Prevalence of Infectious Complications in Children with Cancer

Background: Infections are the most common complications during chemotherapy. The trends have been changing over time due to use of multi-agent intensive chemotherapy. Procedure: We looked over our data to see what complications we get in our patients. The data was collected on patients treated in King Fahad Medical City from July 2009 to Dec 2015. Results: We found that 86 patients had one episode only while 92 had 2 or more episodes reaching up to 11 episodes in 1 patient. We found positive cultures in 17.3% of episodes with staphylococcus as common gram positive and Klebsiella pneumoniae as common gram negative bacteria, respiratory viral infections in 13.8% and GI infections in 9%. We found Candida albicans as the most common fungus while other yeasts followed. Acute lymphoblastic leukaemia was the most common diagnosis. The episodes were associated with neutropenia of 7 days in 1st episode and 56.8% in cases with repeated episodes. We had 2 deaths one from recurrent infections with CNS (Central Nervous System) damage and one from Pulmonary infections causing pulmonary haemorrhage. We had one with persistent neurological sequele from prolonged fungal infection. Conclusions:Neutropenia of 7 days came out to be significant risk factors for infection across all diseases. We have an acceptable level of morbidity and mortality due to good supportive services. We need prospective studies to get an up-to-date picture of our practice. We need prophylactic antibiotics and antifungals for high-risk patients like AML.


Introduction
Infections have caused significant problems in patients with neutropenia over time as the survival improved in cancer due to better and intensified treatments [1]. Life-threatening complications due to bacterial infections have been reported in a significant percentage of febrile episodes in children with cancer [2] [3]. From 1960s to 1980s, aerobic Gram-negative bacilli were the major cause of infection in the neutropenic patient [1]. Schimpff et al. [4] have reported that aerobic Gram-negative bacilli were involved in approximately 60% -80% of the microbiologically proven infections, with P. aeruginosa being a leading isolate and S. aureus was the most important gram-positive isolate. Later, in the mid-80s, the spectrum of organisms causing infection began to change. A steady increase in Gram-positive infections occurred until presently, 60% -70% of bacteremia's with a single organism identified are caused by Gram-positive cocci [5] [6] [7]. Coagulase-negative staphylococci and S. aureus are the predominant organisms. This change from Gram-negative to Gram-positive organisms is due to many factors important among them include aggressive chemotherapeutic regimens causing more severe mucositis, protracted course of neutropenia, almost uniform use of centrally placed catheters, use of Histamine receptor 2 antagonists and use of prophylactic antibacterial agents with relatively weak coverage of Gram-positive organisms [8]. In addition to this the move from Gram-negative Koskenvuo et al. [11] documented the presence of respiratory infection in 44% of the cases of children and adolescents with leukaemia and fever, and Srinivasan et al. [12] observed rates of 75% in their study.
Another important cause of mortality in children with cancer is the invasive fungal infection, especially haematological disorders, who undergo high dose chemotherapy or bone marrow transplant [13] [14] [15]. One of the most common infections is invasive aspergillus's but we also see other non-Aspergillus fungi being increasingly reported [16]. This increase in the incidence of invasive fungal infections in children appears to have increased over the past few decades, due primarily to the prolonged survival of children with immune deficiency syndromes [17] [18] [19].
There are few studies from Middle East and Saudi Arabia showing the same trends but the number is very small and one study looked at only bacterial isolates [20] [21].
Prophylactic antibiotics and antifungals have been shown to reduce the number of episodes of febrile neutropenia and severity of infections especially in cases on intensive chemotherapy and in post-transplant patients [22].
The primary objective of this study was to collect data about our patients to form Middle East and specifically from Saudi Arabia. Also, we wanted to see the effect of the strength of chemotherapy on the trends and to recognize those patients or diseases that will benefit from prophylactic antibiotics and antifungals.
This will also help us plan our antibiotic and antifungal policies and reduce the burden on the healthcare system by reducing infection rate and admission rate so reducing hospital days.

Aims and Objectives
Primary: To study the prevalence of infections during chemotherapy in our centre as compared to other centres and devise ways to improve it. Secondary: To see the effect of degree and duration of Neutropenia on the rate of infection Inclusion Criteria:  All patients from 0 -14 years who received chemotherapy at KFMC presenting with fever or positive culture in cases with suspected sepsis. Exclusion Criteria:  Patients who have comorbidities which predispose to infections e.g. immunodeficiency, down syndrome.

Materials and Methods
The data was collected on patients treated (completed treatment) in King Fahad Medical City from July 2009 to Dec 2015. Any patient presenting with a fever of 37.8˚C on 2 occasions 30 minutes apart or one episode of 38˚C or a positive culture reported in a child with suspected sepsis presenting with other symptoms i.e. diarrhoea, vomiting, flu, etc. Neutropenia was defined as ANCas < 1500 (mild), <1000 Moderate, <500 as severe and <200 as very severe. Duration of Neutropenia of <7 days as mild, 7 -14 days moderate and >14 days as prolonged. The common antibiotics used were Piptazobactam, Amikacin, Vancomycin, Meropenem, Clindamycin, etc. Patients were screened for fungal infections after 5 days of unresolved fever with CT chest, abdomen and pelvis and in some cases with chest x-ray and Ultrasound of the abdomen. The collection of data was from patient files, Hospital Information Management system, CORTEXX (hospital management system) and patient road maps. Specific forms were used for the collection of data by one person and then uploaded on spreadsheets by another so to make sure data is checked by 2 people. Deficient data was rechecked with patient file. The data was analysed, and results compiled which was then compared with other international groups. A comparison was done to see the effect of different chemotherapy regimens on the incidence of infections to formulate a prophylactic antibiotic regimen for those at high risk of infections.

Results
A total of around 754 patients were treated from 2009 to 2015. Files of 178 patients were analysed who presented with 480 episodes but the data was not complete in about 75 episodes so 405 episodes were analysed (Table 1). Age ranged from 3 -168 months with a mean of 69.5 +/− 43.3 months. Male to female ratio is 60:40 respectively ( Table 2).
42.5% of episodes happened at home while 57% happened in the ward and one each in Emergency room and PICU (Table 3).
86 patients had one episode, 45 had two, 25 had three, while the rest had four or more episodes going up to 11 episodes in one case. Ave episodes per patient were 2.8 in Burkett's lymphoma, followed by 2.6 in ALL, 1.7 in AML, 1.6 in Hodgkin's disease and 1.54 in Medulloblastoma. We had to remove line in 5.2% (17). ALL comprises 68.5% of cases followed by AML with 5.5%, Burkett's lymphoma 4.2%, Medulloblastoma 4.2%, Hodgkin's disease 4% and the rest other diseases (Table 4).

Discussion
The treatment of cancer has been transformed in the last 50 years due to improvement in supportive care services. Infections have always been a major threat to cancer patients because of neutropenia associated with chemotherapy.
As time has passed, emergence of resistance in bacteria and fungi has become a major problem in treating high-risk cases that need intensive multiagent che-  [25] from Pakistan with 44% positive cultures from 62 episodes with blood as the most common site 24% as compared to our 16%. A recent study from Qatar was published by N AlMulla et al. [26] with the same pattern of organisms as our study with Staphylococcus as the most common gram positive and Klebsiella as the most common gram negative organism. H Ashour and A Alshareef [27] from Cairo reported the same organisms (G negative) in 2009. SS Purewal et al. [28] also reported similar findings from India in 2011. TC Yeh [29] from Taiwan reported in 2014 that prophylactic antibiotics prevented severe infections in high-risk cases thus suggesting a role for prophylactic antimicrobials in these situations.
Sarah Georgaudou et al. [30]  were building our patient number and we did not have many relapsed patients.
There are some limitations of this study due to the retrospective nature of the study, lack of consecutive case reporting and a lot of missing information, so it may not be representative but none the less presents the overall picture. Therefore, I have decided to extend this study and collect consecutive prospective data so that we can get a clearer picture and make our recommendations on that.

Conclusion
Infections are still a big problem in cancer patients on chemotherapy and we need to look for other ways to improve our antimicrobial coverage and select cases with high risk and give them prophylactic antibiotics during neutropenic episodes. We need prospective data on our patients to get a clearer picture of the risks facing our patients. We need more education for the patients and their families to bring the child quickly to the hospital and make sure these patients are seen immediately to prevent simple infection progressing to a severe one.