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Neutropenic Fever in the Intensive Care Unit Neutropenic Fever in the Intensive Care Unit R. Scott Stephens Contents Introduction .............................................................................. 2 Etiology ................................................................................... 2 Epidemiology ............................................................................ 2 Neutropenic Fever ........................................................................ 2 Neutropenic Sepsis ....................................................................... 3 Pathophysiology ......................................................................... 3 Clinical Features ......................................................................... 5 Diagnosis ................................................................................. 5 Management ............................................................................. 7 Pharmacologic ............................................................................ 7 Non-pharmacologic ....................................................................... 9 Management Algorithm .................................................................. 9 Prognosis ................................................................................. 9 Conclusion and Summary .............................................................. 10 References ................................................................................ 10 Abstract higher for gram-negative infections. Multidrug- Neutropenic fever is a common and potentially resistant organisms are an emerging threat to life-threatening condition in patients treated neutropenic patients. Increasing data suggest for cancer. Rapid initiation of appropriate that the pathophysiology of neutropenic fever antimicrobial therapy is necessary to decrease and neutropenic sepsis is substantially different the risk of mortality. Most infections are due to from non-neutropenic fever and sepsis. Addi- gram-positive organisms, but the mortality rate is tional research is needed to both further elucidate the pathogenesis of neutropenic fever and to develop additional effective antimicrobials. R. S. Stephens (*) Oncology and Bone Marrow Transplant Critical Care, Keywords Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA Neutropenia · Neutropenic · Fever · Sepsis · e-mail: [email protected] Gram negative · Gram positive · Fungal © Springer Nature Switzerland AG 2019 1 J. L. Nates, K. J. Price (eds.), Oncologic Critical Care, https://doi.org/10.1007/978-3-319-74698-2_118-1 2 R. S. Stephens Introduction Epidemiology Neutropenic fever is one of the defining condi- Neutropenic Fever tions of oncologic critical care. Neutropenic fever is defined as a single temperature higher than Neutropenic fever occurs in up to 50% of patients 38.3 C or a sustained temperature greater than with solid tumors receiving cytotoxic chemother- 38.0 C for more than 1 h, in the presence of an apy and in more than 80% of patients receiving absolute neutrophil count [ANC]) less than 1500 chemotherapy for hematologic malignancies or cells/mm3, though many centers and guidelines undergoing HSCT [28]. In 2012, more than use an ANC cutoff of less than 500 cells/mm3 90,000 adults were hospitalized for cancer-related [28, 33]. Exceedingly common in patients receiv- neutropenia, with a total cost of $2.3 billion ing cytotoxic chemotherapy, neutropenic fever is [75]. In-hospital mortality for all patients admitted a medical emergency which requires urgent initia- with neutropenic fever is nearly 10%; this tion of broad-spectrum antibiotics. Any oncologic increases to a hospital mortality rate of more patient receiving myelosuppressive chemotherapy than 15% for patients with leukemia admitted for is at risk of developing neutropenia and opportu- neutropenic fever [37]. nistic infections, but profound neutropenia with Bacteremia is documented in up to 25% of life-threatening infectious complications is most neutropenic fever patients [28]. Whereas in the commonly seen in patients with hematologic past gram-negative organisms were commonly malignancies. This can occur during aplasia and cultured, gram-positive organisms, including before engraftment in patients receiving hemato- staphylococci, enterococci, and streptococci, are poietic stem cell transplant (HSCT) or from currently the most commonly isolated bacteria disease-related or treatment-induced cytopenias in [28, 50] (Table 1). This shift is presumably due other hematologic malignancy patients. to the increased use of long-term indwelling vas- cular catheters and may also be affected by increased use of prophylaxis against gram- Etiology While there are many potential causes of fevers in Table 1 Typical pathogens during bacterial sepsis in neu- neutropenic hosts, both infectious and non- tropenic patients infectious, fevers must be presumed to be infec- Origin Frequent pathogens tious in origin. Potential infectious agents and Unknown Coagulase-negative Staphylococci, sources of infection are legion and include Escherichia coli, Enterococcus species viruses, bacteria, and fungus. Viral pathogens Lung Pseudomonas aeruginosa, include respiratory viruses (e.g., respiratory syn- Streptococcus pneumonia, Viridans cytial virus, rhinovirus, adenovirus, coronavirus, streptococci, Acinetobacter species influenza, parainfluenza), reactivated or de novo Abdomen Escherichia coli, Pseudomonas herpes viruses (e.g., herpes simplex, cytomegalo- aeruginosa, Clostridium species, Enterococcus species, Klebsiella virus, Epstein-Barr virus), and many other poten- species tial candidates. Bacterial infections may arise Urogenital Escherichia coli, Pseudomonas from gut translocation, oral mucosal transloca- aeruginosa, Klebsiella species tion, infection of indwelling vascular catheters, Soft tissue Staphylococcus aureus, alpha- skin and soft tissue infections, pneumonias, and hemolytic streptococci urinary sources. Fungal infections typically arise Central venous Coagulase-negative Staphylococci, catheter Coryneform bacteria, from gut translocation, fungal pneumonias (e.g., Propionibacterium species, Candida aspergillosis), and vascular catheters. Drug fevers albicans, Candida tropicalis, or “tumor fevers” are the most common example Candida parapsilosis, of noninfectious fevers, but these are diagnoses of Stenotrophomonas maltophilia exclusion. Modified from [57] (Springer) Neutropenic Fever in the Intensive Care Unit 3 negative organisms [50, 59]. Though gram- 65 mmHg or a serum lactate >2 mmol/L despite positive infections are more common, gram- adequate volume resuscitation. negative infections confer a higher risk of mortal- There is no specific consensus definition for ity [77]. Fungal infections, particularly Candida neutropenic sepsis, other than sepsis occurring in and Aspergillus, are also frequent, especially in the presence of neutropenia. Any evidence of patients with prolonged or profound neutropenia organ dysfunction, including an elevated lactate, [33]. Respiratory viruses can be isolated in in the presence of neutropenia should be treated as approximately 20% of patients [34]. Despite best a potential indicator of sepsis. There are few reli- efforts, no causative organism can be identified in able data on the incidence of neutropenic sepsis or about 50% of cases of neutropenic fever [28, 33]. neutropenic septic shock. It has been estimated that 50% of patients with neutropenic fever will develop sepsis, and up to 10% of patients with Neutropenic Sepsis neutropenic fever will progress to septic shock [33]. Among neutropenic allogeneic HSCT Sepsis has been most recently defined as “life- patients, approximately 10% will develop severe threatening organ dysfunction caused by a sepsis during the engraftment period [38]. dysregulated host response to infection” [70]. A premium is placed on identification of organ dys- function using either the Sequential Organ Failure Pathophysiology Assessment (SOFA) score or the Quick SOFA (qSOFA) score; the presence of organ dysfunction Cytotoxic chemotherapy or cytotoxic radiation, in the setting of a suspected or proven infection is whether given as an antitumor agent or condition- sufficient to diagnose sepsis (Tables 2 and 3). ing regimen for HSCT, induces neutropenia by Septic shock is defined by the need for vasopres- injuring or destroying hematopoietic precursor sors to maintain a mean arterial pressure (MAP) cells within the bone marrow as well as injuring the bone marrow structure itself [44]. Circulating Table 2 Sequential organ failure assessment score Score System 0 1 2 3 4 Respiration: 400 <400 <300 <200a <100a PaO2/FiO2, mmHg Coagulation: 150 <150 <100 <50 <20 platelets, Â 103/μL Liver: <1.2 1.2–1.9 2.0–5.9 6.0–11.9 >12 bilirubin, mg/dL Cardiovascular MAP MAP Dopamine <5 Dopamine 5.1–15 or Dopamine >15 or 70 mmHg <70 mm or dobutamine epinephrine 0.1 or epinephrine >0.1 or Hg (any dose) norepinephrine 0.1 norepinephrine CNS: GCS 15 13–14 10–12 6–9 <6 Renal: Creatinine <1.2 1.2–1.9 2.0–3.4 3.5–4.9 >5.0 (mg/dL) Urine output <500 <200 (ml/day) Modified from Vincent et al. [79] CNS central nervous system, GCS Glasgow Coma Scale aWith respiratory support, catecholamine doses given as mcg/kg/min 4 R. S. Stephens Table 3 Quick SOFA criteria (qSOFA) Because cytotoxic chemotherapy is not selec- Respiratory rate 22/min tive, neutropenic patients are also lymphopenic, Altered mentation thrombocytopenic, and anemic. Lymphocytes, Systolic blood pressure 100 mm Hg including T cells, B cells, and
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