Vinh Dao MD1, Shoon Oo MD1, Kenneth Snell MD2, David Goldenberg DO2, Frank Lodeserto MD3
Affiliations
1. Department of Internal Medicine, Cape Fear Valley Medical Center, Fayetteville, North Carolina
2. Department of Anesthesiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
3. Department of Critical Care, Cape Fear Valley Medical Center, Fayetteville, North Carolina
Neutropenic Fever in Patients with Cancer
The definition of neutropenic fever varies from institution to institution, but the most commonly accepted definition is a temperature ≥100.4℉ for 1 hour or ≥101℉ in a single instance with an absolute neutrophil count (ANC) <500/µL. It can be further subdivided into severe neutropenia (ANC <500/µL) and profound neutropenia (< 100/µL).
For the initial workup of neutropenic fever with an unclear source, the standard workup should include vital signs, 2 sets of blood cultures, urine culture, and sputum culture (questionable value if the patient has a dry cough and does not bring up a significant amount of sputum), CXR, CBC with a differential, procalcitonin, and lactate. In intubated patients with neutropenic fever, a bronchoscopy with BAL would be appropriate.
Typical management of neutropenic fever involves broad-spectrum antibiotics that are dependent on the risk factors currently present in cancer patients. Risk stratification can be done with a variety of scoring systems, such as the Multinational Association for Supportive Care in Cancer (MASCC) score, Clinical Index of Stable Febrile Neutropenia (CISNE), or Talcott’s rules. Low-risk scores can be managed with oral antibiotics in the outpatient setting. In contrast, higher scores should prompt more careful evaluation with consideration to admitting to either a step-down/ICU level of care.1
Table 1. MASCC Score Criteria
For low-risk patients (MASCC score ≥ 21, CISNE score 0), empiric oral antibiotics would include coverage with fluoroquinolones and amoxicillin/clavulanate.2 For high-risk patients (MASCC score < 21, CISNE score ≥ 3, Talcott’s Group 4), empiric coverage can include either cefepime, piperacillin-tazobactam, or meropenem with the consideration to add vancomycin in cases with suspected catheter-related infections, those at risk for MRSA infections, skin infections, soft tissue infections, pneumonia, or in hemodynamically unstable patients.3 Antibiotics can be de-escalated once culture results are finalized. The minimum duration of antibiotics depends on the particular organism and source of origin. However, antibiotics should be continued until the ANC rises to above 500/µL even if an appropriate duration of antibiotics has been given for a specific organism.4 It should also be noted that if patients have completed a course of antibiotics but are still neutropenic, they should continue to be on oral fluoroquinolone prophylaxis until the ANC is greater than 500/µL.4 Furthermore, broadening to fungal coverage would be appropriate in patients with continued febrile episodes after 4-7 days of broad-spectrum antibiotics or those at risk for fungal infections.3
Regardless of being high or low risk, these patients can have mortality rates as high as 57.4% depending on if they have >4 comorbidities.5 They are also at an increased risk of developing gram-negative sepsis. As such, all recommendations for empiric coverage cover pseudomonas. One of the most important factors to consider for neutropenic fever and to improve mortality is the time for antibiotic initiation. Within the first hour of diagnosis, empiric antibiotics should be initiated.6 Even in low-risk patients, one can consider providing a one-time dose of IV antibiotics and discharging on PO. Furthermore, even low-risk patients are still at risk for serious complications and can be admitted depending on clinical judgment.
With regards to hematopoietic colony-stimulating factors (CSFs), the American Society of Clinical Oncology (ASCO) has strict guidelines regarding its usage. The ideal subset of patients should be those with a solid tumor or lymphoma who are being treated with chemotherapy. Usually, CSFs are used as primary prophylaxis in patients starting their first cycle of chemotherapy and who are continuing multiple cycles if they have ≥ 20% risk for febrile neutropenia.7 Alternatively, if patients have a neutropenic complication following a cycle of chemotherapy and did not receive primary prophylaxis, they can be a candidate for secondary prophylaxis with the caveat that they a given a reduced dose or treatment delay.7 The ASCO also strongly discourages the use of CSFs in afebrile neutropenic patients.7 Current literature regarding adjunctive use of CSF in patients with febrile neutropenia has also not shown much benefit. Mhaskar et al. conducted a review among fourteen randomized control trials including 1553 participants to clarify the role of CSF in febrile neutropenia. It was found that there was no significant reduction in overall mortality in the use of CSF plus antibiotics versus antibiotics alone (hazard ratio 0.74, 95% confidence interval 0.47 to 1.16, p = 0.23) and noted infection-related mortality was also not significant (hazard ratio 0.5, 95% confidence interval 0.47 to 1.2, p = 0.23).8 However, the study did find that the patients who received CSF were less likely to be hospitalized for more than 10 days (risk ratio 0.65, 95% confidence interval 0.44 to 0.95, p = 0.03) and that these patients had a shorter duration of time for neutrophil recovery (standardized mean difference -1.7, 95% confidence interval -2.83 to -0.18, p = 0.0004). 8
Thrombocytopenia and Platelet Transfusion
The definition of thrombocytopenia is having a platelet count of < 150000/µL and is further subdivided into moderate thrombocytopenia < 50000/µL and severe thrombocytopenia <20000/µL. However, the degree of thrombocytopenia will often dictate the symptoms one may exhibit.9 For instance, platelets greater than 50000/µL rarely have symptoms while platelets from 30000/µL to 50000/µL can result in purpura. On the other hand, once platelet counts decrease to <10000/µL, minimal trauma can sometimes result in bleeding, and in severe cases, once platelets are < 5000/µL, spontaneous bleeding may occur.9 When thinking of thrombocytopenia, one can classify it into decreased platelet production, increased platelet consumption, and increased sequestration.
Initial workup should include an in-depth history and physical, medication reconciliation, CBC with differential, and/or peripheral smear.
Management for thrombocytopenia often includes platelet transfusions, of which there are varying thresholds, and can be for both treatment of bleeding or prophylaxis. The only strong recommendation for platelet prophylaxis is to reduce the risk of spontaneous bleeding when the platelet count is ≤ 10000/µL.10 Otherwise, there is no strong evidence supporting other platelet thresholds. Table 2 shows some guidelines set by various organizations.
Table 2. Platelet Transfusion Thresholds11
With regards to therapeutic platelet transfusions, platelets should be transfused at different thresholds depending on the World Health Organization Bleeding Scale (≥2). In patients with clinically significant bleeding (WHO Grade 2), the platelet goal would be ≥ 30000/µL while patients with severe bleeding (WHO Grade 3) would need a goal of ≥ 50,000/µL12. The only exception is in patients with multiple trauma, traumatic brain injury, or spontaneous intracerebral hemorrhage, in which the platelet goal would be ≥ 100,000/µL.12
Rotational thromboelastography (ROTEM) and thromboelastography (TEG) are tests to determine blood clotting efficiency. They do this by quantitatively assessing clot formation, which is subdivided into clotting time or factors associated with coagulation factors and clot kinetics, and fibrinolysis or thrombolysis. Table 3 contains key parameters included in ROTEM and TEG and their physiologic counterparts.13
Table 3. TEG and ROTEM parameters and physiologic counterparts13
Regarding the efficacy of TEG or ROTEM on guiding transfusions, a Cochrane review of 17 studies with a total of 1493 participants was done. It should be noted though that of the 1493 patients, 1435 of the patients were undergoing elective cardiac surgery. The study also noted that the TEG/ROTEM group had a mortality of 14/364 (3.9%) compared to the control group 26/353 (7.4%).14 The full set of patients was not used as not all of the studies reported mortality. However, the authors of the paper noted that there was a large distribution in the confidence interval and that the trials were carried out with a high risk of bias and clinical heterogeneity. They noted that the evidence presented was of low quality. As such, the authors concluded that the study notes that using TEG/ROTEM to guide transfusions may reduce the need for additional blood products but further evaluation and testing will need to be done14
In the setting of trauma, most studies have been observational single-center cohort studies with most indicating that there was a reduction in the amount of blood products transfused and a mortality benefit.15 However there are no formal guidelines regarding when to transfuse according to TEG/ROTEM. Baksaas et al. developed a data-driven algorithm to guide viscoelastic hemostatic assays and enrolled 2287 trauma patients in the study. They analyzed the VHAs and correlated them to trauma-induced coagulopathy, hypofibrinogenemia, and thrombocytopenia. Their algorithm is listed below with CCT being a conventional coagulation test.16 However, studies are currently being done validating these types of algorithmic approaches and assessing their benefit.
Table 4. Viscoelastic Hemostatic Assays Algorithm16
Regarding the use of VHA in liver transplants, end stage liver disease, and sepsis, the literature appears to be limited. Most of these studies have been extrapolating the data from cardiac surgeries to make their argument.13 Although the data is limited on using VHA from a clinical standpoint, there still are several benefits to it. VHA provides a point-of-care test that can let physicians know how a patient is doing from a coagulation aspect within 10-15 minutes compared to conventional coagulation tests. Although the data is insufficient at this point, early trends do show that it can lead to a reduction in the amount of blood product needed and can benefit patients from a cost standpoint as well as avoid some of the risks associated with platelet transfusion.
There is a variety of risks associated with platelet transfusions. Some of the risks include but are not limited to febrile non-hemolytic transfusion reaction (incidence 0.4-4.6%), anaphylaxis (incidence 0.09-21%), bacterial and viral infections (incidence 0.064-0.72%), TRALI (incidence 0.81%), and transfusion-associated graft-versus-host disease.17,18 The most frequent ones are typically febrile non-hemolytic transfusion reactions and anaphylaxis. Using VHA would most likely limit some of these risks. However, further higher-quality studies need to be done to clarify the role of VHA in clinical practice.
Hyperviscosity Syndrome
Hyperviscosity Syndrome refers to an increase in serum viscosity, which can occur from excess of immunoglobulin proteins. This syndrome is most commonly caused by Waldenström macroglobulinemia but can also be caused by multiple myeloma, high levels of IgG, and type I and II cryoglobulinemia due to their effects of increasing production of serum proteins.15 Having an increased viscosity will in turn lead to a decrease in blood flow with subsequent concerns of hypoperfusion and decreased microvascular circulation. Furthermore, a higher viscosity will result in increased shear forces to the blood vessels, which can result in bleeding as the smaller veins in particular lack the underlying tissue support to sustain such high sheer forces. The areas where this would be most impactful are the brain, the retina, and mucosal lining of the GI tract, the gum line, and the lining of the nose.15 In particular, the visual disturbances would be a result of the increased plasma viscosity leading to retinal venous engorgement and subsequently hemorrhage and papilledema. The classic triad of symptoms present in Hyperviscosity Syndrome of mucosal bleeding (gingival bleeding and epistaxis), visual abnormalities (bilateral retinal hemorrhage or thrombosis, papilledema, or blurring), and neurological abnormalities (somnolence, coma, cerebral hemorrhage, headache, altered mental status, seizure, and ataxia).15
Hyperviscosity Syndrome is a clinical diagnosis and labs only tend to support the clinical diagnosis. An appropriate lab workup would include a CMP, serum viscosity, peripheral blood smear, coagulation panel, and quantitative Ig levels. In particular, a serum viscosity > 4 centipoises should make providers have a higher suspicion to suspect Hyperviscosity Syndrome.3
Other consequences of Hyperviscosity Syndrome are congestive heart failure, ischemic acute tubular necrosis, and pulmonary edema, which can all be fatal if not treated promptly.3 However, there are no clinical thresholds for suspecting hyperviscosity syndrome.
Treatment of Hyperviscosity Syndrome is done by attempting to lower the serum viscosity through IV fluid resuscitation, plasmapheresis, leukapheresis, or phlebotomy. However, these treatments only provide symptom relief and play no role in disease progression.19 Figure 1 contains an algorithm for management. Plasma exchange can result in a reduction of serum viscosity by approximately 30-50%, with most cases needing 1-3 rounds before symptoms resolve.20 However, in the cases where the patient has cardiovascular comorbidities, hemodynamic instability, or is hypercoagulable, induction chemotherapy would be the next best step with careful consideration for possible tumor lysis syndrome.21
Figure 1. Hyperviscosity Treatment Algorithm 20
Key Takeaways:
• Neutropenic fever is defined as a temperature ≥100.4℉ for 1 hour or ≥101℉ in a single instance with an absolute neutrophil count (ANC) <500/µL (or ANC is expected to decrease < 500 cells/µL over the next 48 hours).
• Empiric antibiotic therapy should be started within 60 minutes of presentation with an antipseudomonal antibiotic +/- vancomycin
• For patients in the critical care setting, start with cefepime/piperacillin-tazobactam/meropenem +/- vancomycin
• CSFs are only recommended to be given prophylactically. There is no role in adjunctive CSFs in the setting of febrile neutropenia.
• The only strong recommendation for prophylactic platelet transfusion is if the platelet count ≤ 10000/µL.
• Hyperviscosity Syndrome should be suspected in patients with mucosal bleeding (gingival bleeding and epistaxis), visual abnormalities (bilateral retinal hemorrhage or thrombosis, papilledema, or blurring), and neurological abnormalities (somnolence, coma, cerebral hemorrhage, headache, altered mental status, seizure, and ataxia)
• Treatment of Hyperviscosity Syndrome is done by attempting to lower the serum viscosity through IV fluid resuscitation, plasmapheresis, or leukapheresis.
• Follow Figure 1 for the treatment algorithm.
Guest Post By:
Vinh Dao MD
Internal Medicine Resident
Cape Fear Valley Health System
Fayetteville NC
Expert Peer Review:
Kenneth Snell MD
Surgical & Medical Oncology ICU
Department of Anesthesiology
H. Lee Moffitt Cancer Center and Research Institute
Assistant Professor
Morsani College of Medicine
University of South Florida, Tampa
David Goldenberg MD
Surgical & Medical Oncology ICU
Department of Anesthesiology
H. Lee Moffitt Cancer Center and Research Institute
Assistant Professor
Morsani College of Medicine
University of South Florida, Tampa
References
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Post Peer Reviewed By: Frank Lodeserto, MD
