Independent Factors for Prediction of Poor Outcomes in Patients with Febrile Neutropenia

Background

Advances in cancer treatment have resulted in improved relative survival rates [1]. However, many oncology patients are faced with treatment-related symptoms and conditions that lead to increased use of health services, including emergency departments (EDs). Febrile neutropenia (FN) is such a condition and remains one of the most common causes of oncological patient presentation to the ED [2].

Febrile neutropenia is a life-threatening treatment-related condition that requires urgent management in the ED. Although there have been many advances in the treatment of FN, such patients are known to be at risk of serious infections that are associated with 12–42% mortality [3,4].

The management of febrile neutropenic patients should be based on their clinical course and possible infection source. Early prediction of bacteremia with timely and tailored empiric antimicrobial therapy will improve the prognosis of patients with FN. Recent progress in the treatment of neutropenic fever has underscored the importance of risk stratification and indicated the need to evaluate predictive factors for outcomes in FN [5].

Patient-specific risk factors, comorbid conditions, performance status, type of cancer and stage, age, number of previous febrile neutropenic episodes, and the severity and duration of neutropenia have been considered important predictors of outcomes. Based on the characteristics of FN patients, several predictive models have been developed to classify patients into low- or high-risk groups [6].

Klastersky et al. (2000) developed an internationally validated scoring system called the Multinational Association of Supportive Care in Cancer (MASCC) risk index score. The MASCC score also allows the selection of low-risk patients who can be safely treated with orally administered antibiotics. A MASCC score ≥21 indicates that the patient is at low risk of complications and mortality [7] (Table 1).

The clinical risk-prediction model proposed by the MASCC is widely used in clinical practice to define low-risk febrile neutropenia [8]. In the present study, we analyzed the clinical factors predictive of poor outcomes in patients with chemotherapy-induced FN at initial patient evaluation in the ED.

Material and Methods

STATISTICAL ANALYSES:

Differences between the 2 groups were evaluated using the t-test for continuous variables. Categorical variables were assessed using the chi-square test, and odds ratios were calculated. To define the risk factors of the outcome variables (mortality and complications), multiple logistic regression analysis was used, and adjusted odds ratios were calculated. The sensitivity, specificity, and positive and negative predicted values were calculated for diagnostic performance of the multiple logistic regression model. P values of less than 0.05 were considered significant.

Results

PATIENT CHARACTERISTICS AND CLINICAL FEATURES:

During the study period, there were 200 episodes of FN in 200 patients with cancer. The mean and median age of the study patients were 56.4±13.46 (mean ± standard deviation) and 57.5, respectively. Of the 200 patients, 89 (44.5%) were female. Of the 200 febrile episodes, 72 (36%) had bacteremia and 128 (64%) were categorized as an unexplained fever (Table 2). Serious medical complications were observed in 105 (52.5%) patients and 64 (32%) patients died during hospitalization (Table 3).

RISK STRATIFICATION FOR SERIOUS COMPLICATIONS:

Univariate analyses of the clinical parameters available from the ED and MASCC scoring system were performed (Table 4).

In the multiple logistic regression analysis, a platelet count <50 000 cells/mm3 (OR 3.93, 95% CI 1.42–10.92), serum CRP >50 mg/dl (OR 3.80, 95% CI 1.68–8.61), hypoproteinemia (OR 7.81, 95% CI 3.43–17.78), eGFR ≤90 ML/min/1.73 m2 (OR 3.06, 95% CI 1.13–8.26), and MASCC risk-index score <21 (OR 3.45, 95% CI 1.53–7.79) were determined to be independent risk factors for the prediction of poor clinical outcomes of FN patients admitted to the ED (Table 5). These risk factors were predictive of serious complications with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81%, 78%, 81%, and 79%, respectively.

RISK STRATIFICATION FOR DEATH:

As shown in Table 6, the clinical parameters and MASCC scores were evaluated with univariate analysis.

In the multiple logistic regression analysis, a platelet count <50 000 cells/mm3 (OR 3.90, 95% CI 1.62–9.43), pulmonary infiltration (OR 3.45, 95% CI 1.48–8.07), hypoproteinemia <6g/dl (OR 3.30, 95% CI 1.27–8.56), respiratory rate >24/min (OR 8.75, 95% CI 2.18–35.13), and MASCC risk-index score <21 (OR 9.20, 95% CI 3.98–21.26) were determined to be independent risk factors for death (Table 7). These parameters were predictive of death with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 75%, 89%, 77%, and 88%, respectively.

Discussion

The development of multi-drug chemotherapy protocols in the treatment of hematological conditions and solid organ tumors, use of high-dose drugs, and improved supporting treatment options have improved the chances of survival for cancer patients in recent years. However, these treatment regimens also result in immunosuppression and neutropenia, conditions that make patients prone to developing severe infections. Currently, clinicians are aiming to prolong life with these new anti-cancer treatments while also reducing adverse effects such as FN.

Patients who develop FN show varying clinical courses. One of the most important subjects of recent research is the ability to predict the prognosis of these patients. Guidelines have been developed to categorize FN patients into low- or high-risk groups. A commonly used scoring system for this purpose is the MASSC. This scoring system, which predicts prognosis, is believed to be more useful in low-risk patients. High fever in a neutropenic patient requires prompt treatment with broad-spectrum antibiotics until the culture results are obtained. This urgent approach requires emergency physicians to predict independent risk factors for FN apart from those indicated by the MASSC risk-scoring system. However, only a few studies have been conducted in the ED setting to identify independent factors associated with serious complications after the emergent diagnosis of FN.

In this study, independent predictive factors for serious complications in patients diagnosed with FN were identified with a sensitivity of 81% and specificity of 78%. Previous studies that aimed to predict complicated FN in the ED found that laboratory parameters (e.g., platelet count, CRP, and pulmonary infiltration as revealed by chest X-ray) identified patients likely to develop complications [5,11]. Our results are in agreement with these studies; platelet counts of ≤50 000cells/mm3 and CRP, an indicator of inflammation, were associated with serious complications. Platelets are unique blood cells with specialized molecular repertoires that have evolved to accomplish crucial functions in host integrity, defense, and repair. Growing evidence shows that platelets play an active role in fighting infection and innate immunity, and thrombocytopenia is frequently observed in systemic infections. Previous studies have found that the severity of thrombocytopenia is associated with increased mortality rates [13–15]. In our study, the level of serum CRP was also recognized as an independent factor. Because infections are the major cause of morbidity and mortality in neutropenic patients, considerable attention has focused on the value of acute-phase reactants in identification of high-risk patients. However, results from previous studies have been inconsistent, and their cut-off points are variable [6]. Moreover, the predictive value of the CRP concentration remains unclear. We used a cut-off value of CRP of 50 mg/dl, as proposed in a previous study [11]. Several studies have reported that CRP is a significant predictor of severe sepsis, while other studies have stated that CRP was not useful in predicting infectious complications in neutropenic patients. However, in our study, we found CRP (OR 3.8, 95% CI 1.68–8.61) to be a significant predictor of serious complications.

In our study, eGFR <90 mL/min/1.73 m2 is associated with increased risk of serious complications. The observed increased risk of serious complications from neutropenic patients with reduced eGFR is considerable, and we suggest that decreased kidney function itself is a predictor of poor outcomes. There are a few potential reasons for this suggestion. First, previous studies have shown that patients with chronic kidney diseases (CKD) are less likely to undergo cancer screening, and patients with CKD also have multiple comorbid conditions [16]. Second, the management of cancer in patients with decreased kidney function is complex. There is little information regarding the optimal timing and necessary dose adjustment of cytotoxic agents for patients with reduced kidney function. In a previous study, Iff et al. stated that an eGFR <60 mL/min/1.73 m2 is a risk factor for cancer deaths and is also a predictor of poor cancer outcomes in the older population [17]. Except for their study, we were unable to find another study that evaluated the eGFR threshold associated with an increased risk of cancer death. In another study, hypoproteinemia (<62 g/L) was found to be associated with severe sepsis in neutropenic patients [18]. In our study, hypoproteinemia was another independent factor that could predict serious complications in febrile neutropenic patients. This finding can be explained by the fact that intensive chemotherapy can lead to energy consumption and high protein catabolism. Malnutrition and altered oral intake can cause protein-losing enteropathy resulting in hypoproteinemia. These are common features in progressive advanced cancer and are responsible for increased severe hematological toxicity. Clinical malnutrition, which negatively affects patient response to therapy, increases the incidence of treatment-related adverse effects and can decrease survival [19]. Numerous studies have shown that patients with a MASCC risk index score of less than 21 should be considered at high risk for complications, as we did in our study [6,20,21].

In this study, independent predictive factors for death in patients diagnosed with FN have been identified with a sensitivity of 75% and specificity of 89%. We found that hypoproteinemia, platelet counts of ≤50 000 cells/mm3, and the MASCC risk index score were independent predictive factors. Additionally, a respiratory rate >24/min (OR 8.75, 95% CI 2.18–35.13) was the only component in vital signs that was predictive of exitus in multivariate analysis. In a recent study of patients with hematological malignancies, tachypnea was a predictor of septic shock and of poor prognosis of febrile neutropenic patients [22,23].

In previous studies, infiltration or abnormality in the chest X-ray was significantly associated with poor outcome. Both aspects could be responsible for the mortality rate of up to 25–50% (24–26). In our study, pulmonary infiltration was significantly predictive for mortality (OR 3.25, 95% CI 1.47–8.07).

This was a retrospective analysis of a small population in a single-center study. There are limited data about the types of chemotherapy and the duration of neutropenia. Therefore, our results may not be representative of all other institutions and require validation.

Conclusions

The results of our study may help emergency medicine physicians to prevent the development of serious complications and death in FN patients by the proper use of simple independent risk factors in addition to the MASCC score. Early stratifications of patients into low- and high-risk groups with timely and tailored empiric antimicrobial therapy can improve the prognosis of patients with FN.