Risk Factors and Infectious Agents in Children With Cancer: Fever and Granulocytopenia

Anatomic Disruptions and Devices

Alterations of skin or mucosal integrity or obstruction of an organ or body cavity predisposes to infection ( Table 97.1 ). Cytotoxic chemotherapy induces neutropenia and concomitantly damages oral and gastrointestinal (GI) tract mucosa; mucositis has been implicated as a risk factor for infection. Devices that violate skin integrity, such as central venous catheters (CVCs) and peripherally inserted central catheters (PICCs), also lead to a significantly increased (∼40-fold) risk of infection. ^, The rates of infection range from 9% to 80%, depending on the specific patient population, techniques of catheter insertion and care, treatment regimens, and the definition of CVC-related infections. ^,

Some studies suggest that the incidence of infection is lower for patients with totally implanted devices compared with external, tunneled CVCs, whereas others failed to document this difference. ^, The use of a CVC for delivery of parenteral nutrition increases the risk of infection by about 2.4-fold, independent of the type of CVC used. A systematic review of published studies concluded that all types of intravascular catheters pose a risk for local and catheter-related BSIs and that appropriate guidelines for prevention of catheter-related infections, from insertion to maintenance, should be followed. ^,

Devices other than CVCs also have been implicated in the risk of infection in immunocompromised patients. Limb-sparing procedures for patients with osteosarcoma use prosthetic bone-joint hardware that can also be associated with a high rate of infections. In some institutions, children with such prosthetic devices are not considered candidates for permanent CVCs because of the potential higher risk of bacteremia and seeding of the prosthesis. The relative risk of infection in children with limb prostheses is not known, and optimal management has not been defined. With any device, the importance of microbial biofilm formation and the mechanisms by which these organisms may perpetuate seeding of the bloodstream and the emergence of antibiotic resistance cannot be overemphasized. ^,

Neutropenia

By far the most important risk factor in the development of infections in children with cancer is neutropenia resulting from cytotoxic chemotherapy. The relationship between neutrophil numbers and the risk of infectious complications in patients with leukemia was first described in detail in 1966 by Bodey and colleagues at the National Cancer Institute (NCI). The investigators concluded that (1) the risk of infection was inversely related to the absolute neutrophil count (ANC), with infections being more prevalent when the ANC is <1500 cells/μL and increasing in both likelihood and severity, being most severe with ANC ≤100 cells/μL; (2) relapse of leukemia was associated with higher rates of infection than remission at all levels of neutrophil count; and (3) duration of neutropenia was the single most important factor in predicting risk of infection. Severe neutropenia that lasted longer than 3 weeks was associated with 100% risk of infection and the highest mortality rates. These observations have been confirmed over the ensuing years and led to the current approach to management of patients with fever and neutropenia. ^, Organisms causing infections in children with neutropenia are listed in Table 97.2 .

Normal Microbiota

Commensal microbes stimulate the GI epithelium to produce antimicrobial proteins (AMPs) that act as a first line of defense against invading pathogenic bacteria. When indigenous commensals are depleted after antibiotic administration, select pathogenic bacteria (e.g., vancomycin-resistant enterococci [VRE]) can overgrow and cause invasive disease. Stimulating intestinal Toll-like receptor (TLR) 4 by oral administration of lipopolysaccharide (LPS) or by stimulating TLR-5 with purified flagellin, reinduces AMP RegIIIγ and results in a decrease of VRE in the GI tract. Thus methods for maintaining microbial homeostasis during chemotherapy and receipt of antibiotic therapies may provide a novel means for preventing colonization and dissemination of pathogenic microbes and impact mortality.

Other Defects

Repeated cycles of cytotoxic therapy decrease circulating neutrophils and deplete lymphocytes and natural killer cells. Reduced lymphocyte subset populations were linked to the occurrence of opportunistic infections in a group of patients receiving dose-intensive chemotherapeutic regimens. TLRs are key components of innate host response that are responsible for recognition of pathogens and cytokine response to surface molecules. ^, An association between donor TLR4 haplotype and the risk of invasive aspergillosis was noted among recipients of hematopoietic stem cell transplants from unrelated donors. Similarly, other TLR4 single-nucleotide polymorphisms have been associated with susceptibility to infections caused by gram-negative bacteria, C. albicans, and respiratory syncytial virus. Organisms causing infections in children related to defects in cell-mediated immunity are listed in Table 97.3 , and those related to immunoglobulin and complement abnormalities as well as splenic dysfunction (or absence) are listed in Table 97.4 .

Bacteria

Infections in immunocompromised children can result from organisms from the host’s endogenous bacterial flora. Studies have documented that hospitalization, antibiotic, and antineoplastic chemotherapy result in a shift in normal flora to include potentially pathogenic gram-negative bacteria. ^{50 51} Approximately one-half of pathogens responsible for documented infections are acquired by oncology patients after initial admission to the hospital, including antibiotic-resistant gram-positive and gram-negative organisms. Bacteremia is the most frequent infectious complication in patients receiving CD-19 targeted chimeric antigen receptor-modified T cell (CAR-T) immunotherapies. ^,

The relative prevalence of gram-negative versus gram-positive infections among children with fever and neutropenia varies by institution. Gram-positive organisms (particularly coagulase-negative staphylococci, Staphylococcus aureus —and especially methicillin-resistant S. aureus [MRSA], α-hemolytic streptococci, enterococci, and Corynebacterium spp.) account for more than half of documented infections in patients with cancer at some centers, and Escherichia coli, Pseudomonas , and the Enterobacter-Klebsiella-Serratia group are identified in a smaller but significant proportion of patients. ^,

Although BSI with gram-positive organisms is generally associated with lower mortality rates than BSI with gram-negative organisms, the syndrome of α-hemolytic streptococcal septicemia deserves special attention. The α-hemolytic streptococci (also known as viridans group streptococci) are normal inhabitants of the oral cavity, GI tract, and respiratory tracts. Neutropenic patients with acute myeloid leukemia, those receiving cytosine arabinoside, and hematopoietic cell transplant recipients are at highest risk of infection and development of viridans streptococcal sepsis syndrome. ^, Streptococcus mitis and Streptococcus sanguis are the most common α-hemolytic streptococci associated with this syndrome, which manifests as septic shock or respiratory distress syndrome and may rapidly progress to death, with mortality rates ranging from 10%–100%. ^, Importantly, fever may be the only symptom and may persist despite sterilization of blood cultures. Patients can progress to shock after 48–72 hours despite clearance of the bacteremia and appropriate antimicrobial therapy. Rare reports of secondary myositis and even myocarditis have also been reported with α-hemolytic streptococcal bacteremia. ^, Of particular concern are reports of penicillin resistance among these previously susceptible organisms. ^{, ,} Increased use of systemic antibiotics for treatment and as prophylaxis (especially with fluoroquinolones and trimethoprim-sulfamethoxazole) has led to an increase in penicillin-resistant α-hemolytic streptococci within the microbiota of children which can predispose to invasive infections. Therefore it is important to know local antibiotic resistance patterns and to request that antimicrobial susceptibility testing be performed on all clinically relevant isolates.

Widespread use of vancomycin has been linked with the development of increasing vancomycin resistant Enterococcus species and S. aureus. ^, Community-acquired MRSA (CA-MRSA) has emerged as an important cause of invasive infections including sepsis, necrotizing fasciitis, and pneumonia in adults and children without recognized risk factors. ^, S. aureus can lead to significant infections in pediatric oncology patients. ^, Although CA-MRSA isolates are likely to be susceptible to non–β-lactam antibiotics (e.g., as clindamycin, trimethoprim-sulfamethoxazole, and rifampin), macrolide-lincosamide-streptogramin resistance and constitutive and inducible resistance to clindamycin are reported with variable geographic prevalence. ^, Knowledge of the prevalence of MRSA in the community and local hospital susceptibility patterns are important factors when considering empiric antibiotics in children with fever and neutropenia.

Infections resulting from gram-negative bacilli, in particular Pseudomonas aeruginosa bacteremia, continue to have the highest mortality rates. Thus providing empiric antibiotic therapy for P. aeruginosa remains important in children presenting with fever and neutropenia. Increasing antibiotic resistance of gram-negative bacteria to all the β-lactam agents (e.g., extended-spectrum penicillins and cephalosporins) as well as the carbapenems, aminoglycosides, and quinolones has been reported. Of particular concern are Enterobacter and Serratia species, which are prone to rapid development of resistance due to inducible β-lactamases.

Infections with anaerobic organisms occur infrequently in febrile, neutropenic patients despite their predominance in the normal gut microbiota. However, anaerobic infections are associated with serious infections, including bacteremia (<5%) that may be polymicrobial, and associated with high mortality. ^, The most commonly isolated anaerobic organisms are Bacteroides spp. and Clostridium spp . ^, These organisms have been associated with specific syndromes, such as peritonitis, abdominal or pelvic abscesses, and perirectal cellulitis. ^, They can also contribute to infections of the oral cavity, especially necrotizing gingivitis. Clostridium perfringes and Clostridium septicum are responsible for a devastating infection characterized by septic shock and rapidly progressive necrotizing fasciitis with myonecrosis, which rarely can occur without fever. Infection arises from a traumatic or surgical wound or spontaneously from an abdominal source, such as necrotic bowel. Pseudomembranous colitis (sometimes referred to as antibiotic-associated colitis ) caused by toxins of Clostridioides difficile can result in a wide spectrum of clinical manifestations, from mild diarrhea and cramping to toxic megacolon and intestinal perforation. Bacteremia with Fusobacterium spp. has also been described and associated with severe mucositis and fluoroquinolone prophylaxis. The possibility of an anaerobic infection should be considered in neutropenic patients with abdominal or perirectal symptoms or necrotic skin lesions and in those who remain hemodynamically unstable despite broad antibiotic therapy that does not cover anaerobic bacteria (e.g., cefepime).