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ORIGINAL ARTICLE
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Retrospective analysis of 34 febrile neutropenia episodes - therapeutic implication of multiplex polymerase chain reaction in infection diagnosis


1 Department of Hemato Oncology, BGS Global Gleneagles Hospital, Bengaluru, Karnataka, India
2 Department of Clinical Research, XCyton Diagnostics Pvt. Ltd., Bengaluru, Karnataka, India
3 Department of Pharmacy Practice, BGS Global Institute of Medical Sciences, Bengaluru, Karnataka, India
4 Senior Consultant Oncologist and Radiotherapist, National Cancer Institute, Sri Lanka

Date of Submission25-Dec-2018
Date of Decision14-Apr-2019
Date of Acceptance21-Apr-2019
Date of Web Publication16-Jul-2021

Correspondence Address:
Sachin Jadhav,
Department of Hemato Oncology, BGS Global Gleneagles Hospital, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_835_18

PMID: 34380857

  Abstract 


Background: Hemato-oncologic patients on chemotherapy or undergoing bone marrow transplantation are susceptible to infections due to neutropenia. Incidences of febrile neutropenia (FN) in these patients are common, contributing to high mortality and morbidity. Lack of diagnosis of pathogens responsible for infections in these patients is a major healthcare challenge. Newer molecular diagnostics are increasingly becoming relevant. The objective of this retrospective study was to evaluate the effectiveness of Syndrome Evaluation System (SES), a multiplex molecular diagnostic platform for diagnosis of pathogens, and its impact on the management of FN.
Methods: In total, 34 neutropenic episodes from 21 patients admitted during September 2013 to April 2015 were analyzed in this study. Clinical samples from patients were tested on SES and routine culture. Treatment was as per standard of care.
Results: SES showed a 5-fold higher clinical sensitivity (55.9%) as compared to automated culture (11.1%). SES results were available within 14 hours as compared to >72 hours for culture, and elucidated change in antimicrobial therapy in 50% of episodes. Mortality rates were lower when SES was used early in the episode. De-escalation of antimicrobials according to SES results was possible, which translated into substantial cost saving.
Conclusion: Newer non–culture-based molecular technologies like SES are changing the way we manage FN. It is faster, has a higher diagnostic yield as compared to traditional culture, and helps in making rapid, evidence-based therapeutic decision-making including de-escalation of antimicrobials. It would potentially lead to a reduction in mortality and healthcare cost in the long run.


Keywords: Bone marrow transplantation, febrile neutropenia, hemato-oncology, Leukemia, molecular diagnostics, syndrome evaluation system
Key Message: Multiplex molecular diagnostics for infections overcome challenges of low clinical sensitivity and delay in blood cultures. In febrile neutropenia, it is faster, more sensitive, actionable, and cost effective.



How to cite this URL:
Jadhav S, Rajashekaraiah M, Chakraborty D, Bharath N, Sharieff SU, Vignesh G, Gandhamaneni K, Pasupuleti B, Thomas P, Balawardhana J. Retrospective analysis of 34 febrile neutropenia episodes - therapeutic implication of multiplex polymerase chain reaction in infection diagnosis. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=321675





  Introduction Top


Infections are a leading cause of death in cancer patients, with febrile neutropenia (FN) resulting in 9–11% mortality in hematologic malignancies.[1],[2],[3] Approximately, 80% of patients with hematologic malignancies and 10–50% of patients on solid tumor chemotherapy develop one or more episodes of FN, a major risk factor for developing infections.[4],[5] Patients experience prolonged neutropenia, making them susceptible to different episodes of infections at different phases of the treatment. It is also a major cause of morbidity, cost and compromised efficacy, and outcomes of chemotherapy.

Lack of diagnosis of the causative pathogen and the use of empiric therapy contribute to this high mortality rate. Initial empirical antibiotic regimen frequently requires modifications in the absence of specific identification of the pathogen. Prolonged use of high-end antimicrobials leads to increased resistance and toxicity.[6] This impacts overall chemotherapy treatment plan, resulting in dose reductions, treatment delays, chemotherapy discontinuation, longer ICU and hospital stay, increased cost for therapy, risk of nosocomial infections, etc.[7],[8],[9],[10],[11] Blood culture positivity ranges from 15–20% and takes 24–72 hours for actionable reports. Detection of viruses and fungal species remains a challenge.[12],[13] In a hemato-oncology setting, in spite of multiple repeat cultures, answers are hard to come by. This is a rather helpless and unique situation where life-threatening infection in a highly susceptible patient population has to be treated empirically.

Multiplex polymerase chain reaction (PCR) has been used for the detection of pathogens in FN patients.[14],[15],[16] It has shown to be useful in fungal detection.[17] Real-time PCR has improved detection of bacteria associated with high-risk FN episodes.[18],[19] Real-time PCR in combination with blood culture improves microbiological documentation of FN episodes.[20] However, most of the molecular methods suffer from issues of cross-reactivity and lack of specificity owing to amplification of common housekeeping genes by universal primers.

Syndrome Evaluation System (SES) is a rapid, multi-pathogen molecular diagnostic platform. SES amplifies virulence-specific genes rather than housekeeping ones, thereby ensuring the detection of a true pathogen. SES FN panel looks for 5 Gram-positive bacteria, 10 Gram-negative bacteria, 2 fungal species, and 8 viruses. SES also detects common antibiotic resistance markers such as CTXM1 and CTXM2 conferring resistance to 3rd and 4th generation cephalosporins; KPC, NDM1, VIM, NMC, OXA-23, IMP, and OXA-58 for carbapenems; Van-A and Van-B for vancomycin and teicoplanin; and Mec-A for methicillin. It is routinely used in our department for etiological diagnosis of critical infections. SES has been shown to increase etiological diagnosis of adult septic patients as compared to traditional methods and thereby aid in de-escalation of unnecessary empirical antibiotics.[21]

In this retrospective analysis, we have analyzed the impact of SES in the etiological diagnosis and the subsequent impact on patient management in FN. To the best of our knowledge, this is the first systematic study done in India on the diagnosis of infections in febrile neutropenic bone marrow transplant patients or hemato-oncologic patients on chemotherapy, using a multiplex PCR based diagnostic test.


  Materials and Methods Top


This retrospective chart review was conducted in the department of Hematology at BGS Gleneagles Global Hospital, Bangalore, India. Systematic data collection and analysis were done for patients admitted during the period from September 2013 to April 2015. These patients were admitted in our hospital for the treatment of leukemia, myelodysplastic syndrome, and aplastic anemia and some of them underwent bone marrow transplantation. The study was approved by the Institutional Scientific Advisory and Ethics Committee. Inclusion criteria for patients included suspicion of infection due to a febrile spike post-BMT (Bone Marrow Transplant) or chemotherapy. FN is defined as per standard Infectious Diseases Society of America (IDSA) guidelines.[4] Data were collected for those patients where blood or any other focal specific sample was sent for SES. Scientifically, for the purpose of concordance between SES and culture, we considered different aliquots of the same sample tested by both the methods. However, multiple blood and other body fluid cultures were done additionally during the hospitalization episode for each patient. To better understand the effectiveness of pathogen identification by these two methods, we also collected data from culture reports tested within ± 5 days of testing on SES, as a part of routine protocol. Two milliliter of blood (28 samples) or other focal specific samples such as Bronchoalveolar Lavage (BAL), Cerebro Spinal Fluid (CSF), pleural fluid, pus (1 each), and nasopharyngeal wash (2 samples) were aseptically collected and sent to XCyton Diagnostics' central laboratory at Bangalore to perform SES FN panel test [Table 1] as a part of our battery of investigations. SES was not necessarily done on the first suspicion of an infection. Routine blood culture was performed at the hospital laboratory using BACTEC™, automated blood culturing system from Becton & Dickinson. Patients with FN who did not undergo testing with SES were not included in the study. Treatment was according to IDSA guidelines adapted to the local microbiological sensitivity patterns.
Table 1: SES febrile neutropenia panel

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SES is a three-step diagnostic test offered as a service to hospitals across India from the central laboratory of XCyton at Bangalore, India. It involves nucleic acid extraction, nucleic acid amplification, and sequence specific hybridization, as described by Bhat et al. and Ramalingam et al.[22],[23] The primary aim of the study is to compare conventional culture systems and SES in terms of detection rate of pathogens. We also analyzed the impact of SES in elucidating a change in the management of patients, outcomes (mortality), usage of antimicrobials, and the financial implications of these.

Descriptive statistics was used to analyze qualitative and discrete variables. Two-tailed Z-tests were conducted to test significance between two variables. We considered P value of less than 0.05 as statistically significant correlation between two variables. Mean values are presented with standard deviation.


  Results Top


Thirty-four FN episodes were analyzed. These episodes were recorded from 21 patients (15 Males, 6 Females, and Mean age 42 ± 20 (Range: 6-73) years]) involving 27 episodes of hospitalization. The demographics and underlying hematological condition of these patients, their microbiological diagnosis, change in antimicrobial therapy, and outcomes have been tabulated in [Table 2].
Table 2: Hematological condition, microbiological diagnosis, change in antimicrobial therapy, and outcomes in FN episodes

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In 7 patients, there were multiple FN episodes. Mean hospital admission duration for these FN episodes was 13.15 ± 10.03 (Range: 1-43) days (Median 12 Days). SES was done for each FN episode. Details have been mentioned in [Figure 1].
Figure 1: Febrile Neutropenia episodes of 21 patients. SES: Syndrome Evaluation System

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Microbiological results

In 34 FN episodes, 152 routine cultures were done. Twenty-seven cultures among these 152 were done on the same day as SES. These 27 cultures include 19 blood, 1 BAL, 1 CSF, 2 nasal swabs, 1 pleural fluid, 1 urine, and 2 pus. Remaining 125 cultures were done within ± 5 days of SES testing for the same episode, out of which, 86 were blood cultures. Overall, 21 samples were positive in 152 cultures, yielding a clinical sensitivity of 13.8%. Among the 27 cultures used to analyze for concordance with SES, 3 of them were positive, yielding a clinical sensitivity of 11.11% for this subset. SES was done for all 34 episodes. Nineteen cases were positive, and 15 cases were negative. The clinical sensitivity of SES was 55.9%.This difference is statistically significant (P = 0.0003).

The routine culture was positive for 3 cases out of 27 used in this analysis. One of them was positive for Salmonella typhimurium in both SES and culture. SES also detected cytomegalovirus (CMV) in the same sample. In the 2nd case, SES detected Pseudomonas aeruginosa and Epstein-Barr virus (EBV) in blood while culture grew E. coli from a pus sample. The 3rd culture positive case grew Burkholderia cepacia from blood sample. This organism does not feature in the SES FN panel. However, SES detected CMV in blood for this patient. Details of microbiological comparison between SES and blood culture has been described in [Figure 2].
Figure 2: Comparison of syndrome evaluation system (SES) and blood culture results; FN: febrile neutropenia

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Each of the three routine culture positives was unimicrobial in nature. The rank order of organisms detected by SES is mentioned in [Figure 3].
Figure 3: Rank order of organisms detected by syndrome evaluation system (SES); CMV: Cytomegalovirus; HSV: Herpes Simplex Virus; EBV: Epstein–Barr Virus; CoNS: Coagulase-negative Staphylococci; HHV6: Human Herpesvirus 6

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Eight out of the 19 SES positives (42.1%) detected polymicrobial infections. The average time to results from a sample drawn to receiving SES report was 14 hours. The laboratory processing time of SES is 7 hours. Culture reports were available after 48 hours.

Antimicrobial usage and change in management

SES results elicited change in the antimicrobial therapy from the initial empirical choice of antimicrobials for 50% of the FN episodes. This includes both escalation (76% of the changes elicited) and de-escalation (47% of the changes elicited). There were 4 cases where both escalation and de-escalation were done for the same patient. In terms of usage, the major antibiotics were meropenem, teicoplanin, colistin, and piperacillin plus tazobactam combination. Apart from these, there were 9 and 14 cases where antiviral (acyclovir and gancyclovir) and antifungal (posoconazole, fluconazole, and voriconazole) drugs were administered, respectively. In 8 cases, we had started antifungals depending on Candida or Aspergillus reported by SES. In one case, fluconazole was changed to voriconazole, whereas meropenem and colistin were stopped owing to Candida reported by SES. In 9 cases, we had started antivirals depending on HSV, HHV6, EBV, and CMV reported by SES. In 2 cases, we had stopped antivirals according to SES being negative for viruses. In 8 cases we do not have medication history records. For the rest of the cases, we have records of 6 cases of antibiotic de-escalations, similar to the case mentioned above. There was no fungal detection by blood culture. Changes in antimicrobial therapy were instituted at least 36 hours prior to receiving the culture report because SES results were available to us within a day. All the 29 FN episodes of survival were indicated by afebrile status of the patient along with normalization of routine clinical and laboratory parameters such as C-reactive Protein (CRP), Procalcitonin (PCT), etc. Repeat SES to confirm the resolution of infection in the same FN episode was not done for any patient.

Episode outcome

There were 5 deaths in this study. The mortality rate was 14.7%. The reasons for these deaths were (i) acute interstitial pneumonia, Hodgkins lymphoma, and pulmonary fibrosis; (ii) septic shock; (iii) cardiorespiratory arrest; and (iv) relapsed, refractory, rapidly progressive multiple myeloma with septic shock. Four out of these 5 deaths were positive on SES. Three out of these 4 SES positive cases had polymicrobial infections, whereas the 4th case had Candida. The 5th patient who died was negative on SES. He had AML and dengue fever.

SES test results and patient outcomes – Early or late into the episode

We have stratified the data according to which day in the episode of FN was a sample sent for SES. The clinical sensitivity of SES remained the same even late during the episode of FN. However, 4 out of 5 deaths were in cases where SES was used after at least 11 days of an ongoing FN episode. The 5th death in this study was when SES was used after 6 days of an ongoing FN episode. Details have been represented in [Figure 4].
Figure 4: Timeline of syndrome evaluation system (SES) tests and corresponding outcomes

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Multiple SES tests from different FN episodes on samples from same patient

There are 4 cases wherein SES tests were done multiple times for same patients either during the same hospitalization episode, or different hospitalization episode, depending on the febrile spike triggering suspicion of infection. In all these cases, SES was repeated at least after 7 days. We have seen a clearance of the organisms/s detected in the first instance by SES upon antimicrobial therapy. These include clearance of pathogens such as Pseudomonas aeruginosa, E. Coli, Staphylococcus aureus, HSV, Candida, and Acinetobacter baumanii. However, there was 1 case of Klebsiella pneumoniae, which was detected by SES even after the repeat test after 7 days but was not detected when we repeated the test after 15 days. SES detected different organism/s in subsequent tests.

Economic impact of SES based change in therapy decision

There are 8 antimicrobial de-escalations on the basis of the SES results. These were possible owing to SES reports and not culture results. They include de-escalations of high-end antibiotics such as meropenem and colistin and antivirals such as acyclovir. All these 8 cases of de-escalation resulted in episode resolution. These de-escalations led to a total cost saving of 7,84,500 INR for these 8 cases. The average cost saving for these 8 patients is 98,062 INR (±66077; Range 25200–238000; Median 93600). This economic impact is calculated on antimicrobial costs only and is strictly restricted to our hospital setting. Details have been described in [Table 3].
Table 3: Economic impact of SES based antimicrobial de-escalations

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  Discussion Top


Comparison with culture

Blood culture, considered as the gold standard in the microbiological diagnosis of bloodstream infections, suffers from lack of rapidity and sensitivity. Multiplex PCR directly from blood has been suggested as a promising method for rapid identification of pathogens causing sepsis. Unfortunately, most of these multiplex molecular methods suffer from low clinical sensitivity and lack of concordance with culture results owing to the amplification of common housekeeping genes as the primary technology. Guido et al., Idelevich et al., and Mitsuda et al. reported microbial detection rates of 22.9%, 26.5%, and 7.5%, respectively using multiplex molecular diagnostics in FN patients.[24],[25],[26] In our study, we report a detection rate of 55.9% by SES. The clinical sensitivity of culture in our study is 11.11% for 27 cultures, a subset of data used to compare with SES results. This is a 5-fold increase in detection rate by SES as compared to automated culture. Additionally, we have done 125 cultures within a period of 5 days of testing with SES, wherein 18 were positive, yielding an overall clinical sensitivity of 13.8%. SES has 4-fold higher detection rate compared to this overall culture sensitivity. In a hemato-oncology setting, this is a helpless situation. Doing 152 cultures for 34 episodes, in a span of 10 days with an average yield of only 13.8% neither help in improving outcomes, nor in reduction of healthcare costs. SES has been previously shown to have four times the detection rate when compared to automated blood culture in neonatal sepsis.[22] SES was concordant with culture findings (Samonella typhimurium) for 1 out of 2 samples, where blood sample was simultaneously drawn from the patient. The 2nd blood sample grew Burkholderia cepacia, which is not a part of SES panel. In the 3rd case, SES result expectedly differed as the clinical specimen drawn (blood versus pus) was different. Most importantly, SES could detect pathogens in 66% of culture negative samples (16 out of 24), thus giving us vital leads for potential evidence-based change in antimicrobial therapy within 14 hours.

SES detected at least one fungus in 8 samples out of 19 positives (42%), at least one virus in 8 samples (42%), at least one Gram-negative bacteria in 8 samples (42%), and at least one Gram-positive bacteria in 4 samples (21%). In terms of rank order of organisms detected by SES, Candida species topped the list. Teixeira et al. reported a prevalence of 36% of Candidiasis detected by multiplex PCR in FN patients.[17] Our findings are in line with this.

Polymicrobial infection

SES detected polymicrobial infection in 42.1% of its positives. Kenneth et al. reported the prevalence of 15% polymicrobial infections in immunocompromised patients suffering from cancer, whereas Gupta et al. reported 47.8% polymicrobial infections in FN patients, both in culture.[27],[28] Polymicrobial infections in FN patients are common because of two factors. First, in addition to neutropenia, patients who receive cytotoxic therapy experience mucosal barrier injury or mucositis, resulting in breach and subsequent invasion of multiple bacterial species into the bloodstream.[29] Second, due to extreme immunosuppression, secondary infection, mostly nosocomial, gets superimposed on primary infection. In fact, bombardment with multiple broad-spectrum antibiotics due to lack of diagnosis of causative pathogen, rather than a targeted therapy, aggravates this situation. Unfortunately, culture has a limitation in detecting polymicrobial infection owing to two reasons. First, empiric antibiotics damage viable bacteria to varying degrees, making them non viable to grow in a culture medium. Second, even if bacteria are viable, superseding infections outgrow them, rendering culture results unimicrobial in nature. In essence, treatment with multiple broad spectrum antibiotics does not seem to help. Tests like SES can detect nucleic acid content from both viable and non viable (damaged by antibiotics) bacterial cells responsible for an ongoing episode of infection, thereby increasing the diagnostic yield. The knowledge of the presence of bacteria by virtue of the detection of their genetic material is an extremely helpful tool to make an informed therapeutic decision in FN patients.

Change in antimicrobial therapy

In our study, SES results elicited a change in antimicrobial therapy in 50% of the FN episodes. In a randomized controlled study on multiplex PCR in FN patients, Idelevich et al. reported 9.5% PCR induced antimicrobial therapy change in the study group, with no statistically significant difference with the control group.[25] This included one case of antibiotic de-escalation. In our study, out of the 50% of episodes (17 episodes) where SES results elucidated a change in antimicrobial therapy, 76% (13 episodes) and 47% (8 episodes) were escalations and de-escalations, respectively, with 4 cases where both escalations and de-escalations were done for the same patient. This is a very important finding in our study. Owing to the high-negative rate of culture, it did not induce any actionable therapeutic change in antimicrobials. Among the 3 culture positives, there were neither escalations nor de-escalations. However, SES results induced both. We continued to treat SES negative cases empirically because clinical parameters suggested the presence of an infection. Our interpretation of SES negatives among these FN cases is that the infection is either due to extremely low bacterial load below the limit of detection of SES, or organisms not detected by SES test. Hence, we did not de-escalate antibiotics from negative results in SES. At the same time, we did not escalate antimicrobials in SES negative cases.

Mortality

We report an episode mortality rate of 14.7% in this retrospective study. Kuderer et al., Gupta et al., and Matilde et al. reported mortality rates of 9.5%, 12%, and 18.5%, respectively in patients with FN.[2],[28],[29],[30] The fact that SES was positive in 4 out of 5 deaths establishes our belief that severity of infections increases mortality in FN patients. In fact, 3 of these 4 SES positive cases were polymicrobial in nature, whereas the remaining 1 was Candida infection, which confirms the same hypothesis. SES negatives have earlier been associated with no deaths in neonatal sepsis, pointing out to >98% Negative Predictive Value (NPV).[22]

Impact of early diagnosis of pathogens on mortality

We had stratified the data on the basis of which day in the episode of FN was a sample sent for SES. The reason for doing this is to analyze our evolving practice of using molecular diagnostics. During 2013 and early 2014, we used SES only after traditional cultures were negative. It is only after initial days that we gradually started to use SES early, in order to allow for enough time to make a change in the antimicrobial therapy, so that it can potentially improve the patient outcome. Although the detection rate of SES was unaltered, the delay in doing the test increased mortality. Approximately, 80% of the deaths were in episodes where the clinical sample was tested in SES after at least 11 days into the FN episode, whereas the remaining 20% was after at least 6 days. The mortality rates came down after we started to use this test within 5 days into the FN episode. The fact that there are no deaths when SES is done within 5 days of an FN episode supports our evolving practice of early intervention according to advanced molecular testing. It is known that FN patients have an impaired inflammatory response wherein infection can occur with minimal signs and symptoms and progress rapidly. Often, fever constitutes the only isolated sign in these patients. In the absence of classical signs and symptoms of sepsis, these febrile spikes should be considered as a real medical emergency and tested for the causative pathogens. Early recognition of pathogens responsible for FN is critical to initiate targeted antimicrobial therapy to avoid progression to sepsis and possible death. Treatment depending on SES results has been shown to reduce mortality in neonates suffering from sepsis by 5-fold, apart from reduction in the usage of antibiotics and reduction in hospital stay.[22] Empiric antibiotics are simply not good enough because the choice of these drugs and their coverage spectrum is traditionally depending on less than 15% of culture-positive data. This is further complicated by the high prevalence of antibiotic-resistant bacteria in our country.[31]

Multiple tests for same patients

Results of repeat SES tests for different FN episodes in the same patient suggest that subsequent febrile spikes were probably caused by nosocomial infection. Pathogens detected by SES in the first instance were cleared upon treatment in subsequent tests, with different organisms being detected in subsequent febrile spikes. In addition to nosocomial infections in neutropenia, disruption of mucociliary barriers, extensive use of invasive devices, and shift in inherent microbial flora due to prolonged antimicrobial usage predispose these patients to infection.

Cost implications

Cost of antimicrobial therapy often contributes significantly to the overall cost burden in a hemato-oncology setting. Pharmacoeconomic studies have estimated that the cost of each FN event varies between US$ 2000 and US$ 11000. According to Canadian and British studies, 25.8% of this cost is related to antibiotics. It is further estimated that about US$ 5000 can be saved per FN episode when the patient can be discharged early and followed-up as an outpatient. The use of orally instead of intravenously administered antibiotics reduces the cost by about 80%.[32],[33],[34] In our study, we report a reduction in antimicrobial associated healthcare cost burden. For 8 episodes (23.5% of the total FN episodes) where we could de-escalate antimicrobials, we could reduce, on average, 1,485 US$ (INR 98062) on antimicrobial usage. We had started empirical antimicrobials as per our treatment protocol, but stopped antimicrobials solely according to SES results, thereby reducing unwarranted antimicrobial usage, which in turn leads to cost saving and reduces toxic side effects. We achieved 100% episode resolution in all these 8 cases. We are currently evolving a practice of outpatient ambulatory day care follow-up for our bone marrow transplant patients, which we believe, would result in significant cost savings. We are recording the data in our ongoing prospective study.

Limitations

We believe this is the first study on the impact of molecular diagnostics in the management of infections in FN patients in India. However, this being a retrospective study has its limitations in terms of low sample size, lack of control group, study design rigor, and data lost to follow-up. Therefore, to improve upon these shortcomings, we are currently conducting a prospective study involving more than 100 episodes in our department. We aim to analyze additional endpoints in terms of clinical and pharmacoeconomic parameters as well as the evolution of new management guidelines for our patients with FN.

Financial support and sponsorship

Nil.

Conflicts of interest

Mr. Dipanjan Chakraborty, Head, Clinical Research and Mr. Bharath N, Manager-Data management and Analytics are affiliated to XCyton Diagnostics Pvt. Ltd. where SES testing has been performed. Hence, there may be a potential conflict of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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