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Brief Reports Indian Pediatrics 2002; 39:952-957 |
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With the advances in the management of various neoplastic diseases and subsequent improvement in "disease free" states, infectious complications have evolved as stumbling blocks to survival. Among neutropenic patients with cancer, infection is the major autopsy determined cause of death. Fever frequently accompanies neutropenia in hematological malignancies and may be the first and only sign of sepsis. The distinction of sepsis from other causes of fever presents a common and challenging clinical problem. Although a significant proportion of fever and neutropenia episodes is associated with documented sources of infection, in many instances no specific source of infection can be identified. The number of patients at risk of infection continues to grow as the intensity and duration of chemotherapeutic regimens are extended. The spectrum of bacterial isolate has changed considerably over past four decades. In a review of various studies by European Organization for Research and Treatment of Cancer (EORTC) it has been shown that the pattern of micro-organisms isolated change almost every 2-3 years(1). Hence it is advisable to study the pattern of infections and causative organisms at an interval of 2-3 years. Knowledge regarding the locally prevalent infectious agents and their susceptibility testing helps considerably in preparing empiric antibiotic therapy and subsequent modifications according to the investigations. Most of the febrile episodes in the neutropenic patients can be treated successfully with early initiation of empirical anti-microbial therapy. Although administration of empirical antibiotic therapy(2,3) has now become a standard practice in the management of febrile neutropenia, there is still considerable controversy about the selection of an efficacious empirical anti-microbial regimen. Over the last ten years there has been only one study from Delhi on this subject(4). We, therefore decided to study the pattern of infections, their causative organisms and antibiotic sensitivity pattern in febrile episodes occurring in children admitted with malignancies. Subjects and Methods The study material comprised all children with malignancy and fever admitted in the Department of Pediatrics, Lok Nayak Hospital, New Delhi between January 1998 and March 1999. Forty-two febrile episodes developing in children of either sex aged below 12 years with malignanices were studied. The inclusion criteria were children of either sex who were diagnosed cases of cancer and developed fever defined as single temperature reading of > 38.5º C or a persistent fever (temperature reading of > 38º C) on at least three consecutive evalua-tions (at > 4 hours intervals) within 24 hours period. Exclusion criteria were: (i) developed fever and had received blood products in last 12 hours; (ii) developed fever within 24 hours after administration of chemotherapy and subsiding within next 24 hours after completion of chemotherapy. All the episodes were worked up in detail including their complete history, physical examination, hematolgoical profile, micro-biolgoical and radiological investigations as required. Bacterial cultures were done on routine Agar plate. Two ml blood was inoculated into bottles containing 20 ml of brain heart infusion broth. These were transported to microbiology laboratory where they were incubated at 37º C overnight. The next day subcultures were made from the broth into Blood Agar and macConkey medium and were incubated at 37º C overnight. If the plates showed growth, the cultures were identified. Fungal cultures were not done. After initial sampling, the patients were put on empiric antibiotic therapy as per the treating unit protocol. The antibiotics were modified on getting culture reports and assessing patients’ response. Table I–Absolute Neutrophil Count (ANC) and Febrile Episodes
Table II–Correlation Between ANC and Duration of Febrile Episodes
Results Out of the 42 episodes studied, 15 (36%) occurred in children with acute leukemias, 20 (48%) occurred in children with lymphomas and 7 (17%) were seen in children with solid tumors. Twenty six episodes (62%) occurred in children during chemotherapy, 5 (12%) in those who were freshly diagnosed, 6 (14%) were in relapse and 5 (12%) in remission. The categorized Absolute Neutrophil Count (ANC) of these febrile episodes is depicted in Table I. The ANC of each episode was correlated with the duration of the episode. ANC of < 1500 was seen in 21 episodes out of which 6 children with 8 febrile episodes died. The follow-up ANC of the remaining 13 episodes along with duration is shown in Table II. The ANC had increased to > 1000 at the time of subsidence of fever in all cases. The value of correlation coefficient obtained was r = – 0.21 (P > 0.05) indicating that as the ANC increased, the duration of febrile episode decreased. Table III–Febrile Episodes with Clinical Confirmation
URI - Upper Respiratory Infection UTI - Urinary Tract Infection *One each had P. Vivax and P. falciparum infection Table IV– Sites of Bacterial Isolates
All the febrile episodes were divided into the following 3 categories: (a) Microbio-logically confirmed episodes in 15 (36%). In these episodes organisms could be isolated from blood or from some other site, e.g., urinary tract, meninges, throat, etc.; (b) Clinically confirmed episodes in 15 (36%). In these episodes cultures were negative but site of infection could be localized by clinical or radiolgocial parameters (Table III); and (c) Fever of undetermined origin episodes in 12 (28%). These were identified when clinical and microbiologic evaluation failed to reveal a site or isolate, indicative of infection within the first 72 hrs of admission. The ANC of each episode was not significantly (P > 0.05) correlated with the above 3 categories of infection (analysis of variance). Seven per cent of episodes occurred in children who were severely neu-tropenic (ANC < 100). Half of the episodes occurred in children with ANC < 1,500 and remaining in those having ANC > 1,500. Regarding the organisms cultured from various sites, 15 (83%) isolates were Gram-negative and 3 (17%) were Gram-positive. Blood culture positivity was seen in 7 (17%) cases. The organisms and sites of isolation are shown in Table IV. The commonest Gram-negative organism was Klebsiella species accounting for 46% of the Gram-negative bacilli isolated. The antibiotic sensitivity pattern of the 3 most frequently isolated organisms (i.e., Klebsiella, E. coli and Pseudomonas aerugi-nosa) revealed ciprofloxacin sensitivity in 75% of Klebsiella isolates and 67% of E. coli isolates. Next to follow was amikacin - 50% in cases of both Klebsiella and E. coli isolates. Similar sensitivity (50%) was seen to cefotaxime in cases of both Klebsiella species and E. coli. Most of the patients showed good response. Out of the total 42 febrile episodes studied in 30 children, 8 (27%) children died while the remaining showed improvement. Thus there was good correlation between in-vitro sensitivity and clinical response. Antibiotics were given for variable periods according to patients’ response. Antifungal therapy was used in 12 episodes. Septicemia was the commonest cause of death (in 75% cases). In 6 (75%) fatal cases, children had an ANC of < 1,500/mm3 at the onset of fever. Discussion Septicemia in children with malignancy is still a frequent and life threatening complication, particularly so in developing countries. With the advent of empiric antibiotic therapy, the mortality rate in such patients has now shown a drastic reduction. In a similar study from AIIMS(4) on febrile episodes developing in children with leukemia, demonstrable leukemic activity was seen in 89.7% of the febrile episodes and just 10% when the disease was in remission. In our study also only 13% of the febrile episodes occurred when the disease was in complete remission. According to most of the studies(1-5), the crucial determinant for development of infection is neutropenia both by its degree and the duration. In our study also, 17(40%) episodes occurred in children with ANC < 1000/mm3. When the ANC of each episode was correlated with duration, the value of correlation coefficient obtained (r = -0.21) indicated that as the ANC increased, the duration of febrile episode decreased. On doing repeat ANC on day 3 and also subsequently it was observed that in all cases with neutropenia, the ANC was > 1000/mm3 when the fever had responded. Clinically confirmed cases of infection were seen in 36% of the febrile episodes in comparison to 21% in EORTC study(1). The higher prevalence of clinically confirmed infection in the present study could be due to the fact that thorough investigation for parasite, fungal (except Candida) and viral isolates could not be performed. Microbioloigcal evidence of infection has been reported in 30-40% of cases in earlier series(1,6). Our study also showed similar results where 36% of the episodes were microbiologically confirmed. In 2 patients, malarial parasite was seen in the peripheral smear and both these patients responded to chloroquine. Although malaria has not been reported from western studies in such patients, our finding stresses the importance of doing peripheral smear for malaria parasite routinely. Gram-negative infections were more commonly observed by us [15 (83%)]. This is in contrast to the recent Western data(7) which show Gram-positive infections to be the commonest organisms in such patients. In contrast to the earlier Indian study where E. coli was the commonest organism, the most common organism isolated by us was Klebsiella species. Most of the micro-organisms showed multiple drug resistance(8,9). Sensitivity to ciprofloxacin was seen in 75% for Klebsiella species and in 65% for E. coli. In comparison to gentamicin, a higher percentage of organisms were sensitive to amikacin (50% of Klebseilla species and E. coli). Pseudomonas aeruginosa, isolated in only 2 cases, was found to be sensitive to amikacin, ciprofloxacin, cefotaxime and piperacillin. Out of the total 30 cases studied, eight (27%) children died. In 6 (75%) out of 8 deaths that occurred, children had an ANC of < 1500/mm3 at the onset of fever. Septicemia was the cause of death in 6 (75%) cases. These figures show that infections during febrile episodes still carry a very high mortality (27%) in our set up. Based on this study now we recommend a combination of ciprofloxacin and amikacin for use as empiric antibiotic therapy in such children. Contributors: APD conceived the idea, co-ordinated the study and drafted the paper; he will act as the guarantor of the paper. DS collected and analyzed the data and helped in drafting the paper. SKP was responsible for the microbiological workup. Funding: None. Competing interests: None stated.
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