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 » Introduction
 »  Study Design and...
 » Results
 » Discussion
 » Conclusion
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ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 4  |  Page : 432-437
 

Risk predictors for adverse outcome in pediatric febrile neutropenia: Single center experience from a low and middle-income country


1 Department of Medical Oncology, Division of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Clinical Research Secretariat, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication1-Feb-2016

Correspondence Address:
M Prasad
Department of Medical Oncology, Division of Pediatric Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.175321

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 » Abstract 

Background: Risk stratification of patients with febrile neutropenia (FN) into those at "High Risk" and "Low Risk" of developing complications helps in making decisions regarding optimal treatment, such as whether to treat with oral or intravenous antibiotics, whether to treat as inpatient or outpatient and how long to treat. Risk predictors obtained from Western studies on pediatric FN are unlikely to be relevant to low middle-income country (LMICs). Our study aimed to identify clinical and laboratory parameters predictive of poor outcomes in children with chemotherapy-induced FN in a LMIC. Procedure: Two hundred and fifty consecutive episodes of chemotherapy-induced FN in pediatric (<15 years) patients were analyzed prospectively. Adverse outcomes were defined as per SPOG 2003 FN study as serious medical complications (SMC) due to infection, microbiologically defined infection, and radiologically defined pneumonia (RDP). Variables found to be significant for adverse outcome (P < 0.05) on univariate analysis were selected for multivariate analysis. Results: Five factors that were found to independently predict adverse outcome were (a) previously documented infection in the past 6 months, (b) presence of significant focus of infection, (c) absolute phagocyte count <100/mm3, (d) peak temperature more than 39°C in this episode of FN, and (e) fever lasting more than 5 days during this episode of FN. Conclusions: Identifying the risk factors for adverse outcome in pediatric FN, which are objective and applicable across LMICs would contribute in developing guidelines for the management of FN in a resource-limited setting.


Keywords: Febrile neutropenia, infections in immunocompromised host, low-middle-income countries


How to cite this article:
Prasad M, Chinnaswamy G, Arora B, Vora T, Hawaldar R, Banavali S. Risk predictors for adverse outcome in pediatric febrile neutropenia: Single center experience from a low and middle-income country. Indian J Cancer 2014;51:432-7

How to cite this URL:
Prasad M, Chinnaswamy G, Arora B, Vora T, Hawaldar R, Banavali S. Risk predictors for adverse outcome in pediatric febrile neutropenia: Single center experience from a low and middle-income country. Indian J Cancer [serial online] 2014 [cited 2019 Dec 16];51:432-7. Available from: http://www.indianjcancer.com/text.asp?2014/51/4/432/175321



 » Introduction Top


Advances in all fields of oncology have led to an increase and improvement in outcomes and in the majority of pediatric malignancies, 5-year survival rates approach 80%.[1] Specifically, advances in supportive care have allowed for more intensive chemotherapy to be incorporated in frontline treatment regimens.[2],[3] Neutropenia and infections are common and anticipated side effects of chemotherapy.[4] Febrile neutropenia (FN) is a potentially life-threatening complication and is treated as an emergency worldwide. Conventional guidelines for the treatment of FN recommend immediate hospitalization, empirical antibiotic therapy, and close supervision.[5],[6],[7] However, with improvements in supportive care, the vast majority of patients have no complications during the episode of FN, and may not require the aggressive management strategy which is currently in vogue.[8] There are established clinical scores for risk stratifying adult FN patients.[9] There have been many studies which have attempted to define risk factors for complications in pediatric FN, and to develop clinical risk decision rules and risk prediction models factors for adverse outcome in pediatric FN.[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] However, these studies have used various definitions of adverse outcome, and the risk prediction variables across these studies have not been consistent. To date, few pediatric models have undergone multinational prospective validation,[10],[11],[12],[13] and there is no single accepted score in pediatric FN.[28],[29],[30],[31],[32]

In resource-limited settings, there are many logistical issues in the treatment of FN: Constraints in the form of limited hospital beds and manpower; the higher costs resulting from prolonged hospital stays and intravenous (IV) antibiotics; and disruption of the quality of life of patient and family.[33] Due to these constraints, approximately 60–70% of children (predominantly those conventionally classified as "low risk," but also several "high risk") with FN at our center are managed as outpatients and are admitted as inpatients only when complicated.[5],[6],[7] Outpatient treatment of selected "low risk" patients with oral/IV antibiotics can go a long way in overcoming the dearth of resources.

However, the increasing load in outpatient departments makes it difficult to monitor and preempt complications, especially in "high risk" patients. Hence, there is a need to stratify patients at higher risk for complications due to FN, over and above existing conventional criteria.

Risk stratification is of special importance across all resource-limited low/middle-income country (LMIC) settings where advances in supportive care have not matched those of Western countries.[33] Apart from the resource limitations detailed above, poor access to hospital emergency services might prolong time to antibiotic administration and other supportive care. Due to all these reasons, FN and infections still account for a considerable proportion of morbidity and mortality in children undergoing cancer chemotherapy in most centers.[15],[33],[34],[35],[36] The profile of FN in children from LMICs also differs significantly from that in more affluent nations, for instance, the spectrum and sensitivity of bacterial pathogens, and incidence of invasive fungal infections.[15],[34],[35],[36] Moreover, very pertinent is the high level of malnutrition and often poor tolerance to chemotherapy in children from LMICs.[33],[37],[38],[39],[40],[41],[42],[43] Thus, risk predictors obtained from Western studies on pediatric FN are unlikely to be relevant to LMICs, necessitating us to identify clinical and laboratory parameters predictive of poor outcomes in FN in our patient population.


 » Study Design and Methods Top


Study design and patient population

Our study was conducted in the Pediatric Oncology Division of Tata Memorial Hospital Mumbai, which is a tertiary referral oncology center. All children (<15 years) admitted over a period of 6 months (November 2011 to April 2012) with FN were enrolled prospectively. Multiple episodes of FN per patient were allowed, and each episode was recruited as a new event. Children who had undergone hematopoietic stem cell transplant were excluded, as were children who had FN at the time of cancer diagnosis. This prospective study was approved by the Institutional Review Board.

Patients diagnosed with FN were managed as per standard departmental protocol and reassessed at 24 h. The first-line empirical antibiotic used for high-risk FN at our institution at the time of the study was IV cefepime (50 mg/kg every 8 h). Vancomycin (10 mg/kg every 6 h) was added in specific conditions.[9] The third line antibiotic was IV meropenem (20 mg/kg every 8 h). Antibiotics were tailored according to culture/sensitivity reports. Antifungals were added if the patient continued to be febrile on day 5 of antibiotics or if there was a history of fungal infection or if there was any suspicion of fungal infection on clinical examination or radiological evaluation. Due to an ongoing institutional trial, patients who were not on prophylactic granulocyte colony-stimulating factor (G-CSF) were randomized to receive antibiotics with G-CSF or antibiotics alone. Patients on intensive leukemia/lymphoma protocols received prophylactic G-CSF as per departmental protocol. Patients were discharged on oral cefpodoxime or IV ceftriaxone after fever resolution for >24 h, if the clinical condition was stable with evidence of bone marrow recovery (absolute neutrophil count [ANC] >100/mm 3), and if blood cultures remained sterile. Data regarding patient characteristics, clinical examination findings, laboratory parameters, and the course during hospital stay were noted on a predesigned proforma. Patients were followed up until 7 days of cessation of antimicrobial therapy and resolution of severe neutropenia to monitor for adverse events (AE).

Definitions

Fever was defined as an oral temperature of >38.3°C (recorded once) or of >38.0°C persisting for >1 h.[6] High-grade fever was defined as the temperature above 39°C. Neutropenia [6] was defined as an ANC of <500 cells/mm 3. Absolute phagocyte count (APC) was defined as the sum of ANC and absolute monocyte count (AMC). Hypotension was defined as a systolic blood pressure less than the fifth percentile for age and sex. The patient was considered to have a "significant clinical focus of infection" if there were apparent localizing signs/symptoms likely to be causing fever either at the first presentation, or during the course of FN. The degree of protein-energy malnutrition (PEM) was assessed and classified according to the Indian Academy of Paediatrics classification based on the weight for age (>% of expected: normal; grade 1 PEM: 71–80%; grade 2 PEM:61–70% of expected; grade 3 PEM: 51–60% and grade 4 PEM: <50% of expected) weight for age.[44] "Previous documented infection" was defined as either radiologically defined pneumonia or microbiologically defined infection (MDI) which had been diagnosed in the past 6 months of treatment, either during an episode of FN or otherwise.

Definition of adverse event

AEs included (1) serious medical complication (SMC) due to infection, (2) MDI, and (3) radiologically defined pneumonia (RDP). SMC was defined as death, complication requiring Intensive Care Unit (ICU) treatment, and potentially life-threatening complication as judged by the treating physician. MDI included positive bacterial or fungal culture from a normally sterile body fluid or compartment and detection of a viral antigen or product of polymerase chain reaction (PCR) by a validated microbiologic method.[11]

Statistical analysis

Univariate analysis was used to screen for parameters potentially associated with high risk for AEs. Parameters found to be significant (P < 0.01 by univariate analysis) were selected for multivariate logistic regression analysis. The multiple logistic regression models were fit to the data by using a stepwise selection method. The Hosmer–Lemeshow test was used to evaluate the model's goodness-of-fit to the data. A P < 0.05 was considered significant by multivariate analysis. All P values were two-sided. For each variable found to be significant by logistic regression analysis, the odds ratio (OR) was calculated with the corresponding 95% confidence interval. Results for continuous variables were expressed as median with range. All statistical analyses were performed with PASW Statistics version 18 (SPSS, Inc., Chicago, IL, USA).


 » Results Top


[Table 1] describes the demographics and clinical profile of patients enrolled in this study.
Table 1: Clinical profile of patients in this study

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Adverse events

The total number of episodes in which there was at least one AE in this study was 73 (29.2%).

  • Serious medical complications (SMCs) were documented in 20 (8%) episodes with 10 deaths (4%) and 14 episodes (5.6%) where patients required ICU care. Other life-threatening events were noted in 9 episodes: Subacute intestinal obstruction in 4 episodes, and one each with necrotizing enterocolitis, hematemesis, meningitis, subdural haemorrhage, and severe anasarca
  • Thirty-five (14%) episodes had radiologically detected pneumonia (RDP). The probable etiology as reported by the radiologist was fungal in 6 episodes, bacterial in 7 episodes, and of nonspecific etiology in the rest. Four of these episodes had organisms isolated in either sputum or bronchoalveolar lavage – 2 grew pseudomonas, one grew acinetobacter, and the last had both pseudomonas and group A beta hemolytic streptococcus
  • MDI was seen in 48 episodes (19.2%). The microbial isolates are depicted in [Table 2]. Multiple organisms were isolated from 8 patients. Cytomegalovirus was detected in blood samples by PCR method in 2 patients. Four patients were diagnosed to have varicella during the present episode of FN; however, they were not considered as MDI or included in the analysis as the diagnosis was purely clinical with no microbiological confirmation.
Table 2: Spectrum of microbiologically defined infection in our study

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Risk factors for adverse outcome

Multiple factors were found to be predictive of any of the defined adverse outcome by univariate analysis [Table 3]. Five variables were found to be significant on multivariate analysis [Table 4]: Previously documented infection in the past 6 months (P - 0.011), presence of significant focus of infection (P < 0.001), APC < 100/mm 3 (P - 0.016), peak temperature more than 39°C (P - 0.007), and fever lasting more than 5 days during this episode (P < 0.001).
Table 3: Risk factors for adverse outcome in univariate analysis

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Table 4: Independent risk factors for adverse outcome in multivariate analysis

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 » Discussion Top


Although we found multiple factors on univariate analysis, only eleven of these variables were included in multivariate analysis. All factors chosen were clinically relevant and could be assessed either at presentation or within the first 4 h of presentation except, in some instances, the duration of fever. The strongest independent predictor on multivariate analysis (OR - 18) was the presence of a significant focus of infection at presentation or during the course of FN - this has been reported in earlier studies.[10],[13],[23] An APC <100/mm 3, but not an ANC of <100/mm 3 or low AMC, at presentation was found to be predictive of a worse outcome (OR - 2.6). Traditionally, the risk stratification of FN rests on both ANC and AMC.[9],[10],[19],[24],[25] The observation from our study might reflect the fact that APC correlates better with early bone marrow recovery.[45],[46] The clinical prediction rule set by Rackoff et al.[25] which had the criteria of AMC and high temperature to exclude bacteremia has been assessed across multiple data sets. History of a previously documented infection diagnosed in the past 6 months of treatment, (either during an episode of FN or otherwise) was also an independent predictor of adverse outcome, and has also been described earlier.[15],[20],[21] In our study, fever >39°C was an independent prognostic factor.[10],[23],[24] To the best of our knowledge, the duration of fever has not been found to be significant in any study of pediatric FN, although the duration of neutropenia >7 days [6] is commonly accepted as a risk predictor.

Several variables were excluded from the multivariate analysis because they are conventionally known to be "high risk" factors, which would anyway necessitate inpatient admission and monitoring, e.g., hematolymphoid malignancy, sick looking status, hemodynamic instability, the need for a packed cell or platelet transfusion, and altered organ function.

Although malnutrition and low serum albumin were not found to be independent predictors of adverse outcome, they were significant on univariate analysis and deserve mention since they are often of concern in LMICs. In our study, 43.6% of children had grades 2–4 PEM (<70% of expected weight-for-age). Studies from LMICs have shown that malnutrition exists in a significant proportion of children diagnosed to have malignancy.[37],[38],[39],[40] Patients with malnutrition at the diagnosis of malignancy tend to have more treatment-related profound neutropenia and infectious complications during initial chemotherapy compared to those with a normal nutritional status.[33],[41],[42] Recent statistics show that 48% of under five children in India have moderate to severe undernutrition as per WHO/NCHS criteria and that the prevalence of undernutrition in other LMICs is comparable.[43] The high proportion of malnutrition in children with malignancy in these countries, therefore, most likely mirrors that of the general community, whereas in more developed nations, it is often related to the type of tumor and extent of disease. However, none of the published risk prediction models for pediatric FN (including those from LMICs) have found malnutrition to be associated with adverse outcome, and to our knowledge, our study is the first to analyze this factor.

There have been several studies [10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] which have helped develop clinical prediction rules for complications in FN over the past decade, especially in the past few years. There have also been improvements in study methodology and statistical analysis overtime. However, there is still no consensus on a risk prediction model in pediatric FN [28],[29],[30],[31],[32] and only a few pediatric models which have been tested in LMIC or have undergone prospective multinational validation.[10],[11],[12],[13] The major drawbacks have been the lack of a uniform definition for adverse outcome and the lack of consistent risk prediction variables across different studies. Our study used the outcome measures as defined by the SPOG 2003 study,[11] in an attempt at maintaining uniformity. Moreover, the study was conducted prospectively in inpatients for the sake of uniformity and accuracy of data collection. Although this study was conducted in an LMIC setting, there was access to all standard investigations required in pediatric FN, including C-reactive protein, microbiology, and radiology.

The profile of pediatric FN differs considerably in LMICs, as has been described in the introduction. Apart from the different infection profile, severe financial and space constraints can lead to conventionally "high risk" patients with FN being managed as outpatients with IV antibiotics. We often have to triage within this high-risk group to select patients who require admission. Therefore, a risk prediction model is a dire practical necessity rather than a theoretical or academic question. Our study found other (more objective) variables which were relevant in LMIC – a significant clinically detected focus of infection, fever which has persisted more than 5 days with peak temperature more than 39°C, low APC, and a history of previously documented infection. The risk prediction variables are a mixture of clinical findings, as well as basic laboratory investigations, which are readily available at admission or at early reassessment, and which are convenient and easy to use across all LMIC settings.


 » Conclusion Top


Our study is one of the few prospective studies done in LMIC, which has assessed the risk factors predictive of adverse outcome in pediatric patients with FN. Although this model would need validation across other resource-limited settings, it should have risk factors that are pertinent to the local population as well. Hence, it is hoped that the information gained from this study will help in formulating a risk prediction model which is easy to use, widely applicable, and clinically relevant in LMICs.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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