Developing countries lack necessary knowledge, medical practitioners, infrastructure, quality medications and finances which contribute to a shortage of accessible healthcare. There are no standard local protocols, guidelines or guidelines suited for low -income countries resulting in variability in practice and inferior patient out-come.
Sepsis is a major cause of non-relapsed mortality in patients with haematological cancers and has been shown to have 3-fold higher incidence of sepsis compared to general oncology patients (8, 9). Furthermore the average cost of hospitalisation due to neutropenic sepsis in patients with haematological malignancies is higher than in patients with solid tumours (10). It is a well recognised complication of chemotherapy and various measures were implemented to prevent this (11, 12).
Sri Lanka is a low-income country with heterogenous health care system. There are no local guidelines on prevention and treatment of neutropenia in Haemato-Oncology patients. Although there are international guidelines with recommendations, decision making in clinical practice is a challenge due to diverse population with varying comorbidities and health care facilities. Furthermore, there are no statistics or published data on response, survival or treatment related mortality in blood cancer patients in Sri Lanka.
Patients receiving chemotherapy for hematological malignancies have prolonged neutropenia and most patients experience at least one episode of neutropenic sepsis. Neshe L et al, showed bacterial infections generally occur during early stage of neutropenia (7 to 10 days) (13). In line with published guidelines, eighty five percent of patients in our cohort had more than one episode of sepsis while median time to neutropenia from chemotherapy was 9 days while onset of neutropenia to sepsis was 1 day.
Weyker D et al., showed the risk of febrile neutropenia during the chemotherapy regimen course was 16.8% (14). They analysed solid cancers and Non-Hodgkin Lymphoma (NHL). Thirty six percent of patient episodes with NHL in our cohort had neutropenic sepsis. In addition, the mean hospital stay in their study was 8.4 days. Comparatively, hospital stay in our study was 5 days while mean duration of neutropenia was 3 days in our cohort. However direct comparison was not possible due to heterogeneity of the patient population chosen to study.
Forty one percent of episodes of neutropenia in patients with acute leukaemia in our cohort had neutropenic sepsis compared to 35–48% in Acute Myeloid Leukaemia (AML) and 13–30% Acute Lymphoblastic Leukaemia (ALL) reported by others (15). However, it is not possible to differentiate the contribution by chemotherapy and disease towards neutropenia, particularly during the first cycle of chemotherapy in acute leukaemia.
Severe neutropenia (absolute neutrophil count of less than 0.1X109 / L) associated with increased risk of severe infections (16, 17). However, others have not seen a significant association between neutrophil count and severe infections (18). Three percent of episodes in this study in the group with chemotherapy related neutropenia had neutrophil count of less than 0.1X109 / L. There was a significant difference in the neutrophil count in the CINS group compared to CIN in this study. In addition, we could see a significant difference in hospital admission in the group with severe neutropenia.
Prevention as well as appropriate treatment of neutropenia and neutropenic sepsis are of great importance to maintain dose intensity and continuation of treatment according to schedules. In addition, there are medical, psychological, and financial benefits of staying home (19). It has been shown that in-patient management of neutropenic complications of myelosuppressive chemotherapy cost more than the cost of chemotherapy (20). Prophylactic antibiotics, neutropenic diet and growth factors are used to prevent patients progress to neutropenic sepsis as advised by guidelines from high-income countries (21, 22). However data from clinical trials may not be representative of real-world scenarios and may be not applicable to wider population (23).
We used Ciprofloxacin prophylaxis in all patients when the neutrophil count was below 1X109/L. We were aware that that the risk of gram-negative blood stream infections with quinolone resistance is on the rise and this may be due to higher ciprofloxacin usage in haematology (24). However we considered all patients in LHBCC as high risk due to heterogenous nature in health care facilities available, uncertainty about out-come due to lack of published data, diverse socio-economic status. In addition substantial financial implications due to admissions to a self-financing hospital in Sri Lanka also a factor considered in implementing stringent preventive measures.
Nucci M et al, showed that Itraconazole prophylaxis reduces the frequency of systemic fungal infections and use of empirical amphotericin B in a double-blind, randomised, placebo-controlled study (25). In line with their findings we had no proven fungal infections and used amphotericin B on no patients during the study period.
Use of Colony Stimulating Factors (CSF) is recommended when the risk of CINS is 20% or greater but there is a variability in the start time and duration of CSF (23). We used CSF in all patients with non-myeloid malignancies with CIN. Wider use of CSF in our centre is not in line with and may be inappropriate according to studies and guidelines from high-income countries. However we believe ‘appropriateness’ should be assed according to cost effectiveness, expertise and facilities available locally. Also similar data is reported in the real-world practice by others (26) and National Comprehensive Cancer Network (NCCN) guidelines advocate wider use of colony-stimulating factor (27).
Fresh fruit and vegetables contain gram negative bacilli that can cause life threatening infections (28, 29). However subsequent studies have documented that neutropenic diet given in the belief that it can prevent infections has no effect (30). We allowed only well-cooked food in neutropenic patients in LHBCC. Once again, it is questionable how applicable studies done in high-income countries are in the local setting where differences exist between sanitary practices including disposal of human waste and access to safe drinking water.
Gram-negative coverage in neutropenic sepsis has evolved from beta-lactam plus aminoglycoside to single agent broad spectrums such as Cefepime, Piperacillin-Tazobactam and Carbapenems (31). However the applicability of recommendations from high-income countries in the local setting is questionable. We used nurse-led first dose with dual anti-gram-negative antibiotic treatment policy in suspected or proven neutropenic sepsis. We used Piperacillin-Tazobactam and aminoglycoside combination as preferred empirical antibiotic regimen. Our policy to offer dual gram-negative cover is mainly driven by availability of facilities. We did not have specialised trainees but patient care was covered by generalists. Cost of treatment in intensive care is substantial in self-financed hospitals and bed availability in the government subsidised centres is limited. In a country with heterogenous heath care system and sparse resources, we considered it is safer to start dual-antibiotic therapy and change over to single agent or oral therapy once patients were stable.
Guarana et al., 2019 reported shock or early death was mainly due to gram-negative infections but was not associated with gram-positive bacteremia; catheter-related, skin, or soft tissue infection; or inadequate gram-positive coverage (32). Despite stringent preventive measures and emphatical use of antibiotics neutropenic sepsis carries a high mortality which can range from 2–21 % (33) and is higher in adults compared to children (34). Ghosh S et al, has shown a mortality rate of 19.5% in an Indian study running over one year (35). They have used single-agent cefepime or piperacillin-tazobactam/tigecycline combination as empirical agents. Thirty seven percent of neutropenic episodes in our cohort ended up as in-patients due to sepsis. There were 3 deaths during the study period and two were related to disease related neutropenic sepsis (2/52 episodes) and one non-neutropenic sepsis (1/16 episodes). However no deaths were reported due to post chemotherapy sepsis during the study period.
It has previously been shown the effect of giving antibiotics within an hour in reducing morbidity and mortality in haematological cancers. Rosa R et al, showed time to antibiotic administration is independently associated with 28-day mortality (36). They have shown starting antibiotics within 30 minutes has a lowest mortality compared to 31 to 60-minute group and each increase in 1 h has increased the 28-day mortality by 18%. We had a median time to antibiotics (TTA) of 20 minutes which was within the acceptable range compared to other studies. Ali N., et al., published a study in 2015 about the compliance of 1 hour for TSA (37). They had a median TTA of 45 minutes (range ± SD: 10 minutes to 6 hours ± 1 hour 10 minutes). There were long delays particularly over week ends. Our data did not show a significant difference over week -ends or out-side standard working hours (p-value 0.78). We had an admission policy where patients were admitted directly to the Haemato-Oncology ward, by-passing the busy multi-disciplinary single emergency unit of the hospital. A stock of antibiotics was kept on the ward and nurses were trained to immediately treat with empirical antibiotics for suspected or proven neutropenic sepsis even before medical review over the phone advice.
Median antibiotic days and median hospital stay were 4 and 5 days respectively in CINS in LHBCC. We continued antibiotics till the neutrophil count was above 1 in CINS but stopped it once sepsis settles in DINS. Median duration of neutropenia was 3 days in CINS and 2.5 days in CIN group. Several studies have shown that intravenous antibiotics can be stopped before neutrophil count recovers above 1(38, 39). Social circumstances in Sri Lanka are different to those in high-income countries and the cost of prolonged treatment self-financing hospital is substantial. Guidelines from high-income countries does not take facilities, expertise, epidemiology of organisms or financial impact of treatment in to account. We were guided by Western guidelines but with appropriate changes taking in to account facilities available locally.
Understanding the epidemiology of bacterial infections enable in prevention and effective treatment (40). An infectious etiology is only identified in 40–50% of neutropenic fevers, with 10–30% having bacteremia (41, 42). We continuously investigated incidence of infections in the LHBCC to understand the changing spectrum of organisms and their antibiotic sensitivity. We had bacteraemia only in 4 out of 89 cultures performed during the study period (4%). It has been reported that positive microbiological detection can vary considerably depending whether they are on antibiotic prophylaxis or not (43). As reported by Klastersky J et al., in a trail in patients with haematological malignancies, 17% in the group given prophylaxis compared to 31% the group with no prophylaxis had positive microbiological detection. The incidence of culture positive episodes of sepsis among our patients are lower than reported elsewhere. However as authors highlighted in the study by Carvalho A et al, variability in reporting of rates makes comparison difficult and there is a need for reporting standardization (44).
The success we encountered may reflect staff and patient awareness and commitment. Clear guidelines, improved communication and strong leadership are necessary to prevent early deaths. Having a resident clinical haematologist experienced in managing neutropenic sepsis, system for rapid clinical evaluation, facilities for intravenous administration of antibiotics, close monitoring of patients for medical complications may have contributed in the lowering mortality.
This is a limited study and further studies are needed over a longer period prior to reaching more definitive conclusions. In addition, we understand the importance of continuously assessing the risks and benefits of the practice and deviations from guidelines from the Western world. Furthermore, we may have to use single agent piperacillin tazobactam and also rotate it with cefepime to reduce emergence of resistance to aminoglycosides as reported by others (45).