Clinical Profile of Febrile Neutropenia in Children with Hematological Malignancies

INTRODUCTION

Out of the common causes of mortality in the pediatric population, childhood malignancies are on a rising trend.^[1] The rising incidence of the pathology thus requires a time-sensitive and more effective approach to diagnosis and intervention. Nearly one-third of childhood malignancies are hematological.^[2]

A broad classification of the common hematological malignancies encountered in childhood are as follows – acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia, Juvenile myelomonocytic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and Langerhans cell histiocytosis.^[3]

Patients commonly present with symptoms including weakness, fatigue, fever, bleeding manifestations, bone pain, and either abruptly or gradually.^[4] Children with ALL frequently exhibit signs and symptoms of extramedullary disease or bone marrow involvement.^[5] Bone marrow failure due to infiltration by blasts manifests as anemia, thrombocytopenia, and neutropenia. History of prior treatment in the form of transfusion or drugs prescribed, especially steroids, should be taken as these factors may interfere with diagnosis.

Neutropenia in hematological malignancies can be due to the chemotherapeutic agents or the disease process itself. When such neutropenic patients encounter a pathogen, they develop fever. Prompt initiation of an empiric and broad-spectrum antibiotic is the single most important lifesaving intervention in these patients.

Thus, a high index of suspicion is needed in these patients as fever might be the only presenting complaint in many patients. A detailed history and physical examination with special attention to clues suggesting the etiology or focus of the infection is a necessity to risk stratify the patient and treat appropriately. Hence, this study is done to evaluate the clinical profile of febrile neutropenia in children with hematological malignancies.

MATERIAL AND METHODS

An observational study was conducted in a tertiary care hospital in Madurai. The study period was for 1 year. All children who are already diagnosed and under treatment for hematological malignancies presenting with febrile neutropenia during the study period were included in the study. Those who did not give consent were excluded from the study. Forty children who met the selection criteria during the study period were chosen. Ethical clearance was obtained from the Institutional Ethical Committee, Madurai Medical College.

A complete blood count was sent for all children with hematological malignancies who presented with fever >101 F or 100.4 F for >1 h. If absolute neutrophil count (ANC) <500 mm³, they were included in the study. Clinical profiles, hematological profiles, and microbiological investigations were conducted for the child. The details were collected in a pre-tested semi-structured interviewer administered questionnaire.

The data were entered in Microsoft Excel and were analyzed using the Statistical Package for the Social Sciences version 24. Descriptive statistics, such as frequencies and proportions, were used, and inferential statistics, such as the Chi-square test, were used. P < 0.05 was considered significant. Data were expressed in tables and figures wherever necessary.

RESULTS

The mean age of the children was 6.45 ± 2.08 years [Figure 1]. About 65% were male and 35% were female. The most common hematological malignancy was B-cell ALL (80%), followed by T-cell ALL (15%) [Figure 2]. About 77.5% of the episodes were in children who were risk stratified as high risk. About 87.50% were in newly diagnosed malignancy, and the mean interval between the onset of symptoms and diagnosis of hematological malignancy was 5.10 ± 2.48 months [Table 1].

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Figure 1:

Age group of the study participants.

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Figure 2:

Diagnosis of the study participants. ALL: Acute lymphoblastic leukemia.

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About 37.5% had a previous history of febrile neutropenia. Fifteen children had a history of more than 1 episode of febrile neutropenia in the past. Among them, six children reported one previous episode, followed by six reported two previous episodes and three had three previous episodes. Among the children who had three previous episodes of febrile neutropenia, one child had a diagnosis of Burkitt lymphoma, which expired during the febrile neutropenic episode recorded during the study. The other two children had been diagnosed with B-cell ALL, and both of them recovered with intensive care unit (ICU) care. About 20% were in the consolidation phase of chemotherapy, 20% in the induction IA phase, 22.5% in the induction IB phase, 15% in the reinduction phase, 5% in the maintenance phase, 15% in relapse protocol and radiotherapy, and 2.5% was not yet started chemotherapy. About 52.5% of the febrile neutropenia episodes occurred within 7 days of chemotherapy. The most common chemotherapy drugs used for treatment were cytarabine (22.5%) and methotrexate (22.5%), followed by vincristine (20%). The main clinical features of the children with hematological malignancies presented with neutropenia were IV line cellulitis (22.5%), oral mucositis (22.5), and gastrointestinal involvement (22.5%) [Table 2].

About 55% had severe neutropenia, and 45% had profound neutropenia. About 45% had microbiologically documented infection, whereas the remaining 55% had only clinically documented infection. Among the appropriate cultures sent for children with febrile neutropenia, 32.5% were positive for microbes. The most common organisms found in blood culture were coagulase-negative Streptococci (10%), Klebsiella (10%), and non-fermentative Gram-negative bacilli (10%), followed by Staphylococcus aureus (5%) and Pseudomonas (5%). The organism isolated from pus culture in one child was Escherichia coli (2.5%). About 22.5% (9) of the children died, 12.5% recovered following intensive treatment care (ICU care), and the remaining 65% recovered following medical care at the ward and discharged. The mean time taken for recovery of febrile neutropenia with care in the ward was 5.08 ± 2.29 (2–12) days, and from ICU was 9.40 ± 4.43 (3–20) days [Table 3].

With respect to gender, there was no statistically significant difference in case of outcome (P > 0.05). On comparing the type of hematological malignancy with the outcome of febrile neutropenia, it was observed that 5 (15.6%) children of B cell ALL, 2 (33.3%) children of T-cell ALL, 1 (100%) child with Burkitt lymphoma, and 1 (100%) of AML died which was not statistically significant (P > 0.05). About 16.1% of episodes in the high-risk category required ICU care, 61.3% of the episodes in the high-risk category, and 77.8% in standard risk recovered with care in the ward itself. About 25% of those in Induction 1A, 22.2% in Induction 1B, 25% in the maintenance phase, and 16.7% in the reinduction phase died. One child died even before starting chemotherapy. However, there was no statistical difference with respect to phases of chemotherapy and outcome (P > 0.05) [Table 4].

The time interval between chemotherapy and the occurrence of neutropenia has an impact on the outcome, which was also statistically significant. Among children with profound neutropenia, 38.9% died, 16.7% recovered following ICU care, and 44.4% recovered following medical care from the ward. With severe neutropenia, 9.1% died, 9.1% were treated in ICU, and 81.8% recovered with medical care. Chances of poor outcome were higher in profound neutropenia compared to severe neutropenia (P < 0.05). On comparing hemoglobin count with the outcome of febrile neutropenia, it was observed that 71.6% of the children with hemoglobin <5 g/dL died compared to 12.1% of children with hemoglobin more than 5 g/dL, which was statistically significant (P < 0.05). Among 40 children with hematological malignancy with febrile neutropenia, 7 (46.7%) out of 15 children with platelet count <50000 died, 20% were treated at ICU, and 33.3% recovered with care from the ward. Among those children with platelet count >50,000, 8% died, 8% required ICU care, and 84% were discharged following medical care from the ward, which was statistically significant (P < 0.05). Hence, it was observed that low platelet count was associated with poor outcomes. With respect to infection profile, it was found that 47.2% of episodes with microbiologically documented infection died, 17.6% required ICU care, and 35.2% recovered following medical care from the ward. Among those with clinically documented infection, 4.3% died, 12.5% required ICU care, and 86.9% recovered following medical care from the ward. Those with microbiologically confirmed infection had poor outcomes compared to clinically documented infection (P < 0.05) [Table 4].

Among four children with coagulase-negative streptococci in culture, it was observed that all four were sensitive to cefotaxime, followed by carbapenem and linezolid (50%). Four children tested positive for Klebsiella infection. Among them, three children were sensitive to carbapenem, followed by amikacin, gentamicin, and ciprofloxacin (50%). For children with positive to non-fermentative Gram-negative bacilli, all four were sensitive to amikacin and ciprofloxacin, followed by gentamicin and cefotaxime (75%). All the children positive for S. aureus infection were sensitive to gentamicin, piperacillin, tazobactam, clindamycin, cotrimoxazole, erythromycin, and tetracycline. Among two children sensitive to Pseudomonas, both were sensitive to amikacin, gentamicin, ciprofloxacin, and cefotaxime. One child with a positive for E. coli was sensitive to both carbapenem and amikacin.

DISCUSSION

Among the 40 episodes, 80% of the episodes were presented in children with B-cell ALL, 15% of the episodes in T-cell ALL, and 2.5% each in lymphoma and AML. The results differ from the study done by Lakshmaiah et al., which analyzed 108 febrile neutropenic episodes in 72 children. Their study concluded that the occurrence of febrile neutropenia is higher in AML and the outcome is also poor in AML.^[6] In our study, only one child with AML was included during the study period, and the child died following the first neutropenic episode due to DIVC.

Nearly 22.5% of the episodes in our study occurred in the induction 1B phase and 20% in the induction 1A phase, which accounts for a total of 42.5% of the episodes in the induction phase of chemotherapy. This data aligned with many different studies in India and also various countries in the world, where nearly 40–45% of the episodes occurred during the induction phase.

Most of the episodes of febrile neutropenia occurred following the administration of cytarabine and methotrexate. The interval between the chemotherapy and the occurrence of febrile neutropenia had an impact on the outcome. Lesser the time interval between the chemotherapy administration and occurrence of febrile neutropenia, poorer the prognosis. In our study, children who developed neutropenia within 7 days of chemotherapy had longer recovery periods, and seven out of nine children who died developed febrile neutropenia within 7 days of chemotherapy, which was statistically significant. The study done by Prasad et al. found hat receiving chemotherapy <7 days ago was a risk factor for adverse outcomes, but this result was not statistically significant in their study.^[7]

Children who had profound neutropenia at presentation had a poor outcome, which was statistically significant. This result was similar to the results of the study done by Lehrnbecher et al., where ANC of <100/cu.mm has been identified as a risk factor for adverse outcomes.^[8]

In our study, along with neutropenia, a hemoglobin of <5 g/dL and a platelet count of <50,000/cu.mm have been identified to have an impact on the outcome, which was also statistically significant. The results from the studies by Santolaya et al., Swiss pediatric oncology group (SPOG) adverse events rule were similar in that a platelet count <50,000/cu.mm is a risk factor for adverse outcomes.^[9] The hemoglobin level taken as a cutoff for predicting adverse outcomes in other studies, such as Lehrnbecher et al., was 7 g/dL, whereas, in our study, it is 7 g/dL.^[8]

Microbiologically proven infections were found to have an adverse effect on the outcome. Children with microbiologically proven infections required admission to the ICU, and those who did not require ICU admission took a longer time to recover. All nine children who died due to febrile neutropenia had a microbiologically proven infection. On the contrary, children with a clinically documented infection recovered earlier.

Out of the 13 culture positive sepsis, the most common organisms isolated from cultures are Gram-negative bacilli (64.7%). Among the Gram-negative bacilli, Pseudomonas growth was observed in 15%, Klebsiella growth in 30%, nonfermentative Gram-negative bacilli in 30%, and E. coli growth in 7.7%. These results are higher than the percentage of Gram-negative infections observed in the studies conducted in Maulana Azad Medical College by Dubey et al.^[10] and by Lakshmaiah et al.^[6], where the incidence was around 36– 40%. These Gram-negative organisms are sensitive to the drugs in the order as follows – amikacin (69%), ciprofloxacin (61%), carbapenem (46%), and gentamicin (38%).

Our study is one of the few prospective studies conducted on the clinical profile of febrile neutropenia in hematological malignancies. We want to emphasize the fact that every institute with a hemato-oncology unit should have a periodic assessment of the clinical variables, pattern of microbial infections, and mortality in febrile neutropenia.

CONCLUSION

Febrile neutropenia is common during the induction phase and the most common drug causing febrile neutropenia is methotrexate and cytarabine. The risk factors associated with poor outcomes are the time interval between chemotherapy and occurrence of neutropenia, profound neutropenia at presentation, culture-positive sepsis, hemoglobin <5 g/dL, and platelet count <50,000/cu.mm. Gram-negative bacteria are the most common organisms isolated from the culture, and most of them are sensitive to ciprofloxacin and amikacin. Although this study would need validation across other research-limited settings, it is hoped that the information gained from this study will be useful in deciding the treatment of children with febrile neutropenia and the risk factors of the outcome.