Diagnosis and antimicrobial therapy of lung infiltrates in febrile neutropenic patients (allogeneic SCT excluded): updated guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32: 2240-2247. 17. Karthaus M, Schwartzberg L, Rivera F et al. Updated overall survival (OS) analysis of novel predictive KRAS/NRAS mutations beyond KRAS exon 2 in PEAK: A 1st-line phase 2 study of FOLFOX6 plus panitumumab ( pmab) or bevacizumab (bev) in metastatic colorectal cancer (mCRC). Eur J Cancer 2013; 49: S516. 18. Ciardiello F, Lenz HJ, Kohne CH et al. Treatment outcome according to tumor RAS mutation status in CRYSTAL study patients with metastatic colorectal cancer (mCRC) randomized to FOLFIRI with/without cetuximab. J Clin Oncol 2014; 32: abstr 3506. 19. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26: 1626-1634. 20. Jonker DJ, O'Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357: 2040-2048. 21. Venook AP, Niedzwiecki D, Lenz HJ et al. CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients ( pts) with KRAS wild-type Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory viruses may be involved. In at-risk patients who have received trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis, filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation.  This manuscript does not refer to patients undergoing allogeneic hematopoietic stem cell transplantation. These patients are subject to a separate AGIHO guideline [1].Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, -D-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however, most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unrestrictedly provided in patients whose prognosis is not desperate due to other reasons.

## Diagnostic procedures
With respect to the critical prognosis of lung infiltrates (LI) in febrile neutropenic patients, diagnostic procedures are of major importance, but should not cause a substantial delay in the start of adequate antimicrobial therapy.
imaging Conventional chest radiographs show abnormalities in <2% of febrile neutropenic patients without clinical findings indicating lower respiratory tract infection [bib_ref] Is routine chest radiography necessary for the initial evaluation of fever in..., Korones [/bib_ref] [bib_ref] Conventional chest radiography in the initial assessment of adult cancer patients with..., Navigante [/bib_ref] [bib_ref] Routine radiography does not have a role in the diagnostic evaluation of..., Nijhuis [/bib_ref]. It is undetermined how many of these patients would have abnormalities on computed tomography (CT) scans, because no randomized head-to-head comparisons have been published so far. In patients persistently febrile after >48 h of broad-spectrum antibacterial therapy, 10% of chest radiographs are abnormal, whereas highresolution CT scans at this time reveal pathological findings in 50% of patients [bib_ref] Early detection of pneumonia in febrile neutropenic patients: use of thin-section CT, Heussel [/bib_ref] [bib_ref] Pneumonia in febrile neutropenic patients and in bone marrow and blood stem-cell..., Heussel [/bib_ref]. Early detection of lesions indicating invasive mold infection or Pneumocystis pneumonia (PcP) is of utmost importance, facilitating targeted bronchoscopy and bronchoalveolar lavage (BAL) and a prompt institution of preemptive antimicrobial treatment [bib_ref] Role of early diagnosis and aggressive surgery in the management of invasive..., Caillot [/bib_ref] [bib_ref] The diagnostic value of halo and reversed halo signs for invasive mold..., Georgiadou [/bib_ref] [bib_ref] Bronchoscopy guided by high-resolution computed tomography for the diagnosis of pulmonary infections..., Ramila [/bib_ref] , enabling better survival of these patients. CT findings such as consolidation, 'halo sign' and 'air-crescent sign', obtained by high-resolution or multislice CT scans, may be important signs of filamentous fungal disease [bib_ref] The diagnostic value of halo and reversed halo signs for invasive mold..., Georgiadou [/bib_ref] [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref]. While the 'halo sign' has been described typically in neutropenic patients, other CT findings indicative of IPA are comparable in neutropenic and in non-neutropenic patients [bib_ref] Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic..., Cornillet [/bib_ref]. A 'reversed halo sign', showing a focal rounded area of groundglass opacity surrounded by a crescent or complete ring of consolidation, has been reported as relatively specific for fungal pneumonia due to zygomycetes/mucorales [bib_ref] The diagnostic value of halo and reversed halo signs for invasive mold..., Georgiadou [/bib_ref] ; however, it may represent a broad spectrum of other differential diagnoses including tuberculosis, sarcoidosis or cryptogenic organizing pneumonia [bib_ref] The reversed halo sign: update and differential diagnosis, Godoy [/bib_ref].
Beyond early identification of LI, CT findings may allow for distinguishing fungal from nonfungal LI [bib_ref] Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid..., Suzuki [/bib_ref] [bib_ref] Computer tomography in pulmonary invasive aspergillosis in hematological patients with neutropenia: a..., Caillot [/bib_ref] [bib_ref] Pulmonary infections after bone marrow transplantation: high-resolution CT findings in 111 patients, Escuissato [/bib_ref] [bib_ref] High-resolution CT findings of respiratory syncytial virus pneumonia after bone marrow transplantation, Gasparetto [/bib_ref] [bib_ref] Clinical and radiologic predictors of invasive pulmonary aspergillosis in cancer patients: should..., Hachem [/bib_ref] [bib_ref] Pneumonia in neutropenic patients, Heussel [/bib_ref]. Diffuse bilateral perihilar infiltrates, patchy areas of ground-glass attenuation ( peripheral sparing), cysts and septal thickening, consolidation and centrilobular nodules may indicate PcP [bib_ref] Pneumocystis jiroveci pneumonia: highresolution CT findings in patients with and without HIV..., Kanne [/bib_ref] [bib_ref] Comparison of clinical and radiological features of Pneumocystis pneumonia between malignancy cases..., Tasaka [/bib_ref] [bib_ref] HRCT-features of Pneumocystis jiroveci pneumonia and their evolution before and after treatment..., Vogel [/bib_ref]. Nodular or cavitary lesions are suggestive of invasive filamentous fungal infection; however, differential diagnoses include pneumonia due to other microorganisms including mycobacteria (which may be relevant in regions with high prevalence), Nocardia, Pneumocystis or Pseudomonas aeruginosa (P. aeruginosa) as well as lung involvement by underlying malignancies , so that comparison to previous CT scans in an individual patient is essential. Combination of CT scan with angiography has been found to increase the diagnostic specificity in some patients with pulmonary mold infections ; however, this more labor intensive method has not yet become widely applied and is therefore not included into current clinical practice guidelines. In selected patients where pulmonary CT scan is not wanted or feasible, magnetic resonance tomography (MRI) is a valid alternative (B-II) [bib_ref] Pulmonary abnormalities in immunocompromised patients: comparative detection with parallel acquisition MR imaging..., Eibel [/bib_ref]. As yet, consensus definitions of invasive fungal diseases [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] have not included thoracic MRI findings. In selected patients with unexplained fever during neutropenia, [ 18 F]2-fluoro-2-deoxy-D-glucose-positron emission tomography combined with computed tomography (PET-CT) may be helpful, particularly to rule out undetected infection [bib_ref] 18F-FDG PET/CT for diagnosing infectious complications in patients with severe neutropenia after..., Vos [/bib_ref].
Follow-up thoracic CT scans should in general not be ordered <7 days after start of treatment (A-II). In patients with IPA may show increasing volume of pulmonary infiltrates during the first week despite effective antifungal therapy [bib_ref] Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic..., Caillot [/bib_ref]. This finding alone should not give reason to assess the treatment course as refractory (A-II). Reduction of the 'halo' and the development of an 'aircrescent' sign, however, typically indicate favorable response [bib_ref] Long-term CT follow-up in 40 non-HIV immunocompromised patients with invasive pulmonary aspergillosis, Brodoefel [/bib_ref].

## Microbiology and histopathology
In the majority of febrile neutropenic patients with LI, no proving microbiological finding is available, so that the therapeutic management is based upon clinical and imaging findings (see below). In microbiologically documented cases, pathogens typically are isolated from blood cultures, bronchial secretions or BAL fluid. It often means a challenge to assess the diagnostic relevance of culture results [bib_ref] Open lung biopsy provides a higher and more specific diagnostic yield compared..., Ellis [/bib_ref] [bib_ref] Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure, Azoulay [/bib_ref] [bib_ref] Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic..., Hummel [/bib_ref] [bib_ref] Polymicrobial infection in patients with cancer: an underappreciated and underreported entity, Rolston [/bib_ref] , because unselected bronchial samples from these patients grow colonizing and contaminating microorganisms with no etiological significance [bib_ref] Surveillance of nosocomial sepsis and pneumonia in patients with a bone marrow..., Dettenkofer [/bib_ref] , or blood cultures may show isolates not etiologically related to pneumonias. At the same time, if autopsies show invasive fungal infections, 75% of them have not been detected ante mortem [bib_ref] Invasive fungal infections in patients with hematologic malignancies in a tertiary care..., Chamilos [/bib_ref] [bib_ref] Pulmonary complications in adult blood and marrow transplant recipients: autopsy findings, Sharma [/bib_ref]. Therefore, in contrast to the majority of other microbiological findings, isolation of Aspergillus spp. or other filamentous fungi from upper respiratory tract specimens of severely immunocompromised patients typically indicates a respiratory tract mycosis [bib_ref] The impact of culture isolation of Aspergillus species: a hospital-based survey of..., Perfect [/bib_ref].
The diagnostic yield and the outcome of clinical management in critically ill, febrile cancer patients with severe pulmonary infiltrates have not been improved by invasive diagnostic procedures including BAL [bib_ref] Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized..., Azoulay [/bib_ref]. The detection rate of potential pathogens from BAL samples has been described to be 25%-50% or even higher [bib_ref] Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic..., Cornillet [/bib_ref] [bib_ref] Bronchoscopic diagnosis of pulmonary infiltrates in granulocytopenic patients with hematologic malignancies: BAL..., Boersma [/bib_ref] [bib_ref] Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates, Jain [/bib_ref] [bib_ref] Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell..., Zihlif [/bib_ref] , depending on the risk profile of patients included. A retrospective analysis of microbiological findings from BAL samples in cancer patients with LI showed 34% bacteria, 22% cytomegalovirus (CMV), 15% Pneumocystis jirovecii (P. jirovecii) and 2% Aspergillus spp. [bib_ref] Pulmonary infiltrates in patients with haematologic malignancies: transbronchial lung biopsy increases the..., Mulabecirovic [/bib_ref] , and another report of 246 bronchoscopies in 199 febrile patients with hematological malignancies described pathogens with possible etiological significance in 48% of samples, of which 70 samples grew only bacteria, 13 showed both fungi and bacteria, 15 samples Aspergillus spp., 16 samples Candida species and 2 samples both Aspergillus and Candida spp. [bib_ref] Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic..., Hummel [/bib_ref]. Many LI in severely immunocompromised patients may also have polymicrobial etiology [bib_ref] Polymicrobial infection in patients with cancer: an underappreciated and underreported entity, Rolston [/bib_ref] , with molds ( predominantly Aspergillus spp.) plus bacteria in 12% and multiple fungal species in 22% of samples. Although the etiological relevance of BAL findings may be questionable in many cases, the results trigger the change of antimicrobial treatment in up to 50% of patients [bib_ref] Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic..., Hummel [/bib_ref] [bib_ref] The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and..., Patel [/bib_ref] [bib_ref] Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with..., Peikert [/bib_ref]. As a diagnostic 'gold standard' is lacking, the number of false-positive and false-negative findings are unknown, and the rates of success or failure of 'pathogen-directed' antimicrobial treatment therefore remain undetermined. A proposal for the assessment of the etiological significance of microbiological findings in febrile neutropenic patients with LI is given in antimicrobial treatment in patients with documented pathogens section.
While for the proven diagnosis of IPA, cultural isolation of fungi and histological proof from lung tissue are regarded as diagnostic 'gold standard' [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] , quality standards for diagnostic procedures are not available and patients undergoing biopsy are highly selected. Histological proof alone has an accuracy for Aspergillus of around 78%, so that histology should always be combined with fungal culture and with a culture independent method, e.g. nucleic acid based [bib_ref] Diagnostic accuracy of histopathologic and cytopathologic examination of Aspergillus species, Shah [/bib_ref]. Polymerase chain reaction (PCR) may be helpful especially in patients who already receive antifungal treatment and for difficult-to-culture pathogens such as Mucorales.
Transbronchial biopsy is not recommended in severely thrombocytopenic patients with lung infiltrates [bib_ref] Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with..., Peikert [/bib_ref]. Open-lung biopsy (OLB), mini-thoracotomy or video-assisted thoracoscopic surgery may be safely carried out in patients with treatment-refractory LI not cleared-up by other diagnostic approaches, primarily in order to rule out noninfectious origin [bib_ref] Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell..., Zihlif [/bib_ref] [bib_ref] Organizing pneumonia in patients with hematologic malignancies: a steroid-responsive lesion, Daniels [/bib_ref] [bib_ref] Drug-induced respiratory disease in patients with hematological diseases, Camus [/bib_ref] [bib_ref] Evaluation of persistent pulmonary infiltrates in pediatric oncology patients, Armenian [/bib_ref] [bib_ref] Surgical management of invasive pulmonary fungal infection in hematology patients, Theodore [/bib_ref]. OLB is a relatively safe procedure with a complication rate of 6% [bib_ref] Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary..., Georgiadou [/bib_ref] , including the risk of hemorrhage [bib_ref] Evaluation of persistent pulmonary infiltrates in pediatric oncology patients, Armenian [/bib_ref] [bib_ref] The utility of open lung biopsy in patients with hematologic malignancies, White [/bib_ref] even in thrombocytopenic patients [bib_ref] Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary..., Georgiadou [/bib_ref] [bib_ref] Accuracy of percutaneous lung biopsy for invasive pulmonary aspergillosis, Hoffer [/bib_ref]. Histologically, no infection or malignancy, but nonspecific inflammation is detected in the majority of patients [bib_ref] Open lung biopsy provides a higher and more specific diagnostic yield compared..., Ellis [/bib_ref] [bib_ref] Open-lung biopsy in patients with undiagnosed lung lesions referred at a tertiary..., Georgiadou [/bib_ref] [bib_ref] Accuracy of percutaneous lung biopsy for invasive pulmonary aspergillosis, Hoffer [/bib_ref]. Notably, findings from OLB and BAL obtained simultaneously may show different microbiological results [bib_ref] Open lung biopsy provides a higher and more specific diagnostic yield compared..., Ellis [/bib_ref].
CT-guided percutaneous side-cut core needle biopsy may provide informative results in 80% of cases, allowing for species identification using molecular methods for tissue workup [bib_ref] Utility of computed tomography and of fine needle aspiration biopsy in early..., Carrafiello [/bib_ref] [bib_ref] CT-guided percutaneous lung biopsies in patients with haematologic malignancies and undiagnosed pulmonary..., Gupta [/bib_ref] [bib_ref] The value of computed tomographyguided percutaneous lung biopsy for diagnosis of invasive..., Lass-Florl [/bib_ref] [bib_ref] Aspergillus PCR-based investigation of fresh tissue and effusion samples in patients with..., Reinwald [/bib_ref] [bib_ref] Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect..., Rickerts [/bib_ref]. Percutaneous biopsy requires platelet counts >50 000/l plus sufficient coagulation indices, e.g. an aPTT ratio of 1.4 [bib_ref] Guidelines for radiologically guided lung biopsy, Manhire [/bib_ref] , and should be limited to patients without an obvious risk of respiratory failure in case of complications such as a pneumothorax. As yet, there are no reports from prospective studies comparing different methods for invasive approaches to identify the causes of LI in febrile neutropenic patients.
nonculture-based diagnostic methods cytomegalovirus and respiratory viruses. In patients with profound cellular immunosuppression, respiratory viruses may be the cause of LI, so that diagnostic programs used for workup of BAL or oro-/nasopharyngeal swabs should include CMV as well as Influenza, Parainfluenza, Respiratory Syncytial Virus, Coronavirus, Rhinovirus and Human Metapneumovirus [bib_ref] The characteristics and outcomes of parainfluenza virus infections in 200 patients with..., Chemaly [/bib_ref] [bib_ref] ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza..., Hirsch [/bib_ref] [bib_ref] Human metapneumovirus infection in hematopoietic stem cell transplant recipients, Debur [/bib_ref] [bib_ref] A prospective study comparing human metapneumovirus with other respiratory viruses in adults..., Williams [/bib_ref]. In febrile neutropenic patients with LI, CMV PCR applied on BAL samples has a high negative, but low positive predictive value [bib_ref] Bronchoalveolar lavage in immunocompromised patients with haematological malignancy-value of new microbiological methods, Hohenthal [/bib_ref] , while positive rapid culture, immediate early antigen, direct fluorescent antibody tests, DNA hybridization or cytology from BAL cultures are required to confirm the diagnosis of CMV pneumonia [bib_ref] Complications, diagnosis, management, and prevention of CMV infections: current and future, Boeckh [/bib_ref] [bib_ref] Definitions of cytomegalovirus infection and disease in transplant recipients, Ljungman [/bib_ref].
Pneumocystis jirovecii. Besides microscopic identification, which has been the classical reference method for detecting P. jirovecii, PCR has been introduced in the 1990s for early detection of this pathogen with a high sensitivity [bib_ref] Evaluation of diagnostic value and epidemiological implications of PCR for Pneumocystis carinii..., Sing [/bib_ref]. It is essential to distinguish between infection and colonization, which may be present in >50% of individuals without signs or symptoms of PcP [bib_ref] Pneumocystis colonization is highly prevalent in the autopsied lungs of the general..., Ponce [/bib_ref]. A meta-analysis showed a very high sensitivity of 99% and a specificity of 90% [bib_ref] PCR diagnosis of Pneumocystis pneumonia: a bivariate meta-analysis, Lu [/bib_ref] , so that a negative Pneumocystis-PCR from a BAL sample at the time of diagnosis allows to put aside anti-Pneumocystis therapy [bib_ref] Polymerase chain reaction for diagnosing Pneumocystis pneumonia in non-HIV immunocompromised patients with..., Azoulay [/bib_ref]. More recently developed quantitative PCR assays appear to increase the specificity [bib_ref] Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and..., Alanio [/bib_ref] [bib_ref] Outcome of Pneumocystis jirovecii pneumonia diagnosed by polymerase chain reaction in patients..., Hardak [/bib_ref]. A report on 71 non-HIV patients with proven PcP showed a positive predictive value of 98% when >1450 pathogens per ml were detected in BAL samples [bib_ref] Quantitative PCR to diagnose Pneumocystis pneumonia in immunocompromised non-HIV patients, Muhlethaler [/bib_ref]. Determining -D-glucan in serum may add to the differential diagnosis [bib_ref] Diagnostic accuracy of serum 1,3--D-glucan for Pneumocystis jiroveci pneumonia, invasive candidiasis, and..., Onishi [/bib_ref] [bib_ref] Detection of (1, 3)--D-glucan in bronchoalveolar lavage and serum samples collected from..., Theel [/bib_ref] , because a negative result of this test makes PcP highly unlikely [bib_ref] Accuracy of -D-glucan for the diagnosis of Pneumocystis jirovecii pneumonia: a meta-analysis, Karageorgopoulos [/bib_ref].
filamentous fungi. Numerous methods have been developed for detecting fungal cell antigens such as Aspergillus galactomannan (GM), 1,3--D-glucan or nuclear amplification assays to identify fungal DNA for early noninvasive detection of filamentous fungi in febrile neutropenic patients with LI of undetermined etiology [bib_ref] Usefulness of sequential Aspergillus galactomannan antigen detection combined with early radiologic evaluation..., Busca [/bib_ref] [bib_ref] Detection and identification of fungal pathogens in blood by using molecular probes, Einsele [/bib_ref] [bib_ref] Autopsy-controlled prospective evaluation of serial screening for circulating galactomannan by a sandwich..., Maertens [/bib_ref] [bib_ref] Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay, Maertens [/bib_ref] [bib_ref] Development of a LightCycler PCR assay for detection and quantification of Aspergillus..., Spiess [/bib_ref]. A positive (i.e. >0.5 OD) GM test from blood or from BAL samples, where a cutoff of 1.0 might be more appropriate [bib_ref] Systematic review and meta-analysis of detecting galactomannan in bronchoalveolar lavage fluid for..., Zou [/bib_ref] , has been accepted as a significant finding indicating a probable invasive fungal infection in severely immunocompromised patients [bib_ref] Galactomannan detection in computerized tomography-based broncho-alveolar lavage fluid and serum in haematological..., Becker [/bib_ref] [bib_ref] Detection of Aspergillus species in blood and bronchoalveolar lavage samples from immunocompromised..., Buchheidt [/bib_ref]. It is questionable if Aspergillus GM in blood will become positive earlier than a chest CT scan [bib_ref] Galactomannan does not precede major signs on a pulmonary computerized tomographic scan..., Weisser [/bib_ref]. Notably, the GM test may give false-positive results in patients treated with semisynthetic -lactam antibiotics such as amoxicillin-clavulanate, piperacillintazobactam, carbapenems, ceftriaxone or cefepime [bib_ref] Occurrence and kinetics of false-positive Aspergillus galactomannan test results following treatment with..., Aubry [/bib_ref] [bib_ref] Falsepositive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics, Boonsarngsuk [/bib_ref] as well as in those given enteral nutrition [bib_ref] Enteral nutrition may cause false-positive results of Aspergillus galactomannan assay in absence..., Girmenia [/bib_ref] , those with other fungal infections such as fusariosis [bib_ref] Cross-reactivity of Fusarium spp. in the Aspergillus galactomannan enzyme-linked immunosorbent assay, Tortorano [/bib_ref] and in BAL samples obtained using specific lavage solutions such as PlasmalyteTM [bib_ref] Plasmalyte as a cause of false-positive results for Aspergillus galactomannan in bronchoalveolar..., Hage [/bib_ref]. Falsepositive Aspergillus antigenemia may also be due to blood product conditioning fluids [bib_ref] False-positive Aspergillus antigenemia due to blood product conditioning fluids, Martin-Rabadan [/bib_ref]. A significant decline in the galactomannan Aspergillus antigen signal was described during storage of serum samples, in contrast to BAL samples, so that the time from taking a blood sample to testing should be minimized [bib_ref] Significant decline in galactomannan signal during storage of clinical serum samples, Johnson [/bib_ref].
Details on antigen testing for fungal infection, including those other than aspergillosis [bib_ref] Multicenter clinical evaluation of the (1,3) beta-D-glucan assay as an aid to..., Ostrosky-Zeichner [/bib_ref] , have been reviewed in a separate evidence-based guideline of our group [bib_ref] Diagnosis of invasive fungal infections in hematology and oncology guidelines from the..., Ruhnke [/bib_ref].
Studies on panfungal or Aspergillus-specific PCR assays indicate that the use of these techniques on BAL samples seems superior when compared with blood samples, particularly in patients undergoing systemic antifungal therapy [bib_ref] Development of a LightCycler PCR assay for detection and quantification of Aspergillus..., Spiess [/bib_ref] [bib_ref] Detection of Aspergillus species in blood and bronchoalveolar lavage samples from immunocompromised..., Buchheidt [/bib_ref] [bib_ref] Diagnosing invasive aspergillosis during antifungal therapy by PCR analysis of blood samples, Lass-Florl [/bib_ref] [bib_ref] The value of CMV and fungal PCR for monitoring for acute leukaemia..., Ljungman [/bib_ref] [bib_ref] Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis..., Musher [/bib_ref]. On lung biopsy specimens, PCR added to histopathology and culture may improve specification of pathogens [bib_ref] Comparison of histopathological analysis, culture, and polymerase chain reaction assays to detect..., Rickerts [/bib_ref]. Since there is no widely accepted international standardization of these assays available as yet for blood and BAL samples [bib_ref] Aspergillus PCR: one step closer to standardization, White [/bib_ref] , PCR results have not become part of definition criteria for invasive fungal infections by now [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] [bib_ref] Diagnosis of invasive fungal infections in hematology and oncology guidelines from the..., Ruhnke [/bib_ref] [bib_ref] Use of PCR for diagnosis of invasive aspergillosis: systematic review and meta-analysis, Mengoli [/bib_ref]. PCR presumably will become part of a diagnostic program for LI, including thoracic CT scans, serology and conventional microbiology from blood and BAL samples [bib_ref] The evolution and evaluation of a whole blood polymerase chain reaction assay..., White [/bib_ref]. The combination of Aspergillus PCR and GM in BAL samples enhances diagnostics since positive results for both GM and PCR make a pulmonary aspergillosis highly likely [bib_ref] The evolution and evaluation of a whole blood polymerase chain reaction assay..., White [/bib_ref] , as confirmed recently by meta-analyses [bib_ref] Diagnostic accuracy of PCR alone compared to galactomannan in bronchoalveolar lavage fluid..., Avni [/bib_ref] [bib_ref] Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR..., Heng [/bib_ref].
Previous exposure to antifungal therapy may reduce the sensitivity of the galactomannan as well as quantitative PCR assays [bib_ref] Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay, Marr [/bib_ref] [bib_ref] Antifungal treatment affects the laboratory diagnosis of invasive aspergillosis, Mcculloch [/bib_ref].
Legionella pneumophila serogroup 1 antigen. While nosocomial outbreaks of legionellosis among cancer and leukemia patients have become very rare, a single-center report from 2007 has indicated that this differential diagnosis should not be ignored [bib_ref] Outbreak of Legionnaires' disease in immunosuppressed patients at a cancer centre: usefulness..., Gudiol [/bib_ref]. Testing of Legionella pneumophila serogroup 1 in urine helps to detect this diagnosis rapidly. Controlled clinical studies on the usefulness of routine testing for this antigen among febrile neutropenic patients with lung infiltrates are not available.
biomarkers. Nonspecific proinflammatory laboratory parameters like C-reactive protein, interleukin-6 [bib_ref] Markers of bacteremia in febrile neutropenic patients with haematological malignancies: procalcitonin and..., Von Lilienfeld-Toal [/bib_ref] , interleukin-8, tumor necrosis factor- or procalcitonin plasma levels [bib_ref] Procalcitonin as a specific marker of bacterial infection in adults, Monneret [/bib_ref] are frequently used to assess the severity of infections and the response to antimicrobial therapy. In febrile neutropenic patients with LI, the predictive value of these parameters has not been investigated in prospective studies as yet. In clinical practice, the repeated measurement of these parameters typically parallels clinical observation and should be used for therapeutic decisions only in the context with clinical and imaging findings. Persisting fever, progressive or newly emerged LI and rising proinflammatory parameters typically indicate the need for a change in the antimicrobial treatment regimen [bib_ref] Monitoring procalcitonin in febrile neutropenia: what is its utility for initial diagnosis..., Robinson [/bib_ref].

## Algorithms for the clinical management of febrile neutropenic patients with li
An algorithm for the clinical management of febrile neutropenic patients with LI is proposed in [fig_ref] Figure 1: Diagnostic procedures and treatment of neutropenic patients with fever and suspected or... [/fig_ref]. Synopses of recommendations for diagnostic measures are given in [fig_ref] Table 1: Recommendations for imaging diagnostic procedures [/fig_ref]. Recommendations for antimicrobial treatment and clinical management are summarized in [fig_ref] Table 5: Recommendations for antimicrobial treatment and clinical management-I [/fig_ref].

## Diagnostic procedures
In patients with acute myeloid leukemia or myelodysplastic syndrome undergoing aggressive myelosuppressive chemotherapy expecting severe neutropenia lasting 10 days, serial monitoring of Aspergillus galactomannan from blood samples is recommended (B-II). The place for 1,3--D-glucan is not yet clearly defined, and PCR should be studied in the frame of clinical trials only. Serial panfungal PCR monitoring in patients with acute leukemia undergoing intensive myelosuppressive Persistent fever and/or signs and/or symptoms of lower respiratory tract infection reviews chemotherapy has failed to identify patients with a particularly high risk of developing invasive fungal disease [bib_ref] Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile..., Maschmeyer [/bib_ref]. Importantly, diagnostic procedures aim at obtaining microbiological results that confirm or help to modify the antimicrobial therapy, which should be initiated without awaiting results from diagnostic procedures (A-II). Patients with fever of unknown origin not responding to an appropriate first-line therapy after 72-96 h should undergo thorough physical re-examination, imaging [fig_ref] Table 1: Recommendations for imaging diagnostic procedures [/fig_ref] and microbiological diagnostics including a native thoracic CT scan and a CT scan of paranasal sinuses if symptoms or signs of sinusitis are present (A-II). A high-resolution or multislice thoracic CT scan must be available at a maximum of 24 h after clinical indication has been established (A-II). When LI are documented, noninvasive diagnostic tests should be repeated and bronchoscopy and BAL should be arranged within a maximum of 24 h (B-III). BAL samples must be sent immediately to the microbiological laboratory for workup, to be started within 4 h after sampling (A-III). Recommended microbiological procedures are listed in. A standardized procedure for bronchoscopy and BAL is recommended (A-II) [bib_ref] Performance of a standardized bronchoalveolar lavage protocol in a comprehensive cancer center:..., Sampsonas [/bib_ref].
Invasive procedures such as open-lung or percutaneous core needle biopsy should be considered in patients with

## Antimicrobial therapy in patients without documented causative pathogens
Considering the dismal prognosis of febrile neutropenic patients with LI not treated promptly with an appropriate antimicrobial regimen, it is recommended to start therapy on the basis of clinical, imaging and/or laboratory findings indicative of a particular infection in patients at risk for, but without proof of this infection. The type of underlying malignancy or immunosuppression has an instrumental impact on the selection of antimicrobial agents suitable for systemic therapy. In patients without a conclusive microbiological finding [fig_ref] Table 4: Clinical assessment of microbiological findings in febrile neutropenic patients with lung infiltratesThe... [/fig_ref] and a lack of response to antimicrobial treatment, re-assessment including thoracic CT scan and eventually also bronchoscopy and BAL should be arranged after 7 days (A-II).
patients with severe neutropenia due to chemotherapy for acute leukemia or other aggressive hematologic malignancy. This subgroup of febrile neutropenic patients with LI should be treated with a broad-spectrum -lactam with antipseudomonal activity, as used for empirical treatment of fever of unknown origin (A-II). Streptococci including cephalosporin-resistant strains [bib_ref] Bacteremic pneumonia in neutropenic patients with cancer: causes, empirical antibiotic therapy, and..., Carratala [/bib_ref] must be included in the antimicrobial spectrum (B-II). Additionally, patients with LI not typical for PcP or lobar bacterial pneumonia should receive mold-active systemic antifungal therapy with voriconazole or liposomal amphotericin B (A-II) [bib_ref] Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of..., Walsh [/bib_ref]. This high-risk subgroup of patients has a significant benefit from prompt when compared with delayed mold-active antifungal therapy [bib_ref] A prospective, randomized multicenter trial of the empirical addition of antifungal therapy..., Schiel [/bib_ref]. It has been shown that patients with invasive aspergillosis treated with voriconazole or liposomal amphotericin B had superior response and survival rates when treated early versus later in the course of the disease (A-II) [bib_ref] Efficacy outcomes in a randomised trial of liposomal amphotericin B based on..., Cornely [/bib_ref] [bib_ref] Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo..., Greene [/bib_ref]. In patients pretreated with voriconazole or posaconazole for systemic antifungal prophylaxis and in whom a breakthrough filamentous fungal pneumonia is suspected, measurement of antifungal drug levels and invasive diagnostic procedures should be taken into consideration (B-III) and treatment should be switched to liposomal amphotericin B (C-III). Particularly in patients in whom mucormycosis (zygomycosis) is suspected, liposomal amphotericin B is recommended (A-II). - Positive quantitative P. jirovecii PCR with >1450 copies/ml - Conversely, negative -D-glucan in blood samples makes
Pneumocystis pneumonia highly unlikely The following findings 'do not' represent pathogens causative for lung infiltrates:
- Isolation of enterococci from blood culture, swabs, sputum or BAL - Coagulase-negative staphylococci or Corynebacterium spp. In patients without a microbiologically proven indication, the addition of an aminoglycoside or 5-flucytosine is not recommended due to a lack of benefit (E-I) [bib_ref] Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia:..., Paul [/bib_ref]. In patients who had not received routine anti-Pneumocystis prophylaxis, have a thoracic CT scan suggesting PcP, and who have a rapid and otherwise unexplained rise of serum lactate dehydrogenase, prompt start of highdose trimethoprim-sulfamethoxazole (TMP/SMX) therapy should be considered before bronchoscopy and BAL (B-II) [bib_ref] Analysis of clinical features of non-HIV Pneumocystis jirovecii pneumonia, Ainoda [/bib_ref]. In case of PcP, BAL will remain positive for this pathogen over several days despite appropriate antimicrobial therapy [bib_ref] Persistence of Pneumocystis carinii after effective treatment of P. carinii pneumonia is..., Roger [/bib_ref].
Except from selected patients who also have a severe cellular immunosuppression, antiviral agents such as ganciclovir are not recommended for early pre-emptive therapy in febrile neutropenic patients with LI (E-II). In general, glycopeptides, fluoroquinolones or macrolide antibiotics without a specific pathogen documented from clinically significant samples should not be used as well (D-III).
other subgroups of febrile patients with hematological malignancies. In individual patients undergoing high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (AHSCT) with febrile neutropenia and LI of unknown origin, whose conditioning regimen included total body irradiation or who have been treated with alemtuzumab, antithymocyte globulin or fludarabine, bronchoscopy with BAL to check for CMV disease may be considered (B-III) [bib_ref] Cytomegalovirus infection and non-neutropenic fever after autologous stem cell transplantation: high rates..., Fassas [/bib_ref]. A positive rapid culture or 'immediate early antigen' should prompt ganciclovir treatment (5 mg/kg every 12 h) (B-III), while foscarnet has not been investigated in this setting. Since patients after AHSCT have a very low risk of fungal pneumonia [bib_ref] Fungal infections in recipients of hematopoietic stem cell transplants: results of the..., Pagano [/bib_ref] [bib_ref] Invasive fungal infections in allogeneic and autologous stem cell transplant recipients, Post [/bib_ref] [bib_ref] Infectious complications after high-dose chemotherapy and autologous stem cell transplantation, Reich [/bib_ref] , pre-emptive antifungal therapy should not be given (D-II).

## Antimicrobial treatment in patients with documented pathogens
The interpretation of microbiological findings in neutropenic patients with LI is difficult [fig_ref] Table 4: Clinical assessment of microbiological findings in febrile neutropenic patients with lung infiltratesThe... [/fig_ref]. Isolates typically originate from blood cultures or BAL samples. They may represent nonpathogenic contaminants, colonizers, co-pathogens or microorganisms causing a separate infection. If etiologically significant pathogens are detected, particularly multidrug-resistant bacteria, critical reappraisal of antimicrobial treatment to avoid fatal outcome due to delayed effective therapy is recommended (A-II) [bib_ref] Impact of inadequate initial antimicrobial therapy on mortality in infections due to..., Hyle [/bib_ref].
antimicrobial treatment of complicated bacterial pneumonias. In patients with a documented P. aeruginosa pneumonia, primary combination antibacterial therapy including an antipseudomonal -lactam plus preferably an aminoglycoside or (if an aminoglycoside is contraindicated) ciprofloxacin is recommended by many authors [bib_ref] Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study..., Garnacho-Montero [/bib_ref] [bib_ref] Impact of adequate empirical combination therapy on mortality from bacteremic Pseudomonas aeruginosa..., Park [/bib_ref] [bib_ref] Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis, Safdar [/bib_ref] [bib_ref] Clinical approach to the patient with suspected ventilator-associated pneumonia, Vidaur [/bib_ref]. However, meta-analyses have not unequivocally supported this recommendation [bib_ref] Recent experience with Pseudomonas aeruginosa bacteremia in patients with cancer: retrospective analysis..., Chatzinikolaou [/bib_ref] [bib_ref] Effect of adequate single-drug vs combination antimicrobial therapy on mortality in Pseudomonas..., Pena [/bib_ref] [bib_ref] Falagas ME. -Lactam plus aminoglycoside or fluoroquinolone combination versus -lactam monotherapy for..., Vardakas [/bib_ref] , so that adequate -lactam monotherapy may also be appropriate in this setting (B-II). Antipseudomonal -lactams suitable for treatment of P. aeruginosa pneumonia are piperacillin (tazobactam), ceftazidime, imipenem/cilastatin, meropenem and cefepime (A-I).
Depending on their in vitro susceptibility pattern, multi-resistant Gram-negative aerobes such as extended-spectrum--lactamase-(ESBL-) producing E. coli, Enterobacter spp. or Klebsiella spp. as well as Acinetobacter spp. or P. aeruginosa require antimicrobial treatment selected appropriately according to this pattern (A-II). Pharmacokinetic aspects (penetration to lung tissue, possible inactivation by surfactant) must always be included in this selection (A-II). In individual patients with pneumonia caused by multi-resistant Gram-negative pathogens, aerosolized colistin has been successfully used as a part of the antimicrobial strategy [bib_ref] Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative..., Michalopoulos [/bib_ref]. Stenotrophomonas maltophilia (S. maltophilia) rarely causes pneumonia, while it is more frequently isolated from respiratory secretions representing selection of opportunistic microorganisms under broad-spectrum antibacterial treatment. [bib_ref] Stenotrophomonas maltophilia pneumonia in cancer patients without traditional risk factors for infection, Aisenberg [/bib_ref] [bib_ref] Stenotrophomonas maltophilia infection in hematopoietic SCT recipients: high mortality due to pulmonary..., Tada [/bib_ref]. In individual patients, tigecycline-based treatment may be an appropriate alternative (C-II) [bib_ref] Tigecycline as a therapeutic option in Stenotrophomonas maltophilia infections, Tekce [/bib_ref]. It should be kept in mind that in vitro susceptibility may not predict clinical efficacy of antimicrobial agents in S. maltophilia infections [bib_ref] Comparison of various in vitro susceptibility methods for testing Stenotrophomonas maltophilia, Carroll [/bib_ref]. While pneumonia caused by methicillin-susceptible Staphylococcus aureus (S. aureus) should be treated with oxacillin or flucloxacillin, methicillin-resistant S. aureus should preferably be treated with vancomycin, if no serious renal insufficiency is present (B-II). Linezolid is a possible alternative for first-line treatment (B-II) [bib_ref] Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and..., Kalil [/bib_ref] [bib_ref] Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus..., Walkey [/bib_ref] [bib_ref] Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant..., Wunderink [/bib_ref] ; however, the risk of severe thrombocytopenia or even pancytopenia associated with linezolid must be taken into consideration [bib_ref] Linezolid-related pancytopenia in organtransplant patients: report of two cases, Faguer [/bib_ref]. Daptomycin should not be used for treatment of pneumonia, because it is inactivated by surfactant (E-I) [bib_ref] Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact, Silverman [/bib_ref].
treatment of CMV pneumonia. CMV pneumonia typically affects allogeneic stem-cell transplant recipients, but is also relevant in patients treated with lymphocyte-depleting agents like alemtuzumab or fludarabine. First-choice antiviral treatment options are foscarnet or ganciclovir (A-II). Foscarnet is associated with less myelosuppression, which is a serious adverse effect of ganciclovir [bib_ref] Cytomegalovirus infection/disease after hematopoietic stem cell transplantation, Mori [/bib_ref]. On the other hand, reversible nephrotoxicity is one of the typical side-effects of foscarnet [bib_ref] A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in..., Wagstaff [/bib_ref]. treatment of documented fungal pneumonia. Detailed recommendations for treatment of documented fungal pneumonia are provided in evidence-based guidelines [bib_ref] Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of..., Walsh [/bib_ref] [bib_ref] American Thoracic Society Fungal Working Group. An official American Thoracic Society statement:..., Limper [/bib_ref] [bib_ref] Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious..., Mousset [/bib_ref]. Intravenous voriconazole (6 mg/kg every 12 h day 1, 4 mg/kg every 12 h thereafter) (A-I) or liposomal amphotericin B (3 mg/ kg/day) (A-II) are recommended first-line choices for treatment of IPA. For mucormycosis (zygomycosis), liposomal amphotericin B is preferred (A-II), the recommended dose is 5 mg/kg/day (A-II). In patients with worsening LI and gas exchange within the first week of treatment, failure of antifungal therapy should only be considered if new LI emerge on control CT scans (B-III). At the same time, other causes such as a second infection, immune reconstitution syndrome, infiltrates caused by the underlying malignancy, toxicity from cancer treatment or yet insufficient duration of antifungal treatment should be ruled out (B-III) [bib_ref] Defining clinical failure for salvage studies, Maschmeyer [/bib_ref] [bib_ref] Defining responses to therapy and study outcomes in clinical trials of invasive..., Segal [/bib_ref]. Combination antifungal first-line treatment in patients with invasive mold infections is controversial. A prospective clinical study comparing voriconazole alone with the combination of voriconazole with anidulafungin in patients with proven and probable aspergillosis has not yet been published in detail [bib_ref] Double-Blind Study of Combination Antifungal Therapy with Voriconazole and Anidulafungin Versus Voriconazole..., Marr [/bib_ref]. For treatment of mucormycosis, a combination of liposomal amphotericin B and an echinocandin may be promising [bib_ref] Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis, Reed [/bib_ref] [bib_ref] Combination therapy for mucormycosis: why, what, and how?, Spellberg [/bib_ref] ; however, randomized studies on this subject have not been conducted. A combination of liposomal amphotericin B and the iron chelator deferasirox for the treatment of mucormycoses has shown inferior clinical results for the combination when compared with the antifungal agent alone [bib_ref] The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled..., Spellberg [/bib_ref]. treatment of documented Pneumocystis pneumonia. If PcP is suspected, treatment with TMP/SMX (co-trimoxazole) at a dosage of TMP 15-20 mg/kg plus SMX 75-100 mg/kg daily (A-II) should be initiated immediately after asservation of representative samples (e.g. induced sputum or BAL) (B-II), since treatment delay may enhance mortality [bib_ref] Early diagnosis and treatment are crucial for the survival of Pneumocystis pneumonia..., Asai [/bib_ref] [bib_ref] Pneumocystis jiroveci pneumonia in immunocompromised patients: delayed diagnosis and poor outcomes in..., Li [/bib_ref]. In mild-to-moderate cases (oxygen partial pressure pO 2 70 mmHg or alveolar-arterial oxygen difference AaDO 2 <45 mmHg) an oral therapy can be discussed, otherwise it should be administered i.v. In patients with proven PcP, treatment with TMP/SMX should be continued for at least 2 weeks (A-II). Clinical improvement should develop within 8 days, otherwise a second infection should be considered and diagnostic procedures repeated. In individual patients with persistent PcP, mutations in the genes for dihydropteroate synthase or dihydrofolate reductase may be taken into consideration [bib_ref] High prevalence of dihydropteroate synthase mutations in Pneumocystis jirovecii isolated from patients..., Dini [/bib_ref] [bib_ref] Circulation of Pneumocystis dihydropteroate synthase mutants in France, Gal [/bib_ref] [bib_ref] Association between a specific Pneumocystis jiroveci dihydropteroate synthase mutation and failure of..., Nahimana [/bib_ref] [bib_ref] Trimethoprim resistance of dihydrofolate reductase (DHFR) variants from clinical isolates of Pneumocystis..., Queener [/bib_ref]. In case of treatment failure or TMP/SMX intolerance, atovaquone oral suspension (750 mg twice times daily with meal), i.v. pentamidine (4 mg/kg daily) or clindamycin (600 mg four times daily or 900 mg three times daily i.v.) plus primaquine (30 mg daily p.o.) may represent treatment alternatives [bib_ref] Pneumocystis pneumonia, Thomas [/bib_ref] , with clindamycin + primaquine presumably being the most effective option (C-III) [bib_ref] A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia, Smego [/bib_ref]. Glucose-6-phosphate dehydrogenase deficiency must be excluded before administration of dapsone or primaquine (A-I). Subsequently, patients should be given secondary prophylaxis (A-II) using oral TMP/SMX at a daily dosage of 160/800 mg given on 3 days per week (B-II) or with monthly pentamidine inhalation at a dose of 300 mg (B-II) [bib_ref] Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis, Hughes [/bib_ref] [bib_ref] A controlled trial of aerosolized pentamidine or trimethoprim-sulfamethoxazole as primary prophylaxis against..., Schneider [/bib_ref]. In patients with respiratory failure due to PcP, systemic corticosteroids may be beneficial in AIDS patients, but data are conflicting in non-HIV patients [bib_ref] Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency..., Delclaux [/bib_ref] [bib_ref] Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia, Pareja [/bib_ref]. Recent studies could not show a clinical benefit [bib_ref] Outcomes of moderate-to-severe Pneumocystis pneumonia treated with adjunctive steroid in non-HIV-infected patients, Moon [/bib_ref] and were even associated with increased mortality [bib_ref] Adjunctive steroid in HIV-negative patients with severe Pneumocystis pneumonia, Lemiale [/bib_ref].

## Intensive care medicine
Reports on the outcome of cancer patients requiring intensive care have shown hospital survival rates of 60%-70% and higher [bib_ref] Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from..., Azoulay [/bib_ref] [bib_ref] Outcomes and prognostic factors in patients with haematological malignancy admitted to a..., Bird [/bib_ref] [bib_ref] Characteristics and outcomes of cancer patients in European ICUs, Taccone [/bib_ref]. Neutropenic patients with respiratory failure due to LI may have a favorable outcome under appropriate intensive care including mechanical ventilation [bib_ref] Predictors of short and long-term outcome in patients with hematological disorders admitted..., Cherif [/bib_ref] [bib_ref] Outcome analysis of 189 consecutive cancer patients referred to the intensive care..., Maschmeyer [/bib_ref] [bib_ref] Patients with haematological malignancies requiring invasive mechanical ventilation: differences between survivors and..., Owczuk [/bib_ref]. Even if respiratory failure is due to IPA, survival can be achieved in around one third of patients [bib_ref] Outcomes of mechanically ventilated hematology patients with invasive pulmonary aspergillosis, Burghi [/bib_ref]. It is therefore not justified to reject cancer patients from intensive care only because of their underlying malignancy [bib_ref] Intensive care and oncology, Sculier [/bib_ref]. Multidisciplinary care involving hematology-oncology professionals should be provided during intensive care treatment of these patients (A-II). Intensive care should unrestrictedly be provided to patients with respiratory failure (A-II), except from those whose prognosis is desperate due to other reasons or who have given a personal directive in order to abstain from it.
[fig] Figure 1: Diagnostic procedures and treatment of neutropenic patients with fever and suspected or proven lung infiltrates.  | Maschmeyer et al. Volume 26 | No. 1 | January 2015 [/fig]
[fig] : Isolation of Candida spp. from swabs, saliva, sputum or tracheal aspirates Findings from surveillance cultures, feces and urine cultures. 'Potentially relevant' findings include: common respiratory viruses, isolation of Staphylococcus aureus, Legionella spp. or atypical mycobacteria in respiratory secretions, positive CMV-or nonquantitative Pneumocystis-PCR (without confirmation by other methods) from BAL. [/fig]
[table] introduction consensus process: See supplementary Material, available at Annals of Oncology online(Table 7).See supplementary Material, available at Annals of Oncology online. [/table]
[table] Table 1: Recommendations for imaging diagnostic procedures [/table]
[table] Table 4: Clinical assessment of microbiological findings in febrile neutropenic patients with lung infiltratesThe following findings 'indicate' pathogens causative for lung infiltrates  P. jirovecii, Gram-negative aerobic pathogens, pneumococci, [/table]
[table] Table 5: Recommendations for antimicrobial treatment and clinical management-I [/table]
[table] Table 6: Recommendations for antimicrobial treatment and clinical management-II In patients with suspected or documented S. maltophilia pneumonia, early antimicrobial intervention with high-dose TMP/ SMX (15-20 mg/kg/day of trimethoprim) is recommended (B-II) [/table]