Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

doi:10.1007/s00277-017-3098-3

Review

. 2017 Nov;96(11):1775-1792.

doi: 10.1007/s00277-017-3098-3. Epub 2017 Aug 30.

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

W J Heinz¹, D Buchheidt², M Christopeit³, M von Lilienfeld-Toal⁴, O A Cornely^{5

6

7

8

9}, H Einsele¹, M Karthaus^{10

11}, H Link¹², R Mahlberg¹³, S Neumann¹⁴, H Ostermann¹⁵, O Penack¹⁶, M Ruhnke¹⁷, M Sandherr¹⁸, X Schiel¹¹, J J Vehreschild^{5

6}, F Weissinger¹⁹, G Maschmeyer²⁰

Affiliations

¹ Department of Internal Medicine II, University of Würzburg Medical Center, Würzburg, Germany.
² Department of Internal Medicine-Hematology and Oncology, Mannheim University Hospital, Mannheim, Germany.
³ Department of Stem Cell Transplantation, University Hospital UKE, Hamburg, Germany.
⁴ Department of Hematology and Oncology, University Hospital of Jena, Jena, Germany.
⁵ Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
⁶ German Centre for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
⁷ Clinical Trials Centre Cologne, ZKS Köln, Cölogne, Germany.
⁸ Center for Integrated Oncology CIO Köln-Bonn, Cologne, Germany.
⁹ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany.
¹⁰ Department of Hematology, Oncology and Palliative Care, Klinikum Neuperlach and Klinikum Harlaching, München, Germany.
¹¹ Department of Hematology, Oncology and Palliative Care, Klinikum Harlaching, Munich, Germany.
¹² Hematology and Medical Oncology Private Practice, Kaiserslautern, Germany.
¹³ Klinikum Mutterhaus der Borromäerinnen, Trier, Germany.
¹⁴ Medical Oncology, AMO MVZ, Wolfsburg, Germany.
¹⁵ Department of Hematology and Oncology, University of Munich, Munich, Germany.
¹⁶ Internal Medicine, Hematology, Oncology and Tumor Immunology, University Hospital Charité, Campus Virchow Klinikum, Berlin, Germany.
¹⁷ Department of Hematology and Oncology, Paracelsus-Klinik, Osnabrück, Germany.
¹⁸ Hematology and Oncology Practice, Weilheim, Germany.
¹⁹ Department of Internal Medicine, Hematology, Oncology and Palliative Care, Evangelisches Klinikum Bethel, Bielefeld, Germany.
²⁰ Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany. gmaschmeyer@klinikumevb.de.

PMID: 28856437
PMCID: PMC5645428
DOI: 10.1007/s00277-017-3098-3

Review

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

W J Heinz et al. Ann Hematol. 2017 Nov.

. 2017 Nov;96(11):1775-1792.

doi: 10.1007/s00277-017-3098-3. Epub 2017 Aug 30.

Authors

Affiliations

¹ Department of Internal Medicine II, University of Würzburg Medical Center, Würzburg, Germany.
² Department of Internal Medicine-Hematology and Oncology, Mannheim University Hospital, Mannheim, Germany.
³ Department of Stem Cell Transplantation, University Hospital UKE, Hamburg, Germany.
⁴ Department of Hematology and Oncology, University Hospital of Jena, Jena, Germany.
⁵ Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
⁶ German Centre for Infection Research, partner site Bonn-Cologne, Cologne, Germany.
⁷ Clinical Trials Centre Cologne, ZKS Köln, Cölogne, Germany.
⁸ Center for Integrated Oncology CIO Köln-Bonn, Cologne, Germany.
⁹ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany.
¹⁰ Department of Hematology, Oncology and Palliative Care, Klinikum Neuperlach and Klinikum Harlaching, München, Germany.
¹¹ Department of Hematology, Oncology and Palliative Care, Klinikum Harlaching, Munich, Germany.
¹² Hematology and Medical Oncology Private Practice, Kaiserslautern, Germany.
¹³ Klinikum Mutterhaus der Borromäerinnen, Trier, Germany.
¹⁴ Medical Oncology, AMO MVZ, Wolfsburg, Germany.
¹⁵ Department of Hematology and Oncology, University of Munich, Munich, Germany.
¹⁶ Internal Medicine, Hematology, Oncology and Tumor Immunology, University Hospital Charité, Campus Virchow Klinikum, Berlin, Germany.
¹⁷ Department of Hematology and Oncology, Paracelsus-Klinik, Osnabrück, Germany.
¹⁸ Hematology and Oncology Practice, Weilheim, Germany.
¹⁹ Department of Internal Medicine, Hematology, Oncology and Palliative Care, Evangelisches Klinikum Bethel, Bielefeld, Germany.
²⁰ Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam, Germany. gmaschmeyer@klinikumevb.de.

PMID: 28856437
PMCID: PMC5645428
DOI: 10.1007/s00277-017-3098-3

Abstract

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

Keywords: Antibacterial; Antifungal; Empirical therapy; Fever; Infection; Neutropenia.

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Conflict of interest statement

DB is a consultant to Gilead Sciences and received research grants from Gilead and Pfizer, honoraria for lectures from Astellas, Gilead, MSD/Merck, TEVA, and Pfizer and travel grants from Astellas, Merck/MSD, and Pfizer. GM has been a consultant to Gilead and F2G and received honoraria for lectures from Gilead, Pfizer, Basilea, and Astellas. HL has received research grants from Amgen, Merck/MSD, Hexal, and TEVA; is a consultant to Amgen, Chugai, Grifols, Hexal, Merck/MSD, and TEVA; and received honoraria for lectures from Amgen, Hexal, Merck/MSD, and TEVA. HO received research grants from Gilead and MSD; is consultant to Astellas and MSD; and received lecture honoraria and travel grants from Astellas, Basilea, Gilead, Pfizer, and Merck/MSD. JJV has been a speaker for Astellas, Gilead, Merck/MSD, and Pfizer; has been a consultant to Astellas, Merck/MSD, and Pfizer; has received research funding by Astellas, Gilead, Merck/MSD, and Pfizer; and has received travel grants from Astellas, Gilead, Merck/MSD, and Pfizer. MC has been a consultant to Basilea and Merck/MSD and received travel grants and congress support (fees) from Gilead, Merck/MSD, and Basilea and honoraria for lectures from Gilead, Merck/MSD, and Basilea. MR is a consultant to Basilea and served at the speakers’ bureau of Basilea. MvLT is supported by the German Federal Ministry of Research and Education (BMBF grants 01EO1002 and 13GW0096D); has received research grants from Pfizer and MSD, is a consultant to Merck/MSD; and received honoraria or travel grants from Basilea, Gilead, Merck/MSD, and Astellas. OAC is supported by the German Federal Ministry of Research and Education and the European Commission and has received research grants from, is an advisor to, or received lecture honoraria from Achaogen, Actelion, Amplyx, Anacor, Aranis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Da Volterra, F2G, Gilead, GSK, Janssen, Matinas, MedPace, Melinta, Menarini, Merck/MSD, Miltenyi, Paratek, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres, Summit, Tetraphase, Medicines Company, and Vical. OP received research grants from Bio-Rad and Gilead; is consultant to Merck/MSD and Gilead; and received lecture honoraria and travel grants from Astellas, Gilead, Pfizer, and Merck/MSD. SN received travel grants from Bristol-Myers Squibb, Gilead, Roche, and Sanofi. WJH received research grants from Merck/MSD and Pfizer; serves on the speakers’ bureaus of Alexion, Astellas, Bristol-Myers Squibb, Chugai Pharma, Gilead, Janssen, Merck/MSD, and Pfizer; and received travel grants from Alexion, Astellas, Merck/MSD, Novartis, and Pfizer. XS received lecture honoraria from Merck/MSD and Riemser Pharma. FW, HE, MK, MS, and RM declare that they have no conflict of interest.

Figures

**Fig. 1**
Treatment algorithm for febrile neutropenic high-risk patients: 1, e.g., urine cultures, CT of sinuses, echocardiography, and viral PCR; 2, in the case of carbapenem-resistant MDR bacteria individual choice according to in vitro susceptibility; 3, monitor blood levels; 4, e.g., tachypnea, dyspnea, cough, and pleuritic symptoms; 5, strong recommendation for patients with high-risk neutropenia without mold-active prophylaxis. *CVC* central venous catheter, *MDR* multidrug resistant, CT computed tomography scan, iv intravenous, AB antibiotics, *MRSA* methicillin-resistant *Staphylococcus aureus*, *ESBL-E* extended spectrum beta-lactamase-producing enterobacteria, *VRE* vancomycin-resistant enterococci, *PCR* polymerase chain reaction

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References

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1. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258–2266. doi: 10.1002/cncr.21847. - DOI - PubMed
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1. Neumann S, Krause SW, Maschmeyer G, Schiel X, von Lilienfeld-Toal M. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) Ann Hematol. 2013;92(4):433–442. doi: 10.1007/s00277-013-1698-0. - DOI - PMC - PubMed

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[1] Bodey GP. Infectious complications of acute leukemia. Med Times. 1966;94(9):1076–1085. - PubMed

[2] Bodey GP. Infectious complications of acute leukemia. Med Times. 1966;94(9):1076–1085. - PubMed

[3] Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258–2266. doi: 10.1002/cncr.21847. - DOI - PubMed

[4] Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106(10):2258–2266. doi: 10.1002/cncr.21847. - DOI - PubMed

[5] Link H, Böhme A, Cornely OA, Höffken K, Kellner O, Kern WV, Mahlberg R, Maschmeyer G, Nowrousian MR, Ostermann H, Ruhnke M, Sezer O, Schiel X, Wilhelm M, Auner HW. Antimicrobial therapy of unexplained fever in neutropenic patients—guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society) Ann Hematol. 2003;82(Suppl 2):S105–S117. doi: 10.1007/s00277-003-0764-4. - DOI - PubMed

[6] Link H, Böhme A, Cornely OA, Höffken K, Kellner O, Kern WV, Mahlberg R, Maschmeyer G, Nowrousian MR, Ostermann H, Ruhnke M, Sezer O, Schiel X, Wilhelm M, Auner HW. Antimicrobial therapy of unexplained fever in neutropenic patients—guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society) Ann Hematol. 2003;82(Suppl 2):S105–S117. doi: 10.1007/s00277-003-0764-4. - DOI - PubMed

[7] Penack O, Becker C, Buchheidt D, Christopeit M, Kiehl M, von Lilienfeld-Toal M, Hentrich M, Reinwald M, Salwender H, Schalk E, Schmidt-Hieber M, Weber T, Ostermann H. Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of hematology and medical oncology (AGIHO) Ann Hematol. 2014;93(7):1083–1095. doi: 10.1007/s00277-014-2086-0. - DOI - PMC - PubMed

[8] Penack O, Becker C, Buchheidt D, Christopeit M, Kiehl M, von Lilienfeld-Toal M, Hentrich M, Reinwald M, Salwender H, Schalk E, Schmidt-Hieber M, Weber T, Ostermann H. Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of hematology and medical oncology (AGIHO) Ann Hematol. 2014;93(7):1083–1095. doi: 10.1007/s00277-014-2086-0. - DOI - PMC - PubMed

[9] Neumann S, Krause SW, Maschmeyer G, Schiel X, von Lilienfeld-Toal M. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) Ann Hematol. 2013;92(4):433–442. doi: 10.1007/s00277-013-1698-0. - DOI - PMC - PubMed

[10] Neumann S, Krause SW, Maschmeyer G, Schiel X, von Lilienfeld-Toal M. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) Ann Hematol. 2013;92(4):433–442. doi: 10.1007/s00277-013-1698-0. - DOI - PMC - PubMed

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Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

Affiliations

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

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