Journal of Clinical Virology 61 (2014) 453–455
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Persistent spiking fever in a child with acute myeloid leukemia and disseminated infection with enterovirus J.L. Murk a,∗ , A.C. de Vries c , C.H. GeurtsvanKessel a , G. Aron a , A.D. Osterhaus a , K.C. Wolthers b , P.L. Fraaij a,d a
Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands c Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands d Department of Pediatrics, Subdivision of Infectious Diseases and Immunology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 23 July 2014 Received in revised form 8 September 2014 Accepted 14 September 2014 Keywords: Enterovirus Echovirus 20 Acute myeloid leukemia Spiking fever Immunoglobulin therapy
a b s t r a c t We here report a 7 year old acute myeloid leukemia patient with persistent spiking fever likely caused by chronic echovirus 20 infection. After immunoglobulin substitution fevers subsided and the virus was cleared. Enterovirus infection should be considered in immunocompromised patients with unexplained persistent fever. © 2014 Elsevier B.V. All rights reserved.
1. Why this case is important Infections are a leading cause of morbidity and mortality in severely immunocompromised oncology patients. Therefore, when neutropenic oncology patients develop fever they require immediate medical attention and antimicrobial treatment. The case we present suffered from spiking fever that was most likely caused by a persistent infection with echovirus 20 (E-20). The case is of importance because non-polio enteroviruses (NPEV) are not routinely tested for or associated with spiking fever. Identification of a causative agent is pivotal to start targeted therapy and reduce unnecessary prescription of antibiotics. 2. Case description A seven year old boy was referred to our hospital after two months of weight loss, malaise, anorexia, vomiting and fever. In addition, he had suffered from concomitant respiratory tract infection in the weeks before admission. The boy had a history of mild
∗ Corresponding author. Current address: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. E-mail address: [email protected] (J.L. Murk). http://dx.doi.org/10.1016/j.jcv.2014.09.006 1386-6532/© 2014 Elsevier B.V. All rights reserved.
asthma, allergic rhinitis, and recurrent respiratory tract infections. At the age of five, he had suffered from aseptic meningitis associated with an enterovirus from which he had fully recovered. He was vaccinated according to the Dutch national vaccination program and had protective antibody levels to DTaP, poliovirus and measles. Physical examination revealed a boy of 27 kg with a non-tender enlarged lymph node next to his right sternocleidomastoid muscle, a herpetic ulcer on his lower lip, petechia on his trunk and ecchymosis on his earlobes. Laboratory diagnosis showed anemia (8.2 g/dl), thrombocytopenia and normal leukocyte count with 13% blasts. Hepatic and renal functions were normal, C-reactive protein (CRP) was slightly elevated (19 mg/l). Cytological examination at the day of admission of bone marrow was consistent with AML, and subsequently induction chemotherapy was started according to the AML-DB01 protocol, consisting of etoposide, cytarabine, idarubicine and tioguanine. During treatment for AML the child developed spiking fevers up to 40.5 ◦ C (see Fig. 1) with CRP elevations up to 95 mg/l (normal reference interval: 0–10). Extensive investigations were performed to find a causative agent. Daily bacterial blood cultures remained negative except for an incidental culture with a contaminant (Sphingomonas paucimobilis and coagulase-negative Staphylococcus on day 24 of admission, Lactobacillus on day 32, Abiotrophia adiacens on day 38). There were
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J.L. Murk et al. / Journal of Clinical Virology 61 (2014) 453–455
Local infiltration by malignant cells in the CNS was ruled out by examination of CSF. However, now CSF tested positive for E-20 (CT-value enterovirus PCR 26.6, CSF contained no erythrocytes). IVIg therapy was attempted again, but from a different provider (Flebogamma 1 g/kg, Lamepro/Grifols Inc.) to avoid the previous hypersensitivity reaction. This time IVIg was tolerated. After IVIg infusion, body temperature rapidly normalized and the enterovirus load in blood diminished (Fig. 1). IVIg therapy of the same lot was administered two times a week and continued for two months. The boy’s recovery from E-20 infection was uneventful, although he subsequently developed fever due to a catheter associated infection with coagulase negative Staphylococci, which was treated with vancomycin and by eventually replacing all lines. After one month the enterovirus was undetectable in blood and on routine testing at 6 months in CSF. Fig. 1. Measurements of temperature and enteroviral load in child with AML. Course of temperature in ◦ C (upper panel) and CT-value of enterovirus PCR (lower panel) in blood samples of patient. Numbers on x-axis represent day after admission. Solid black line: administration of chemotherapy. Striped line: administration of IVIg (first time: Kiovig, second time: Flebogamma).
no signs of fungal infection or candidaemia. With real-time PCR on plasma no adenovirus, herpes simplex viruses, varicella zoster virus, Epstein–Barr virus, cytomegalovirus and human herpes virus type 6 was detected. The child was not infected with HIV or hepatitis B virus. The fever persisted under broad spectrum antibiotics (first vancomycin and ceftazidime, later vancomycin and meropenem). Due to the presence of leukemia cells in bone marrow aspirates routinely obtained after 21 days of therapy, chemotherapy was resumed with fludarabine, cytarabine, daunorubicine and methotrexate. Meanwhile spiking fevers continued. Replacement of Hickman catheter had no effect on the temperature. The presence of a fine macular rash and ongoing enterovirus infections in the community prompted us to test a serum sample for the presence of enterovirus by PCR (using an in house assay based on [9]). The serum tested positive with a cycle threshold (CT) value of 32.9. Sequence analysis of enterovirus VP1 and serotyping of the virus that was isolated from the patient’s stools showed he was infected with E-20. Serology (Virion-Serion, Würzburg, Germany) showed IgM antibodies to echovirus without IgG, but specific E20 neutralizing antibodies could not be detected with our virus neutralization assay. This prompted us to test previously stored samples for enterovirus to see if infection was present when spiking fevers started. A throat swab and cerebrospinal fluid (CSF) sample, obtained on day 1 of admission and two days before start of chemotherapy, respectively tested positive and negative with enterovirus PCR. A serum sample, obtained 3 days after administration of induction chemotherapy and 5 days after admission also was PCR positive (CT value 33.9, see Fig. 1). Sequencing of positive samples identified E-20. Blood samples from before chemotherapy were not available for testing. These findings indicate our patient had contracted E-20 before chemotherapy. In an attempt to treat the persistent enterovirus infection and correct for the boy’s low level of total serum IgG (480 mg/dl), intravenous immunoglobulin (IVIg) (Kiovig 1 g/kg, Baxter Inc.) was administered. However, administration had to be stopped and discontinued, because it induced hypertension (BP from 113/70 to 145/87, normal upper 95% for age for diastole 80) accompanied with high fever. After the second course of chemotherapy our patient continued to suffer from unremitted spiking fever without localizing symptoms or signs of central nervous system (CNS) infection. Again extensive investigations were performed to exclude an infection with bacteria, fungi, respiratory viruses or herpesviruses. All tests were negative, except for persistence of enterovirus in plasma (CT value 30.3). PET CT scan revealed no abnormalities.
3. Other similar and contrasting cases in the literature Infections with NPEV are among the most common viral infections in humans [5,11]. They often cause no symptoms at all or give rise to fever without localizing symptoms, but may generate a wide spectrum of febrile diseases with involvement of gastrointestinal or respiratory tracts, CNS or heart. NPEV infections can be accompanied by skin eruptions. In neonates infections may present with sepsis-like disease and be life threatening. Patients suffering from agammaglobulinemia are particularly at risk for developing complications, which points to the importance of the humoral immune response to control enterovirus infections. Before therapy with immunoglobulins was practised these patients often died from chronic infections of CNS [6]. In hematological patients life threatening infections with myopericarditis, multi-organ failure, encephalitis and hemophagocytic syndrome have been reported, but also benign disease with involvement of gastrointestinal or respiratory tract [1–4,8,12]. Unfortunately systematic studies have not been published. The association of NPEV infection with spiking fever has never been reported.
4. Discussion The disseminated infection with echovirus was the only potential causative agent we found for the spiking fever. We find the causal relationship likely because (1) fever is often the only symptom of NPEV infections, (2) long-lasting fever has been noted in patients with persistent echovirus infections of the CNS, (3) fever did not respond to broad spectrum antibiotics, (4) temperature rapidly normalized after IVIg infusion with concomitant decrease of E-20 load in blood. Unfortunately, fever reappeared after three days and blood cultures became positive with coagulase negative Staphylococci and a line-associated infection was diagnosed eventually. No evidence for a line-associated infection had been found in preceding fever episodes. Observations on the duration of NPEV viremia in hematological patients are almost non-existent. The general belief is that viremia is rare and short-lived, even in patients with agammaglobulinemia [10]. To the best of our knowledge, our case shows for the first time that children with AML may suffer from long-lasting E-20 viremia. A possible explanation for viral persistence is the suppression of both T and B-cell numbers and function as observed in patients suffering from the combined effects AML and chemotherapy. This was also reflected by the low level of total serum IgG. An alternative explanation may be a pre-existing humoral immune deficiency; however, this is unlikely because normal for age antibody titers and vaccination response to measles, DTaP and polio vaccines were present before chemotherapy.
J.L. Murk et al. / Journal of Clinical Virology 61 (2014) 453–455
IVIg therapy has been used before to treat life-threatening infections with enteroviruses [13]. Abzug observed, after one dose of 750 mg/kg, that treatment in neonates was only effective when the neutralizing antibody titer was ≥1:800 (reviewed in [13]). In another report a patient temporarily improved after repeated infusions of immunoglobulins with neutralizing antibody titers of 1:32, but eventually died after the infection had reappeared [7]. It is uncertain which neutralizing antibody titers are required to induce a clinical response or viral clearance. Our patient appears to have responded to 1 g/kg IVIg with a neutralizing antibody titer of 1:128 (using the patient’s E-20 isolate in the neutralization test). At that time the child was leukopenic and received chemotherapy, which suggests the effect was not due to immune reconstitution. IVIg was continued for one month after E-20 had become undetectable in blood to prevent reoccurrence of viremia from a potential site of E-20 persistence such as CSF. In conclusion we report that in pediatric hematological patients NPEV infections may cause long-lasting viremia and present like bacterial infections with persistent spiking fever. Our case is a reminder that during the enterovirus season a correct diagnosis may not only reduce unneeded antibiotics but also allow for targeted therapy. More research is needed to elucidate how enterovirus infections affect severely immunocompromised pediatric patients. Funding PF and AO participate in the IRIS trail sponsored by Hoffmann-La Roche, Inc. AO is a part time employee of Viroclinics Biosciences BV and performs contact research for pharmaceutical companies. PF and AO are financially supported by the Virgo consortium, which is funded by the Dutch government project number FES0908. Competing interests None declared.
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Ethical approval Not required. References [1] Aquino VM, Farah RA, Lee MC, Sandler ES. Disseminated coxsackie A9 infection complicating bone marrow transplantation. Pediatr Infect Dis J 1996;15:1053–4. [2] Biggs DD, Toorkey BC, Carrigan DR, Hanson GA, Ash RC. Disseminated echovirus infection complicating bone marrow transplantation. Am J Med 1990;88:421–5. [3] Galama JM, de Leeuw N, Wittebol S, Peters H, Melchers WJ. Prolonged enteroviral infection in a patient who developed pericarditis and heart failure after bone marrow transplantation. Clin Infect Dis 1996;22:1004–8. [4] Katsibardi K, Moschovi MA, Theodoridou M, Spanakis N, Kalabalikis P, Tsakris A, et al. Enterovirus-associated hemophagocytic syndrome in children with malignancy: report of three cases and review of the literature. Eur J Pediatr 2008;167:97–102. [5] Kogon A, Spigland I, Frothingham TE, Elveback L, Williams C, Hall CE, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VII. Observations on viral excretion, seroimmunity, intrafamilial spread and illness association in coxsackie and echovirus infections. Am J Epidemiol 1969;89:51–61. [6] McKinney Jr RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334–56. [7] Mease PJ, Ochs HD, Corey L, Dragavon J, Wedgwood RJ. Echovirus encephalitis/myositis in X-linked agammaglobulinemia. N Engl J Med 1985;313:758. [8] Moschovi MA, Katsibardi K, Theodoridou M, Michos AG, Tsakris A, Spanakis N, et al. Enteroviral infections in children with malignant disease: a 5-year study in a single institution. J Infect 2007;54:387–92. [9] Nix WA, Oberste MS, Pallansch MA. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698–704. [10] Rotbart HA, Romero JR. Laboratory diagnosis of enteroviral infections. In: Rotbart HA, editor. Human enterovirus infections. Washington, DC: ASM Press; 1995. p. 413–4. [11] Tapparel C, Siegrist F, Petty TJ, Kaiser L. Picornavirus and enterovirus diversity with associated human diseases. Infect Genet Evol 2013;14:282–93. [12] Townsend TR, Bolyard EA, Yolken RH, Beschorner WE, Bishop CA, Burns WH, et al. Outbreak of Coxsackie A1 gastroenteritis: a complication of bone-marrow transplantation. Lancet 1982;1:820–3. [13] Wildenbeest JG, Harvala H, Pajkrt D, Wolthers KC. The need for treatment against human parechoviruses: how, why and when? Expert Rev Anti Infect Ther 2011;8:1417–29.
Contents lists available at ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Persistent spiking fever in a child with acute myeloid leukemia and disseminated infection with enterovirus J.L. Murk a,∗ , A.C. de Vries c , C.H. GeurtsvanKessel a , G. Aron a , A.D. Osterhaus a , K.C. Wolthers b , P.L. Fraaij a,d a
Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands Laboratory of Clinical Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands c Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands d Department of Pediatrics, Subdivision of Infectious Diseases and Immunology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 23 July 2014 Received in revised form 8 September 2014 Accepted 14 September 2014 Keywords: Enterovirus Echovirus 20 Acute myeloid leukemia Spiking fever Immunoglobulin therapy
a b s t r a c t We here report a 7 year old acute myeloid leukemia patient with persistent spiking fever likely caused by chronic echovirus 20 infection. After immunoglobulin substitution fevers subsided and the virus was cleared. Enterovirus infection should be considered in immunocompromised patients with unexplained persistent fever. © 2014 Elsevier B.V. All rights reserved.
1. Why this case is important Infections are a leading cause of morbidity and mortality in severely immunocompromised oncology patients. Therefore, when neutropenic oncology patients develop fever they require immediate medical attention and antimicrobial treatment. The case we present suffered from spiking fever that was most likely caused by a persistent infection with echovirus 20 (E-20). The case is of importance because non-polio enteroviruses (NPEV) are not routinely tested for or associated with spiking fever. Identification of a causative agent is pivotal to start targeted therapy and reduce unnecessary prescription of antibiotics. 2. Case description A seven year old boy was referred to our hospital after two months of weight loss, malaise, anorexia, vomiting and fever. In addition, he had suffered from concomitant respiratory tract infection in the weeks before admission. The boy had a history of mild
∗ Corresponding author. Current address: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands. E-mail address: [email protected] (J.L. Murk). http://dx.doi.org/10.1016/j.jcv.2014.09.006 1386-6532/© 2014 Elsevier B.V. All rights reserved.
asthma, allergic rhinitis, and recurrent respiratory tract infections. At the age of five, he had suffered from aseptic meningitis associated with an enterovirus from which he had fully recovered. He was vaccinated according to the Dutch national vaccination program and had protective antibody levels to DTaP, poliovirus and measles. Physical examination revealed a boy of 27 kg with a non-tender enlarged lymph node next to his right sternocleidomastoid muscle, a herpetic ulcer on his lower lip, petechia on his trunk and ecchymosis on his earlobes. Laboratory diagnosis showed anemia (8.2 g/dl), thrombocytopenia and normal leukocyte count with 13% blasts. Hepatic and renal functions were normal, C-reactive protein (CRP) was slightly elevated (19 mg/l). Cytological examination at the day of admission of bone marrow was consistent with AML, and subsequently induction chemotherapy was started according to the AML-DB01 protocol, consisting of etoposide, cytarabine, idarubicine and tioguanine. During treatment for AML the child developed spiking fevers up to 40.5 ◦ C (see Fig. 1) with CRP elevations up to 95 mg/l (normal reference interval: 0–10). Extensive investigations were performed to find a causative agent. Daily bacterial blood cultures remained negative except for an incidental culture with a contaminant (Sphingomonas paucimobilis and coagulase-negative Staphylococcus on day 24 of admission, Lactobacillus on day 32, Abiotrophia adiacens on day 38). There were
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J.L. Murk et al. / Journal of Clinical Virology 61 (2014) 453–455
Local infiltration by malignant cells in the CNS was ruled out by examination of CSF. However, now CSF tested positive for E-20 (CT-value enterovirus PCR 26.6, CSF contained no erythrocytes). IVIg therapy was attempted again, but from a different provider (Flebogamma 1 g/kg, Lamepro/Grifols Inc.) to avoid the previous hypersensitivity reaction. This time IVIg was tolerated. After IVIg infusion, body temperature rapidly normalized and the enterovirus load in blood diminished (Fig. 1). IVIg therapy of the same lot was administered two times a week and continued for two months. The boy’s recovery from E-20 infection was uneventful, although he subsequently developed fever due to a catheter associated infection with coagulase negative Staphylococci, which was treated with vancomycin and by eventually replacing all lines. After one month the enterovirus was undetectable in blood and on routine testing at 6 months in CSF. Fig. 1. Measurements of temperature and enteroviral load in child with AML. Course of temperature in ◦ C (upper panel) and CT-value of enterovirus PCR (lower panel) in blood samples of patient. Numbers on x-axis represent day after admission. Solid black line: administration of chemotherapy. Striped line: administration of IVIg (first time: Kiovig, second time: Flebogamma).
no signs of fungal infection or candidaemia. With real-time PCR on plasma no adenovirus, herpes simplex viruses, varicella zoster virus, Epstein–Barr virus, cytomegalovirus and human herpes virus type 6 was detected. The child was not infected with HIV or hepatitis B virus. The fever persisted under broad spectrum antibiotics (first vancomycin and ceftazidime, later vancomycin and meropenem). Due to the presence of leukemia cells in bone marrow aspirates routinely obtained after 21 days of therapy, chemotherapy was resumed with fludarabine, cytarabine, daunorubicine and methotrexate. Meanwhile spiking fevers continued. Replacement of Hickman catheter had no effect on the temperature. The presence of a fine macular rash and ongoing enterovirus infections in the community prompted us to test a serum sample for the presence of enterovirus by PCR (using an in house assay based on [9]). The serum tested positive with a cycle threshold (CT) value of 32.9. Sequence analysis of enterovirus VP1 and serotyping of the virus that was isolated from the patient’s stools showed he was infected with E-20. Serology (Virion-Serion, Würzburg, Germany) showed IgM antibodies to echovirus without IgG, but specific E20 neutralizing antibodies could not be detected with our virus neutralization assay. This prompted us to test previously stored samples for enterovirus to see if infection was present when spiking fevers started. A throat swab and cerebrospinal fluid (CSF) sample, obtained on day 1 of admission and two days before start of chemotherapy, respectively tested positive and negative with enterovirus PCR. A serum sample, obtained 3 days after administration of induction chemotherapy and 5 days after admission also was PCR positive (CT value 33.9, see Fig. 1). Sequencing of positive samples identified E-20. Blood samples from before chemotherapy were not available for testing. These findings indicate our patient had contracted E-20 before chemotherapy. In an attempt to treat the persistent enterovirus infection and correct for the boy’s low level of total serum IgG (480 mg/dl), intravenous immunoglobulin (IVIg) (Kiovig 1 g/kg, Baxter Inc.) was administered. However, administration had to be stopped and discontinued, because it induced hypertension (BP from 113/70 to 145/87, normal upper 95% for age for diastole 80) accompanied with high fever. After the second course of chemotherapy our patient continued to suffer from unremitted spiking fever without localizing symptoms or signs of central nervous system (CNS) infection. Again extensive investigations were performed to exclude an infection with bacteria, fungi, respiratory viruses or herpesviruses. All tests were negative, except for persistence of enterovirus in plasma (CT value 30.3). PET CT scan revealed no abnormalities.
3. Other similar and contrasting cases in the literature Infections with NPEV are among the most common viral infections in humans [5,11]. They often cause no symptoms at all or give rise to fever without localizing symptoms, but may generate a wide spectrum of febrile diseases with involvement of gastrointestinal or respiratory tracts, CNS or heart. NPEV infections can be accompanied by skin eruptions. In neonates infections may present with sepsis-like disease and be life threatening. Patients suffering from agammaglobulinemia are particularly at risk for developing complications, which points to the importance of the humoral immune response to control enterovirus infections. Before therapy with immunoglobulins was practised these patients often died from chronic infections of CNS [6]. In hematological patients life threatening infections with myopericarditis, multi-organ failure, encephalitis and hemophagocytic syndrome have been reported, but also benign disease with involvement of gastrointestinal or respiratory tract [1–4,8,12]. Unfortunately systematic studies have not been published. The association of NPEV infection with spiking fever has never been reported.
4. Discussion The disseminated infection with echovirus was the only potential causative agent we found for the spiking fever. We find the causal relationship likely because (1) fever is often the only symptom of NPEV infections, (2) long-lasting fever has been noted in patients with persistent echovirus infections of the CNS, (3) fever did not respond to broad spectrum antibiotics, (4) temperature rapidly normalized after IVIg infusion with concomitant decrease of E-20 load in blood. Unfortunately, fever reappeared after three days and blood cultures became positive with coagulase negative Staphylococci and a line-associated infection was diagnosed eventually. No evidence for a line-associated infection had been found in preceding fever episodes. Observations on the duration of NPEV viremia in hematological patients are almost non-existent. The general belief is that viremia is rare and short-lived, even in patients with agammaglobulinemia [10]. To the best of our knowledge, our case shows for the first time that children with AML may suffer from long-lasting E-20 viremia. A possible explanation for viral persistence is the suppression of both T and B-cell numbers and function as observed in patients suffering from the combined effects AML and chemotherapy. This was also reflected by the low level of total serum IgG. An alternative explanation may be a pre-existing humoral immune deficiency; however, this is unlikely because normal for age antibody titers and vaccination response to measles, DTaP and polio vaccines were present before chemotherapy.
J.L. Murk et al. / Journal of Clinical Virology 61 (2014) 453–455
IVIg therapy has been used before to treat life-threatening infections with enteroviruses [13]. Abzug observed, after one dose of 750 mg/kg, that treatment in neonates was only effective when the neutralizing antibody titer was ≥1:800 (reviewed in [13]). In another report a patient temporarily improved after repeated infusions of immunoglobulins with neutralizing antibody titers of 1:32, but eventually died after the infection had reappeared [7]. It is uncertain which neutralizing antibody titers are required to induce a clinical response or viral clearance. Our patient appears to have responded to 1 g/kg IVIg with a neutralizing antibody titer of 1:128 (using the patient’s E-20 isolate in the neutralization test). At that time the child was leukopenic and received chemotherapy, which suggests the effect was not due to immune reconstitution. IVIg was continued for one month after E-20 had become undetectable in blood to prevent reoccurrence of viremia from a potential site of E-20 persistence such as CSF. In conclusion we report that in pediatric hematological patients NPEV infections may cause long-lasting viremia and present like bacterial infections with persistent spiking fever. Our case is a reminder that during the enterovirus season a correct diagnosis may not only reduce unneeded antibiotics but also allow for targeted therapy. More research is needed to elucidate how enterovirus infections affect severely immunocompromised pediatric patients. Funding PF and AO participate in the IRIS trail sponsored by Hoffmann-La Roche, Inc. AO is a part time employee of Viroclinics Biosciences BV and performs contact research for pharmaceutical companies. PF and AO are financially supported by the Virgo consortium, which is funded by the Dutch government project number FES0908. Competing interests None declared.
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Ethical approval Not required. References [1] Aquino VM, Farah RA, Lee MC, Sandler ES. Disseminated coxsackie A9 infection complicating bone marrow transplantation. Pediatr Infect Dis J 1996;15:1053–4. [2] Biggs DD, Toorkey BC, Carrigan DR, Hanson GA, Ash RC. Disseminated echovirus infection complicating bone marrow transplantation. Am J Med 1990;88:421–5. [3] Galama JM, de Leeuw N, Wittebol S, Peters H, Melchers WJ. Prolonged enteroviral infection in a patient who developed pericarditis and heart failure after bone marrow transplantation. Clin Infect Dis 1996;22:1004–8. [4] Katsibardi K, Moschovi MA, Theodoridou M, Spanakis N, Kalabalikis P, Tsakris A, et al. Enterovirus-associated hemophagocytic syndrome in children with malignancy: report of three cases and review of the literature. Eur J Pediatr 2008;167:97–102. [5] Kogon A, Spigland I, Frothingham TE, Elveback L, Williams C, Hall CE, et al. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VII. Observations on viral excretion, seroimmunity, intrafamilial spread and illness association in coxsackie and echovirus infections. Am J Epidemiol 1969;89:51–61. [6] McKinney Jr RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334–56. [7] Mease PJ, Ochs HD, Corey L, Dragavon J, Wedgwood RJ. Echovirus encephalitis/myositis in X-linked agammaglobulinemia. N Engl J Med 1985;313:758. [8] Moschovi MA, Katsibardi K, Theodoridou M, Michos AG, Tsakris A, Spanakis N, et al. Enteroviral infections in children with malignant disease: a 5-year study in a single institution. J Infect 2007;54:387–92. [9] Nix WA, Oberste MS, Pallansch MA. Sensitive, seminested PCR amplification of VP1 sequences for direct identification of all enterovirus serotypes from original clinical specimens. J Clin Microbiol 2006;44:2698–704. [10] Rotbart HA, Romero JR. Laboratory diagnosis of enteroviral infections. In: Rotbart HA, editor. Human enterovirus infections. Washington, DC: ASM Press; 1995. p. 413–4. [11] Tapparel C, Siegrist F, Petty TJ, Kaiser L. Picornavirus and enterovirus diversity with associated human diseases. Infect Genet Evol 2013;14:282–93. [12] Townsend TR, Bolyard EA, Yolken RH, Beschorner WE, Bishop CA, Burns WH, et al. Outbreak of Coxsackie A1 gastroenteritis: a complication of bone-marrow transplantation. Lancet 1982;1:820–3. [13] Wildenbeest JG, Harvala H, Pajkrt D, Wolthers KC. The need for treatment against human parechoviruses: how, why and when? Expert Rev Anti Infect Ther 2011;8:1417–29.
