MANAGEMENT OF FEVER IN PEDIATRIC PATIENTS FOLLOWING HEMATOPOIETIC STEM CELL TRANSP There are no translations available. MANAGEMENT OF FEVER IN PEDIATRIC PATIENTS FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION by Petr Sedlacek, Charles University, Prague, Czech Rep. BACKGROUND Fever may be the first manifestation of a life-threatening infection, particularly during periods of neutropenia. Febrile episodes occur frequently during neutropenic periods in children with chemotherapy-induced neutropenia or after hematopoietic stem cell transplantation (HSCT). Fever is a frequent symptom seen in patients during conditioning regimen, after stem cell infusion, during engraftment period and even later after discharge from transplant unit. Often fever is one of early signs of infection, however, it could be caused by several other mechanisms. Fever during conditioning regimen could be caused by infection, especially in patients with poor immunity status before transplantation (aplastic, immunodeficient). But it could be observed also as a consequence of administered drugs (chemotherapy), irradiation, blood products (including graft), serotherapy (ATG, Campath, ). Systemic chemotherapy agents, particularly in high doses, result in concomitant mucosal damage and exfoliation; this increases the risk of microbial translocation through a compromised gastrointestinal tract, may predispose to herpes simplex virus infection, and may hamper adequate enteral nutrition. Development of severe mucositis is very frequent in patients undergoing fully myeloablative conditioning (using busulfan, total body irradiation, etc.). Apart from mucosal exfoliation, patients may have indwelling medical equipment (e.g. central venous access devices, urinary catheters, etc.) and are likely to be taking other therapeutic agents that suppress immunity such as corticosteroids or monoclonal anti lymphocyte antibodies. Febrile neutropenia following conditioning regimen (after infusion of graft) is a frequent complication requiring prompt empirical broad-spectrum antibacterial therapy. Isolation of a pathogen may not be possible on several occasions of febrile episodes; stillan infectious etiology is highly likely in most cases.. It is important to evaluate all symptoms accompanying the fever to make a proper diagnosis. DEFINITIONS A fever is any body temperature elevation (taken from axillary site) over 38 C (100 F 1 / 6
respectively). A healthy person's body temperature fluctuates between 36.1 C and 37.8 C (based on age), with the average being 37 C. Body temperature (in C) below 32 C Mostly fatal, death below 35 C Hypothermia 36 36,9 C Normothermia 37 38,0 C Subfebrile (low grade fever) 38,1 40 C 2 / 6
Fever 40,1 42 C Hyperpyrexia above 42 C Mostly fatal, death Diagnostic approach Neutropenia is defined by an absolute neutrophil count (ANC) of less than 0.5 109/l or an ANC of >0.5 109/l and <1.0 109/l with a predicted drop during several days to less than 0.5 109/1. A febrile neutropenic episode (FE) is generally defined as an axillary temperature >38.5 C once or 38 C on two or more occasions (at least one hour apart) during a 12-h period. A new febrile episode was defined as a relapsing fever after more than 72 hours of apyrexia (<38 C). There are some important caveats when using this definition during clinical assessments of patients: firstly, some neutropenic patients with infection may not develop fever, especially patients taking corticosteroids or antipyretics (for analgesia, etc.), or patients whose clinical infection is paradoxically heralded by hypothermia. Neutropenic patients with 3 / 6
concomitant mucositis may have a disproportionately elevated oral temperature, resulting in a false positive documentation of systemic fever. In patients with mucositis, measurement of temperature by other means is recommended, such as via the tympanic or axillary route. The term immunocompromised host defines individuals with either nonspecific (skin and mucous membranes, phagocytic activity, complement) or specific (humoral or cellular immunity) impaired defense mechanisms. The alteration of one or more of the defense mechanisms is a consequence of underlying disease (e.g. tumors) or therapies in place to counter it (chemotherapy, steroids, immunosuppressants, radiation, transplantation). The extended use of high-dose chemotherapy, autologous or allogeneic transplantation of hematopoietic stem cells has offered new therapeutic options, but also has increased the number of immunocompromised patients. Initial management The primary step in the management of a patient with suspected febrile neutropenia (FN) is a detailed history and physical examination, with specific and careful attention to the presence of tachypnea, tachycardia, hypotension, and possible sources of infection. Particular attention should be paid to indwelling devices such as central venous lines and urinary catheters. Laboratory analyses are essential in order to document the presence and degree of neutropenia, coincident cytopenias, and to establish whether complications have ensued such as electrolyte deficiencies and renal or hepatic impairment. HSCT patients that develop their first fever will have a fever workup completed within 1 hour of the fever spike. For each febrile episode the initial laboratory diagnostic work-up (locally precisely defined) consists of sets of aerobic and/or anaerobic blood cultures drawn by phlebotomy (in small children routine peripheral cultures are not always performed), and/or via each line of the central venous catheter, urine analysis, urine culture, sputum culture (if patient cooperates and can produce sputum specimen) and chest X-ray. Antibiotics must by started within 1 hour of the first fever spike. Additional specific investigations could be performed according to the clinical presentation (e.g.: PCR for HSV on oropharyngeal swabs in patients with severe mucositis, screening of respiratory viruses with specific PCRs in patients with suggestive symptoms/signs). In persistent fever lasting more than 3 days, the diagnostic reassessment includes repeated blood cultures as described above, prospective frequent measurement of viral PCR (CMV, EBV, ), galactomannan antigenemia, a thoraco-abdominal CT-scan, a bronchoscopy with BAL in presence of a lung infiltrate, and biopsy for culture and histopathology at any clinically suspected site of infection. Cultures and clinical examination fail to detect a pathogen and/or an infectious focus in 30 60% of episodes, which are classified as fever of unknown origin (FUO). As infectious and non-infectious etiologies of FUO cannot be differentiated, all patients should receive empirical antibacterial therapy. Persistence of fever despite ongoing antibiotics may suggest uncontrolled and potentially life-threatening infection due to resistant bacteria or fungi. Unresolved fever represents a major challenge for diagnosis and therapy, often resulting in multiple investigations and empirical modifications of antibacterial and/or addition of antifungal therapy. New diagnostic tools are thus needed for guiding management of patients with fever 4 / 6
after HSCT when initial microbiological and clinical documentation is lacking and in persistent fever, when resistant bacterial infection or invasive fungal disease or systemic viral infection is suspected. Management of fever The body maintains stability within certain range of temperature by balancing the heat produced by the metabolism with the heat lost to the environment. A fever occurs primarily in response to an infection. To reach the higher temperature, the body moves blood to the warmer interior, increases the metabolic rate, and induces shivering. The "chills" that often accompany a fever is caused by the movement of blood to the body's core, leaving the surface and extremities cold. Once the higher temperature is achieved, the shivering and chills stop. Most children feel bad when they are sick and they have a fever, especially when the fever spikes real high. This is often because of some of the secondary fever symptoms they may have, such as: - chills - shivering - headache - irritability - muscle aches - hallucinations - sweating A dramatic rise in body temperature often includes the following symptoms: - - increased pulse rate - skin becomes more heat-sensitive. - loss of fluid results in dehydration - blood vessels in skin dilate - sweat glands produce excess perspiration - the hypothalamic set-point is increased, raising metabolism, may introduce chills and shivering to promote heat production from muscles 5 / 6
A fever is diagnosed using a thermometer. A variety of different thermometers are available, including traditional glass and mercury ones used (not used in EU countries) for oral or rectal temperature readings and more sophisticated electronic (digital) ones that can be inserted in the ear (tympanic) to quickly register the body's temperature. For adults and older children, temperature readings are usually taken orally. Younger children who cannot or will not hold a thermometer in their mouths can have their temperature taken by placing an oral thermometer under their armpit. Severe mucositis/stomatitis limits reliable measurment of temperature orally. Infants generally have their temperature taken rectally using a rectal thermometer. However, due to general mucosal damage in some patiens following HSCT, this option might not be optimal due to the risk of mechanical injury. Drugs to lower fever (antipyretics) should be given as a standard care in such cohort of patients. Aspirin, should not be given to a child or adolescent with a fever since this drug has been linked to an increased risk of Reye's syndrome and may cause bleeding tendency in a transplant patient with low platelets. 6 / 6