Neutropenia with fever is a common complication and the leading cause of emergency department presentation in children undergoing chemotherapy for hematologic malignancies or solid tumors. Immediate intravenous broad-spectrum antibiotics are the standard** for patients with febrile neutropenia and are associated with a significant reduction in infection-related mortality. Recently, there has been an international update on the antimicrobial treatment of neutropenia with fever, and the above issues are discussed in this article.
Initial management of neutropenia with fever
All children with febrile neutropenia should have a complete history and a thorough physical examination. In addition, catheter blood cultures should be performed in children with central venous catheterization according to guidelines. The decision to perform peripheral blood cultures is controversial, and although peripheral venous blood cultures increase the positive rate of fungemia by 12% compared with catheter blood cultures alone, the effect on prognosis is unclear, and the potential benefits need to be weighed against patient pain and discomfort. Chest x-ray is limited to children with respiratory symptoms and signs, and pneumonia occurs in less than 3% of children with asymptomatic neutropenia and fever.
Empiric antibiotics**
Currently, there is no universally applicable risk model for children with febrile neutropenia. Rapid use of broad-spectrum antibiotics has become the gold standard, but how to administer empiric antibiotics, when to start them, and how to select, change, and discontinue antibiotics still need further discussion.
The latest guidelines recommend the use of a lactam, cephalosporin, or carbapenem monotherapy empirical. If there is suspicion of drug-resistant infection, or if the center has a high proportion of drug-resistant bacteria, or if the clinical symptoms are unstable, another antigram-negative drug or glycopeptide should be used. However, empiric administration needs to be adapted to local microbial prevalence and resistance patterns. Fluoroquinolones may increase the development of drug resistance. If the patient responds to ** and there is no specific microbiological evidence to support continuation of the combination, the combination of anti-gram-negative drugs or glycopeptides is discontinued after 72 hours.
Empiric antibiotics** can be discontinued after at least 24 hours without fever, blood picture has recovered, and no pathogen has been isolated for 48 hours. Low-risk patients with no prior microbiological infection or documented clinical infection should consider discontinuing antibiotics 72 hours after initiation** for patients who have been afebrile for at least 24 hours, regardless of blood picture recovery.
Febrile agranulocytopenia ineffective to broad-spectrum antibiotics
Empiric antifungal therapy is recommended for high-risk patients who do not respond to broad-spectrum antibiotics after 96 hours in febrile patients with neutropenia**. Patients at high risk of invasive fungal disease (IFD) are patients with acute myeloid leukemia, high-risk acute lymphoblastic leukemia receiving intensive chemotherapy, ** acute leukemia, and patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Patients with other risk factors, such as high-dose steroid use or older age, may also have a higher risk of IFD.
The concept of empiric antifungal** is based on the early diagnosis of IFD and the ability of timely** to improve patient outcomes. However, early diagnosis of IFD is extremely difficult, especially in children. The clinical symptoms of IFD are often nonspecific and difficult to distinguish from other pathogens. In contrast to Candida**, invasive molds such as Aspergillus are rarely identified from blood cultures. Other assays have been developed, such as galactomannan or -D-glucan (BDG) tests, to identify a wider range of pathogenic fungi, including Aspergillus, Candida, Fusarium, Trichosporum or Pneumocystis jirovecii. One systematic review analysed the diagnostic reliability of serum galactomannan and BDG for fungal infections in children with persistent febrile neutropenia or pulmonary symptoms or signs. In this study, pooled specificity and sensitivity were 85% (95% CI, 51-97%) and 89% (95% CI, 79-95%), respectively. Imaging studies, particularly chest CT, are another important diagnostic tool for early detection of IFD. However, the typical "halo sign", "air crescent sign", or "cavitation" of pulmonary aspergillosis is uncommon in pediatric patients. A retrospective study of 139 children with invasive aspergillosis found that,6Halo sign occurs in 4% of patients,1Air crescent signs occur in 6% of children,14Cavities occur in 4% of patients. Nodules occur in another 21% of affected children.
Empiric antifungal**
Because it is difficult to diagnose or rule out IFD early and reliably, empiric antifungal** is the standard of care for children with persistent fever with neutropenia who do not respond to empirical antimicrobial**. Meta-analysis of ** showed that empirical antifungal ** significantly reduced IFD compared with non-**. For children and adolescents, caspofungin (50 mg daily; On day 1, the maximum dose is 70 mg M d) and liposome amphotericin B (1-3 mg kg d)** until neutropenia returns.
Empiric antifungal guidance may not be given to children at low risk of IFD compared with children at high risk of IFD, such as those with solid tumors, brain tumors, or Hodgkin lymphoma. Since a low risk of IFD does not mean no risk, empiric antifungals** may be beneficial for low-risk patients with additional risk factors.
Prophylactic antifungal**
Because antifungal** can lead to increased adverse events and prolonged hospital stays, pre-prophylactic antifungal** evaluation is important and requires a complete screening regimen, including biomarkers and imaging. Only patients with index-positive IFD receive antifungal **. Results from a prospective, randomized study of empiric (n = 73) versus prophylactic antifungal (n = 76)** IFD in children with persistent febrile neutropenia at high risk showed that the two approaches were equally effective, and that prophylactic medication significantly reduced antifungal use. However, prophylactic antifungal prophylaxis** should be validated in multiple international multicenter studies before being recommended by guidelines.
Summary
Prompt hospitalization and broad-spectrum antibiotics are the mainstay of most children with neutropenia and febrile. Research is currently underway to optimize patient care. Examples include the safety and selection of patients to discontinue antifungal therapy before myelosuppression returns. In addition, better stratification of patients in need of antifungals** is expected to reduce drug use and reduce adverse effects. Antimicrobial resistance in bacteria and fungi is a constant challenge in the fight against infection**.
Reference: Thomas Lehrnbecher treatment of fever in neutropenia in pediatriconcology patients. curr opin pediatr 2019, 31:35-40
Please note that this article is for the purpose of learning and reference of relevant professionals, and all information in this article is not used as a basis for diagnosing and ** diseases. If you experience any of the symptoms described in this article, seek medical attention promptly. In addition, this article is only an excerpt of the original text, and the content may be incomplete or deviate from the original text, please refer to the original text for more complete information.
Written by Cao Jinyu.
Reviewer: Zhao Chi, Zhang Junping.
Typesetting: Zhang Jingjing.