Viral Findings in Adult Hematological Patients with Neutropenia
Identifieur interne : 000A14 ( Pmc/Corpus ); précédent : 000A13; suivant : 000A15Viral Findings in Adult Hematological Patients with Neutropenia
Auteurs : Lars Öhrmalm ; Michelle Wong ; Carl Aust ; Per Ljungman ; Oscar Norbeck ; Kristina Broliden ; Thomas TolfvenstamSource :
- PLoS ONE [ 1932-6203 ] ; 2012.
Abstract
Until recently, viral infections in patients with hematological malignancies were concerns primarily in allogeneic hematopoietic stem cell transplant (HSCT) recipients. During the last years, changed treatment regimens for non-transplanted patients with hematological malignancies have had potential to increase the incidence of viral infections in this group. In this study, we have prospectively investigated the prevalence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT.
Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group. Furthermore, viral findings in NPA were associated with upper respiratory symptoms (URTS) (p<0.0001).
Both respiratory viral infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. These findings motivate further studies on viruses' impact on this patient category and their potential role as causative agents of fever during neutropenia.
Url:
DOI: 10.1371/journal.pone.0036543
PubMed: 22570724
PubMed Central: 3343003
Links to Exploration step
PMC:3343003Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Viral Findings in Adult Hematological Patients with Neutropenia</title><author><name sortKey="Ohrmalm, Lars" sort="Ohrmalm, Lars" uniqKey="Ohrmalm L" first="Lars" last="Öhrmalm">Lars Öhrmalm</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wong, Michelle" sort="Wong, Michelle" uniqKey="Wong M" first="Michelle" last="Wong">Michelle Wong</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aust, Carl" sort="Aust, Carl" uniqKey="Aust C" first="Carl" last="Aust">Carl Aust</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ljungman, Per" sort="Ljungman, Per" uniqKey="Ljungman P" first="Per" last="Ljungman">Per Ljungman</name><affiliation><nlm:aff id="aff2"><addr-line>Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Hematology Centre, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Norbeck, Oscar" sort="Norbeck, Oscar" uniqKey="Norbeck O" first="Oscar" last="Norbeck">Oscar Norbeck</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Broliden, Kristina" sort="Broliden, Kristina" uniqKey="Broliden K" first="Kristina" last="Broliden">Kristina Broliden</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tolfvenstam, Thomas" sort="Tolfvenstam, Thomas" uniqKey="Tolfvenstam T" first="Thomas" last="Tolfvenstam">Thomas Tolfvenstam</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22570724</idno><idno type="pmc">3343003</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343003</idno><idno type="RBID">PMC:3343003</idno><idno type="doi">10.1371/journal.pone.0036543</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000A14</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A14</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Viral Findings in Adult Hematological Patients with Neutropenia</title><author><name sortKey="Ohrmalm, Lars" sort="Ohrmalm, Lars" uniqKey="Ohrmalm L" first="Lars" last="Öhrmalm">Lars Öhrmalm</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wong, Michelle" sort="Wong, Michelle" uniqKey="Wong M" first="Michelle" last="Wong">Michelle Wong</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Aust, Carl" sort="Aust, Carl" uniqKey="Aust C" first="Carl" last="Aust">Carl Aust</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ljungman, Per" sort="Ljungman, Per" uniqKey="Ljungman P" first="Per" last="Ljungman">Per Ljungman</name><affiliation><nlm:aff id="aff2"><addr-line>Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>Hematology Centre, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Norbeck, Oscar" sort="Norbeck, Oscar" uniqKey="Norbeck O" first="Oscar" last="Norbeck">Oscar Norbeck</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Broliden, Kristina" sort="Broliden, Kristina" uniqKey="Broliden K" first="Kristina" last="Broliden">Kristina Broliden</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tolfvenstam, Thomas" sort="Tolfvenstam, Thomas" uniqKey="Tolfvenstam T" first="Thomas" last="Tolfvenstam">Thomas Tolfvenstam</name><affiliation><nlm:aff id="aff1"><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Until recently, viral infections in patients with hematological malignancies were concerns primarily in allogeneic hematopoietic stem cell transplant (HSCT) recipients. During the last years, changed treatment regimens for non-transplanted patients with hematological malignancies have had potential to increase the incidence of viral infections in this group. In this study, we have prospectively investigated the prevalence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT.</p></sec><sec><title>Methodology/Principal Findings</title><p>Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group. Furthermore, viral findings in NPA were associated with upper respiratory symptoms (URTS) (p<0.0001).</p></sec><sec><title>Conclusions/Significance</title><p>Both respiratory viral infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. These findings motivate further studies on viruses' impact on this patient category and their potential role as causative agents of fever during neutropenia.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Martin, Et" uniqKey="Martin E">ET Martin</name></author><author><name sortKey="Kuypers, J" uniqKey="Kuypers J">J Kuypers</name></author><author><name sortKey="Wald, A" uniqKey="Wald A">A Wald</name></author><author><name sortKey="Englund, Ja" uniqKey="Englund J">JA Englund</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Englund, J" uniqKey="Englund J">J Englund</name></author><author><name sortKey="Feuchtinger, T" uniqKey="Feuchtinger T">T Feuchtinger</name></author><author><name sortKey="Ljungman, P" uniqKey="Ljungman P">P Ljungman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arola, M" uniqKey="Arola M">M Arola</name></author><author><name sortKey="Ruuskanen, O" uniqKey="Ruuskanen O">O Ruuskanen</name></author><author><name sortKey="Ziegler, T" uniqKey="Ziegler T">T Ziegler</name></author><author><name sortKey="Salmi, Tt" uniqKey="Salmi T">TT Salmi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koskenvuo, M" uniqKey="Koskenvuo M">M Koskenvuo</name></author><author><name sortKey="Mottonen, M" uniqKey="Mottonen M">M Mottonen</name></author><author><name sortKey="Rahiala, J" uniqKey="Rahiala J">J Rahiala</name></author><author><name sortKey="Saarinen Pihkala, Um" uniqKey="Saarinen Pihkala U">UM Saarinen-Pihkala</name></author><author><name sortKey="Riikonen, P" uniqKey="Riikonen P">P Riikonen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lindblom, A" uniqKey="Lindblom A">A Lindblom</name></author><author><name sortKey="Bhadri, V" uniqKey="Bhadri V">V Bhadri</name></author><author><name sortKey="Soderhall, S" uniqKey="Soderhall S">S Soderhall</name></author><author><name sortKey="Ohrmalm, L" uniqKey="Ohrmalm L">L Ohrmalm</name></author><author><name sortKey="Wong, M" uniqKey="Wong M">M Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ljungman, P" uniqKey="Ljungman P">P Ljungman</name></author><author><name sortKey="Von Dobeln, L" uniqKey="Von Dobeln L">L von Dobeln</name></author><author><name sortKey="Ringholm, L" uniqKey="Ringholm L">L Ringholm</name></author><author><name sortKey="Lewensohn Fuchs, I" uniqKey="Lewensohn Fuchs I">I Lewensohn-Fuchs</name></author><author><name sortKey="Klingspor, L" uniqKey="Klingspor L">L Klingspor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ng, Ap" uniqKey="Ng A">AP Ng</name></author><author><name sortKey="Worth, L" uniqKey="Worth L">L Worth</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author><author><name sortKey="Seymour, Jf" uniqKey="Seymour J">JF Seymour</name></author><author><name sortKey="Prince, Hm" uniqKey="Prince H">HM Prince</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Persson, L" uniqKey="Persson L">L Persson</name></author><author><name sortKey="Dahl, H" uniqKey="Dahl H">H Dahl</name></author><author><name sortKey="Linde, A" uniqKey="Linde A">A Linde</name></author><author><name sortKey="Engervall, P" uniqKey="Engervall P">P Engervall</name></author><author><name sortKey="Vikerfors, T" uniqKey="Vikerfors T">T Vikerfors</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pizzo, Pa" uniqKey="Pizzo P">PA Pizzo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lawson, Rd" uniqKey="Lawson R">RD Lawson</name></author><author><name sortKey="Gentry, Lo" uniqKey="Gentry L">LO Gentry</name></author><author><name sortKey="Bodey, Gp" uniqKey="Bodey G">GP Bodey</name></author><author><name sortKey="Keating, Mj" uniqKey="Keating M">MJ Keating</name></author><author><name sortKey="Smith, Tl" uniqKey="Smith T">TL Smith</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hughes, Wt" uniqKey="Hughes W">WT Hughes</name></author><author><name sortKey="Armstrong, D" uniqKey="Armstrong D">D Armstrong</name></author><author><name sortKey="Bodey, Gp" uniqKey="Bodey G">GP Bodey</name></author><author><name sortKey="Bow, Ej" uniqKey="Bow E">EJ Bow</name></author><author><name sortKey="Brown, Ae" uniqKey="Brown A">AE Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mancini, N" uniqKey="Mancini N">N Mancini</name></author><author><name sortKey="Clerici, D" uniqKey="Clerici D">D Clerici</name></author><author><name sortKey="Diotti, R" uniqKey="Diotti R">R Diotti</name></author><author><name sortKey="Perotti, M" uniqKey="Perotti M">M Perotti</name></author><author><name sortKey="Ghidoli, N" uniqKey="Ghidoli N">N Ghidoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Whimbey, E" uniqKey="Whimbey E">E Whimbey</name></author><author><name sortKey="Kiehn, Te" uniqKey="Kiehn T">TE Kiehn</name></author><author><name sortKey="Brannon, P" uniqKey="Brannon P">P Brannon</name></author><author><name sortKey="Blevins, A" uniqKey="Blevins A">A Blevins</name></author><author><name sortKey="Armstrong, D" uniqKey="Armstrong D">D Armstrong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Viscoli, C" uniqKey="Viscoli C">C Viscoli</name></author><author><name sortKey="Cometta, A" uniqKey="Cometta A">A Cometta</name></author><author><name sortKey="Kern, Wv" uniqKey="Kern W">WV Kern</name></author><author><name sortKey="Bock, R" uniqKey="Bock R">R Bock</name></author><author><name sortKey="Paesmans, M" uniqKey="Paesmans M">M Paesmans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Englund, Ja" uniqKey="Englund J">JA Englund</name></author><author><name sortKey="Whimbey, E" uniqKey="Whimbey E">E Whimbey</name></author><author><name sortKey="Atmar, Rl" uniqKey="Atmar R">RL Atmar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gustafson, I" uniqKey="Gustafson I">I Gustafson</name></author><author><name sortKey="Lindblom, A" uniqKey="Lindblom A">A Lindblom</name></author><author><name sortKey="Yun, Z" uniqKey="Yun Z">Z Yun</name></author><author><name sortKey="Omar, H" uniqKey="Omar H">H Omar</name></author><author><name sortKey="Engstrom, L" uniqKey="Engstrom L">L Engstrom</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author><author><name sortKey="Holloway, B" uniqKey="Holloway B">B Holloway</name></author><author><name sortKey="Dare, Rk" uniqKey="Dare R">RK Dare</name></author><author><name sortKey="Kuypers, J" uniqKey="Kuypers J">J Kuypers</name></author><author><name sortKey="Yagi, S" uniqKey="Yagi S">S Yagi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nijhuis, M" uniqKey="Nijhuis M">M Nijhuis</name></author><author><name sortKey="Van Maarseveen, N" uniqKey="Van Maarseveen N">N van Maarseveen</name></author><author><name sortKey="Schuurman, R" uniqKey="Schuurman R">R Schuurman</name></author><author><name sortKey="Verkuijlen, S" uniqKey="Verkuijlen S">S Verkuijlen</name></author><author><name sortKey="De Vos, M" uniqKey="De Vos M">M de Vos</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Tiveljung Lindell, A" uniqKey="Tiveljung Lindell A">A Tiveljung-Lindell</name></author><author><name sortKey="Rotzen Ostlund, M" uniqKey="Rotzen Ostlund M">M Rotzen-Ostlund</name></author><author><name sortKey="Gupta, S" uniqKey="Gupta S">S Gupta</name></author><author><name sortKey="Ullstrand, R" uniqKey="Ullstrand R">R Ullstrand</name></author><author><name sortKey="Grillner, L" uniqKey="Grillner L">L Grillner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brittain Long, R" uniqKey="Brittain Long R">R Brittain-Long</name></author><author><name sortKey="Nord, S" uniqKey="Nord S">S Nord</name></author><author><name sortKey="Olofsson, S" uniqKey="Olofsson S">S Olofsson</name></author><author><name sortKey="Westin, J" uniqKey="Westin J">J Westin</name></author><author><name sortKey="Anderson, Lm" uniqKey="Anderson L">LM Anderson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Terlizzi, Me" uniqKey="Terlizzi M">ME Terlizzi</name></author><author><name sortKey="Massimiliano, B" uniqKey="Massimiliano B">B Massimiliano</name></author><author><name sortKey="Francesca, S" uniqKey="Francesca S">S Francesca</name></author><author><name sortKey="Sinesi, F" uniqKey="Sinesi F">F Sinesi</name></author><author><name sortKey="Rosangela, V" uniqKey="Rosangela V">V Rosangela</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chemaly, Rf" uniqKey="Chemaly R">RF Chemaly</name></author><author><name sortKey="Ghosh, S" uniqKey="Ghosh S">S Ghosh</name></author><author><name sortKey="Bodey, Gp" uniqKey="Bodey G">GP Bodey</name></author><author><name sortKey="Rohatgi, N" uniqKey="Rohatgi N">N Rohatgi</name></author><author><name sortKey="Safdar, A" uniqKey="Safdar A">A Safdar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hakim, H" uniqKey="Hakim H">H Hakim</name></author><author><name sortKey="Flynn, Pm" uniqKey="Flynn P">PM Flynn</name></author><author><name sortKey="Knapp, Km" uniqKey="Knapp K">KM Knapp</name></author><author><name sortKey="Srivastava, Dk" uniqKey="Srivastava D">DK Srivastava</name></author><author><name sortKey="Gaur, Ah" uniqKey="Gaur A">AH Gaur</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johansson, N" uniqKey="Johansson N">N Johansson</name></author><author><name sortKey="Kalin, M" uniqKey="Kalin M">M Kalin</name></author><author><name sortKey="Tiveljung Lindell, A" uniqKey="Tiveljung Lindell A">A Tiveljung-Lindell</name></author><author><name sortKey="Giske, Cg" uniqKey="Giske C">CG Giske</name></author><author><name sortKey="Hedlund, J" uniqKey="Hedlund J">J Hedlund</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Erard, V" uniqKey="Erard V">V Erard</name></author><author><name sortKey="Kim, Hw" uniqKey="Kim H">HW Kim</name></author><author><name sortKey="Corey, L" uniqKey="Corey L">L Corey</name></author><author><name sortKey="Limaye, A" uniqKey="Limaye A">A Limaye</name></author><author><name sortKey="Huang, Ml" uniqKey="Huang M">ML Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haines, Hl" uniqKey="Haines H">HL Haines</name></author><author><name sortKey="Laskin, Bl" uniqKey="Laskin B">BL Laskin</name></author><author><name sortKey="Goebel, J" uniqKey="Goebel J">J Goebel</name></author><author><name sortKey="Davies, Sm" uniqKey="Davies S">SM Davies</name></author><author><name sortKey="Yin, Hj" uniqKey="Yin H">HJ Yin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fairchok, Mp" uniqKey="Fairchok M">MP Fairchok</name></author><author><name sortKey="Martin, Et" uniqKey="Martin E">ET Martin</name></author><author><name sortKey="Chambers, S" uniqKey="Chambers S">S Chambers</name></author><author><name sortKey="Kuypers, J" uniqKey="Kuypers J">J Kuypers</name></author><author><name sortKey="Behrens, M" uniqKey="Behrens M">M Behrens</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ljungman, P" uniqKey="Ljungman P">P Ljungman</name></author><author><name sortKey="Ward, Kn" uniqKey="Ward K">KN Ward</name></author><author><name sortKey="Crooks, Bn" uniqKey="Crooks B">BN Crooks</name></author><author><name sortKey="Parker, A" uniqKey="Parker A">A Parker</name></author><author><name sortKey="Martino, R" uniqKey="Martino R">R Martino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chakrabarti, S" uniqKey="Chakrabarti S">S Chakrabarti</name></author><author><name sortKey="Mautner, V" uniqKey="Mautner V">V Mautner</name></author><author><name sortKey="Osman, H" uniqKey="Osman H">H Osman</name></author><author><name sortKey="Collingham, Ke" uniqKey="Collingham K">KE Collingham</name></author><author><name sortKey="Fegan, Cd" uniqKey="Fegan C">CD Fegan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hakki, M" uniqKey="Hakki M">M Hakki</name></author><author><name sortKey="Riddell, Sr" uniqKey="Riddell S">SR Riddell</name></author><author><name sortKey="Storek, J" uniqKey="Storek J">J Storek</name></author><author><name sortKey="Carter, Ra" uniqKey="Carter R">RA Carter</name></author><author><name sortKey="Stevens Ayers, T" uniqKey="Stevens Ayers T">T Stevens-Ayers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Engstrand, M" uniqKey="Engstrand M">M Engstrand</name></author><author><name sortKey="Lidehall, Ak" uniqKey="Lidehall A">AK Lidehall</name></author><author><name sortKey="Totterman, Th" uniqKey="Totterman T">TH Totterman</name></author><author><name sortKey="Herrman, B" uniqKey="Herrman B">B Herrman</name></author><author><name sortKey="Eriksson, Bm" uniqKey="Eriksson B">BM Eriksson</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">22570724</article-id><article-id pub-id-type="pmc">3343003</article-id><article-id pub-id-type="publisher-id">PONE-D-11-25370</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0036543</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Hematology</subject><subj-group><subject>Hematologic Cancers and Related Disorders</subject><subj-group><subject>Leukemias</subject><subject>Lymphomas</subject><subject>Myelodysplastic Syndromes</subject><subject>Myelomas and Lymphoproliferative Diseases</subject></subj-group></subj-group></subj-group><subj-group><subject>Infectious diseases</subject><subj-group><subject>Viral diseases</subject><subj-group><subject>Bk virus infection</subject><subject>Common cold</subject><subject>Cytomegalovirus infection</subject><subject>Epstein-Barr virus infectious mononucleosis</subject><subject>Human parainfluenza virus infection</subject><subject>Influenza</subject><subject>Respiratory syncytial virus infection</subject><subject>Rhinovirus infection</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Viral Findings in Adult Hematological Patients with Neutropenia</article-title><alt-title alt-title-type="running-head">Viral Findings in Neutropenic Patients</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Öhrmalm</surname><given-names>Lars</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wong</surname><given-names>Michelle</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Aust</surname><given-names>Carl</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ljungman</surname><given-names>Per</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Norbeck</surname><given-names>Oscar</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Broliden</surname><given-names>Kristina</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tolfvenstam</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Department of Medicine, Solna, Infectious Disease Unit, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Hematology Centre, Karolinska University Hospital, Stockholm, Sweden</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Costa</surname><given-names>Cristina</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University Hospital San Giovanni Battista di Torino, Italy</aff><author-notes><corresp id="cor1">* E-mail: <email>lars.ohrmalm@ki.se</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: LÖ MW PL ON KB TT. Performed the experiments: LÖ MW CA ON TT. Analyzed the data: LÖ MW CA PL ON KB TT. Contributed reagents/materials/analysis tools: PL ON KB TT. Wrote the paper: LÖ MW CA PL ON KB TT.</p></fn></author-notes><pub-date pub-type="collection"><year>2012</year></pub-date><pub-date pub-type="epub"><day>3</day><month>5</month><year>2012</year></pub-date><volume>7</volume><issue>5</issue><elocation-id>e36543</elocation-id><history><date date-type="received"><day>19</day><month>12</month><year>2011</year></date><date date-type="accepted"><day>8</day><month>4</month><year>2012</year></date></history><permissions><copyright-statement>Öhrmalm et al.</copyright-statement><copyright-year>2012</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><sec><title>Background</title><p>Until recently, viral infections in patients with hematological malignancies were concerns primarily in allogeneic hematopoietic stem cell transplant (HSCT) recipients. During the last years, changed treatment regimens for non-transplanted patients with hematological malignancies have had potential to increase the incidence of viral infections in this group. In this study, we have prospectively investigated the prevalence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT.</p></sec><sec><title>Methodology/Principal Findings</title><p>Patients with hematological malignancies and therapy induced neutropenia (n = 159) were screened regarding a broad range of common respiratory viruses in the nasopharynx and for viruses commonly detected in severely immunosuppressed patients in peripheral blood. Quantitative PCR was used for detection of viruses. A viral pathogen was detected in 35% of the patients. The detection rate was rather similar in blood (22%) and NPA (18%) with polyoma BK virus and rhinovirus as dominating pathogens in blood and NPA, respectively. Patients with chronic lymphocytic leukemia (CLL) (p<0.01) and patients with fever (p<0.001) were overrepresented in the virus-positive group. Furthermore, viral findings in NPA were associated with upper respiratory symptoms (URTS) (p<0.0001).</p></sec><sec><title>Conclusions/Significance</title><p>Both respiratory viral infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. These findings motivate further studies on viruses' impact on this patient category and their potential role as causative agents of fever during neutropenia.</p></sec></abstract><counts><page-count count="7"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Reactivation of viruses in blood as well as viral respiratory tract infections has a significant impact on the morbidity and mortality of allogeneic hematopoietic stem cell transplant (HSCT) recipients <xref rid="pone.0036543-Martin1" ref-type="bibr">[1]</xref>–<xref rid="pone.0036543-Koskenvuo1" ref-type="bibr">[4]</xref>. Although a rather high prevalence of respiratory viruses in neutropenic patients with fever is reported <xref rid="pone.0036543-Koskenvuo1" ref-type="bibr">[4]</xref>, <xref rid="pone.0036543-Lindblom1" ref-type="bibr">[5]</xref>, the impact of viral infections in the non-transplant setting of neutropenic hematological patients is less studied. In addition, reactivation of cytomegalovirus (CMV) is reported in hematological neutropenic patients that have not undergone allogeneic HSCT <xref rid="pone.0036543-Ljungman1" ref-type="bibr">[6]</xref>–<xref rid="pone.0036543-Persson1" ref-type="bibr">[8]</xref>. Fever is often the only sign of infection in the immunocompromised patient, and since establishing the cause of fever in neutropenic patients is difficult, empiric administration of broad spectrum antibiotics is in common usage <xref rid="pone.0036543-Pizzo1" ref-type="bibr">[9]</xref>, <xref rid="pone.0036543-Lawson1" ref-type="bibr">[10]</xref>. This strategy has substantially decreased the mortality rate in this patient group, but bacterial infection is documented in only approximately one-third or fewer of the febrile episodes <xref rid="pone.0036543-Hughes1" ref-type="bibr">[11]</xref>–<xref rid="pone.0036543-Viscoli1" ref-type="bibr">[14]</xref>. Most patients with hematological malignancies remain at home between courses of chemotherapy, including neutropenic phases, and are thus exposed to all common pathogens circulating in the society. Consequently, the epidemiology of these infections in hospitalized patients mirrors that in outpatients <xref rid="pone.0036543-Englund2" ref-type="bibr">[15]</xref>.</p><p>Here, in a setting of neutropenic hematological patients, other than allogeneic HSCT recipients, we prospectively evaluated the presence of a broad range of respiratory viruses in nasopharyngeal aspirate (NPA) as well as viruses that commonly reactivate after allogeneic HSCT.</p></sec><sec sec-type="materials|methods" id="s2"><title>Materials and Methods</title><sec id="s2a"><title>Ethics Statement</title><p>Patients were, after giving their informed written consent, eligible for enrollment. The study was approved by The Regional Ethical Review Board in Stockholm (<ext-link ext-link-type="uri" xlink:href="http://www.epn.se">www.epn.se</ext-link>).</p></sec><sec id="s2b"><title>Study population</title><p>During a 26-month period (Jan 2008–Feb 2010) adult patients with hematological disorders who presented at the Karolinska University Hospital, Stockholm, with neutropenia were asked to participate in this study. Patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) within the previous two years and patients admitted to the Intensive Care Unit were excluded from the study.</p></sec><sec id="s2c"><title>Sampling procedure</title><p>Patients with neutropenic fever were sampled for routine microbial cultures upon admission or at the onset of fever during a hospitalization. The additional study samples for detection of viruses in blood and nasopharyngeal aspirates (NPA) were collected within 72 hours of fever onset. Upon routine medical appointments, unselected afebrile neutropenic patients were prospectively sampled for the study samples only. Within 6 hours from sampling, each NPA was stored at −80°C before analysis by quantitative real-time PCR (qPCR). Serum was used for all blood assays except those for cytomegalovirus (CMV) and adenovirus (AdV), where whole blood and plasma were used, respectively.</p></sec><sec id="s2d"><title>Extraction and qPCR methods</title><p>Blood specimens for detection of Epstein-Barr virus (EBV), CMV, and AdV were extracted and analyzed by qPCR as described <xref rid="pone.0036543-Gustafson1" ref-type="bibr">[16]</xref>. For the other qPCRs, total viral nucleic acids were extracted with QIAamp MinElute Virus Spin Kit (QIAGEN, US) according to the manufacturer's protocol with 200 µL of specimens eluted into 50 µL of extract. The analysis of BK virus (BKV) is described elsewhere [Multiplex real-time PCR assay for simultaneous detection of cytomegalovirus, Epstein-Barr virus, adenovirus, and BK polyomavirus, Öhrmalm et al. In manuscript]. The qPCR for parvovirus B19 (B19) was performed on an ABI 7500 Real-Time PCR System (Applied Biosystems) and carried out in a total 50-µL reaction mixture including 25 µL of TaqMan Universal PCR Master Mix (Applied Biosystems) and 5 µL of template (<xref ref-type="table" rid="pone-0036543-t001">Table 1</xref>). The NPAs were analyzed on the same ABI System described above. However, for RNA viruses, a MultiScribe and RNase Inhibitor Mix (Applied Biosystems) was used. Newly developed primers and probes are described in <xref ref-type="table" rid="pone-0036543-t001">Table 1</xref>, whereas for human rhinovirus (HRV) <xref rid="pone.0036543-Lu1" ref-type="bibr">[17]</xref>, human enterovirus (HEV) <xref rid="pone.0036543-Nijhuis1" ref-type="bibr">[18]</xref>, influenza A virus (IFA) <xref rid="pone.0036543-World1" ref-type="bibr">[19]</xref>, influenza B virus (IFB) <xref rid="pone.0036543-TiveljungLindell1" ref-type="bibr">[20]</xref>, respiratory syncytial virus (RSV) <xref rid="pone.0036543-BrittainLong1" ref-type="bibr">[21]</xref>, and parainfluenza virus type 1 (PIV1) <xref rid="pone.0036543-Terlizzi1" ref-type="bibr">[22]</xref>, the design is described elsewhere. Quantification of viruses in blood was achieved by comparing with plasmids of known concentrations. Virus detection in nasopharynx was however judged qualitatively as NPA was used as starting material. For CMV, EBV, and AdV the dynamic range was 500 to 2×10<sup>8</sup> copies/mL. Values of detectable viral copies below this range were given as “<500". For BKV and B19, the lower part of the dynamic range was 5 copies/reaction. Values of detectable viral copies below 250 copies/mL blood were considered as “<250.</p><table-wrap id="pone-0036543-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.t001</object-id><label>Table 1</label><caption><title>Description of newly developed primers and probes used in the qPCR assays.</title></caption><alternatives><graphic id="pone-0036543-t001-1" xlink:href="pone.0036543.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Virus</td><td align="left" rowspan="1" colspan="1">Primer/Probe</td><td align="left" rowspan="1" colspan="1">Sequence (5′-3′)</td><td align="left" rowspan="1" colspan="1">Conc. (nM)</td><td align="left" rowspan="1" colspan="1">PCR program</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">hCoV</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">YGATAAAGCTGTAGCTCGCAAACT</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1">48°C for 30 min→95°C for 10 min→40 cycles of 15 sec at 95°C and 60 sec at 60°C</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">ACGCGACCGTGCTGTAGC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">GATCATGAGATATCTGTTCAGAAGAAAATT</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">CAGGGAATCATCTGTTCAAAAGAA</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">GATTATCCAATTTACGAACCATGCTA</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">GCTTGATTATCTAACTTACGCACCATACTA</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">ACATATCCAAACGTCTTAACATTCCA</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">AAACGTCGGAGCATGCCA</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">VIC-<named-content content-type="gene">GATAAGAAGAGTAARGTTGTTTC</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">225</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">VIC-<named-content content-type="gene">TGGCTGAACAAGCTG</named-content>-MGB</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">hMPV</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">AAAGCATTAGGCTCATCCTCTACAG</named-content></td><td align="left" rowspan="1" colspan="1">300</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">AAAGCTTTAGGCTCATCTTCAACAG</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">AAAGCATTAGGCTCATCATCTACAGG</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">ATTGTTAGATGACCTGGCAATGAC</named-content></td><td align="left" rowspan="1" colspan="1">300</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">GTTGGATGACCTGGCAATGAC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TGTTGGATGATCTGGCAATGAC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TGTTGTTAGATGATCTGGCAATGAC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TGTTAGATGACCTGGCGATGAC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">NED-<named-content content-type="gene">AGCAAAGCAGAAAGT</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">225</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">IFB</td><td align="left" rowspan="1" colspan="1">PRO<xref ref-type="table-fn" rid="nt102">a</xref></td><td align="left" rowspan="1" colspan="1">6FAM-<named-content content-type="gene">CAGATCTGTGCAGTTGAG</named-content>-MGB</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">PIV2</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TTACCTAAGTGATGGAATCAATCGC</named-content></td><td align="left" rowspan="1" colspan="1">300</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TCTTTYTCAGAYCTTGTAGCTACATAGCA</named-content></td><td align="left" rowspan="1" colspan="1">300</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">NED-<named-content content-type="gene">AAGCTGTTCAGTCACTGC</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">175</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">PIV3</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TCCCCATGGACATTCATYGTT</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TGGCAYAGCAARTTACAATTAGGAA</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">NED-<named-content content-type="gene">TGCCATGTCCATTTTA</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">175</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">PIV4</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">CCAGTCAAATCAAYTGCCTCYG</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">GATCTCTRATGCATAGTTCGCAAATT</named-content></td><td align="left" rowspan="1" colspan="1">900</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">NED-<named-content content-type="gene">CATGTGGAAGATGTCC</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">225</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">B19</td><td align="left" rowspan="1" colspan="1">FW</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">CCAGGCGCCTGGAACA</named-content></td><td align="left" rowspan="1" colspan="1">50</td><td align="left" rowspan="1" colspan="1">50°C for 2 min→95°C for 10 min→40 cycles of 15 sec at 95°C and 60 sec at 60°C</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">REV</td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TCGGAGGAAACTGGGCTTC</named-content></td><td align="left" rowspan="1" colspan="1">300</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"><named-content content-type="gene">TTCGGAGGAAACTGAGCTTCC</named-content></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">PRO</td><td align="left" rowspan="1" colspan="1">6FAM-<named-content content-type="gene">CGGGACCAGTTCAGGA</named-content>-MGB</td><td align="left" rowspan="1" colspan="1">250</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label></label><p><bold>NOTE.</bold> Conc, concentration; FW, forward; REV, reverse; PRO, probe; hCoV, human coronavirus; hMPV, human metapneumovirus; IFB, influenza B virus; PIV, parainfluenza virus; B19, parvovirus B19.</p></fn><fn id="nt102"><label>a</label><p>Probe modified, otherwise as described by Tiveljung et al <xref rid="pone.0036543-TiveljungLindell1" ref-type="bibr">[20]</xref>.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s2e"><title>Flow cytometry</title><p>In 99 patients where peripheral blood mononuclear cells were isolated phenotype characterization was made by staining with two sets of antibodies, BD Multitest (BD Biosciences, Sweden), against the following cell surface markers; Set 1: CD3-FITC, CD8-PE, CD45-PerCP, CD4-APC; Set 2: CD3-FITC, CD16/CD56-PE, CD45-PerCP, CD19-APC according to the manufacturer's instructions. TruCount tubes (BD Biosciences) were used for an absolute cell count.</p></sec><sec id="s2f"><title>Definitions and diagnostic criteria</title><p>Neutropenia was defined as an absolute neutrophil count ≤500/mm<sup>3</sup>. Fever was defined as a single temperature reading ≥38.5°C or >38.0°C that persisted for 1 hour. Upper respiratory tract symptoms (URTS) were defined as onset of rhinorrhea, sneezing, nasal congestion, cough, or hoarseness. For a diagnosis of coagulase-negative staphylococci bacteremia, at least two positive blood cultures were required.</p></sec><sec id="s2g"><title>Data collection and statistical analysis</title><p>Clinical and routinely collected laboratory data were extracted from all patients' medical records. Univariate analyses were performed using Fischer's exact test for categorical data. Non-categorical variables were compared with the Mann-Whitney U-test. Forward conditional binary logistic regression analysis was performed with presence of virus as the dependent variable and all parameters described in <xref ref-type="table" rid="pone-0036543-t002">Table 2</xref> with a p-value <0.10 as covariates. All tests were two-sided with p-value of <0.05 considered significant. Software products used were Prism 5.00 for Windows and PASW Statistics 18.</p><table-wrap id="pone-0036543-t002" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.t002</object-id><label>Table 2</label><caption><title>Characteristics and laboratory data on neutropenic patients with and without viral findings.</title></caption><alternatives><graphic id="pone-0036543-t002-2" xlink:href="pone.0036543.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td colspan="2" align="left" rowspan="1">Any virus</td><td colspan="2" align="left" rowspan="1">No virus</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Characteristics</td><td colspan="2" align="left" rowspan="1">(n = 56)</td><td colspan="2" align="left" rowspan="1">(n = 103)</td><td align="left" rowspan="1" colspan="1">OR (95%CI)<xref ref-type="table-fn" rid="nt104">a</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">No. of females (%)</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">(38)</td><td align="left" rowspan="1" colspan="1">44</td><td align="left" rowspan="1" colspan="1">(43)</td><td align="left" rowspan="1" colspan="1">0.80 (0.41–1.6)</td></tr><tr><td align="left" rowspan="1" colspan="1">Age, [years], median (range)</td><td align="left" rowspan="1" colspan="1">62</td><td align="left" rowspan="1" colspan="1">(20–86)</td><td align="left" rowspan="1" colspan="1">60</td><td align="left" rowspan="1" colspan="1">(25–86)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1">Underlying disease (%)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Acute leukemia/MDS</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">(34)</td><td align="left" rowspan="1" colspan="1">51</td><td align="left" rowspan="1" colspan="1">(50)</td><td align="left" rowspan="1" colspan="1">0.52 (0.27–1.0)<xref ref-type="table-fn" rid="nt104">†</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Chronic myeloid leukemia</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">(0)</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(1)</td><td align="left" rowspan="1" colspan="1">0.60 (0.02–15)</td></tr><tr><td align="left" rowspan="1" colspan="1">Chronic lymphocytic leukemia</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">(11)</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(1)</td><td align="left" rowspan="1" colspan="1">12 (1.4–104)<xref ref-type="table-fn" rid="nt106">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Non-Hodgkin lymphoma</td><td align="left" rowspan="1" colspan="1">25</td><td align="left" rowspan="1" colspan="1">(45)</td><td align="left" rowspan="1" colspan="1">29</td><td align="left" rowspan="1" colspan="1">(28)</td><td align="left" rowspan="1" colspan="1">2.1 (1.0–4.1)<xref ref-type="table-fn" rid="nt104">†</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Myeloma</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">(7)</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">(16)</td><td align="left" rowspan="1" colspan="1">0.4 (0.13–1.3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Hodgkin's disease</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(2)</td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">(3)</td><td align="left" rowspan="1" colspan="1">0.61 (0.06–6.0)</td></tr><tr><td align="left" rowspan="1" colspan="1">Others</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(2)</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">(2)</td><td align="left" rowspan="1" colspan="1">0.92 (0.08–10.4)</td></tr><tr><td align="left" rowspan="1" colspan="1">No. of autologous HSCT (%)</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">(4)</td><td align="left" rowspan="1" colspan="1">27</td><td align="left" rowspan="1" colspan="1">(26)</td><td align="left" rowspan="1" colspan="1">0.10 (0.02–0.46)<xref ref-type="table-fn" rid="nt107">***</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Latest immunosuppressive treatment (%)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Monoclonal antibodies<xref ref-type="table-fn" rid="nt108">b</xref></td><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">(27)</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">(10)</td><td align="left" rowspan="1" colspan="1">3.4 (1.4–8.2)<xref ref-type="table-fn" rid="nt106">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Antineoplastic chemotherapy</td><td align="left" rowspan="1" colspan="1">49</td><td align="left" rowspan="1" colspan="1">(88)</td><td align="left" rowspan="1" colspan="1">98</td><td align="left" rowspan="1" colspan="1">(95)</td><td align="left" rowspan="1" colspan="1">0.36 (0.11–1.2)</td></tr><tr><td align="left" rowspan="1" colspan="1">Steroids</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">(39)</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">(18)</td><td align="left" rowspan="1" colspan="1">2.9 (1.4–5.9)<xref ref-type="table-fn" rid="nt106">**</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Days from treatment to sampling</td><td align="left" rowspan="1" colspan="1">12</td><td align="left" rowspan="1" colspan="1">(1–1064)</td><td align="left" rowspan="1" colspan="1">13</td><td align="left" rowspan="1" colspan="1">(2–632)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1">Cell count<xref ref-type="table-fn" rid="nt109">c</xref> [/mm<sup>3</sup>], median (range)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Leukocytes</td><td align="left" rowspan="1" colspan="1">200</td><td align="left" rowspan="1" colspan="1">(<100–1870)</td><td align="left" rowspan="1" colspan="1">400</td><td align="left" rowspan="1" colspan="1">(<100–3000)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1"> Neutrophils</td><td align="left" rowspan="1" colspan="1"><100</td><td align="left" rowspan="1" colspan="1">(<100–500)</td><td align="left" rowspan="1" colspan="1"><100</td><td align="left" rowspan="1" colspan="1">(<100–500)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1"> Lymphocytes</td><td align="left" rowspan="1" colspan="1">127</td><td align="left" rowspan="1" colspan="1">(14–18552)</td><td align="left" rowspan="1" colspan="1">202</td><td align="left" rowspan="1" colspan="1">(2.3–1332)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1"> CD4<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">38</td><td align="left" rowspan="1" colspan="1">(0.06–769)</td><td align="left" rowspan="1" colspan="1">93</td><td align="left" rowspan="1" colspan="1">(1.4–606)</td><td align="left" rowspan="1" colspan="1"><xref ref-type="table-fn" rid="nt105">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1"> CD8<sup>+</sup> T cells</td><td align="left" rowspan="1" colspan="1">45</td><td align="left" rowspan="1" colspan="1">(1.1–1568)</td><td align="left" rowspan="1" colspan="1">51</td><td align="left" rowspan="1" colspan="1">(0.14–537)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1"> B cells</td><td align="left" rowspan="1" colspan="1">0.2</td><td align="left" rowspan="1" colspan="1">(0.02–15061)</td><td align="left" rowspan="1" colspan="1">0.4</td><td align="left" rowspan="1" colspan="1">(0.02–439)</td><td align="left" rowspan="1" colspan="1">n.s</td></tr><tr><td align="left" rowspan="1" colspan="1"> NK cells</td><td align="left" rowspan="1" colspan="1">11</td><td align="left" rowspan="1" colspan="1">(1.0–96)</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">(0.32–196)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1"> Monocytes</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">(0.03–495)</td><td align="left" rowspan="1" colspan="1">86</td><td align="left" rowspan="1" colspan="1">(0.03–1337)</td><td align="left" rowspan="1" colspan="1">n.s.</td></tr><tr><td align="left" rowspan="1" colspan="1">Prophylactic aciclovir (%)</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">(38)</td><td align="left" rowspan="1" colspan="1">58</td><td align="left" rowspan="1" colspan="1">(56)</td><td align="left" rowspan="1" colspan="1">0.47 (0.24–0.91)<xref ref-type="table-fn" rid="nt105">*</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Presence of fever</td><td align="left" rowspan="1" colspan="1">52</td><td align="left" rowspan="1" colspan="1">(93)</td><td align="left" rowspan="1" colspan="1">71</td><td align="left" rowspan="1" colspan="1">(69)</td><td align="left" rowspan="1" colspan="1">5.9 (2.0–18)<xref ref-type="table-fn" rid="nt107">***</xref></td></tr><tr><td align="left" rowspan="1" colspan="1">Bacterial infection<xref ref-type="table-fn" rid="nt110">d</xref></td><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">(27)</td><td align="left" rowspan="1" colspan="1">26</td><td align="left" rowspan="1" colspan="1">(25)</td><td align="left" rowspan="1" colspan="1">1.1 (0.52–2.3)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt103"><label></label><p><bold>NOTE.</bold> Characteristics are presented in number and percentage of each group. Medians are followed by range. OR, odds ratio; CI, confidence interval; MDS, myelodysplastic syndrome; NPA, nasopharyngeal aspirate.</p></fn><fn id="nt104"><label>a†</label><p>, p≤0.10;</p></fn><fn id="nt105"><label>*</label><p>, p<0.05;</p></fn><fn id="nt106"><label>**</label><p>, p<0.01;</p></fn><fn id="nt107"><label>***</label><p>, p<0.001; ns, not significant.</p></fn><fn id="nt108"><label>b</label><p>Consisting of rituximab, alemtuzumab, ofatumumab, anti thymoglobulin, or gemtuzumab.</p></fn><fn id="nt109"><label>c</label><p>Except for the leukocyte and neutrophil count, data on cell count were only available from 34 of the episodes with virus and 72 of the episodes without virus.</p></fn><fn id="nt110"><label>d</label><p>No bacterial diagnostics were performed on patients without fever but are here assumed to be negative.</p></fn></table-wrap-foot></table-wrap></sec></sec><sec id="s3"><title>Results</title><sec id="s3a"><title>Study population</title><p>A total of 159 neutropenic patients were included (<xref ref-type="table" rid="pone-0036543-t002">Table 2</xref>); 123 patients with fever, and 36 unselected afebrile neutropenic patients. In case of participation at multiple neutropenic episodes only the first was considered in this study. Of the 123 febrile patients, 15 declined NPA and another one declined collection of extra blood samples. The afebrile patients were sampled completely. Thus, a total of 123 patients were included after presenting with febrile neutropenia and study samples for virus analysis were collected upon admission (27 patients) or within 24 hours (48 patients), within 48 hours (31 patients), and within 72 hours (17 patients) from admission.</p></sec><sec id="s3b"><title>Viral findings</title><p>In a total of 56 patients (35%) at least one virus type was detected (<xref ref-type="table" rid="pone-0036543-t003">Table 3</xref>). The detection rate was rather similar in blood (22%) and in NPA (18%). In blood, BKV dominated followed by CMV. In NPA HRV dominated followed by AdV. More than one virus type was simultaneously detected in nine (16%) of the 56 virus-positive patients and all except one were sampled upon fever. The viral load in blood samples was below 1 000 copies/mL with only the following exceptions; one CMV finding of 1800 copies/mL; four BKV findings of 3500, 4800, 7000 and 38000 copies/mL; and one B19 finding of 9500 copies/mL (<xref ref-type="fig" rid="pone-0036543-g001">Figure 1</xref>). All these were among the fever episodes.</p><fig id="pone-0036543-g001" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.g001</object-id><label>Figure 1</label><caption><title>Titers of viruses detected in blood.</title></caption><graphic xlink:href="pone.0036543.g001"></graphic></fig><table-wrap id="pone-0036543-t003" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.t003</object-id><label>Table 3</label><caption><title>Presence of viruses in peripheral blood and nasopharynx in the 159 patients with neutropenia.</title></caption><alternatives><graphic id="pone-0036543-t003-3" xlink:href="pone.0036543.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Specimen</td><td align="left" rowspan="1" colspan="1">Virus</td><td colspan="2" align="left" rowspan="1">No. of positive (%)</td><td align="left" rowspan="1" colspan="1">Co-existing viruses (n)<xref ref-type="table-fn" rid="nt112">a</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Blood</td><td align="left" rowspan="1" colspan="1">BK polyoma virus (BKV)</td><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">(11.4)</td><td align="left" rowspan="1" colspan="1">B19 (1), EBV (1), IFB (1), HRV (2)</td></tr><tr><td align="left" rowspan="1" colspan="1">n = 158</td><td align="left" rowspan="1" colspan="1">Cytomegalovirus (CMV)</td><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">(5.1)</td><td align="left" rowspan="1" colspan="1">B19 (1), RSV (1), AdV in NPA+HRV (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Parvovirus B19 (B19)</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">(3.8)</td><td align="left" rowspan="1" colspan="1">CMV (1), BK (1), EBV (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Epstein-Barr virus (EBV)</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">(3.8)</td><td align="left" rowspan="1" colspan="1">BK (1), B19 (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Adenovirus (AdV)</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(0.6)</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td colspan="2" align="left" rowspan="1">No. of patients with at least one virus detected in blood</td><td align="left" rowspan="1" colspan="1">35</td><td align="left" rowspan="1" colspan="1">(22.2)<xref ref-type="table-fn" rid="nt113">b</xref></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">NPA</td><td align="left" rowspan="1" colspan="1">Rhinovirus (HRV)</td><td align="left" rowspan="1" colspan="1">11</td><td align="left" rowspan="1" colspan="1">(7.6)</td><td align="left" rowspan="1" colspan="1">AdV in NPA+CMV (1), BK (2)</td></tr><tr><td align="left" rowspan="1" colspan="1">n = 144</td><td align="left" rowspan="1" colspan="1">Adenovirus (AdV)</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">(4.2)</td><td align="left" rowspan="1" colspan="1">HRV+CMV (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Respiratory syncytial virus (RSV)</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">(3.5)</td><td align="left" rowspan="1" colspan="1">CMV (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Influenza A virus (IFA)</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">(0.7)</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Influenza B virus (IFB)</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">(1.4)</td><td align="left" rowspan="1" colspan="1">BK (1)</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Metapneumovirus (HMPV)</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">(1.4)</td><td align="left" rowspan="1" colspan="1">-</td></tr><tr><td colspan="2" align="left" rowspan="1">No. of patients with at least one virus detected in NPA</td><td align="left" rowspan="1" colspan="1">26</td><td align="left" rowspan="1" colspan="1">(18.1)<xref ref-type="table-fn" rid="nt114">c</xref></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td colspan="2" align="left" rowspan="1">No. of patients with at least one virus detected in any specimen</td><td align="left" rowspan="1" colspan="1">56</td><td align="left" rowspan="1" colspan="1">(35.2)</td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt111"><label></label><p><bold>NOTE.</bold> NPA, nasopharyngeal aspirate.</p></fn><fn id="nt112"><label>a</label><p>All co-existing viruses are also listed in the column of viruses. Thus, they are presented, but not counted, twice.</p></fn><fn id="nt113"><label>b</label><p>Percentage of total sampling occasions where blood was investigated.</p></fn><fn id="nt114"><label>c</label><p>Percentage of total sampling occasions where NPA was investigated.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3c"><title>Symptoms and signs of respiratory tract infection</title><p>Fifteen (58%) out of the 26 patients with a respiratory virus detected in NPA had URTS compared to 20 (17%) out of 118 patients without URTS (OR = 6.7, p<0.0001; <xref ref-type="table" rid="pone-0036543-t004">Table 4</xref>). The predominating reported URTS was cough followed by rhinorrhea, sneezing or nasal congestion.</p><table-wrap id="pone-0036543-t004" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.t004</object-id><label>Table 4</label><caption><title>Upper respiratory tract symptoms and fever in the 144 neutropenic patients where NPA were obtained.</title></caption><alternatives><graphic id="pone-0036543-t004-4" xlink:href="pone.0036543.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">URTS</td><td align="left" rowspan="1" colspan="1">No URTS</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Fever</td><td align="left" rowspan="1" colspan="1">No fever</td><td align="left" rowspan="1" colspan="1">OR (p)</td></tr><tr><td align="left" rowspan="1" colspan="1">Respiratory virus</td><td align="left" rowspan="1" colspan="1">(n = 35)</td><td align="left" rowspan="1" colspan="1">(n = 109)</td><td align="left" rowspan="1" colspan="1">OR (p)</td><td align="left" rowspan="1" colspan="1">(n = 109)</td><td align="left" rowspan="1" colspan="1">(n = 35)</td><td align="left" rowspan="1" colspan="1"></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Rhinovirus</td><td align="left" rowspan="1" colspan="1">6</td><td align="left" rowspan="1" colspan="1">5<xref ref-type="table-fn" rid="nt116">a</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">10<xref ref-type="table-fn" rid="nt116">a</xref></td><td align="left" rowspan="1" colspan="1">1<xref ref-type="table-fn" rid="nt117">b</xref></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">RSV</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Adenovirus</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">4<xref ref-type="table-fn" rid="nt116">a</xref></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">6<xref ref-type="table-fn" rid="nt116">a</xref></td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza A virus</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Influenza B virus</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Metapneumo virus</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Total (%)</td><td align="left" rowspan="1" colspan="1">15 (43)</td><td align="left" rowspan="1" colspan="1">11 (10)</td><td align="left" rowspan="1" colspan="1">6.7 (<.0001)</td><td align="left" rowspan="1" colspan="1">25 (23)</td><td align="left" rowspan="1" colspan="1">1 (3)</td><td align="left" rowspan="1" colspan="1">10 (<.01)</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt115"><label></label><p><bold>NOTE.</bold> URTS, upper respiratory tract symptoms; OR, odds ratio; RSV, respiratory syncytial virus.</p></fn><fn id="nt116"><label>a</label><p>One case of co-infection of HRV and AdV.</p></fn><fn id="nt117"><label>b</label><p>This patient did not have URTS either.</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3d"><title>Viral and bacterial findings in patients with febrile neutropenia</title><p>As mentioned above, one or more viral pathogens were detected in 42% of the patients with febrile neutropenia. In 15 (29%) of these patients there was concurrently a documented bacterial infection. Conversely, bacterial infection was documented in 41 (33%) of the cases with febrile neutropenia and in 15 (37%) of these virus co-occurred (<xref ref-type="fig" rid="pone-0036543-g002">Figure 2</xref>). There were no statistical significant differences between the groups regarding C-reactive protein (CRP) levels at fever onset or number of days with fever. However, the number of days with intravenous antibiotics was higher for patients with documented bacterial infection (median 9 days, range 4–24) compared to those with virus only (median 6, range 2–17) or no pathogen found (median 6, range 3–15; p<0.01 and p<0.001, respectively).</p><fig id="pone-0036543-g002" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0036543.g002</object-id><label>Figure 2</label><caption><title>Documented microbiological pathogens in the 123 patients with febrile neutropenia.</title></caption><graphic xlink:href="pone.0036543.g002"></graphic></fig></sec><sec id="s3e"><title>Characteristics and clinical parameters of patients with and without virus</title><p>Chronic lymphocytic leukemia (CLL) was overrepresented in the virus-positive group (11% vs. 1%, p<0.01; <xref ref-type="table" rid="pone-0036543-t002">Table 2</xref>) and, even though border line significant, viruses were more likely to be detected among non-Hodgkin lymphoma (NHL) patients (45% vs. 28%, p = 0.05). In contrast, few recipients of autologous HSCT were virus positive (3.6% vs. 26%, p<0.001). Regarding the latest treatment for the underlying disease, both steroid treatment and monoclonal antibody therapy were associated with virus findings, and eight of eleven given the combined drugs were positive. The absolute counts of cell populations examined were lower in the virus-infected group (<xref ref-type="table" rid="pone-0036543-t002">Table 2</xref>). However, the differences did not reach statistical significance with the exception of the CD4<sup>+</sup> T cell count. The patients on prophylactic treatment with aciclovir were underrepresented in the virus-positive group (38% vs. 56%, p<0.05). A total of 52 (42%) out of the 123 patients with febrile neutropenia had virus detected, compared to 4 (11%) out of the 36 patients without fever (OR = 5.9, p<0.001). This was true for viruses detected in blood (OR = 3.9, p<0.05) as well as viruses detected in NPA (OR = 11, p<0.01; <xref ref-type="table" rid="pone-0036543-t004">Table 4</xref>). As reactivation of viruses in blood is associated with immunosuppression, we performed univariate analyses of the characteristics in <xref ref-type="table" rid="pone-0036543-t002">table 2</xref> regarding the febrile and non-febrile patients. There were no differences regarding gender, age, or underlying disease. However, 117 (95%) of the febrile patients and only 30 (83%) of the afebrile patients had antineoplastic drugs included in their latest treatment (p<0.5), and there was also a difference in the use of steroids (30% vs. 11%, p<0.05). The cell count for all populations except monocytes were significantly higher in the afebrile patients (p<0.001). After multivariate regression analysis with presence of virus dependent variable and parameters in <xref ref-type="table" rid="pone-0036543-t002">Table 2</xref> with a p value less than 0.10 as covariates, CLL and fever remained as independently associated to presence of virus (OR = 7.5, p<0.01 and OR = 13, p<0.0001), respectively. There were no reports on hemorrhagic cystitis in the cases of detectable BKV. Furthermore, we were unable to show an association of elevated serum levels of creatinine and presence of BKV (data not shown).</p></sec></sec><sec id="s4"><title>Discussion</title><p>Using highly sensitive methods to identify a broad range of viruses, we have estimated the prevalence of respiratory viruses and viremia in hematological patients with neutropenia other than allogeneic HSCT recipients. Viral infections were commonly detected in patients with CLL and NHL. Among subpopulations of immunological cell types investigated, decline in the CD4<sup>+</sup> T cell count was associated with these infections. Viral infections were associated with fever, and specifically respiratory viruses in NPA were associated with URTS. Although the majority of viral infections did not co-occur with bacterial infection, viral and bacterial co-infections were common.</p><p>The proportion of different virus species in NPA differed from an earlier large study by Chemaly et al on adult hematological patients <xref rid="pone.0036543-Chemaly1" ref-type="bibr">[23]</xref>. HRV was the commonest finding in our study which could be explained by the use of PCR instead of culture. Moreover, the study by Chemaly et al was retrospective and only included patients with documented positive viral culture. However, our findings in NPA were comparable to recent studies on children with febrile neutropenia <xref rid="pone.0036543-Lindblom1" ref-type="bibr">[5]</xref>, <xref rid="pone.0036543-Hakim1" ref-type="bibr">[24]</xref> where PCR was used. Moreover, with the exception of corona virus and PIV, the proportions of viral species corresponded well to a study on community acquired pneumonia in the same geographical area <xref rid="pone.0036543-Johansson1" ref-type="bibr">[25]</xref>. The latter confirms an earlier finding that the temporal occurrence of viral infections in immunocompromised patients tends to mirror their occurrence in the community <xref rid="pone.0036543-Englund2" ref-type="bibr">[15]</xref>.</p><p>Approximately half of the viral findings were viremia with BKV and CMV as dominating pathogens. A comparable screening in young children with febrile neutropenia showed lower frequency <xref rid="pone.0036543-Lindblom1" ref-type="bibr">[5]</xref>, but this discrepancy is probably explained by the fact that the prevalence of latent viral infections increases with age. It has been shown that allogeneic transplanted patients with a BK viral load of more than 10<sup>4</sup> copies/mL had a significantly higher risk of having hemorrhagic cystitis than patients with a viral load of less than 10<sup>4</sup> copies/mL <xref rid="pone.0036543-Erard1" ref-type="bibr">[26]</xref>. In a recent pediatric study on a post-HSCT population, the degree of BK viremia seemed to predict renal, urologic, and overall outcome <xref rid="pone.0036543-Haines1" ref-type="bibr">[27]</xref>. However, in our less immunosuppressed cohort with mostly very low titers, we had no reports on symptoms of disease associated to BKV.</p><p>Although we found an independent association between viral findings and fever, one should interpret the results with caution because of the discrepancy in grade of immunosuppression between the febrile and afebrile patients. Furthermore, multivariate analysis with this low number of patients carries the risk of small sample bias. Even though the levels of virus in blood were lower than those expected from symptomatic disease, the independent association prompts the question whether the viral load was sufficient to generate fever. Furthermore, not all viral respiratory tract infections cause fever, and different virus types are known to be variously pyrogenic <xref rid="pone.0036543-Fairchok1" ref-type="bibr">[28]</xref>. In our study, not all patients with fever were completely sampled for detection of viruses. We thus risk underestimating the association between fever and viral findings. Although bacterial culture is limited in sensitivity, it is of interest to note that virus existed more often as the sole pathogen identified here than as a cofactor with bacteria. The fact that PCR is a highly sensitive method always raises the question of the findings' relevance. We did, however, determine an association between respiratory viruses and URTS, indicating symptomatic infection.</p><p>Until recently, viral infections were regarded as a concern in hematological malignancies primarily in patients who had undergone allogeneic HSCT. However, in the last years, the use of monoclonal antibodies directed against B and/or T cells for treatment of hematological malignancies such as NHL and CLL has had potential to increase the incidence of viral infections in these groups as well. These two diagnoses as well as receiving monoclonal antibody therapy were associated to detection of virus in our material. After multivariate analysis, only CLL showed to be independently associated, but once again, with risk of small sample bias.</p><p>In allogeneic HSCT recipients, lymphocytopenia is a known risk factor for the development of lower respiratory tract infection <xref rid="pone.0036543-Ljungman2" ref-type="bibr">[29]</xref>, and reconstitution of the lymphocyte population is known to reduce the risk for viremia with CMV and AdV <xref rid="pone.0036543-Chakrabarti1" ref-type="bibr">[30]</xref>, <xref rid="pone.0036543-Hakki1" ref-type="bibr">[31]</xref>. In our study, all measured cell counts were lower in the virus-positive patients but only the difference in CD4<sup>+</sup> cell count was statistically significant. The function of lymphocytes can be altered by both the treatment and the underlying disease <xref rid="pone.0036543-Engstrand1" ref-type="bibr">[32]</xref> and it would therefore be interesting to investigate an association between not only the cell count but also the cell function to risk of viral infection in this patient category.</p><p>In conclusion, both respiratory virus infections and low titers of viruses in blood from patients with neutropenia were common. Patients with CLL and patients with fever were independently associated to these infections, and viral findings in NPA were associated to URTS indicating active infection. Although this is a small study in a heterogeneous group of hematological patients, it is possible that a proportion of episodes of febrile neutropenia could originate from virus infections. Larger prospective longitudinal studies should be conducted to investigate the possible causality between neutropenic fever and viral infections.</p></sec></body><back><ack><p>We thank all patients. We are indebted to the nurses, study nurses and Dr Jan Sjöberg and Dr Per-Anders Broliden at the Hematology Center and the staff at the Department of Accident and Emergency, Karolinska University Hospital, for their dedication to the study. We acknowledge the staff at the Department of Clinical Microbiology at Karolinska University Hospital.</p></ack><fn-group><fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="financial-disclosure"><p><bold>Funding: </bold>Grants were received from the Stockholm County Council (<ext-link ext-link-type="uri" xlink:href="http://www.sll.se">www.sll.se</ext-link>)/Karolinska Institutet (<ext-link ext-link-type="uri" xlink:href="http://www.ki.se">www.ki.se</ext-link>), the Swedish Society of Medicine (<ext-link ext-link-type="uri" xlink:href="http://www.sls.se">www.sls.se</ext-link>), the Clas Groschinsky foundation (<ext-link ext-link-type="uri" xlink:href="http://www.groschinsky.org">www.groschinsky.org</ext-link>), Karolinska Institutet Infection Network (<ext-link ext-link-type="uri" xlink:href="http://www.ki.se">www.ki.se</ext-link>) and from The Swedish Childhood Cancer Foundation (<ext-link ext-link-type="uri" xlink:href="http://www.barncancerfonden.se">www.barncancerfonden.se</ext-link>) for method development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</p></fn></fn-group><ref-list><title>References</title><ref id="pone.0036543-Martin1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Martin</surname><given-names>ET</given-names></name><name><surname>Kuypers</surname><given-names>J</given-names></name><name><surname>Wald</surname><given-names>A</given-names></name><name><surname>Englund</surname><given-names>JA</given-names></name></person-group><year>2011</year><article-title>Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children.</article-title><source>Influenza Other Respi Viruses</source></element-citation></ref><ref id="pone.0036543-Englund1"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Englund</surname><given-names>J</given-names></name><name><surname>Feuchtinger</surname><given-names>T</given-names></name><name><surname>Ljungman</surname><given-names>P</given-names></name></person-group><year>2011</year><article-title>Viral infections in immunocompromised patients.</article-title><source>Biol Blood Marrow Transplant</source><volume>17</volume><fpage>S2</fpage><lpage>5</lpage><pub-id pub-id-type="pmid">21195305</pub-id></element-citation></ref><ref id="pone.0036543-Arola1"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arola</surname><given-names>M</given-names></name><name><surname>Ruuskanen</surname><given-names>O</given-names></name><name><surname>Ziegler</surname><given-names>T</given-names></name><name><surname>Salmi</surname><given-names>TT</given-names></name></person-group><year>1995</year><article-title>Respiratory virus infections during anticancer treatment in children.</article-title><source>Pediatr Infect Dis J</source><volume>14</volume><fpage>690</fpage><lpage>694</lpage><pub-id pub-id-type="pmid">8532427</pub-id></element-citation></ref><ref id="pone.0036543-Koskenvuo1"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Koskenvuo</surname><given-names>M</given-names></name><name><surname>Mottonen</surname><given-names>M</given-names></name><name><surname>Rahiala</surname><given-names>J</given-names></name><name><surname>Saarinen-Pihkala</surname><given-names>UM</given-names></name><name><surname>Riikonen</surname><given-names>P</given-names></name><etal></etal></person-group><year>2008</year><article-title>Respiratory viral infections in children with leukemia.</article-title><source>Pediatr Infect Dis J</source><volume>27</volume><fpage>974</fpage><lpage>980</lpage><pub-id pub-id-type="pmid">18833026</pub-id></element-citation></ref><ref id="pone.0036543-Lindblom1"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lindblom</surname><given-names>A</given-names></name><name><surname>Bhadri</surname><given-names>V</given-names></name><name><surname>Soderhall</surname><given-names>S</given-names></name><name><surname>Ohrmalm</surname><given-names>L</given-names></name><name><surname>Wong</surname><given-names>M</given-names></name><etal></etal></person-group><year>2010</year><article-title>Respiratory viruses, a common microbiological finding in neutropenic children with fever.</article-title><source>J Clin Virol</source><volume>47</volume><fpage>234</fpage><lpage>237</lpage><pub-id pub-id-type="pmid">20056482</pub-id></element-citation></ref><ref id="pone.0036543-Ljungman1"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ljungman</surname><given-names>P</given-names></name><name><surname>von Dobeln</surname><given-names>L</given-names></name><name><surname>Ringholm</surname><given-names>L</given-names></name><name><surname>Lewensohn-Fuchs</surname><given-names>I</given-names></name><name><surname>Klingspor</surname><given-names>L</given-names></name><etal></etal></person-group><year>2005</year><article-title>The value of CMV and fungal PCR for monitoring for acute leukaemia and autologous stem cell transplant patients.</article-title><source>Scand J Infect Dis</source><volume>37</volume><fpage>121</fpage><lpage>127</lpage><pub-id pub-id-type="pmid">15773033</pub-id></element-citation></ref><ref id="pone.0036543-Ng1"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ng</surname><given-names>AP</given-names></name><name><surname>Worth</surname><given-names>L</given-names></name><name><surname>Chen</surname><given-names>L</given-names></name><name><surname>Seymour</surname><given-names>JF</given-names></name><name><surname>Prince</surname><given-names>HM</given-names></name><etal></etal></person-group><year>2005</year><article-title>Cytomegalovirus DNAemia and disease: incidence, natural history and management in settings other than allogeneic stem cell transplantation.</article-title><source>Haematologica</source><volume>90</volume><fpage>1672</fpage><lpage>1679</lpage><pub-id pub-id-type="pmid">16330442</pub-id></element-citation></ref><ref id="pone.0036543-Persson1"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Persson</surname><given-names>L</given-names></name><name><surname>Dahl</surname><given-names>H</given-names></name><name><surname>Linde</surname><given-names>A</given-names></name><name><surname>Engervall</surname><given-names>P</given-names></name><name><surname>Vikerfors</surname><given-names>T</given-names></name><etal></etal></person-group><year>2003</year><article-title>Human cytomegalovirus, human herpesvirus-6 and human herpesvirus-7 in neutropenic patients with fever of unknown origin.</article-title><source>Clin Microbiol Infect</source><volume>9</volume><fpage>640</fpage><lpage>644</lpage><pub-id pub-id-type="pmid">12925104</pub-id></element-citation></ref><ref id="pone.0036543-Pizzo1"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pizzo</surname><given-names>PA</given-names></name></person-group><year>1993</year><article-title>Management of fever in patients with cancer and treatment-induced neutropenia.</article-title><source>N Engl J Med</source><volume>328</volume><fpage>1323</fpage><lpage>1332</lpage><pub-id pub-id-type="pmid">8469254</pub-id></element-citation></ref><ref id="pone.0036543-Lawson1"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lawson</surname><given-names>RD</given-names></name><name><surname>Gentry</surname><given-names>LO</given-names></name><name><surname>Bodey</surname><given-names>GP</given-names></name><name><surname>Keating</surname><given-names>MJ</given-names></name><name><surname>Smith</surname><given-names>TL</given-names></name></person-group><year>1984</year><article-title>A randomized study of tobramycin plus ticarcillin, tobramycin plus cephalothin and ticarcillin, or tobramycin plus mezlocillin in the treatment of infection in neutropenic patients with malignancies.</article-title><source>Am J Med Sci</source><volume>287</volume><fpage>16</fpage><lpage>23</lpage></element-citation></ref><ref id="pone.0036543-Hughes1"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hughes</surname><given-names>WT</given-names></name><name><surname>Armstrong</surname><given-names>D</given-names></name><name><surname>Bodey</surname><given-names>GP</given-names></name><name><surname>Bow</surname><given-names>EJ</given-names></name><name><surname>Brown</surname><given-names>AE</given-names></name><etal></etal></person-group><year>2002</year><article-title>2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer.</article-title><source>Clin Infect Dis</source><volume>34</volume><fpage>730</fpage><lpage>751</lpage><pub-id pub-id-type="pmid">11850858</pub-id></element-citation></ref><ref id="pone.0036543-Mancini1"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mancini</surname><given-names>N</given-names></name><name><surname>Clerici</surname><given-names>D</given-names></name><name><surname>Diotti</surname><given-names>R</given-names></name><name><surname>Perotti</surname><given-names>M</given-names></name><name><surname>Ghidoli</surname><given-names>N</given-names></name><etal></etal></person-group><year>2008</year><article-title>Molecular diagnosis of sepsis in neutropenic patients with haematological malignancies.</article-title><source>J Med Microbiol</source><volume>57</volume><fpage>601</fpage><lpage>604</lpage><pub-id pub-id-type="pmid">18436593</pub-id></element-citation></ref><ref id="pone.0036543-Whimbey1"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Whimbey</surname><given-names>E</given-names></name><name><surname>Kiehn</surname><given-names>TE</given-names></name><name><surname>Brannon</surname><given-names>P</given-names></name><name><surname>Blevins</surname><given-names>A</given-names></name><name><surname>Armstrong</surname><given-names>D</given-names></name></person-group><year>1987</year><article-title>Bacteremia and fungemia in patients with neoplastic disease.</article-title><source>Am J Med</source><volume>82</volume><fpage>723</fpage><lpage>730</lpage><pub-id pub-id-type="pmid">3565430</pub-id></element-citation></ref><ref id="pone.0036543-Viscoli1"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Viscoli</surname><given-names>C</given-names></name><name><surname>Cometta</surname><given-names>A</given-names></name><name><surname>Kern</surname><given-names>WV</given-names></name><name><surname>Bock</surname><given-names>R</given-names></name><name><surname>Paesmans</surname><given-names>M</given-names></name><etal></etal></person-group><year>2006</year><article-title>Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients.</article-title><source>Clin Microbiol Infect</source><volume>12</volume><fpage>212</fpage><lpage>216</lpage><pub-id pub-id-type="pmid">16451406</pub-id></element-citation></ref><ref id="pone.0036543-Englund2"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Englund</surname><given-names>JA</given-names></name><name><surname>Whimbey</surname><given-names>E</given-names></name><name><surname>Atmar</surname><given-names>RL</given-names></name></person-group><year>1999</year><article-title>Diagnosis of respiratory viruses in cancer and transplant patients.</article-title><source>Curr Clin Top Infect Dis</source><volume>19</volume><fpage>30</fpage><lpage>59</lpage><pub-id pub-id-type="pmid">10472479</pub-id></element-citation></ref><ref id="pone.0036543-Gustafson1"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gustafson</surname><given-names>I</given-names></name><name><surname>Lindblom</surname><given-names>A</given-names></name><name><surname>Yun</surname><given-names>Z</given-names></name><name><surname>Omar</surname><given-names>H</given-names></name><name><surname>Engstrom</surname><given-names>L</given-names></name><etal></etal></person-group><year>2008</year><article-title>Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients.</article-title><source>J Clin Virol</source><volume>43</volume><fpage>79</fpage><lpage>85</lpage><pub-id pub-id-type="pmid">18550426</pub-id></element-citation></ref><ref id="pone.0036543-Lu1"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>X</given-names></name><name><surname>Holloway</surname><given-names>B</given-names></name><name><surname>Dare</surname><given-names>RK</given-names></name><name><surname>Kuypers</surname><given-names>J</given-names></name><name><surname>Yagi</surname><given-names>S</given-names></name><etal></etal></person-group><year>2008</year><article-title>Real-time reverse transcription-PCR assay for comprehensive detection of human rhinoviruses.</article-title><source>J Clin Microbiol</source><volume>46</volume><fpage>533</fpage><lpage>539</lpage><pub-id pub-id-type="pmid">18057136</pub-id></element-citation></ref><ref id="pone.0036543-Nijhuis1"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nijhuis</surname><given-names>M</given-names></name><name><surname>van Maarseveen</surname><given-names>N</given-names></name><name><surname>Schuurman</surname><given-names>R</given-names></name><name><surname>Verkuijlen</surname><given-names>S</given-names></name><name><surname>de Vos</surname><given-names>M</given-names></name><etal></etal></person-group><year>2002</year><article-title>Rapid and sensitive routine detection of all members of the genus enterovirus in different clinical specimens by real-time PCR.</article-title><source>J Clin Microbiol</source><volume>40</volume><fpage>3666</fpage><lpage>3670</lpage><pub-id pub-id-type="pmid">12354863</pub-id></element-citation></ref><ref id="pone.0036543-World1"><label>19</label><element-citation publication-type="other"><article-title>World Health Organization (WHO) website.</article-title><comment>Available: <ext-link ext-link-type="uri" xlink:href="http://www.who.int/entity/csr/resources/publications/swineflu/CDCRealtimeRTPCR_SwineH1Assay-2009_20090430.pdf">http://www.who.int/entity/csr/resources/publications/swineflu/CDCRealtimeRTPCR_SwineH1Assay-2009_20090430.pdf</ext-link>. Accessed: 2012 Apr 12</comment></element-citation></ref><ref id="pone.0036543-TiveljungLindell1"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tiveljung-Lindell</surname><given-names>A</given-names></name><name><surname>Rotzen-Ostlund</surname><given-names>M</given-names></name><name><surname>Gupta</surname><given-names>S</given-names></name><name><surname>Ullstrand</surname><given-names>R</given-names></name><name><surname>Grillner</surname><given-names>L</given-names></name><etal></etal></person-group><year>2009</year><article-title>Development and implementation of a molecular diagnostic platform for daily rapid detection of 15 respiratory viruses.</article-title><source>J Med Virol</source><volume>81</volume><fpage>167</fpage><lpage>175</lpage><pub-id pub-id-type="pmid">19031448</pub-id></element-citation></ref><ref id="pone.0036543-BrittainLong1"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brittain-Long</surname><given-names>R</given-names></name><name><surname>Nord</surname><given-names>S</given-names></name><name><surname>Olofsson</surname><given-names>S</given-names></name><name><surname>Westin</surname><given-names>J</given-names></name><name><surname>Anderson</surname><given-names>LM</given-names></name><etal></etal></person-group><year>2008</year><article-title>Multiplex real-time PCR for detection of respiratory tract infections.</article-title><source>J Clin Virol</source><volume>41</volume><fpage>53</fpage><lpage>56</lpage><pub-id pub-id-type="pmid">18093871</pub-id></element-citation></ref><ref id="pone.0036543-Terlizzi1"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Terlizzi</surname><given-names>ME</given-names></name><name><surname>Massimiliano</surname><given-names>B</given-names></name><name><surname>Francesca</surname><given-names>S</given-names></name><name><surname>Sinesi</surname><given-names>F</given-names></name><name><surname>Rosangela</surname><given-names>V</given-names></name><etal></etal></person-group><year>2009</year><article-title>Quantitative RT real time PCR and indirect immunofluorescence for the detection of human parainfluenza virus 1, 2, 3.</article-title><source>J Virol Methods</source><volume>160</volume><fpage>172</fpage><lpage>177</lpage><pub-id pub-id-type="pmid">19445964</pub-id></element-citation></ref><ref id="pone.0036543-Chemaly1"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chemaly</surname><given-names>RF</given-names></name><name><surname>Ghosh</surname><given-names>S</given-names></name><name><surname>Bodey</surname><given-names>GP</given-names></name><name><surname>Rohatgi</surname><given-names>N</given-names></name><name><surname>Safdar</surname><given-names>A</given-names></name><etal></etal></person-group><year>2006</year><article-title>Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center.</article-title><source>Medicine (Baltimore)</source><volume>85</volume><fpage>278</fpage><lpage>287</lpage><pub-id pub-id-type="pmid">16974212</pub-id></element-citation></ref><ref id="pone.0036543-Hakim1"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hakim</surname><given-names>H</given-names></name><name><surname>Flynn</surname><given-names>PM</given-names></name><name><surname>Knapp</surname><given-names>KM</given-names></name><name><surname>Srivastava</surname><given-names>DK</given-names></name><name><surname>Gaur</surname><given-names>AH</given-names></name></person-group><year>2009</year><article-title>Etiology and clinical course of febrile neutropenia in children with cancer.</article-title><source>J Pediatr Hematol Oncol</source><volume>31</volume><fpage>623</fpage><lpage>629</lpage><pub-id pub-id-type="pmid">19644403</pub-id></element-citation></ref><ref id="pone.0036543-Johansson1"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Johansson</surname><given-names>N</given-names></name><name><surname>Kalin</surname><given-names>M</given-names></name><name><surname>Tiveljung-Lindell</surname><given-names>A</given-names></name><name><surname>Giske</surname><given-names>CG</given-names></name><name><surname>Hedlund</surname><given-names>J</given-names></name></person-group><article-title>Etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods.</article-title><source>Clin Infect Dis</source><volume>50</volume><fpage>202</fpage><lpage>209</lpage><pub-id pub-id-type="pmid">20014950</pub-id></element-citation></ref><ref id="pone.0036543-Erard1"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Erard</surname><given-names>V</given-names></name><name><surname>Kim</surname><given-names>HW</given-names></name><name><surname>Corey</surname><given-names>L</given-names></name><name><surname>Limaye</surname><given-names>A</given-names></name><name><surname>Huang</surname><given-names>ML</given-names></name><etal></etal></person-group><year>2005</year><article-title>BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients.</article-title><source>Blood</source><volume>106</volume><fpage>1130</fpage><lpage>1132</lpage><pub-id pub-id-type="pmid">15845896</pub-id></element-citation></ref><ref id="pone.0036543-Haines1"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Haines</surname><given-names>HL</given-names></name><name><surname>Laskin</surname><given-names>BL</given-names></name><name><surname>Goebel</surname><given-names>J</given-names></name><name><surname>Davies</surname><given-names>SM</given-names></name><name><surname>Yin</surname><given-names>HJ</given-names></name><etal></etal></person-group><year>2011</year><article-title>Blood, and not urine, BK viral load predicts renal outcome in children with hemorrhagic cystitis following hematopoietic stem cell transplantation.</article-title><source>Biol Blood Marrow Transplant</source><volume>17</volume><fpage>1512</fpage><lpage>1519</lpage><pub-id pub-id-type="pmid">21385622</pub-id></element-citation></ref><ref id="pone.0036543-Fairchok1"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fairchok</surname><given-names>MP</given-names></name><name><surname>Martin</surname><given-names>ET</given-names></name><name><surname>Chambers</surname><given-names>S</given-names></name><name><surname>Kuypers</surname><given-names>J</given-names></name><name><surname>Behrens</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Epidemiology of viral respiratory tract infections in a prospective cohort of infants and toddlers attending daycare.</article-title><source>J Clin Virol</source><volume>49</volume><fpage>16</fpage><lpage>20</lpage><pub-id pub-id-type="pmid">20650679</pub-id></element-citation></ref><ref id="pone.0036543-Ljungman2"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ljungman</surname><given-names>P</given-names></name><name><surname>Ward</surname><given-names>KN</given-names></name><name><surname>Crooks</surname><given-names>BN</given-names></name><name><surname>Parker</surname><given-names>A</given-names></name><name><surname>Martino</surname><given-names>R</given-names></name><etal></etal></person-group><year>2001</year><article-title>Respiratory virus infections after stem cell transplantation: a prospective study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.</article-title><source>Bone Marrow Transplant</source><volume>28</volume><fpage>479</fpage><lpage>484</lpage><pub-id pub-id-type="pmid">11593321</pub-id></element-citation></ref><ref id="pone.0036543-Chakrabarti1"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chakrabarti</surname><given-names>S</given-names></name><name><surname>Mautner</surname><given-names>V</given-names></name><name><surname>Osman</surname><given-names>H</given-names></name><name><surname>Collingham</surname><given-names>KE</given-names></name><name><surname>Fegan</surname><given-names>CD</given-names></name><etal></etal></person-group><year>2002</year><article-title>Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery.</article-title><source>Blood</source><volume>100</volume><fpage>1619</fpage><lpage>1627</lpage><pub-id pub-id-type="pmid">12176880</pub-id></element-citation></ref><ref id="pone.0036543-Hakki1"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hakki</surname><given-names>M</given-names></name><name><surname>Riddell</surname><given-names>SR</given-names></name><name><surname>Storek</surname><given-names>J</given-names></name><name><surname>Carter</surname><given-names>RA</given-names></name><name><surname>Stevens-Ayers</surname><given-names>T</given-names></name><etal></etal></person-group><year>2003</year><article-title>Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation.</article-title><source>Blood</source><volume>102</volume><fpage>3060</fpage><lpage>3067</lpage><pub-id pub-id-type="pmid">12843000</pub-id></element-citation></ref><ref id="pone.0036543-Engstrand1"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Engstrand</surname><given-names>M</given-names></name><name><surname>Lidehall</surname><given-names>AK</given-names></name><name><surname>Totterman</surname><given-names>TH</given-names></name><name><surname>Herrman</surname><given-names>B</given-names></name><name><surname>Eriksson</surname><given-names>BM</given-names></name><etal></etal></person-group><year>2003</year><article-title>Cellular responses to cytomegalovirus in immunosuppressed patients: circulating CD8+ T cells recognizing CMVpp65 are present but display functional impairment.</article-title><source>Clin Exp Immunol</source><volume>132</volume><fpage>96</fpage><lpage>104</lpage><pub-id pub-id-type="pmid">12653843</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/CovidV2/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000A14 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000A14 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= CovidV2
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:3343003
|texte= Viral Findings in Adult Hematological Patients with Neutropenia
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:22570724" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CovidV2
| This area was generated with Dilib version V0.6.33. |  |