lymphocytic leukemia or who are receiving highly myelosuppressive chemotherapies for other cancers or with allogeneic HSCT). Medications, including liposomal amphotericin products and echinocandins , have been studied in children; voriconazole itraconazole, and posaconazole have been successfully used in adults, with increasing experience in children. Studies comparing caspofungin to liposomal amphotericin for children with malignancies and fever and neutropenia showed caspofungin to be noninferior.
The use of antiviral agents in children with 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 viral load in the blood 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. If influenza is identified, specific treatment with an antiviral agent should be administered. Choice of treatment (oseltamivir, zanamivir) should be based on the anticipated susceptibility of the circulating influenza strains.
The use of hematopoietic growth factors shortens the duration of neutropenia but has not been proved to reduce morbidity or mortality. Accordingly, the 2010 IDSA recommendations do not endorse the routine use of hematopoietic growth factors in patients with established fever and neutropenia, although the recommendations do note that hematopoietic growth factors can be considered as prophylaxis in those with neutropenia at high risk for fever.
Fever Without Neutropenia
Infections occur in children with cancer in the absence of neutropenia. Most often these infections are viral in etiology. However, Pneumocystis jiroveci can cause pneumonia regardless of the neutrophil count. Administration of prophylaxis against Pneumocystis is an effective preventive strategy and should be provided to all children undergoing active treatment for malignancy. First-line therapy remains TMP-SMX, with second-line alternatives including pentamidine, atovaquone, dapsone, or dapsone-pyrimethamine. 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 caused by pathogens encountered in healthy children (S. pneumoniae, group A streptococcus) can occur in children with cancer regardless of the granulocyte count.
Transplantation
Transplantation of hematopoietic stem cells and solid organs (including heart, liver, kidney, lungs, pancreas, and intestines) is increasingly used as therapy for a variety of disorders. Children undergoing transplantation are at risk for infections caused by many of the same microbial agents that cause disease in children with primary immunodeficiencies. Although the types of infections after transplantation generally are similar 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 preexisting immunity to specific pathogens.
Stem Cell Transplantation
Infections following HSCT can be classified as occurring during the pretransplantation period, preengraftment period (0-30 days after transplantation), postengraftment period (30-100 days), or late posttransplantation period (>100 days). Specific defects in host defenses predisposing to infection vary within each of these periods (Table 205.2 ). Neutropenia and abnormalities in cell-mediated and humoral immune function occur predictably during specific periods after transplantation. In contrast, breaches of anatomic barriers caused by indwelling catheters and mucositis secondary to radiation or chemotherapy create defects in host defenses that may be present any time after transplantation.
Pretransplantation Period
Children come to HSCT with a heterogeneous history of underlying diseases, chemotherapy exposure, degree of immunosuppression, and previous infections. Approximately 12% of all infections among adult HSCT recipients occur during the pretransplantation period. These infections are often caused by aerobic gram-negative bacilli and manifest as localized infections of the skin, soft tissue, and urinary tract. Importantly, the development of infection during this period does not delay or adversely affect the success of engraftment.
Preengraftment Period
Bacterial infections predominate in the preengraftment period (0-30 days). Bacteremia is the most common documented infection and occurs in as many as 50% of all HSCT recipients during the 1st 30 days after transplantation. Bacteremia is typically associated with the presence of either mucositis or an indwelling catheter but may also be seen with pneumonia. Similarly, >40% of children undergoing HSCT experienced 1 or more infections in the preengraftment period. Gram-positive cocci, gram-negative bacilli, yeast, and, less frequently, other fungi cause infection during this period. Aspergillus has been identified in 4–20% of HSCT recipients, most often after 3 wk of neutropenia. Infections caused by the emerging fungal pathogens Fusarium and Pseudallescheria boydii are associated with the prolonged neutropenia during the preengraftment period.
Viral infections also occur during the preengraftment period. Among adults, reactivation of herpes simplex virus (HSV) is the most common viral disease observed, but this is less common among children. A history of HSV infection or seropositivity indicates the need for prophylaxis. Nosocomial exposure to community-acquired viral pathogens, including respiratory syncytial virus (RSV), influenza virus, adenovirus, rotavirus, and norovirus, represents another important source of infection during this period. There is growing evidence that community-acquired viruses cause increased morbidity and mortality for HSCT recipients during this period. Adenovirus is a particularly important viral pathogen that can occur early, although it typically presents after engraftment.
Postengraftment Period
The predominant defect in host defenses in the postengraftment period is altered cell-mediated immunity. Accordingly, organisms historically categorized as “opportunistic pathogens” predominate during this period. The risk is especially accentuated 50-100 days after transplantation, when host immunity is lost and donor immunity is not yet established. P. jiroveci presents during this period if patients are not maintained on appropriate prophylaxis. Reactivation of T. gondii, a rare cause of disease among HSCT recipients, can also occur after engraftment. Hepatosplenic candidiasis often presents during the postengraftment period, although seeding likely occurs during the neutropenic phase.
Cytomegalovirus is an important cause of morbidity and mortality among HSCT recipients. Unlike patients undergoing solid-organ transplantation, where primary infection from the donor causes the greatest harm, CMV reactivation in an HSCT recipient whose donor is naïve to the virus can cause severe disease. Disease risk from CMV after HSCT is also increased in recipients of cord blood transplants or matched unrelated T cell–depleted transplants and those with GVHD. Adenovirus , another important viral pathogen, has been recovered from up to 5% of adult and pediatric HSCT recipients and causes invasive disease in approximately 20% of cases. Children receiving matched unrelated donor organs or unrelated cord blood cell transplants have an incidence of adenovirus infection as high as 14% during this early postengraftment period. Polyomaviruses such as BK virus have been increasingly recognized as a cause of renal dysfunction and hemorrhagic cystitis after bone marrow transplantation. Infections with other herpesviruses (Epstein-Barr virus [EBV] and human herpesvirus 6) as well as community-acquired pathogens are associated with excess morbidity and mortality during this period, similar to the preengraftment period.
Late Posttransplantation Period
Infection is unusual after 100 days in the absence of chronic GVHD. However, the presence of chronic GVHD significantly affects anatomic barriers and is associated with defects in humoral, splenic, and cell-mediated immune function. Viral infections, including primary infection with or reactivation of varicella-zoster virus (VZV), are responsible for >40% of infections during this period. This may decrease over time as the Oka varicella vaccine strain has a lower rate of reactivation than wild-type varicella. Bacterial infections, particularly of the upper and lower respiratory tract, account for approximately 30% of infections. These may be associated with deficiencies in immunoglobulin production, especially IgG2. Fungal infections account for <20% of confirmed infections during the late posttransplantation period.
Solid-Organ Transplantation
Factors predisposing to infection after organ transplantation include those that either existed before transplantation or are secondary to intraoperative events or posttransplantation therapies (Table 205.3 ). Some of these additional risks cannot be prevented, and some risks acquired during or after the operation depend on decisions or actions of members of the transplant team. Organ recipients are at risk for infection from potential exposure to pathogens in the donor organ. Although some donor-derived infections can be anticipated through donor screening, many pathogens are not routinely screened for, and strategies defining when and how to screen for all but a small subset of potential pathogens have not been identified or implemented. Similar to other children who have undergone surgical procedures; surgical site infections are a frequent cause of infection early after transplantation. Beyond this, the need for immunosuppressive agents to prevent rejection is the major factor predisposing to infection following transplantation. Despite efforts to optimize immunosuppressive regimens to prevent or treat rejection with minimal impairment of immunity, all current regimens interfere with the ability of the immune system to prevent infection. The primary target of the majority of these immunosuppressive agents in organ recipients is the cell-mediated immune system, but regimens can and do impair many other aspects of the transplant recipient's immune system as well.
Table 205.3
Risk Factors for Infections After Solid-Organ Transplantation in Children
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PRETRANSPLANTATION FACTORS INTRAOPERATIVE FACTORS POSTTRANSPLANTATION FACTORS |
Timing
The timing of specific types of infections is generally predictable, regardless of which organ is transplanted. Infectious complications typically develop in 1 of 3 intervals: early (0-30 days after transplantation), intermediate (30-180 days), or late (>180 days); most infections present in the 1st 180 days after transplantation. Table 205.4 should be used as a general guideline to the types of infections encountered but may be modified with the introduction of newer immunosuppressive therapies and by the use of prophylaxis.
Table 205.4
Timing of Infectious Complications After Solid-Organ Transplantation
Adapted from Green M, Michaels MG: Infections in solid organ transplant recipients. In Long SS, Prober C, Fisher M, editors: Principles and practice of pediatric infectious disease , ed 5, Philadelphia, 2018, Elsevier (Table 95-1).
Early infections are usually the result of a complication of the transplant surgery itself, the unexpected acquisition of a bacterial or fungal pathogen from the donor, or the presence of an indwelling catheter. In contrast, infections during the intermediate period typically result from a complication of the immunosuppression, which tends to be at its greatest intensity during the 1st 6 mo after transplantation. This is the period of greatest risk for infections caused by opportunistic pathogens such as CMV, EBV, and P. jiroveci. Anatomic abnormalities, such as bronchial stenosis and biliary stenosis, that develop as a result of the transplant surgery can also predispose to recurrent infection in this period.
Infections developing late after transplantation typically result from uncorrected anatomic abnormalities, chronic rejection, or exposure to community-acquired pathogens. Augmented immunosuppression as treatment for late, acute cellular rejection or chronic rejection can increase the risk for late presentations with CMV, EBV, and other potential opportunistic infections. Acquisition of infection from community-acquired pathogens such as RSV can result in severe infection secondary to the immunocompromised state of the transplant recipient during the early and intermediate periods. Compared with the earlier periods, community-acquired infections in the late period are usually benign, because immunosuppression is typically maintained at significantly lower levels. However, certain pathogens such as VZV and EBV may be associated with severe disease even at this late period.
Bacterial and Fungal Infections
Although there are important graft-specific considerations for bacterial and fungal infections following transplantation, some principles are generally applicable to all transplant recipients. Bacterial and fungal infections after organ transplantation are usually a direct consequence of the surgery, a breach in an anatomic barrier, a foreign body, or an abnormal anatomic narrowing or obstruction. With the exception of infections related to the use of indwelling catheters, sites of bacterial infection tend to occur at or near the transplanted organ. Infections following abdominal transplantation (liver, intestine, or renal) usually occur in the abdomen or at the surgical wound. The pathogens are typically enteric gram-negative bacteria, Enterococcus, and occasionally Candida. Infections after thoracic transplantation (heart, lung) usually occur in the lower respiratory tract or at the surgical wound. Pathogens associated with these infections include S. aureus and gram-negative bacteria. Patients undergoing lung transplantation for cystic fibrosis experience a particularly high rate of infectious complications, because they are often colonized with P. aeruginosa or Aspergillus before transplantation. Even though the infected lungs are removed, the sinuses and upper airways remain colonized with these pathogens, and subsequent reinfection of the transplanted lungs can occur. Children receiving organ transplants are often hospitalized for long periods and receive many antibiotics; thus recovery of bacteria with multiple antibiotic resistance patterns is common after all types of organ transplantation. Infections caused by Aspergillus are less common but occur after all types of organ transplantation and are associated with high rates of morbidity and mortality.
Viral Infections
Viral pathogens, especially herpesviruses, are a major source of morbidity and mortality following solid-organ transplantation. In addition, BK virus is a major cause of renal disease after kidney transplantation. The patterns of disease associated with individual viral pathogens are generally similar among all organ transplant recipients. However, the incidence, mode of presentation, and severity differ according to type of organ transplanted and, for many viral pathogens, pretransplant serologic status of the recipient.
Viral pathogens can be generally categorized as latent pathogens, which cause infection through reactivation in the host or acquisition from the donor (e.g., CMV, EBV) or as community-acquired viruses (e.g., RSV). For CMV and EBV, primary infection occurring after transplantation is associated with the greatest degree of morbidity and mortality. The highest risk is seen in a naïve host who receives an organ from a donor who previously was infected with one of these viruses. This mismatched state is frequently associated with severe disease. However, even if the donor is negative for CMV and EBV, primary infection can be acquired from a close contact or through blood products. Secondary infections (reactivation of a latent strain within the host or superinfection with a new strain) tend to result in milder illness unless the patient is highly immunosuppressed, which can occur in the setting of treatment of significant rejection.
CMV is one of the most commonly recognized transplant viral pathogens. Disease from CMV has decreased significantly with the use of preventive strategies, including antiviral prophylaxis as well as viral load monitoring to inform preemptive antiviral therapy. Some centers have implemented a hybrid approach where surveillance viral load monitoring follows a relatively short period (2-4 wk) of chemoprophylaxis. Clinical manifestations of CMV disease can range from a syndrome of fatigue and fever to tissue invasive disease that most often affects the liver, lungs, and GI tract.
Infection caused by EBV is another important complication of solid-organ transplantation. Clinical symptoms range from a mild mononucleosis syndrome to disseminated posttransplant lymphoproliferative disorder . Posttransplant lymphoproliferative disorder is more common among children than adults, because primary EBV infection in the immunosuppressed host is more likely to lead to uncontrolled proliferative disorders, including posttransplant lymphoma.
Other viruses, such as adenovirus, also have the capacity to be donor associated, but appear to be less common. The unexpected development of donor-associated viral pathogens, including hepatitis B virus, hepatitis C virus, and HIV, is rare today because of intensive donor screening. However, the changing epidemiology of some viruses (e.g., dengue, chikungunya, Zika) raises concerns for the donor-derived transmission of these emerging viral pathogens.
Community-acquired viruses, including those associated with respiratory tract infection (RSV, influenza virus, adenovirus, parainfluenza virus) and GI infection (enteroviruses, norovirus, and rotavirus), can cause important disease in children after organ transplantation. In general, risk factors for more severe infection include young age, acquisition of infection early after transplantation, and augmented immune suppression. Infection in the absence of these risk factors frequently results in a clinical illness that is comparable to that seen in immunocompetent children. However, some community-acquired viruses, such as adenovirus, can be associated with graft dysfunction even when acquired late after transplantation.
Opportunistic Pathogens
Children undergoing solid-organ transplantation are also at risk for symptomatic infections from pathogens that do not usually cause clinical disease in immunocompetent hosts. Although these typically present in the intermediate period, these infections can also occur late in patients, requiring prolonged and high levels of immunosuppression. P. jiroveci is a well-recognized cause of pneumonia after solid-organ transplantation, although routine prophylaxis has essentially eliminated this problem. T. gondii can complicate cardiac transplantations because of tropism of the organism for cardiac muscle and risk for donor transmission; less often it complicates other types of organ transplantation.
Bibliography
Blumberg EA, Danziger-Isakov L, Kumar D, et al. Infectious diseases guidelines, ed 3. [editors] Am J Transplant . 2013;13(Suppl 4):1–371.
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Prevention of Infection in Immunocompromised Persons
Marian G. Michaels, Hey Jin Chong, Michael Green
Although infections cannot be completely prevented in children who have defects in one or more arms of their immune system, measures can be taken to decrease the risks for infection. Replacement immunoglobulin is a benefit to children with primary B cell deficiencies. Interferon (IFN)-γ, TMP-SMX, and oral antifungal agents have long been used to reduce the number of infections occurring in children with CGD, although the relative benefit of INF-γ has been questioned. Children who have depressed cellular immunity resulting from primary diseases, advanced HIV infection, or immunosuppressive medications benefit from prophylaxis against P. jiroveci. Immunizations prevent many infections and are particularly important for children with compromised immune systems who do not have a contraindication or inability to respond. For children rendered immunocompromised because of medication or splenectomy, immunizations should be administered before treatment. This timing allows for superior response to vaccine antigens, avoids the risk of live vaccines, which may be contraindicated depending on the immunosuppression, and importantly provides protection before the immune system is compromised.
Although immunodeficient children are a heterogeneous group, some principles of prevention are generally applicable. The use of inactivated vaccines does not lead to an increased risk for adverse effects, although their efficacy may be reduced because of an impaired immune response. In most cases, children with immunodeficiencies should receive all the recommended inactivated vaccines. Live-attenuated vaccinations can cause disease in some children with immunologic defects, and therefore alternative immunizations should be used whenever possible, such as inactivated influenza vaccine rather than live-attenuated influenza vaccine or inactivated typhoid vaccine rather than the oral live typhoid vaccine for travelers. In general, live-virus vaccines should not be used in children with primary T cell abnormalities; efforts should be made to ensure that close contacts are all immunized to decrease the risk of exposure. In some patients in whom wild-type viral infection can be severe, immunizations, even with live-virus vaccine, are warranted in the immunosuppressed child. For example, children with HIV infection and a CD4 level of >15% should receive vaccinations against measles and varicella. Some vaccines should be given to children with immunodeficiencies in addition to routine vaccinations. As an example, children with asplenia or splenic dysfunction should receive meningococcal vaccine and both the conjugate and the polysaccharide pneumococcal vaccines. Influenza vaccination is recommended for all individuals >6 mo old and should be emphasized for immunocompromised children as well as all household contacts, to minimize risk for transmission to the immunocompromised child.
Bibliography
Blumberg EA, Danziger-Isakov L, Kumar D, et al. Infectious diseases guidelines, ed 3. [editors] Am J Transplant . 2013;13(Suppl 4):1–371.
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis . 2011;52:e56–e93.
Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol . 2012;30:4427–4438.