Infectious Disease in the Pediatric Cancer Patient

Risk Factors for Infection

Children with cancer are predisposed to infection for several reasons. The most common and important risk factor is neutropenia caused by myelosuppressive chemotherapy and cancer itself. Greater depth and duration of neutropenia are directly related to the risk of invasive bacterial and fungal infection and infectious mortality. Corticosteroids are commonly used as anticancer therapy and as supportive care. The negative consequences of corticosteroids on the host immune system predispose to infections such as Pneumocystis jiroveci, other fungi, and bacteria and may be an independent risk factor for sepsis and infectious mortality. Intensive chemotherapy also predisposes to infection through disruption of important protective anatomic barriers. The development of mucositis after chemotherapy administration provides a portal of entry for organisms colonizing the oral cavity and is a particularly important risk factor for viridans group streptococcal bacteremia. Likewise, compromise of the gastrointestinal mucosa may clinically manifest as enteritis, typhlitis, and colitis and can facilitate translocation of enteric pathogens to the bloodstream. Beyond chemotherapy and corticosteroids, certain procedures performed in this patient population may predispose to infection. In many countries central venous lines (CVLs) are routinely used in patients with cancer, resulting in a risk for catheter-related bloodstream and local CVL site infections. Additionally, many children require surgery for various reasons, including tumor resection, and such procedures predispose to surgical site infection. Finally, children who receive allogeneic hematopoietic stem cell transplantation (HSCT) have a unique predisposition to infections related to graft-versus-host disease (GVHD) and therapies used to prevent and treat this complication of transplantation.

Infection Classification

Infections can be classified by etiology as bacterial, fungal, viral, or protozoal, and these pathogens may infect sterile or nonsterile sites. The overall risk of infection varies depending on many factors, with intensity of chemotherapy being very important. Children who receive the most intensive chemotherapy include those with acute myeloid leukemia (AML). One study demonstrated that more than 60% of children with AML have at least one microbiologically documented infection during each phase of therapy, and the cumulative risk of infection-related mortality was 11 ± 2%. In a subsequent pediatric AML analysis, more than 80% of children experienced at least one sterile site bacterial infection and 14% experienced at least one sterile site fungal infection throughout chemotherapy. The risk of sterile site bacterial infection was 30% to 60% per chemotherapy course. In contrast, some children who receive non-myelosuppressive therapy such as those receiving maintenance therapy for acute lymphoblastic leukemia (ALL), have a very low risk of sterile site bacterial or fungal infections.

Infections may also be classified by type of infection: microbiologically documented, clinically documented, or fever of unknown origin (FUO). In an analysis of children with cancer or recipients of HSCT presenting with FN, 80% of episodes were ultimately classified as FUO, 13% had a microbiologically confirmed etiology, 6% were clinically documented infection, and 2% were invasive mycosis. The distribution of the etiology of FN will change depending on the presence of the aforementioned risk factors, especially the intensity of chemotherapy administered.

Intervention Approaches

The major approaches to reduction of infectious morbidity and mortality are prophylactic, empiric, and definitive treatment approaches. With prophylaxis, antimicrobials are administered before onset of fever or other clinical signs of infection. Empiric therapy consists of the administration of antimicrobial agents with early signs of infection, such as fever. Definitive treatment consists of administering specific antimicrobials once an infection has been documented.

Bacteria

Bacteria are the most common cause of invasive infection in pediatric cancer patients. Over the last three decades, there has been a shift from gram-negative organisms being responsible for most infections in patients with cancer to gram-positive infections predominating. The shift toward gram-positive agents has been attributed to the wide-spread use of CVLs, chemotherapy regimens associated with mucositis, and routine use of antibiotics with gram-negative activity. The most common gram-positive infections are coagulase-negative staphylococci, viridans group streptococci, enterococci, and Staph­ylococcus aureus . The major types of gram-negative infections are Escherichia coli, Klebsiella species, and Pseudomonas aeruginosa . Bacterial sterile site pathogens are most commonly tested for and isolated from blood culture, followed by urine and, less frequently, cerebrospinal fluid.

Fungi

Pediatric patients requiring intensive chemotherapy treatment for cancers such as AML, relapsed ALL, and allogeneic HSCT have the highest risk for invasive fungal infection (IFI) because of the resultant depth and duration of neutropenia. Additional IFI risk factors include mucositis, corticosteroid use, and antibiotic exposure. The most common fungal infections in pediatric cancer are Candida spp . and Aspergillus spp. Sterile site candidal infections typically occur in the blood and urine. In contrast, invasive aspergillosis typically involves the lungs, sinuses, gastrointestinal tract, and brain. Emerging fungal pathogens that are increasingly being encountered in pediatric oncology are Mucorales (formerly referred to as zygomycetes) and Scedosporium spp. These are particularly concerning because they tend to be fatal and are challenging to diagnose antemortem.

P. jirovecii is a yeastlike fungal species that classically causes pneumonia in children with acute leukemia who do not receive P. jirovecii pneumonia (PCP) prophylaxis. In addition to chemotherapy exposure, corticosteroid use and age younger than 2 years are also risk factors for PCP. PCP prophylaxis is considered standard care for many pediatric malignancies, including acute leukemia and HSCT recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the prophylactic drug of choice. Although the optimal dosing regimen is not clear, administration regimens of 2 or 3 days per week are most common and have been shown to be reasonably effective. Alternative regimens for allergy or other toxicities include oral dapsone, oral atovaquone, and inhaled pentamidine. Intravenous pentamidine is often used in children younger than 5 years who cannot tolerate the other options. However, clinicians should be aware that the effectiveness of intravenous pentamidine is questionable.

Viral Infections

There are many viruses that can result in infections in pediatric cancer patients. The list of potential agents continues to evolve with improved diagnostic abilities for previously unrecognized pathogens such as human metapneumovirus (HMPV). In one pediatric cancer series, respiratory syncytial virus (RSV) (31%) and rhinovirus (23%) were the most frequently detected respiratory viruses, followed by parainfluenza (12%) and influenza A (11%). RSV usually does not cause life-threatening infections in children with cancer. However, in patients with AML and HSCT recipients who do acquire RSV, infection may progress to lower respiratory tract involvement. In this setting RSV infection is associated with a 14% case fatality rate in patients with AML and a 50% case fatality rate in pediatric HSCT recipients. Adenovirus may also cause serious infection, particularly in HSCT recipients, and is a frequent cause of death in this setting. Other viral infections, including varicella-zoster virus (VZV), influenza, and cytomegalovirus, are typically not life threatening in pediatric patients with cancer who are receiving less intense therapy, but they may cause severe infection and infectious mortality in the most intensively treated children. Conversely, some infections, such as severe acute respiratory syndrome (SARS), can cause fatal infection in immunocompetent patients but is rarely associated with severe illness in pediatric cancer. It is hypothesized that an intact immune system is responsible for severity of illness and fatality in SARS, thus explaining this apparent paradox.