Acute lymphoblastic leukemia.

Patients with ALL are risk-stratified by criteria set forth by the National Cancer Institute into low-risk, standard risk, high-risk, or very high-risk disease groups. Determinants of risk include age, white blood cell count at presentation, cytogenetics, immunologic subtype (B cell, T cell, or MPAL), and response to induction therapy. Patients with ALL are risk-stratified based on predicted survival, and risk assessments are used to guide the intensity of therapy. In general, patients with ALL receive 6 to 9 months of intensive chemotherapy followed by 2 to 2.5 years of low-intensity maintenance chemotherapy. Risk of infection is concentrated during the first 6 to 9 months of treatment and increases with intensity of treatment regimen. The addition of anthracyclines (e.g., daunorubicin) to induction regimens in high-risk and very high-risk patients contributes to neutropenia and mucositis, both significant risk factors for infection. Thus patients treated for high- and very high-risk ALL have more infectious complications than their lower-risk counterparts. Intensive portions of therapy are most commonly delivered via an implantable venous access port, which further increases the risk for infection. To mitigate risk, implanted ports are often removed when a patient begins the maintenance portion of therapy.

ALL is most frequently diagnosed in children 1 to 4 years of age; thus pathogens common to this age group predominantly cause the infectious complications seen in young children with ALL, including upper respiratory infection, otitis media, and gastroenteritis. BSI is common during periods of neutropenia, and the frequency of BSI is correlated with duration of neutropenia. Because duration of neutropenia becomes more prolonged in later phases of chemotherapy, BSI and fungal infections occur with increased frequency in the latter portion of intensive chemotherapy for ALL, especially in higher-risk patients.

T-cell ALL, which is a small fraction of childhood ALL, historically had a worse prognosis than B-cell ALL and was thus treated with more intensive chemotherapy regimens. As the biology of T-cell ALL has been elucidated in recent years and treatment protocols have been refined, outcomes for T-cell and B-cell ALL have become increasingly similar. A notable distinction of T-cell ALL is the predilection for recalcitrant central nervous system (CNS) disease, necessitating CNS-directed therapy. The most recent treatment protocols use dexamethasone rather than prednisone for T-ALL, which provides increased potency and CNS penetration, though it is associated with significantly more infectious complications.

Acute myelogenous leukemia.

Therapy for AML requires repeated cycles of myelosuppressive chemotherapy leading to periods of severe neutropenia averaging approximately 2 to 4 weeks. Thus patients with AML have a high risk of bacterial and fungal infection. Children with AML have a 5–10% infection-related mortality and 20–50% incidence of bacterial infection. Notable exceptions to this treatment regimen are children with APML and those with Down syndrome–associated acute megakaryoblastic leukemia, both of which have excellent prognoses and require far less intensive therapy. Children with AML usually have a CVC in place for the duration of treatment to accommodate their significant supportive care needs during periods of prolonged myelosuppression.

The most common serious infections in pediatric patients with AML are caused by gram-negative bacteria, viridans group streptococci, and fungi. Viridans-group streptococcal bacteremia occurs in nearly 1 in 4 children treated for AML and accounts for approximately 15% of all infection-related deaths in pediatric patients with AML. The incidence of gram-negative bacteria infection in children treated for AML has decreased in recent years, likely as the result of widespread use of quinolone prophylaxis during periods of neutropenia, as well as improved infection control measures relating to the care of CVCs and maintenance of the hospital environment. The most common gram-negative organisms isolated are Pseudomonas aeruginosa , Klebsiella spp., and Escherichia coli. ^, Fungal infections occur in approximately 3% of patients undergoing therapy for de novo AML, although this incidence increases in patients with relapsed and refractory disease. ^,

Chronic myeloid leukemia.

Pediatric patients with CML are treated similarly to adults, and the mainstay of treatment is aimed at inhibition of the ABL tyrosine kinase, driven by the BCR-ABL fusion protein that results from the chromosomal translocation (9;22). The BCR-ABL translocation, named the Philadelphia chromosome, results in constitutive activation of the ABL1 kinase that drives cellular proliferation. CML has become a chronic disease through the use of ABL -class tyrosine kinase inhibitors (TKIs), which keep the disease controlled even when used as monotherapy. TKIs used for pediatric CML include imatinib, dasatinib, and less commonly nilotinib. All are available as oral preparations; thus treatment does not require central venous access. Infectious complications of CML therapy are rarely reported. Although ABL -class TKIs have the potential to cause neutropenia or lymphopenia, largely because of their off-target effects, these laboratory abnormalities are rarely seen in pediatric patients. Children who experience dose-limiting hematologic toxicity of TKIs are managed by adjustment of dose or by switching to an alternative TKI. Adult patients treated with imatinib have an increased risk of hepatitis B reactivation, although this has not been reported in pediatric patients.

Down syndrome.

Children with Down syndrome (DS) have an increased risk of developing hematologic malignancies, most commonly acute leukemia. DS-associated leukemia tends to have a favorable prognosis, although treatment has historically been complicated by significant infection-related morbidity. Children with DS have much higher rates of infectious and other treatment-related complications than children without DS. Recent efforts aimed at decreasing the intensity of therapy have resulted in improved survival rates for children with DS-associated leukemia owing to fewer therapy-related complications. Importantly, a comparison of two sequential clinical trials for therapy of DS-AML published in 2004 and 2016 demonstrated infection-related mortality rates of 20% and 4.9%, respectively. Although the incidence of infection has not significantly decreased, the profile of infectious diseases in children with DS has shifted to an increased proportion of viral infections compared with bacterial and fungal infections. Viral pneumonia and viral gastroenteritis are the most common infections documented in children with DS during leukemia therapy. Importantly, children with DS may have atypical presentations of infection including without fever, and during lower-intensity treatment phases. Supportive care practices specific to children with DS require vigilance regarding skin hygiene and a high index of suspicion for infection despite atypical presentation.

Infant leukemia.

Infant leukemia, defined as acute myeloid or lymphoblastic leukemia in a child younger than 12 months, is a rare cancer and occurs in fewer than 200 children in the United States annually. The prognosis for infants with leukemia is poor, and treatment is challenging given the excess toxicity observed in this young age group. Induction mortality is much higher for infants with acute leukemia compared with older children, and much of the therapy-related mortality observed in infants is due to infectious complications. The majority of infections are caused by gram-positive organisms, followed by gram-negative bacteria and fungi. Efforts to de-intensify therapy are more challenging than in other pediatric oncology populations because infant leukemia is very difficult to treat. However, similar to patients with DS, infants require maximal supportive care, including efforts to prevent infection, close monitoring, and a high index of suspicion for infectious complications.

Lymphoma.

Lymphoma is classically categorized as either Hodgkin (HL) or non-Hodgkin (NHL) disease. HL occurs with a bimodal distribution with the first peak during adolescence and young adulthood (15 to 24 years), which makes it a common pediatric malignancy. HL is indolent and very sensitive to chemotherapy and radiation; survival rates exceed 90% in all age groups. Treatment involves several cycles of chemotherapy, typically administered over a period of less than 2 years. Each cycle can result in episodes of neutropenia generally lasting less than 7 days, and involved-field XRT for some patients. Infection rates are low among children and adolescents treated for HL owing to low treatment intensity, although some specific infectious risks arise during treatment for HL: (1) patients with splenic involvement may receive radiation to the spleen, resulting in splenic dysfunction and a higher risk of infection with encapsulated organisms; and (2) radiation is a common treatment modality for patients with HL and brings with it infectious risks factors beyond myelosuppression, including disruption of skin and mucous membrane barrier integrity.

NHL occurs with higher incidence than HL in all ages and, for the purposes of this chapter, should be conceptualized by prognosis/intensity of therapy rather than cell of origin. Lymphoblastic lymphoma (LL) arises from either T or B cells and pathologically appears identical to ALL, although it is categorized as lymphoma because of a low burden of bone marrow disease (<25%). LL is treated similarly to ALL with 6 to 9 months of intensive therapy followed by several years of maintenance chemotherapy, and thus it has infectious risks similar to those of patients treated for ALL. Mature B-cell lymphomas include Burkitt, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma. These high-grade mature B-cell malignancies are treated with repeated cycles of intensive chemotherapy that often result in severe mucositis, malnutrition, and brief (<7 days) but profound myelosuppression. Anaplastic large cell lymphoma is a T-cell malignancy that occurs in adolescents and young adults, and is treated with chemotherapy regimens similar to those used for mature B-cell NHL. In general, infectious complications in pediatric patients with NHL are infrequent, although common risk factors of myelosuppression, central venous catheters, and mucositis occur with increased frequency in late-stage NHL that requires higher intensity treatment.

Central nervous system tumors.

Brain and spinal cord tumors are the most common type of pediatric solid tumor and account for up to 20% of all childhood malignancies. CNS tumors are an exception to the paradigm that chemotherapy intensity is increased in higher-risk malignancies. Children with CNS tumors are rarely treated with intensive chemotherapy, even those with very poor prognoses. The mainstays of treatment for CNS tumors are surgery and XRT and, although adjuvant chemotherapy is used, it is infrequently given at doses or combinations that cause significant myelosuppression. Thus infectious complications of CNS tumors and their treatment relate to surgical complications, the presence of indwelling catheters and other foreign material, and neurologic dysfunction.

Infectious risks specific to children with brain tumors include surgical site infections, ventriculitis/meningitis related to CSF diversion catheters, and infectious complications of neurologic dysfunction. Few studies have focused on infectious complications in children with brain tumors but have shown that the short-term postoperative infection rate is approximately 20% and consists primarily of wound infections and CSF catheter infections. This infection rate is consistent with neurosurgical infection rates in patients without brain tumors. CSF catheter infections are most often introduced at the time of surgical placement or revision, although, less commonly, they can arise as a retrograde infection from the distal end of the shunt. The latter scenario can occur from bowel contamination of a ventriculoperitoneal shunt or hematogenous seeding of a ventriculoatrial shunt. CNS tumors or resection efforts result in neurologic dysfunction to varying degrees. Infections arise in patients with neurologic dysfunction for many reasons; some examples include aspiration events leading to pneumonia, bladder stasis leading to urinary tract infections, and decubitus ulcer infections.

Of note, there are CNS tumors of embryonal origin—medulloblastoma, atypical teratoid rhabdoid tumors, and primitive neuroectodermal tumors—that tend to occur in younger children and are treated with myelosuppressive chemotherapy, often followed by autologous stem cell rescue. In addition to the infectious risks noted earlier for other CNS tumors, these patients are also at risk for bacteremia, typhlitis, and additional opportunistic infections common to children undergoing periods of profound neutropenia.

Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in children. It arises from embryonal neural crest tissue and may present as a localized, low-grade tumor or as high-grade, widely metastatic disease. Staging is determined by histology, genetic aberrations, and metastasis. High-risk neuroblastoma (HR NBL) has poor outcomes and is treated with multimodality therapy, including cytotoxic and myelosuppressive chemotherapy, surgery, XRT, autologous SCT, and immunotherapy. Infectious risks vary throughout the treatment course, which lasts 1.5 to 2 years, and more than 50% of children treated for HR NBL have a bacterial or fungal infection at some point during therapy. Most infections occur during neutropenic periods resulting from myelosuppressive chemotherapy. Current treatment protocols include four or five cycles of neoadjuvant chemotherapy that result in neutropenic periods averaging 5 to 7 days. Postoperatively, children undergo myeloablative chemotherapy followed by autologous SCT with a longer expected duration of neutropenia (7 to 14 days). However, neuroblastoma therapy is one of the most rapidly evolving fields in pediatric oncology, with a current emphasis on decreased dosing of conventional chemotherapy to limit late-onset toxicity, and a movement toward targeted therapies. As this shift occurs, the infectious risks associated with therapy for HR NBL will also change.

Sarcoma.

The majority of sarcomas arise during childhood and adolescence. The most common types of sarcoma are osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma, although a variety of other bone and soft tissue sarcomas occur in the pediatric age group. Treatment for sarcomas includes repeated cycles of chemotherapy leading to brief (∼7 days) but profound neutropenia, and local control of the tumor, which may involve surgical resection or XRT. Advances in surgical techniques have led to increased use of endoprosthetic reconstruction rather than amputation of affected limbs. Although this approach preserves anatomy and some function, the risk of infection associated with allograft or prosthetic placement is high and constitutes the primary mode of reconstructive failure for pediatric patients. Soft tissue infections occur in up to 50% of limb salvage procedures, and infection of the prosthesis occurs in 8% to 18% depending on prosthetic material, location, and immunologic and nutritional status of the patient. Treatment of an endoprosthetic infection is complex and often requires a combination of surgical debridement and prolonged antimicrobial therapy. In rare cases, amputation is required to definitively manage endoprosthetic infections.

Children with bone and soft tissue sarcomas are treated with highly emetogenic chemotherapy which, combined with disability related to tumor location, frequently results in malnutrition and prolonged deconditioning. These factors increase the risk for and complicate infections that occur in patients with sarcoma. Supportive care in the form of nutritional support and physical therapy are paramount to infection prevention.

Wilms tumor.

Wilms tumor is the most common renal tumor of childhood. Staging is based on histology, location, metastasis, and surgical outcomes, and treatment intensity increases with higher-stage disease. Treatment consists of low-intensity chemotherapy that rarely causes profound neutropenia, surgery, and occasionally XRT. Infectious complications in children with Wilms tumor are rare.

Hepatoblastoma.

Hepatoblastoma is a liver tumor that arises in infancy and early childhood. It is a chemotherapy-sensitive tumor with very good survival rates. Children are treated with a combination of surgical resection and adjuvant chemotherapy. If the primary tumor is unresectable, patients may undergo liver transplantation, which occurs in approximately 20% of cases. For these children, infectious risks are largely those affected by solid organ transplantation (see Chapter 1 ). Infectious complications are uncommon in cases of hepatoblastoma without liver transplant.

Alkylating agents.

Alkylating agents are integral to the treatment of many pediatric cancers, including ALL, HL, NBL, sarcomas, and brain tumors. These drugs work by forming reactive intermediates that attach an alkyl group to DNA base pairs which interfere with DNA replication. Myelosuppression is a common dose-limiting toxicity of alkylating agents. The nadir for absolute neutrophil count occurs 6 to 10 days after administration of alkylators, with recovery after 14 to 21 days. Delayed and prolonged myelosuppression occurs with nitrosoureas, such as carmustine and lomustine, where the nadir in platelets and neutrophils starts 4 to 6 weeks after treatment with a slow recovery thereafter.

Platinum analogs.

Platinum analogs are a backbone of many pediatric solid and brain tumors given their antineoplastic activity resulting from covalent binding of platinum to nucleophilic sites on DNA, leading to intrastrand and interstrand cross-links and DNA breaks. Besides myelosuppression, nephrotoxicity and ototoxicity are common side effects. Platinum analogs are also highly emetogenic, necessitating nutritional monitoring and support. Appropriate hydration is necessary for prevention of renal damage, and dose adjustments may be necessary to mitigate excessive or prolonged nephrotoxicity.

Antimetabolites.

The antimetabolite class consists of analogs of folic acid, pyrimidines, and purines that ultimately inhibit DNA synthesis and replication. Methotrexate is the quintessential folic acid analog and is used in high doses (>1000 mg/m ) for ALL, lymphoma, and osteosarcoma. Methotrexate inhibits dihydrofolate reductase, an enzyme required for reduction of folic acid to tetrahydrofolate or folinic acid. This inhibition leads to a reduced capacity for methylation reactions necessary for the synthesis of DNA bases. High-dose methotrexate can have significant adverse effects, including bone marrow suppression and mucositis. To alleviate these side effects, intravenous hydration necessary for drug clearance and pharmacologic rescue with reduced folate or leucovorin is administered after high-dose methotrexate in pediatric patients.

Pyrimidine and purine analogs include various drugs that inhibit synthesis of essential DNA precursors (e.g., mercaptopurine) or are converted intracellularly to nucleoside analogs and incorporated into DNA, leading to cell-cycle arrest and apoptosis. Nucleoside analogs such as mercaptopurine and cytarabine are specifically used in hematologic malignancies. Clofarabine, a pyrimidine analog, is approved for relapsed/refractory ALL, although it comes with significant toxicities and is usually not well tolerated. Nelarabine is a purine analog and has resulted in improved outcomes for patients with T-cell ALL but causes myelosuppression and peripheral neuropathy.

Natural products.

Chemotherapy derived from natural products can be divided into vinca alkaloids (e.g., vincristine), camptothecin analogs (e.g., irinotecan and topotecan), antibiotics (e.g., anthracyclines or dactinomycin), and epipodophyllotoxin derivatives (e.g., etoposide). These agents affect cell cycle progression or cause double-stranded DNA breaks, resulting in rapid death of dividing cells. Vinca alkaloids are frequently used to treat pediatric cancers and block the cell cycle during mitosis by disrupting microtubule formation. Vincristine, the most common vinca alkaloid, is not myelosuppressive, unlike many other conventional chemotherapeutics. Camptothecin analogs inhibit topoisomerase I, thus promoting genotoxic double-stranded DNA breaks and can cause dose-limiting neutropenia. Anthracyclines/anthracenediones are a major subset of antibiotic chemotherapy agents that are highly active for ALL, AML, lymphoma, and many solid tumor treatment regimens. Finally, epipodophyllotoxin derivatives like etoposide directly inhibit topoisomerase II, which results in double-stranded DNA breaks. Etoposide, which is widely used in pediatric cancer, has a dose-limiting toxicity of neutropenia. Most natural product chemotherapeutics result in neutrophil nadir at 10 to 14 days with recovery by 21 days.