A 36-year-old man presented to an emergency room with fever, fatigue, and severe rectal pain. He was subsequently found to be pancytopenic with a perirectal abscess. A bone marrow examination revealed 58% blasts consistent with acute myeloid leukemia. The patient was initiated on clofarabine, idarubicin, and cytarabine therapy. The first cycle of therapy was complicated by neutropenic fever, bacteremia, and pneumonia. The second cycle was complicated by delayed platelet recovery. As a result, the patient was referred for possible stem cell transplantation.
A 36-year-old man presented to an emergency room with fever, fatigue, and severe rectal pain. He was subsequently found to be pancytopenic with a perirectal abscess. A bone marrow examination revealed 58% blasts consistent with acute myeloid leukemia. The patient was initiated on clofarabine, idarubicin, and cytarabine therapy. The first cycle of therapy was complicated by neutropenic fever, bacteremia, and pneumonia. The second cycle was complicated by delayed platelet recovery. As a result, the patient was referred for possible stem cell transplantation. The patient was enrolled in a phase III trial using standard of care double umbilical cord blood transplantation with myeloblative conditioning to include fludarabine and melphalan, with rabbit antithymocyte globulin. Filgrastim injections were initiated at 600 mcg daily.
The patient’s post-transplantation phase was complicated by sustained rigors and recurrent febrile episodes. The patient experienced 1–6 episodes of rigors daily. During this period, the patient also reported severe lower back pain with a majority of the episodes of rigor. The patient then developed neutropenic fever on Day 17 with persistent fever daily ranging from 38.1°–39.5°C through Day 50, with only six days in which he was afebrile. Filgrastim injections were administered at 4 pm daily, and the febrile episodes were noted to occur primarily in the early to late evening hours, with rigors preceding the febrile events by about 30–60 minutes. By Day 30, the patient’s engraftment had plateaued with a white blood cell count of 1.2 and an absolute neutrophil count of 0.89. As a result, the filgrastim dose was increased to 600 mcg twice daily.
Because of the ongoing symptoms associated with neutropenic fever, including rigors, and pain, an infectious disease consult was obtained on Day 8. Anticipating an infectious etiology corresponding with the neutropenic period, a complete infectious disease work-up was conducted (see Table 1). The patient developed diarrhea on Day 3 post-transplantation, which was positive for Clostridium difficile, and was resolved with metronidazole followed by oral vancomycin.
Diagnostic imaging studies including X-rays, and computed tomography (CT) scans of the chest, abdomen, and pelvis were negative. However, a positron-emission tomography (PET)/CT scan revealed multiple enlarged mediastinal and bilateral hilar lymph nodes. Flexible video bronchoscopy with endobronchial ultrasound and ultrasound-guided transbronchial fine needle aspiration (FNA) of the lymph node, as well as a bronchoalveolar lavage, were completed. Culture results were negative for a complete bacterial, viral, and fungal examination. Pathology revealed no malignant cells, no viral changes, fungal stains were negative, as was staining for pneumocystis. The FNA specimens also were negative. The patient’s central venous catheter also was removed and the tip was sent for bacterial and fungal cultures, which returned negative for central line-associated bloodstream infection. Since the patient was not exhibiting symptoms of viral encephalitis or meningitis, lumbar puncture was not completed.
A bone marrow biopsy and aspiration was completed on Day 34 with no evidence of acute leukemia. All cultures, including cytomegalovirus, human herpesvirus 8 (HHV8), herpes simplex virus, adenovirus, varicella zoster virus, parvovirus, fungal cultures, and bacterial cultures also were negative. HHV6 was positive in the peripheral blood on Day 29, as well as in the bone marrow study on Day 34 (less than 183 DNA copies/ml), but improved with foscarnet therapy. Despite improvement of HHV6 in the blood, the patient’s symptoms persisted. An immunoglobulin-G level was obtained on Day 34, which returned low at 572 mg/dl and was replaced with IV immunoglobulin 50 g daily for four doses. Throughout the course of the rigors and febrile events, the patient received various IV and/or oral antimicrobial, antifungal, antiviral, and an aminoglycoside (amikacin) therapy with limited improvement in the frequency and severity of symptoms.
As infectious sources were ruled out, the attending physician turned his attention to evaluating the potential for hypersensitivity to the pharmacologic regimen. Agents were systematically tapered to observe for changes in symptom severity. The patient also began to voice concerns regarding the filgrastim injections and, as a result of limited improvement in neutrophil recovery, it was decided to reduce the dose on Day 50. The following day, the patient’s fever curve and symptoms of rigors and pain were reduced with the dose reduction of filgrastim. The medication was discontinued on Day 51, with no other febrile events noted, and full symptom resolution within 48 hours of discontinuation.
Sustained rigors with or without fever in various pathologic conditions have been reported and occur for a variety of reasons including, but not limited to, infection, inflammation, pain, anxiety, drug interactions, and immunoglobulin infusion (Leach, Gilbert, Evans, & van Boxel, 2011; Pierce & Jain, 2003; Smack Gregoor, van Saase, Weimar, & Kramer, 1995; Tal et al., 1997). Rigors are one of the most commonly reported adverse events after immunoglobulin administration in the U.S. Food and Drug Administration’s MEDWATCH passive surveillance system (Pierce & Jain, 2003). In the event of infection-associated rigors, bacterial rather than viral infections are most commonly the culprit (Tal et al., 1997). In addition, medication hypersensitivity also has been reported to be responsible for rigors and fever (Smack Gregoor et al., 1995).
The pathophysiology of fever and rigors emerges within the thermoregulatory center located in the hypothalamus. The literature suggests a variety of pyrogens (e.g., bacteria, cytokines) stimulate release of metabolites such as prostaglandins from endothelial cells of blood vessels surrounding the hypothalamus (Boulant, 1997). When these metabolites cross the blood-brain barrier and diffuse into the thermoregulatory center of the hypothalamus, several signaling cascades occur, which lead to an increase in the temperature set point. Consequently, the hypothalamus sends sympathetic signals to cause vasoconstriction of peripheral blood vessels and decrease heat loss through the skin. If these pathophysiological changes do not generate enough heat to match the new temperature set point, the motor nervous system stimulates shivering to occur to increase heat production (Boulant, 1997). In the case of noninfectious conditions, the pathophysiology of rigor could be different. For example, immunoglobulin infusion, commonly used in the stem cell setting, is known to cause immediate or delayed rigors with or without fever. The proposed mechanistic factors in the literature for immunoglobulin-associated rigors are antigen-antibody reaction, aggregate formation, sodium content, and pH of the immunoglobulin (Palabrica, Kwong, & Padua, 2013; Stiehm, 2013). However, exact mechanistic information on rigors in most of the conditions remains fairly unknown.
Filgrastim, an integral part of cancer symptom management, is a commercially available recombinant human granulocyte–colony-stimulating drug. Filgrastim has been approved for neutrophil recovery in patients undergoing stem cell transplantations and also to mobilize hematopoietic progenitor cells from the bone-marrow into the peripheral blood of stem cell donors (Welte, 2014). The most common side effects associated with filgrastim are bone pain (90%) and headache (17%) among stem cell donors (de la Rubia et al., 1999). More severe reactions to filgrastim, including splenic rupture and anaphylactic-like reactions, have been reported in the literature (Tholpady, Chiosea, Lyons, Baird, & Leitman, 2013).
Filgrastim-associated sustained episodes of rigors with or without fever have not been reported in the literature. However, fever of unknown origin without rigors has been reported in a randomized clinical trial comparing safety and efficacy of single dose of pegfilgrastim versus daily filgrastim in pediatric patients undergoing autologus stem cell transplantation (Cesaro et al., 2013). Other studies of adult patients undergoing stem cell transplantation also report fever as one of the reversible adverse events associated with filgrastim administration (Orciuolo et al., 2011). Mechanistic information on filgrastim-associated febrile episodes also has been emerging. The non-glycosylated form of filgrastim has been reported to be associated with increased incidence of febrile episodes compared to glycosylated filgrastim (Orciuolo et al., 2011). Febrile episodes could be attributed to an impairment of neutrophils during exposure to non-glycosylated filgrastim (Ribeiro et al., 2007).
A few cases of filgrastim hypersensitivity have been reported in the literature, but no conclusive patterns or symptoms emerged. Two cases have reported severe systemic anaphylactic-like hypersensitivity during filgrastim administration in allogenic donors (Adkins, 1998; Tholpady et al., 2013). Anaphylactic reaction associated with filgrastim also has been reported in patients with malignancies (Batel-Copel et al., 1995). Delayed hypersensitivity reaction manifested by skin rash one week after pegfilgrastim administration was reported for a patient with breast cancer (Dadla, Tannenbaum, Yates, & Holle, 2014).
Recipients of stem cell transplantation often are prescribed filgrastim post-transplantation to enhance cell recovery and engraftment, particularly true for allogeneic transplantation recipients undergoing partially matched transplantations from haploidentical and cord-blood sources for whom neutrophil recovery may be delayed, thereby necessitating prolonged use of filgrastim. During the period of neutropenia, patients also are predisposed to infection, the symptoms of which could mirror the hypersensitivity symptoms with which the patient in the case study presented. Although infectious sources are most often the cause of fever, and potentially rigors, this case study illustrates the need for nurses to be aware of the potential for hypersensitivity reaction to filgrastim, as well as other agents, for which presenting symptoms may be similar.
Nursing management of the patient with fever and rigors consists of attention to both the symptoms themselves as well as those symptoms arising from pharmacologic management. Meperidine is a commonly prescribed agent because of its ability to act on kappa-receptors to reduce shivers (Ikeda et al., 1997). However, meperidine is associated with sedative effects, severe hypotension (Atalay, Aksoy, Aksoy, Dogan, & Kursad, 2010), and the potential for nausea and vomiting (Anaraki & Mirzaei, 2012). Nurses should be attentive to hemodynamic monitoring and proactive response with antiemetic therapies. Complementary therapies, including warm blankets, have demonstrated a synergistic effect with meperidine, reducing the shivering threshold by lowering vasoconstriction (Kimberger et al., 2007).
The occurrence of fever presents several challenges, including increased physiologic stress resulting from increases in cell metabolism, heart rate, and cardiac output. In the presence of fever with shivering, oxygen consumption may increase by 100%–200% (Henker, Kramer, & Rogers, 1997). This increased demand for oxygen could necessitate the need for oxygen via nasal cannula, as occurred in this case study. Fever is also associated with cytokine release, contributing to weight loss, weakness, and nitrogen imbalance by triggering muscle catabolism. Mental changes such as delirium and seizures could also occur with increase in physiological stress (Gelfand & Dinarello, 1998). Nurses caring for such patients should be aware about underlying physiological changes associated with fever and rigors to initiate appropriate nursing interventions. For management of fever, acetaminophen and hydrocortisone were prescribed for the patient in the case study; however, these agents may be precluded based on chemotherapy regimens for which agents (e.g., busulfan) compete for metabolic pathways.
Pain and anxiety are additional symptom management considerations. Filgrastim-associated back pain should be managed with appropriate analgesic support. Anti-anxiolytics in conjunction with complementary therapies may be used to effectively manage anxiety and pain. In the case study, dilaudid was used for pain management, lorazepam for anxiety, and music therapy was integrated as the patient enjoyed music and played an instrument.
The occurrence of fever and rigors in an immunocompromised patient after stem cell transplantation usually indicates neutropenic fever and underlying infectious etiology. Sensitivity reactions to filgrastim are rare; however, in this case, the occurrence was masked because of the patient’s physiologic status and the multi-drug regimen prescribed related to the transplantation process. Ultimately, tapering drugs individually to identify how symptoms change in severity or resolve after discontinuation of a certain medication contributes to the identification of medication hypersensitivity.
The Naranjo Adverse Drug Reaction (ADR) scale is a tool that may be effectively used to identify the potential for medication hypersensitivity (Naranjo et al., 1981). In this case, the Naranjo score is 6 (see Table 2), which indicates a possible filgrastim-induced adverse event. The occurrence of recurrent fever and sustained rigors could be clinical manifestations of possible filgrastim hypersensitivity.
Although the focal symptoms in the patient in the case study were fever and rigors, the patient also concurrently reported bone pain. Although bone pain is an expected symptom of filgrastim administration, the episodes of rigors in this patient increased from Day 31 to Day 37 as the filgrastim dose was increased. Retrospectively, this could have been an additional indicator that the patient was experiencing hypersensitivity to filgrastim.
With widespread use of filgrastim both for stem cell donors and recipients, healthcare providers could be confronted with filgrastim-associated adverse events and hypersensitivity reactions. As observed in the case study, these adverse events can mimic other conditions and, as a result, differential diagnosis may be problematic. Oncology nurses and their interprofessional colleagues should, therefore, be aware of the potential for filgrastim-associated hypersensitivity and assess for its occurrence early and often during filgrastim administration. The ability to track and trend symptoms of hypersensitivity for this and other agents may contribute significantly to patients’ physiologic and quality-of-life outcomes during cancer treatment.
The authors gratefully acknowledge Yimin Geng, MSLIS, MS, for assistance with the literature review and Alison Gulbis, PharmD, BCOP, for assistance with the Naranjo Adverse Drug Reaction Scale. The authors also express appreciation to the stem cell transplantation unit nurses at MD Anderson Cancer Center, who cared for the patient in the case study and provided relevant information.
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Nilesh Kalariya, RN, PhD, is a clinical nurse, Alyssa Twigg, RN, APRN, is an advanced practice RN, and Kelly Brassil, RN, PhD, is the director of nursing research and innovation, all at the University of Texas MD Anderson Cancer Center in Houston. No financial relationships to disclose. Kalariya can be reached at email@example.com, with copy to editor at ONFEditor@ons.org.