- Email: [email protected]
Fever induced by hydroxycarbamide
Scientific letters / Med Clin (Barc). 2015;145(11):504–506
505
Table 1 Antibody mediated encephalitis.
Antigen Age Association with tumour Response to treatment Relapses
Intracellular, onconeuronal antigen
Intracellular, synaptic antigen
Cell surface or synaptic receptor
Hu, CRMP5, Ri, Yo, Ma2 Predominant in older age Yes 10–30% Uncommon
GAD, anfisina Adults Varies with the antigen Partial improvement 60% Uncommon
NMDAR, AMPAR, GABA (B) R, Caspr2 All ages, although more in children Varies with the antigen and age Partial or complete improvement 75–80% Varies with the antigen (10–25%)
References 1. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77:179–88. 2. Titulaer MJ, McCrackern L, Gabilondo I, Armangué T, Glaser C, Lizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with antiNMDA receptor encephalitis: an observational cohort study. Lancet. 2013;12: 157–65. 3. González-Valcárcel J, Rosenfeld MR, Dalmau J. Diagnóstico diferencial en la encefalitis por anticuerpos contra el receptor NMDA. Neurologia. 2010;25:409–13. 4. Lancaster E, Dalmau J. Neuronal autoantigens. Pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8:380–90. 5. Rosenfeld MR, Titulaer MJ, Dalmau J. Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract. 2012;2:215–23. 6. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
Fever induced by hydroxycarbamide夽 Fiebre por hidroxiurea Dear Editor, Drug-induced fever is a rare clinical problem, although its actual incidence is unknown because it is probably underdiagnosed.1,2 The list of drugs involved is extensive, although beta-lactam antibiotics seem to stand out due to their frequency.3 We present a case of fever induced by hydroxyurea (HU) without any other accompanying clinical manifestations. It is a 66-year-old male with no history of interest except hypertension, dyslipidaemia and depressive syndrome, under treatment with aspirin, simvastatin, clomipramine, olmesartan medoxomil, amlodipine and hydrochlorothiazide. Diagnosed with essential thrombocythemia 7 years before, carrier of the V617F mutation in the JAK2 gene, without treatment during 3 weeks before admission, when HU administration started with a dose of 1000 mg/day. Admitted due to a 10-day long condition of malaise, myalgia and fever without any focal clinical evidence. Examination revealed a temperature of 39 ◦ C and a systolic murmur. No skin lesions were observed. The blood count was normal, without eosinophilia. Biochemical studies showed values of 69 U/L AST, 55 U/L ALT and 24.4 mg/dL C-reactive protein, with no other abnormalities. Blood culture, urine culture, Legionella and pneumococcus antigen detection in urine and cytomegalovirus, Epstein–Barr virus, HIV, syphilis, Brucella, Mycoplasma, Coxiella burnetii and Chlamydia serology were all negative. The chest radiograph was normal and abdominal ultrasonography showed a hyperechogenic liver relative to fatty infiltration and increased prostate size. HU was discontinued at admission, with fever remission in 36 h. Its controlled administration was resumed two weeks later with a single dose of 500 mg, showing recurrence of fever after 8 h.
夽 Please cite this article as: Lizarralde Palacios E, Gutiérrez Macías A, Rámiz Martínez M, Escalante Boleas M. Fiebre por hidroxiurea. Med Clin (Barc). 2015;145:505–506.
7. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.
Rosa Escudero Sánchez a,∗ , María Teresa Montojo Villasanta b , María Isabel González Anglada a a
Servicio Medicina Interna, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain b Servicio Neurología, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (R. Escudero Sánchez).
It has been estimated that drug-induced fever accounts for 0.01–5% of adverse drug reactions in hospitalized patients.1–3 It is defined as a febrile reaction related to drug administration, which disappears as soon as the drug is interrupted and in the absence of other causes that may explain it.3,4 The most common mechanism for fever is a hypersensitivity reaction1 ; although in these cases the fever is usually accompanied by skin lesions, eosinophilia or other manifestations, in the context of a delayed hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.5 In the definition of drug-induced fever, patients in whom the fever is accompanied by skin lesions are specifically excluded.2,3 In the case of antineoplastic agents, the pharmacological action itself, which leads to cell necrosis and release of potential pyrogens, could contribute to the onset of fever.1 Early recognition of drug-induced fever is vital to avoid prolonged hospitalizations, unnecessary diagnostic procedures or treatments as well as new exposures to the inducing drug. Our case meets the criteria of causality established in the algorithm Karch and Lasagna,6 which classifies the adverse effect as clearly defined; however, compliance with these criteria requires rechallenge, which is not without risk and should not be done in severe cases.1 The HU or hydroxyurea is an anticancer drug whose mechanism of action is the blocking of DNA synthesis mediated by the inhibition of the ribonucleotide reductase enzyme. It is used in the treatment of myeloproliferative diseases with negative Philadelphia chromosome and sickle cell anaemia. It is usually well tolerated; the most common side effects are myelosuppression with occurrence of peripheral cytopenias, digestive intolerance and skin lesions associated with its use, among which hyperpigmentation, alopecia and painful skin and mucous ulcers stand out. Pulmonary complications such as pneumonitis or bronchiolitis and drug-induced fever are less frequent.7 In a large series of 3411 patients treated with HU, drug-induced fever was observed in 0.5%.8 38 cases have been reported in the literature, including those reported in the series just mentioned and reviewed by Doutrelon et al.,9 no cases have been published in Spanish literature [Spanish Medical Index; search strategy of “hidroxiurea” (hydroxyurea) or “hidroxicarbamida” (hydroxycarbamide)
506
Scientific letters / Med Clin (Barc). 2015;145(11):504–506
and “fiebre” (fever)]. Fever appeared after an average of 21 days of treatment, was high (median 40 ◦ C), well tolerated and rapidly disappeared after discontinuation of treatment. Re-exposure to HU occurred in 50% of cases, which was positive in all cases except one.9 In short, we present a case of drug-induced fever associated to HU with characteristics consistent with those previously reported, being the first case study on Spanish literature. References 1. Patel RA, Gallagher JC. Drug fever. Pharmacotherapy. 2010;30:57–69. 2. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996;10: 85–91. 3. Vodovar D, LeBeller C, Mégarbane B, Lillo-Le-Louet A, Hanslik T. Drug fever: a descriptive cohort study from the French national pharmacovigilance database. Drug Saf. 2012;35:759–67. 4. Vodovar D, Le Beller C, Lillo-Le-Louet A, Hanslik T, Megarbane B. Fièvre médicamenteuse: Un diagnostic à ne pas oublier. Rev Med Interne. 2014;35: 183–8.
5. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588–97. 6. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977;21:247–54. 7. Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders. Expert Rev Anticancer Ther. 2011;11:403–14. 8. Antonioli E, Guglielmelli P, Pieri L, Finazzi M, Rumi E, Martinelli V, et al. Hydroxyurea-related toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol. 2012;87:552–4. 9. Doutrelon C, Lazaro E, Ribeiro E, Greib C, Pellegrin JL, Viallard JF. Hyperthermie induite par l’hydroxyurée: à propos de 4 cas et revue de la littérature. Rev Med Interne. 2015;36:73–7.
Eva Lizarralde Palacios, Alfonso Gutiérrez Macías ∗ , Mayte Rámiz Martínez, Mikel Escalante Boleas Servicio de Medicina Interna, Hospital Universitario Basurto, Bilbao, Vizcaya, Spain ∗ Corresponding author. E-mail address: [email protected] (A. Gutiérrez Macías).
505
Table 1 Antibody mediated encephalitis.
Antigen Age Association with tumour Response to treatment Relapses
Intracellular, onconeuronal antigen
Intracellular, synaptic antigen
Cell surface or synaptic receptor
Hu, CRMP5, Ri, Yo, Ma2 Predominant in older age Yes 10–30% Uncommon
GAD, anfisina Adults Varies with the antigen Partial improvement 60% Uncommon
NMDAR, AMPAR, GABA (B) R, Caspr2 All ages, although more in children Varies with the antigen and age Partial or complete improvement 75–80% Varies with the antigen (10–25%)
References 1. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology. 2011;77:179–88. 2. Titulaer MJ, McCrackern L, Gabilondo I, Armangué T, Glaser C, Lizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with antiNMDA receptor encephalitis: an observational cohort study. Lancet. 2013;12: 157–65. 3. González-Valcárcel J, Rosenfeld MR, Dalmau J. Diagnóstico diferencial en la encefalitis por anticuerpos contra el receptor NMDA. Neurologia. 2010;25:409–13. 4. Lancaster E, Dalmau J. Neuronal autoantigens. Pathogenesis, associated disorders and antibody testing. Nat Rev Neurol. 2012;8:380–90. 5. Rosenfeld MR, Titulaer MJ, Dalmau J. Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract. 2012;2:215–23. 6. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
Fever induced by hydroxycarbamide夽 Fiebre por hidroxiurea Dear Editor, Drug-induced fever is a rare clinical problem, although its actual incidence is unknown because it is probably underdiagnosed.1,2 The list of drugs involved is extensive, although beta-lactam antibiotics seem to stand out due to their frequency.3 We present a case of fever induced by hydroxyurea (HU) without any other accompanying clinical manifestations. It is a 66-year-old male with no history of interest except hypertension, dyslipidaemia and depressive syndrome, under treatment with aspirin, simvastatin, clomipramine, olmesartan medoxomil, amlodipine and hydrochlorothiazide. Diagnosed with essential thrombocythemia 7 years before, carrier of the V617F mutation in the JAK2 gene, without treatment during 3 weeks before admission, when HU administration started with a dose of 1000 mg/day. Admitted due to a 10-day long condition of malaise, myalgia and fever without any focal clinical evidence. Examination revealed a temperature of 39 ◦ C and a systolic murmur. No skin lesions were observed. The blood count was normal, without eosinophilia. Biochemical studies showed values of 69 U/L AST, 55 U/L ALT and 24.4 mg/dL C-reactive protein, with no other abnormalities. Blood culture, urine culture, Legionella and pneumococcus antigen detection in urine and cytomegalovirus, Epstein–Barr virus, HIV, syphilis, Brucella, Mycoplasma, Coxiella burnetii and Chlamydia serology were all negative. The chest radiograph was normal and abdominal ultrasonography showed a hyperechogenic liver relative to fatty infiltration and increased prostate size. HU was discontinued at admission, with fever remission in 36 h. Its controlled administration was resumed two weeks later with a single dose of 500 mg, showing recurrence of fever after 8 h.
夽 Please cite this article as: Lizarralde Palacios E, Gutiérrez Macías A, Rámiz Martínez M, Escalante Boleas M. Fiebre por hidroxiurea. Med Clin (Barc). 2015;145:505–506.
7. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology. 2012;79:1094–100.
Rosa Escudero Sánchez a,∗ , María Teresa Montojo Villasanta b , María Isabel González Anglada a a
Servicio Medicina Interna, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain b Servicio Neurología, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (R. Escudero Sánchez).
It has been estimated that drug-induced fever accounts for 0.01–5% of adverse drug reactions in hospitalized patients.1–3 It is defined as a febrile reaction related to drug administration, which disappears as soon as the drug is interrupted and in the absence of other causes that may explain it.3,4 The most common mechanism for fever is a hypersensitivity reaction1 ; although in these cases the fever is usually accompanied by skin lesions, eosinophilia or other manifestations, in the context of a delayed hypersensitivity syndrome or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.5 In the definition of drug-induced fever, patients in whom the fever is accompanied by skin lesions are specifically excluded.2,3 In the case of antineoplastic agents, the pharmacological action itself, which leads to cell necrosis and release of potential pyrogens, could contribute to the onset of fever.1 Early recognition of drug-induced fever is vital to avoid prolonged hospitalizations, unnecessary diagnostic procedures or treatments as well as new exposures to the inducing drug. Our case meets the criteria of causality established in the algorithm Karch and Lasagna,6 which classifies the adverse effect as clearly defined; however, compliance with these criteria requires rechallenge, which is not without risk and should not be done in severe cases.1 The HU or hydroxyurea is an anticancer drug whose mechanism of action is the blocking of DNA synthesis mediated by the inhibition of the ribonucleotide reductase enzyme. It is used in the treatment of myeloproliferative diseases with negative Philadelphia chromosome and sickle cell anaemia. It is usually well tolerated; the most common side effects are myelosuppression with occurrence of peripheral cytopenias, digestive intolerance and skin lesions associated with its use, among which hyperpigmentation, alopecia and painful skin and mucous ulcers stand out. Pulmonary complications such as pneumonitis or bronchiolitis and drug-induced fever are less frequent.7 In a large series of 3411 patients treated with HU, drug-induced fever was observed in 0.5%.8 38 cases have been reported in the literature, including those reported in the series just mentioned and reviewed by Doutrelon et al.,9 no cases have been published in Spanish literature [Spanish Medical Index; search strategy of “hidroxiurea” (hydroxyurea) or “hidroxicarbamida” (hydroxycarbamide)
506
Scientific letters / Med Clin (Barc). 2015;145(11):504–506
and “fiebre” (fever)]. Fever appeared after an average of 21 days of treatment, was high (median 40 ◦ C), well tolerated and rapidly disappeared after discontinuation of treatment. Re-exposure to HU occurred in 50% of cases, which was positive in all cases except one.9 In short, we present a case of drug-induced fever associated to HU with characteristics consistent with those previously reported, being the first case study on Spanish literature. References 1. Patel RA, Gallagher JC. Drug fever. Pharmacotherapy. 2010;30:57–69. 2. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am. 1996;10: 85–91. 3. Vodovar D, LeBeller C, Mégarbane B, Lillo-Le-Louet A, Hanslik T. Drug fever: a descriptive cohort study from the French national pharmacovigilance database. Drug Saf. 2012;35:759–67. 4. Vodovar D, Le Beller C, Lillo-Le-Louet A, Hanslik T, Megarbane B. Fièvre médicamenteuse: Un diagnostic à ne pas oublier. Rev Med Interne. 2014;35: 183–8.
5. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588–97. 6. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977;21:247–54. 7. Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders. Expert Rev Anticancer Ther. 2011;11:403–14. 8. Antonioli E, Guglielmelli P, Pieri L, Finazzi M, Rumi E, Martinelli V, et al. Hydroxyurea-related toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol. 2012;87:552–4. 9. Doutrelon C, Lazaro E, Ribeiro E, Greib C, Pellegrin JL, Viallard JF. Hyperthermie induite par l’hydroxyurée: à propos de 4 cas et revue de la littérature. Rev Med Interne. 2015;36:73–7.
Eva Lizarralde Palacios, Alfonso Gutiérrez Macías ∗ , Mayte Rámiz Martínez, Mikel Escalante Boleas Servicio de Medicina Interna, Hospital Universitario Basurto, Bilbao, Vizcaya, Spain ∗ Corresponding author. E-mail address: [email protected] (A. Gutiérrez Macías).