Emergencies in childhood cancer

Emergencies in the care of children with cancer can arise at any time in the course of their care. They can occur as the first manifestation of cancer, as a result of therapy, or at the time of recurrence. Some of the most commonly seen pediatric oncologic emergencies seen at the time of presentation are discussed here: hyperleukocytosis, tumor lysis syndrome, superior mediastinal syndrome, and spinal cord compression.

Emergencies in childhood cancer

Emergencies in the care of children with cancer can arise at any time in the course of their care. They can occur as the first manifestation of cancer, as a result of therapy, or at the time of recurrence. Some of the most commonly seen pediatric oncologic emergencies seen at the time of presentation are discussed here: hyperleukocytosis, tumor lysis syndrome, superior mediastinal syndrome, and spinal cord compression.

Initial risk stratification

Children with FN are not a homogenous group and much effort has been devoted to risk stratification. Determining which children are at lower risk of complications can allow a reduction in the intensity of therapy and monitoring. In contrast, identifying children at higher risk of complications can allow prophylactic approaches, rapid escalation of therapy, and/or close observation.

In adults with FN, the risk stratification schema from the Multinational Association of Supportive Care in Cancer (MASCC) has been validated and is widely accepted as the standard approach. However, the MASCC score cannot be applied to children because age less than 60 years and absence of chronic obstructive pulmonary disease are items in the score and these are not applicable to pediatric patients. At least 25 studies of risk prediction have been conducted in pediatric cancer. These studies have been highly variable using different pediatric cancer populations and different end points (such as bacteremia, serious infection, death, and intensive care unit admission), reducing the ability to generalize from the results.

Six low-risk stratification schemas have been validated in children. Selection of a single schema to be applied across all clinical scenarios has not been feasible, likely owing to divergence in clinical settings. Therefore, clinicians should review the 6 validated low-risk stratification schemas, choose the schema that matches the clinical setting, and determine whether the application of that schema is feasible for the center. Some rules may not be feasible to implement universally. For example, some rules use biomarkers such as C-reactive protein and require expeditious analysis and return of results to be useful. Others require clinician judgment and thus require that trained health care professionals are readily available. Whichever schema is chosen, centers should have a mechanism to routinely review their own results to ensure that the rule continues to have local applicability.

Initial investigations

At initial presentation, an evaluation for the cause of fever should be conducted. The evaluation should include a careful history and physical examination with the assessment focusing on potential sites of infection. Sites that warrant particular attention are the mouth to search for viral and candidal infection, central venous line (CVL) exit site and tunnel, chest, abdomen, and perianal area.

The standard evaluation should include blood cultures from each lumen of the CVL, if present. Peripheral blood culture at the initial evaluation of FN is controversial. There are 2 primary reasons why a peripheral culture may be useful. First, a peripheral culture can help to identify central line–associated bloodstream infection (CLABSI). However, because the diagnosis of CLABSI does not influence the management of the bacteremia, many clinicians argue that this reason does not justify obtaining a peripheral culture. Second, the addition of a peripheral blood culture may detect more bacteremia than a central culture alone. There are 7 studies that evaluated the contribution of peripheral blood cultures in addition to CVL cultures in adults and children with cancer or who were undergoing HSCT. Thirteen percent (95% confidence interval [CI], 8%–18%) of all bacteremias were identified only by the peripheral blood culture. This result is likely explained by false-negative CVL blood cultures when obtained culture volumes are small. It is not known whether this problem can be overcome by increasing the central line culture volumes or whether failure to identify these episodes of bacteremia affects patient outcomes. The role of peripheral blood culture therefore remains uncertain.

Urinalysis and urine culture for the detection of urinary tract infections (UTIs) is also controversial in the evaluation of FN. A UTI is typically suspected from pyuria on urinalysis and nitrate positivity. However, in this population, neutropenia limits the ability to use pyuria as a diagnostic criterion and reliance on nitrite testing is not ideal because the test may be negative in young children with UTI. Therefore, urinalysis testing has limited utility in the setting of FN. It may be reasonable to obtain a sterile urine culture and define the presence of a UTI on the culture results alone. However, sterile urine collection can be difficult in young children and infants, and often requires urinary catheterization, a procedure that is often discouraged in a neutropenic and often thrombocytopenic patients. Therefore, where a clean-catch or midstream urine can be collected, urinalysis and urine culture should be included in the initial FN investigations. Antibiotic administration should not be delayed to obtain a urine sample.

Another controversial evaluation is routine chest radiograph (CXR) for the detection of occult pneumonia at the onset of FN. There have been 4 studies, including 540 episodes of FN, that investigated CXR as a component of the initial FN evaluation. These studies showed that pneumonia is detected in less than 5% of children without respiratory symptoms and that the omission of routine CXR does not lead to adverse outcomes. Thus, routine CXR should not be performed in asymptomatic children with FN.

Initial antibiotic therapy

Empiric broad-spectrum antibiotic therapy at the onset of FN has been the standard of care for many decades because of the risk of life-threatening infections in neutropenic patients. In general, empiric antimicrobial therapy choices should provide good coverage for gram-negative organisms. For high-risk patients with FN, antibiotic therapy should include coverage for viridans group streptococci and Pseudomonas aeruginosa . Various factors need to be considered in determining empiric antibiotic regimen, route of administration, and location of therapy. One of the most important factors to consider is local hospital resistance patterns and sites should have a mechanism to review these patterns on a regular basis. Other factors include patient and family social factors, clinical presentation, ability of the hospital to support an ambulatory approach, and availability and cost of drugs.

The original empiric antibiotic regimens for FN consisted of parental administration of 2 agents with antipseudomonal coverage. Since then, the role of combination antibiotic therapy versus monotherapy for FN has been debated. Monotherapy was supported by 2 meta-analyses that compared monotherapy with an aminoglycoside-containing regimen in FN and in immunocompromised patients with sepsis. These analyses showed that monotherapy is not inferior to, and is less toxic than, combination therapy. The analysis in FN observed fewer treatment failures with monotherapy (odds ratio, 0.88; 95% CI, 0.78–0.99) but only included 4 trials that enrolled patients younger than 14 years of age. In the pediatric setting, monotherapy was supported by a meta-analysis that found similar clinical outcomes when antipseudomonal penicillin monotherapy was compared with antipseudomonal penicillin plus an aminoglycoside. Therefore, monotherapy is strongly recommended for pediatric FN in patients who are clinically stable and who are treated at centers with a low rate of resistant pathogens.

Published monotherapy regimens that have been evaluated in children include antipseudomonal penicillins such as piperacillin-tazobactam and ticarcillin-clavulanic acid, antipseudomonal cephalosporins such as cefepime, and carbapenems such as meropenem or imipenem. Two pediatric-specific evaluations found that treatment failure, mortality, and adverse effects were similar when antipseudomonal penicillins were compared with antipseudomonal cephalosporins or carbapenems. There are potential disadvantages of carbapenems and cefepime. Carbapenems were associated with an increased risk of pseudomembranous colitis compared with other β-lactam antibiotics in a large meta-analysis. Cefepime was associated with increased all-cause mortality in another large meta-analysis compared with other patients treated with β-lactam. However, these findings were not replicated in other studies. As a result, cefepime remains an option for empiric therapy. Ceftazidime monotherapy lacks adequate coverage against viridans group streptococci and resistant gram-negative organisms and thus should not be used if these organisms are of concern.

Routine empiric glycopeptides (such as vancomycin) are not recommended. A meta-analysis of 14 randomized controlled trials (RCTs) showed that inclusion of a glycopeptide did not lead to a difference in success (if addition of glycopeptide in the control arm was not considered failure) but was associated with more adverse effects. Empiric glycopeptides should be reserved for patients who are clinically unstable or who have a signs or symptoms that suggest a gram-positive infection.

Considerations for low-risk patients with fever and neutropenia

Patients with FN at low risk of adverse outcomes may be appropriate for a reduction in therapy intensity. Although there has been some effort to identify a group of patients with FN who do not require any empiric antibiotics, this approach has not had widespread adoption. The 2 strategies commonly considered are outpatient management and oral antibiotic administration. These two strategies are often used together and, in adults with low-risk FN, outpatient management with oral antibiotics is recommended for selected patients. There has been a concern that it may not be possible for these recommendations to be generalized to children. However, over the last several years, data have emerged related to efficacy and safety, costs, and QoL/preference considerations for different management strategies in pediatric FN.

Modification of empiric antibacterial therapy

After empiric antibiotics for FN have been initiated, the initial empiric regimen should be adjusted to provide appropriate coverage for any positive microbiology results or identified clinical focus of infection. The spectrum of antibiotics should not be narrowed until criteria for discontinuation of empiric antibiotics are met. In patients in whom empiric glycopeptides or dual gram-negative coverage was initiated, reassessment at 24 to 72 hours should be conducted. In the absence of a specific microbiological reason to continue these agents, they should be discontinued. For children with persistent fever, careful evaluation for an undetected source of infection is important. In this setting, modification of antibiotics, including addition of empiric vancomycin, is not warranted in children who remain clinically stable. Children who clinically deteriorate warrant broadening of empiric antibacterial therapy to include coverage for resistant gram-positive, gram-negative, and anaerobic organisms.

Empiric antibiotics should be discontinued if cultures are negative, the child is clinically well, fever has resolved, and there is evidence of neutrophil recovery. One randomized trial of pediatric low-risk patients found that cessation of antibiotics on day 3 irrespective of count recovery versus continuation of antibiotics was associated with similar outcomes. However, enterobacter bacteremia occurred in 1 child in the early cessation study arm. It may therefore be reasonable to discontinue antibiotics on day 3 in low-risk children with FN who have become afebrile with negative cultures as long as careful monitoring is in place. In high-risk patients, the optimal duration of antibiotic therapy is unknown in the setting of persistent profound neutropenia. A small study of 33 high-risk patients suggested that cessation of empiric antibiotics on day 7 is associated with bacteremia and poor infection outcomes compared with continuation for 14 days. However, this study was conducted many decades ago and it is not known whether these results can be generalized to the current era. Thus, continuation of empiric antibiotics for at least 14 days for high-risk FN in the absence of evidence of neutrophil recovery is a reasonable strategy.

Evaluation for invasive fungal infection and empiric antifungal therapy

Children with FN and persistent or recurrent fever 96 hours or more after initiation of broad-spectrum antibiotics who are at higher risk of invasive fungal infection (IFI) should undergo an evaluation for fungal infection including careful physical examination, blood and urine cultures, and CT of the chest. The roles of routine CT sinuses and imaging of the abdomen have not been defined in the standard investigation of IFI, although routine CT sinuses should not be conducted in children 2 years of age or younger because of insufficient pneumatization of the sinus cavities. In children with demonstrated pulmonary lesions, investigations may include bronchoalveolar lavage and lung biopsy, although fatal bleeding may occur with biopsy of angioinvasive mold lesions. Thus, the decision to biopsy requires careful consideration. Better understanding of the risks and yields of these procedures is required in pediatric patients.

Empiric antifungal therapy should consist of either caspofungin or liposomal amphotericin B (L-AmB) because these two therapies are similarly effective and L-AmB is slightly better and less nephrotoxic than amphotericin B deoxycholate. Empiric antifungal therapy may be discontinued at resolution of severe neutropenia if the patient is clinically well and without evidence of an IFI.