key: cord-018027-goxdiyv3
authors: Heussel, Claus Peter
title: Diagnostic Radiology in Hematological Patients with Febrile Neutropenia
date: 2014-11-27
journal: Infections in Hematology
DOI: 10.1007/978-3-662-44000-1_7
sha: 
doc_id: 18027
cord_uid: goxdiyv3

Radiologists have a special role in the management of neutropenic patients. The appropriate investigational technique, specific differential diagnoses, and particular risks of these patients need to be understood by referring physicians as well as by radiologists. Thus, communication and cooperation, also including other clinical disciplines such as pulmonology, are required. Early detection of an infectious focus is the major goal in febrile neutropenic patients. As pneumonia is the most common focus, chest imaging is a special radiological task. The sensitivity of chest x-ray, especially in supine position, is low. Therefore, the very sensitive thin-section multislice CT became a gold standard in neutropenic hosts and might be cost effective in comparison to antibiotic treatment. CT-based localization can be used to guide invasive procedures in order to obtain samples for microbiological workup. Furthermore, the radiological characterization of infiltrates gives a first and rapid hint to discriminate between infectious (viral, typical bacterial, atypical bacterial, fungal) and noninfectious etiologies. Radiological follow-up has to take into account aspects according to disease, immune recovery, and treatment modalities. Due to a high incidence of fungal-related lung infiltrates, interpretation of follow-up findings must include further parameters besides lesion size. Apart from the lungs, also other organ systems such as the brain, liver, and paranasal sinuses need attention and are to be imaged with the appropriate technique.

The necessity for early detection of the focus of infection is based upon high fatality of infections in immunocompromised hosts, increasing within hours of delayed appropriate treatment [ 48 ] . (This paper does not refer to immunocompromised patients; maybe Greene 2007 [ 52 ] or Cornely 2010 [ 58 ] could be used), a potential negative impact of delayed diagnosis (i.e., more advanced infection) on future antineoplastic treatment, and high costs of prolonged hospitalization. This has to be compared with the costs of a non-enhanced CT scan, which is around € 230 in German hospitals. After physical examination and interpretation of laboratory fi ndings, the search for an infectious focus starts with the identification of the most suspected organ system(s). The appropriate imaging technique has to be selected demanding for high sensitivity and clinically meaningful negative predictive value [ 4 ] . Exact proportions of organ involvement are diffi cult to determine and may differ from clinical and pathological fi ndings, the latter often obtained from autopsies (i.e., negative selection). Clinically, lungs are affected in 30 % of febrile neutropenic patients and allogeneic hematopoietic stem cell transplant (aSCT) recipients, paranasal sinuses in 3 % of neutropenic patients, and 30 % in the aSCT setting (concomitant to pneumonia), while the gastrointestinal tract, liver, spleen, central nervous system, and kidneys are less frequently involved [ 4 ] .

Chest x-ray (CXR) is still frequently used when pneumonia is suspected or should be ruled out [ 14 , 15 ] . CXR has several advantages: it is quick, widely available (even on the ward), inexpensive, and associated with a low radiation dose. CXR is occasionally done on the ward to keep neutropenic patients in protective isolation, even if performed in supine position. But CXR has the crucial disadvantage of superimposition and therefore a very limited sensitivity for the detection of pneumonia (Figs. 7.2 and 7.6 ) [ 14 , 16 ] . Especially if performed in supine position, lung infl ation is worse and lateral projection is lacking, which limits image quality besides other technical issues. In patients with fever of unknown origin (FUO) after SCT, digital CXR in supine position achieves a sensitivity for early detection of pneumonia of only 46 % [ 17 ] . While CXR provides relevant clinical information concerning central venous catheters (CVC), pleural effusion, and pulmonary congestion [ 17 ] , it fails to enable early detection or exclusion of pneumonia, which is a major task in immunocompromised hosts. CXR in supine position alone is therefore not recommended for the early detection of pneumonia in these patients [ 5 ] . Also, if an infi ltrate is apparent at CXR, the options for its characterization are very limited. If pneumonia is considered in these hosts, thin-section CT should be preferred at any time [ 18 ] .

The radiation dose is of limited concern in patients who eventually underwent local or total body irradiation and received cytotoxic agents, etc., considering that actual CT techniques apply 1-10 mSv per lung scan (in this diagnostic scenario: mSv = mGy) [ 19 , 20 ] . The risk of developing a radiation-induced neoplasm, even after several diagnostic exposures, is low when compared to the high mortality associated to infection and disease as well as the risk of a secondary malignancy due to antineoplastic treatment.

Terms like incremental CT , highresolution CT (HRCT), spiral CT , thinsection CT , multislice CT (MSCT), and lowdose CT are widely used and might confuse non-radiologists. To keep it simple, HRCT is an incremental scanning technique with several respiratory breath-holds resulting in inaccuracy of repositioning of the anatomical lung position. The use of 1 mm sections and gaps in between (e.g., 10 mm) results in representative, detailed images of selected lung areas; however, the noncontiguous scanning has its limitations in nodule detection, quantifi cation, and monitoring. Volumetric techniques as used in spiral CT and MSCT, acquired without gaps, are frequently reconstructed with larger thickness (e.g., 5 mm) resulting in spatial volume effects. This results in limitations to detect infl ammatory lung disease, especially ground-glass opacifi cation [ 22 ] . Since no additional information is expected from supplemental spiral CT to HRCT, as shown in AIDS patients [ 23 ] , HRCT may be used as a diagnostic standard. In contrast, thin-section MSCT provides volumetric scanning as well as detailed images [ 24 , 25 ] . This technique also allows for an adequate monitoring of lung disease since the same anatomical position can be reidentifi ed in baseline and follow-up studies [ 24 -26 ] . While a rapid technical development in CT imaging is ongoing, the different techniques applied today are addressed as "CT" in this chapter.

In general, contrast enhancement is not required for detecting and characterizing pneumonia [ 6 , 18 ] . Only in special situations such as suspicion of pulmonary embolism or hemoptysis caused by vessel erosion is CT angiography benefi cial ( Fig. 7 .1 ) [ 27 ] . In the aSCT setting, bronchiolitis obliterans is to be considered [ 24 , 28 ] where air-trapping is a relevant fi nding. Here, an additional expiratory CT scan is helpful [ 24 , 28 ] .

The advantage of HRCT in comparison to CXR for the early detection of pneumonia was demonstrated in febrile neutropenic patients not responding to empirical antibiotic therapy [ 21 ] . In approximately 60 % of the patients with a normal CXR, HRCT showed pulmonary infi ltrates ( Fig. 7.2 ). In only 10 % of patients with a normal chest x-ray and a normal HRCT, pneumonia occurred during follow-up [ 21 ] . Exclusion of pneumonia is another clinically relevant information. Thus, CT yields very useful results with good sensitivity (87 %) and negative predictive value (88 %). The early use of HRCT achieves a gain of approximately 5 days during which pneumonia may be excluded [ 17 ] . In clinical practice, this may be very helpful for the management of immunocompromised hosts at high risk of life-threatening pulmonary infection [ 5 ] ( Fig. 7. 2 ).

MRI has been evaluated for the investigation of pulmonary disease since it has a known benefi t in lesion characterization [ 29 , 30 ] . Comparing CT to MRI on an intraindividual basis, MRI reveals comparable clinical results (sensitivity 95 %, specifi city 88 %, positive predictive value 95 %, negative predictive value 88 %) [ 53 ] . Besides the lack of radiation, there is no clear advantage of MRI in the early detection of pneumonia ( Fig. 7.3 ). In advanced stages, CT and MRI are comparable in the visualization of infi ltrates [ 30 ] . CT is widely available, easier, and faster to perform as well as less susceptible to breathing artifacts. MRI is superior to CT in the detection of abscesses due to a clearer detection of central necrosis in T2-weighted images and rim enhancement after contrast application in T1-weighted images [ 29 ] . However, this fact has limited clinical impact and duration of MRI, and required compliance is substantially higher compared to CT. MR has problems to detect small lesions and those which are adjacent to the left ventricle due to the cardiac motion [ 53 ] . 

In contrast to systemic infections, identifi cation of the underlying organism in pneumonia is more diffi cult and complex. Attempts to reinforce pathogen identifi cation did not improve the clinical outcome signifi cantly [ 9 ] . Therefore, a calculated (preemptive) decision on antimicrobial therapy in febrile immunosuppressed patients based on imaging studies is widely used. The use of CT is recommended for the early detection of pneumonia [ 9 ] . It may serve for indication and localization of invasive diagnostic procedures such as Neutropenic febrile patient receiving broad-spectrum antibiotic therapy. CXR was normal at day 3 of fever ( a , b ). HRCT performed the same day demonstrates bilateral infi ltrates, which were hidden behind the heart in posterior-anterior and the spine in lateral projection ( c ) bronchoscopy and bronchoalveolar lavage or CT-guided biopsy. On the other hand, the exclusion of pneumonia can be obtained with a higher reliability as compared to conventional CXR. The sequential cascade as shown in Fig. 7 .4 can be modifi ed if the local institutional CT capacity allows for the skipping of CXR.

An increasing size of pulmonary infi ltrates during hematopoietic recovery has been well described by [ 31 ] . Caillot et al. evaluated HRCT in neutropenic patients with proven pulmonary aspergillosis at weekly intervals [ 31 ] and documented the time points of different radiological patterns and evaluated the size of infi ltrates and documented the time points of different radiological patterns and evaluated the size of infi ltrates. They frequently found a "halo sign" (Fig. 7 .5 ) on the fi rst CT scans and reported a low sensitivity of this pattern (68 %), which was no longer visible on follow-up scans. In contrast, the more specifi c "air-crescent sign" ( frequently during follow-up (up to 63 %). The size of infi ltrates increased by fourfold under successful antifungal treatment due to hematopoietic reconstitution. In this study, pneumonia was fi rst detected on day 19 of neutropenia. Enlargement of infi ltrates is probably caused by the invasion of newly generated neutrophil granulocytes at the beginning of bone marrow recovery. In critically ill patients, leukocyte invasion has been described as a risk factor for the development of acute respiratory distress syndrome (ARDS) [ 14 ] ( Fig. 7 .6 and 7.7 ).

Radiologists' dream is to be capable to identify the underlying microorganism in pneumonia of immunocompromised hosts with a suffi cient specifi city. In some cases, imaging can provide very fast useful hints, but no verifi cation. The quality of these clues [ 13 ] . Since the initial CXR is of limited use, this diagnostic step is more and more omitted and CT is performed primarily depends on the cooperation between clinicians and radiologists and on the radiologists' experience with these complications. This requires an informational exchange concerning relevant individual patient data like severe neutropenia or allogeneic stem cell transplantation. For example, information on reactivation of cytomegalovirus (CMV) in a patient with graft-versus-host disease is very helpful for the correct interpretation of pulmonary HRCT fi ndings. Also the chemotherapy or total body irradiation applied for conditioning before aSCT may be relevant for differential diagnostic considerations in patients who might present with clinically similar signs and symptoms [ 6 , 7 , 32 , 33 ] . Some of the most useful clues are listed in Table 7 .1 .

Bacteria are causing approximately 90 % of infections during the early phase of neutropenia [ 8 ] . The radiological appearance of bacterial pneumonia includes consolidation, especially bronchopneumonia and positive pneumobronchogram ( Fig. 7. 2 ) [ 33 , 34 ] . In contrast to immunocompetent patients, ground-glass opacifi cation is found more often and remains nonspecifi c.

Severe neutropenia lasting for more than 10-14 days is associated with an increasing risk of invasive fungal infection [ 3 ] , with Aspergillus species being the primary pathogen, while Candida species very rarely cause primary pneumonia ( Fig. 7.8 ) [ 5 ] . Typical radiological fi ndings of fungal and non-fungal pneumonia as well as of infi ltrates from noninfectious diseases have been reviewed in detail [ 35 ] . The typical appearance of pulmonary infi ltrates from fungal origin are as follows:

Early phase of fungal pneumonia:

Ill-defi ned nodules (Figs. 7.3 , 7.5 and 7.8 ) [ 33 ] in combination with the Halo sign (Figs. 7.5 and 7.8 ) [ 33 ] , which is nonspecifi c Late phase:

Air-crescent sign [ 36 ] Cavitation ( Fig. 7.8 ) a c d b Fig. 7.6 The small ill-defi ned nodule in the right upper lobe ( c ) of this 34-year-old neutropenic AML patient was even retrospectively not visible on conventional chest x-ray done at the same day ( a , b ). Amphotericin B treatment was started due to suspicion of fungal pneumonia; however, the nodule size increased during hematopoietic reconstitution 2 weeks later ( d ). In preparation of bone marrow transplantation, the lesion was surgically resected and Aspergillus pneumonia was verifi ed

For use in the context of clinical and epidemiological research in neutropenic patients, standards for the interpretation of radiological fi ndings in invasive fungal infections have been elaborated [ 10 , 51 ] ; newly emerged "typical" CT patterns (dense, well-circumscribed lesions with or without a halo sign, air-crescent sign) are classifi ed as a clinical criterion for fungal pneumonia Figs. 7.5 and 7.8 . The halo sign, fi rst described in 1984 [ 49 , 50 ] , is nonspecifi c [ 33 ] and not a necessary part of the updated defi nitions [ 51 ] . A nonspecifi c infi ltrate, rated as a minor criterion in the fi rst version [ 10 ] , was abandoned in the update [ 51 ] . In a later workup of a pharmaceutical trial investigating response rates to antifungal treatment, the evidence of the halo sign was associated with an improved response rate (52 % vs. 29 %; p < 0.001), as well as a higher 3-month survival rate (71 % vs. 53 %; p < 0.01) [ 52 ] . This large ( n = 235) antemortem trial suffers, however, from systemic limitations like investigation of halo which was part of inclusion criteria and technical insuffi ciencies like usage of thick-section CT instead of appropriate thin-section CT and evaluation of hardcopies instead of monitor reading [ 52 ] . Histopathological workup of lung biopsies verifi ed fungal pneumonia in 56 % of cases in another study [ 37 ] . Relevant differential diagnoses for the halo sign, such as cryptogenic organizing pneumonia (COP, formerly known as bronchiolitis obliterans organizing pneumonia, BOOP), pulmonary hemorrhage, pulmonary manifestation of the underlying malignancy, lung cancer, and nonfungal infections (CMV, tuberculosis, abscesses (Fig. 7.7 ) , etc.) or Candida (Fig. 7.8 ) , have to be considered [ 37 ] .

Thus, diagnostic clarifi cation will frequently be necessary, particularly when antifungal treatment is not successful. Non-fungal lung infi ltrate: ill-defi ned nodules with cavitation on CT scans done due to repeated febrile episodes. They appeared like fungal pneumonia and were not visible on baseline CT. After removal of a central venous port system, both the pulmonary lesions as well as the febrile episodes, disappeared Air-crescent sign and cavitation occur with hematopoietic reconstitution during the late phase of fungal infection (Fig. 7.8 ) [ 36 ] . Both radiological signs are known to be associated with a favorable prognosis. However, the specifi cities of these fi ndings are limited, and relevant differential diagnoses have to be considered (Fig. 7.7 ) [ 37 ] . There are other useful patterns for the identifi cation of fungal pneumonia, e.g., 

GGO ground-glass opacifi cation, TBI total body irradiation distribution along the bronchovascular bundle resulting in the feeding vessel sign with an angiotrophic location.

The ongoing development of antifungal therapy may have an important impact on the radiological appearance of fungal pneumonia. Thus, in the near future radiologists will not only be confronted with the question for "breakthrough fungal pneumonia," but also for fungal pneumonia caused by non-Aspergillus pathogens.

Pneumocystis jiroveci pneumonia (PcP) [ 38 ] is a typical fi nding in hematological patients affected by severe cellular (T-cell) immunosuppression and those with graft-versus-host disease after aSCT, if they are not protected by effective chemoprophylaxis [ 8 ] . Despite standard trimethoprim-sulfamethoxazole prophylaxis, 8 % of the patients develop PcP, while among patients without prophylaxis, the incidence may reach 29 % [ 8 ] . Up to 15 % of these patients will have a fatal outcome [ 8 ] .

CT provides a valuable characterization for PcP [ 6 , 7 , 18 , 33 ] and is a reliable method for discriminating it from other infectious processes [ 33 , 39 ] of ground-glass opacities and intralobular septae sparing out the subpleural space (i.e., perihilar distribution) is very typical for PcP (Fig. 7.9 ) 

Tuberculosis (TB) has to be considered as a rare but relevant differential diagnosis. In immunocompromised hosts, TB appears different compared to immunocompetent hosts (e.g., gangliopulmonary (primary) forms) [ 41 ] . More widespread lymphogenic and hematogenous dissemination can occur, and therefore, the clinical course might be fulminant [ 41 , 42 ] . On the other hand, TB might mimic or come along with other infections like pulmonary aspergillosis or systemic candidiasis [ 42 ] . In immunocompromised hosts a segmental bronchial spread (resulting in a "treein-bud" sign) of small, sometimes, cavitated ill-defi ned nodules can be obtained as well as a miliar distribution [ 41 , 42 ] . Gangliopulmonary (primary) forms, however, present with nonhomogenous consolidation and necrotizing mediastinal or hilar lymphadenopathy [ 41 ] .

Interstitial pneumonia caused by viral infection may occur primarily in aSCT recipients but also in neutropenic and T-cell-immunosuppressed patients. Mortality rate may be up to 50 %. Most frequently, cytomegalovirus (CMV) is suspected; however, other herpesviruses, infl uenza, parainfl uenza, adenovirus, or respiratory syncytial (RSV) viruses have to be considered as well. There are no specifi c radiological patterns available to differentiate various forms of viral pneumonia. However, confi rming the suspicion of a viral pneumonia may be a clinically useful information, since effective drugs are available for some of these viruses. The typical appearance of viral pneumonia in the early stage is ground-glass opacifi cation [ 33 ] and a mosaic pattern with affected and non-affected secondary lobules lying adjacent to one another (Fig. 7.10 ).

Certain noninfectious diseases have to be considered in hematological patients: graft-versus-host disease (GVHD), radiation or drug toxicity, pulmonary congestion, bleeding, or progressive underlying malignancy. Fever, dyspnea, or clinical chemistry fi ndings (c-reactive protein, elevation of liver function tests) might be a b Fig. 7. 10 Bilateral ground-glass opacifi cation and mosaic pattern in both patients. However, pneumonia in patient A is caused by cytomegalovirus ( CMV ), and patient B by respiratory syncytial virus ( RSV ). Note the mosaic pattern resulting from affected and non-affected secondary lobules lying adjacent to one another caused by some of these processes and obscure the differentiation from infection. CT may help to detect and discriminate these diseases [ 6 , 7 , 18 , 32 ] .

Pulmonary manifestation of chronic GVHD occurs in approximately 10 % of patients after allogeneic hematopoietic stem cell transplantation ( Fig. 7.11 ) [ 43 ] . Bronchiolitis obliterans is the pulmonary manifestation of this rejection [ 28 ] . The radiological appearance is similar to viral pneumonia, and clinical appearance and time point for both diseases are often similar (Fig. 7.11 ). Ground-glass opacifi cation and mosaic pattern, as well as signs of bronchiolitis obliterans such as air-trapping [ 24 , 28 ] and bronchus wall thickening, occur during the early stage of pulmonary GVHD (Fig. 7.11 ), whereas intralobular septae and tree-in-bud sign follow in later stages [ 7 , 43 , 44 ] .

An incidence of 5-25 % pulmonary radiogenic toxicity even after total body irradiation (TBI) applied for conditioning prior to stem cell transplantation is reported Fig. 7 .11 A 28-year-old male after allogeneic retransplantation. HRCT was performed due to fever, cough, and dyspnea. Peripheral intralobular septae ( arrow ) and ground-glass opacifi cation were seen on day 91 posttransplant. Tree-in-bud pattern ( arrowhead ) points at bronchiolitis obliterans. Acute GVHD was diagnosed from transbronchial biopsy. Under appropriate immunosuppression, clinical symptoms and radiological signs disappeared. Note the similarity to Fig. 7.13  Fig. 7 .12 Three weeks after radiation therapy for malignant spine destruction, this patient suffered from fever and dyspnea. Perihilar infi ltrates appeared suddenly. Intralobular septae, consolidation, and ground-glass opacifi cation were visible on HRCT. Especially the paramediastinal distribution of the infi ltrates led to the differential diagnosis of radiation pneumonitis. After failure of antibiotic treatment, steroids were applied, resulting in improvement of symptoms and reduction of infi ltrates [ 45 ] . It emerges approximately 3 weeks after exposure but can also occur several months later [ 44 , 45 ] .

On CT scans, radiation-induced toxicity is characterized by ground-glass opacities with transition to consolidations (Fig. 7 .12 ) [ 44 , 45 ] . The key fi nding is the limitation of these patterns to the exposed parenchyma. For TBI, lungs are shielded, while paramediastinal and apical lung parenchyma is affected from radiation. Of note, demarcation of initially exposed from nonexposed lung parenchyma is blurred frequently due to deformation of lung parenchyma and to bridle.

Chemotherapy protocols may lead to pulmonary toxicity. Some of the frequently used agents are bleomycin, high-dose methotrexate (MTX) or cytarabine (Ara-C), or carmustine (BCNU) (Fig. 7.13 ) [ 46 ] . Radiologists should be informed of previous exposure of patients to these agents when evaluating CT scans for pulmonary abnormalities.

The term "drug-induced pneumonitis" includes mainly nonspecifi c interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP, formerly known as bronchiolitis obliterans organizing pneumonia, BOOP) [ 46 ] . The CT appearance of NSIP consists of ground-glass opacities with transition to consolidations, intralobular septae, traction bronchiectasis, air-trapping, and in a later phase the nonspecifi c "crazy-paving" pattern [ 44 , 46 ] . This is quite similar to radiation toxicity but without being limited to the radiation fi eld.

Dyspnea and infi ltration are frequent in patients suffering from pulmonary congestion. Extensive hydration for renal protection during chemotherapy or to overcome renal impairment may cause pulmonary congestion also in younger patients. It is one of the most frequent disorders in patients undergoing intensive care.

At CXR, pulmonary congestion might be combined with infi ltration. CT shows thickening of lymphatic vessels, corresponding to classical "Kerley lines" on conventional chest radiographs (Fig. 7 .14 ).

Leukemic pulmonary infi ltration is a less common clinical fi nding. Especially the perilymphatic pulmonary interstitium is involved [ 47 ] . This can be visualized on CT scans as thickening of bronchovascular bundles and interlobular septae. Besides Fig. 7.13 A 40 -year-old male who received chemotherapy including bleomycin for testicular cancer and had fever, cough, and dyspnea. CT revealed peripheral intralobular septae and ground-glass opacifi cation ( a ). Bleomycin toxicity was suspected and histologically confi rmed. Symptoms disappeared and fi ndings decreased after application of steroids. Note the similarity to Fig. 7.11 this, non-lobular and non-segmental ground-glass opacifi cations can be seen [ 32 ] . This pattern arrangement might mimic pulmonary congestion (Fig. 7 .14 ).

In pancytopenia, pulmonary bleeding may occur spontaneously, secondary to invasive infections, after interventions (e.g., bronchoscopy and BAL), or during marrow recovery particularly in patients with fungal pneumonia [ 27 ] .

Pulmonary bleeding might cause a focal or diffuse pattern, and the phenomenon of sedimentation within the secondary lobules can sometimes be depicted for few days (Fig. 7.15 ).

Suspicious clinical symptoms or unexplained laboratory fi ndings may suggest an involvement of the liver and spleen [ 13 ] , particularly secondary to fungemia [ 54 ] . In addition to candidiasis, also mycobacteriosis, bacterial granulomatous hepatitis, viral hepatitis, and noninfectious organ involvement such as drug-related hepatotoxicity, GVHD, veno-occlusive disease (VOD), or relapse of the underlying disease have to be considered [ 12 ] . 

Due to its microbial fl ora and the chemotherapy-induced mucosal injury, the gastrointestinal tract is particularly exposed to infection. However, without any history of surgical intervention, gastrointestinal involvement is rare. The main affections of the gastrointestinal tract, such as CMV colitis, pseudomembranous enterocolitis, enterocolitis in the context of rejection (GVHD), appendicitis, and diverticulitis, can be seen in CT as bowel wall thickening even without intravenous contrast after adequate oral, rectal contrast application [ 55 ] .

Cerebral infection is a rare complication of myelosuppressive chemotherapy. It is more likely in the aSCT setting than after conventional chemotherapy [ 2 ] . Besides infectious diseases (e.g., herpesvirus group, toxoplasmosis, aspergillosis, mucormycosis, listeriosis), diagnoses such as bleeding, ischemia, drug toxicity (cyclosporine, ribavirin, voriconazole, etc.), and electrolyte disorders have to be taken into consideration. CT is helpful in emergency situations, while MRI is the method of choice in brain imaging in terms of sensitivity and specifi city for detection and characterization of brain abnormalities [ 12 ] . The bilateral ground-glass opacifi cation has an anterior-to-posterior gradient (1) over the whole lung and (2) within certain secondary lobules. This gravity-dependent sedimentation phenomenon can also occur temporarily and may be localized, e.g., after bronchoscopy and BAL

Since the sinuses are part of the respiratory tract, there is a coincidence of pneumonia [ 56 ] . Since the risk for sinusitis is up to 30 % in allogeneic stem cell transplant recipients, paranasal sinuses are often screened by CT prior to transplantation [ 57 ] . Bone erosion and orbital or brain invasion are classifi ed by the 2008 EORTC guideline as clinical criteria for probable invasive fungal disease [ 51 ] .

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