Neutropenic Sepsis (NS) Prevention and Management in Cancer Patients. NICE Guidelines 151 September 2012

What is Febrile Neutropenia/Sepsis? Neutropenic sepsis is a life threatening complication of anti-cancer therapy. The term describes a significant inflammatory response to a presumed bacterial infection in a person WITH or WITHOUT fever. The RISK of life-threatening infection and mortality in pts receiving treatment for cancer is related to the degree of immunosuppression, commonly assessed by the absolute neutrophil count (ANC) Risk of mortality as the ANC  E.g. pts may also present with hypothermia

How common is neutropenic sepsis? Children with cancer are at an increased risk of NS as a result of their disease or its treatment NS is the second most common reason for hospital admission amongst children and young people with cancer Approximately 4000 episodes occurring annually, with mortality rates between 2- 21% It causes significant morbidity in children and young adults treated for cancer, and accounts for a substantial use of resources and remains fatal in some instances Consequences of episodes of infection in a neutropenic person include (from worst to best outcome): death, ITU admission, medical complications, bacteraemia, signif. bacterial infection, or no adverse after effects. It may also lead to delay or modifications of subsequent courses of chemotherapy Most common reason for hospitalisation is infection How many episodes/annum? NICE were asked to collaborate with centres around the country and produce national guidelines for neutropenic sepsis

Epidemiology There is a national variation in: Primary and secondary prophylaxis Risk stratification for pts with an episode of febrile neutropenia Oral or IV antibiotics Growth factors In or outpatient management policies Evidence based, standardised recommendations on prevention, identification and management of this life threatening complication of cancer treatment are expected to improve outcomes (as over 2/3rd of the aggressive management strategy was found to be excessive)

Recommendations The following recommendations have been identified as priorities for implementation by NICE 1. Diagnosis of neutropenic sepsis Definition used by NICE: ANC < 0.5 or lower and falling and who have either: A temperature higher than 38° C or Other signs or symptoms consistent with clinically significant sepsis 2. Information, support and training Content of information and support Provide patients having anticancer tx and their carers with written and oral information, both before starting and throughout their anticancer treatment on: Neutropenic sepsis How and when to contact 24 hour specialist oncology advice How and when to seek emergency care Training for healthcare professionals NICE reviewed a whole host of data including guidelines from a number of PTCs, evidence based information from literature reviews and trials to produce some set guidance. HCP and staff who come into contact with patients having anticancer treatment should be provided with training on neutropenic sepsis. (training tailored to type of contact likely)

Recommendations 3. Identification and assessment Signs and symptoms that necessitate referral to secondary/tertiary care Suspect neutropenic sepsis in pts receiving anticancer tx who become unwell Refer such pts to secondary/ tertiary care immediately for assessment 4. Reducing the risk of septic complications of anticancer tx Preventing the septic complications of anticancer tx Do not routinely offer GCSF for the prevention of neutropenic sepsis in adults receiving chemotherapy unless they are receiving it as an integral part of the chemo regimen in order to maintain dose intensity Part of I and A in tertiary settings is to ensure appropriate initial assessment of pt incl a full history and examination FBC and kidney and liver function tests include albumin, CRP, lactate and blood cultures E.G in NBL

Recommendations 5. Initial Treatment Timing of initial antibiotic tx Treat suspected neutropenic sepsis as an acute medical emergency and offer empiric antibiotic therapy immediately. Empiric IV antibiotic monotherapy or IV dual therapy Offer beta lactam monotherapy with piperacillin and tazobactam as initial empiric abx therapy to pts with suspected neutropenic sepsis who need intravenous tx, unless there are pt- specific or local microbiological contraindications Do not offer aminoglycoside, either as monotherapy or in dual therapy for empiric tx unless there is microbiological or pt specific indications.

Recommendations Empiric glycopeptide antibiotics to patients with central venous access devices Do not offer empiric glycopeptide antibiotics to patients with suspected neutropenic sepsis unless there is pt specific/microbiological indications. Indications for removing central venous access devices Do not remove central venous access devices as part of the initial empiric management of suspected neutropenic sepsis. Inpatient versus outpatient management strategies Consider outpatient antibiotic therapy for patients with confirmed neutropenic sepsis and a low risk of developing septic complications Taking into account pts social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops.

Recommendations 6. Subsequent tx Changing the initial empiric tx in unresponsive fever For patients with confirmed NS and high risk of developing septic complications, they should be Reviewed clinically on a daily basis Reassessed for pts risk of septic complications using a valid scoring system Do not switch initial empiric abx in patients with unresponsive fever unless there is clinical deterioration or a microbiological indication. Switching from IV to oral antibiotic tx Switch after 48 hours in patients whose risk of developing septic complications has been reassessed as low

Recommendations Duration of inpatient care Offer D/C to patients having empiric antibiotic therapy for neutropenic sepsis only after: Pts risk of developing NS has been assessed as low and Taking into account pts social and clinical circumstances and discussing with them the need to return to hospital promptly if a problem develops Duration of empiric antibiotic tx Continue inpatient empiric antibiotic tx in all pts who have unresponsive fever unless an alternative cause of fever is likely Discontinue empiric antibiotic tx in whose NS has responded to tx, irrespective of neutrophil count

Practical points Paracetamol should not be started in a febrile patient until it is clear that the criteria for starting antibiotics are fulfilled Classic signs of sepsis maybe masked by steroids e.g. during ALL, or steroids in patients with brain tumours. If in doubt and a neutropenic child on steroids seems unwell, start antibiotics

Line Infections

Line Infections Most pts with cancer have an indwelling central venous catheter (CVC), which is at risk of colonisation with gram negative and fungal pathogens including some environmental pathogens E.g. Stenotrophomonas (can be found in soil, plants and surrounding waters) Infection can be introduced into the CVC during line accessing and from other causes including breaches in natural barriers to infection E.g. mouth and gut during mucositis

Line Infections Be suspicious of a line infection if: A child develops a fever or rigor after the line has been accessed However the child may only present with fever +/- neutropenia or with positive blood cultures in a well child where the cultures are taken for reasons other than fever. If in doubt take peripheral blood cultures in addition to cultures from the line.

Line Infection- Treatment Remove line very quickly if : cultures grow gram negative pathogens Klebsiella or Pseudomonas aeruginosa, or a fungal pathogen such as Candida species Dependant on the organism found Most require a prolonged course of antibiotics- at least 10 days

Chicken Pox Contact and Treatment

Chicken Pox (VZV) At diagnosis- find out re antibody status (pre transfusions) and recorded Pts with antibodies acquired from previous infections or from transfusions of blood products are usually protected against varicella zoster. VZV CONTACT- defined as: Play or direct contact for more than 15 minutes at home, school or on ward with an individual with chicken pox, during infectious period (from 2 days prior to the onset of rash until crusting of all vesicles). A significant shingles contact is direct contact with the exposed lesions.

Post Contact Recheck antibody status in previously VZV negative pts. Give VZIG as soon as possible (<72 hours) to all non immune children on chemotherapy or within 6 months of completion of chemotherapy. Given within 10 days of contact can attenuate the infection. If a child is re-exposed after 4 weeks or more and who remain non-immune should have repeat ZIG After ZIG the incubation period of chicken pox can be prolonged to 28 days ZIG doses as per BNF-C

Post Contact If ZIG is not available, alternatives are: High dose ORAL aciclovir from day 7- 21 following contact Dose under 2 yrs: 200mg x 4/day 2-6 yrs: 400mg x 4/day over 6 years: 800mg x 4/day IVIG (give within 72 hours- useful in thrombocytopenic pts) Using a dose of 0.4mg/kg

Prevention of VZV Give ZIG following exposure of seronegative chemotherapy pts during therapy and for 6 months after its cessation The RCPCH green book recommends the vaccination of siblings of cancer children. However, the small risk of varicella breakthrough needs to be discussed with the parents and a decision made on an individual basis. If breakthrough infection does occur in the sibling, then the patient should be given prophylactic ZIG.