3.2.2. Three wire tandem SAW

In the transverse section, droplets from the leading electrode impinged on the weld pool whose height is lower than the initial V-grove point; therefore, deep penetration can be from as shown in Figure 17(a). Moreover, the weld pool flows long after droplet impingement in the longitudinal section so this can be another reason to make the deep penetration due to the dynamic convection heat transfer. On the contrary, when the higher current welding signal in the trailing electrode is applied, the arc center displacement of the leading electrode due to the arc

22 Heat and Mass Transfer - Advances in Modelling and Experimental Study for Industrial Applications

Figure 18. Current waveforms and the corresponding arc center displacement for three wire tandem SAW process [21].

Figure 19. Temperature profiles and streamlines on the longitudinal cross section for three wire tandem SAW process [21].

Kiran et al. [21] modeled and simulated the molten pool flow behavior for three wire tandem SAW in V-groove. They firstly measured welding signals and the arc interaction position of three wire SAW process as shown in Figure 18 and they found that the molten pool behavior from the arc interaction played an important role to increase the penetration of V-groove. It is evident that the middle and trailing arcs are closely concentrated during the attraction (dotted box 'a') compared to that of the same between leading and middle arcs (dotted box 'b'). When the distances of middle and trailing arcs are short (dotted box 'a'), the focused arc heat and arc forces activate the molten pool behavior more dynamic and these increase penetration in the

Figure 20. Temperature profiles and streamlines on the transverse cross section for three wire tandem SAW process [21].

longitudinal cross section as shown in Figure 19. The molten pool flow patterns in the transverse section are also described in Figure 20.

[8] Cho DW, Na SJ, Cho MH, Lee JS. Simulations of weld pool dynamics in V-groove GTA

Modeling and Analysis of Molten Pool Behavior for Submerged Arc Welding Process with Single and Multi-Wire…

http://dx.doi.org/10.5772/intechopen.76725

25

[9] Cho DW, Na SJ, Cho MH, Lee JS. A study on V-groove GMAW for various welding

[10] Cho DW, Lee SH, Na SJ. Characterization of welding arc and weld pool formation in vacuum gas hollow tungsten arc welding. Journal of Materials Processing Technology.

[11] Cho JH, Na SJ. Implementation of real-time multiple reflection and Fresnel absorption of laser beam in keyhole. Journal of Physics D: Applied Physics. 2006;39(24):5372

[12] Cho JH, Na SJ. Three-dimensional analysis of molten pool in GMA-laser hybrid welding.

[13] Han SW, Cho WI, Na SJ, Kim CH. Influence of driving forces on weld pool dynamics in

[14] Cho WI, Na SJ, Cho MH, Lee JS. Numerical study of alloying element distribution in CO2 laser–GMA hybrid welding. Computational Materials Science. 2010;49(4):792-800

[15] Cho DW, Song WH, Cho MH, Na SJ. Analysis of submerged arc welding process by threedimensional computational fluid dynamics simulations. Journal of Materials Processing

[16] Cho DW, Kiran DV, Na SJ. Analysis of molten pool behavior by flux-wall guided metal transfer in low-current submerged arc welding process. International Journal of Heat and

[17] Kiran DV, Cho DW, Song WH, Na SJ. Arc behavior in two wire tandem submerged arc

[18] Cho DW, Kiran DV, Song WH, Na SJ. Molten pool behavior in the tandem submerged arc welding process. Journal of Materials Processing Technology. 2014;214(11):2233-2247 [19] Kiran DV, Cho DW, Lee HK, Kang CY, Na SJ. A study on the quality of two-wire tandem submerged arc welds under iso-heat input conditions. The International Journal of

[20] Cho DW, Kiran DV, Na SJ. Analysis of the flux consumption and metal transfer for tandem submerged arc welding process under iso-heat input condition. Welding Journal. 2015;94:

[21] Kiran DV, Cho DW, Song WH, Na SJ. Arc interaction and molten pool behavior in the three wire submerged arc welding process. International Journal of Heat and Mass Trans-

[22] Franz U. Vorgange in der Kaverne beim UP-Schweissen Teil I. Schweiss Tech. 1965;15:145-150 [23] Van Adrichem JT. Metal transfer in submerged arc welding. International Institute of

welding. Journal of Materials Processing Technology. 2014;214(8):1546-1556

Advanced Manufacturing Technology. 2015;78(1–4):53-62

GTA and laser welding. Welding in the World. 2013;57(2):257-264

positions. Journal of Materials Processing Technology. 2013;213(9):1640-1652

and GMA welding. Welding in the World. 2013;57(2):223-233

2013;213(2):143-152

Welding Journal. 2009;88(2):35-43

Technology. 2013;213(12):2278-2291

Mass Transfer. 2017;110:104-112

396-401

fer. 2015;87:327-340

Welding Document. 1966:212-278


Besides invasive infections of the skin and subcutaneous tissues, moulds involve, as airborne pathogens, the sino-pulmonary tract; the emerging opportunistic moulds have a higher propensity for dissemination, in particular into the central nervous system. Because of the lack of specific clinical, radiographic and histological features and the absence of diagnostic surrogate markers in blood, the diagnosis depends on the identification of the organism by means of culture based methods[12]. **5. Diagnostics**  In general, diagnostic testing should begin with non-invasive methods and only approach invasive steps if needed. Diagnostic Besides invasive infections of the skin and subcutaneous tissues, moulds involve, as airborne pathogens, the sino-pulmonary tract; the emerging opportunistic moulds have a higher propensity for dissemination, in particular into the central nervous system. Because of the lack of specific clinical, radiographic and histological features and the absence of diagnostic surrogate markers in blood, the diagnosis depends on the identification of the organism by means of culture based methods [12].

options include conventional or high-resolution CT (this has less radiation exposure and was performed in this case report), positron emission tomography (PET), magnetic resonance imaging (MRI), GM assay, 1,3-ß-D-Glucan test, Polymerase chain

negative results, particularly in patients with disseminated aspergillosis. Of the listed options, the GM and 1,3-ß-D-Glucan serum

#### reaction (PCR), bronchoalveolar lavage, blood culture and tissue biopsy. At this time, MRI and PET are more research-oriented than commonly used clinical approaches. The utility of standard blood cultures is limited because of a high percentage of false-**5. Diagnostics**

the agar-based MIC test showed good activity for Voriconazole, Posaconazole and Caspofun‐

Accordingly antifungal therapy was switched to Voriconazole (6 mg/kg) for eight weeks intravenously and then orally until the twelfth week. CT imaging studies that followed confirmed a gradual recession of the lesion. The patient underwent right sided thoracotomy with wedge resection of the fungal mass. Histopathology revealed Aspergilloma with surrounding chronic granulomatous inflammation, fibrosis and sheets of macrophages. Postoperative course was uneventful and no recurrence of fungal infection over twenty four months follow up was observed. He underwent allogeneic hematopoietic stem cell transplan‐

Worldwide surveys evaluating the epidemiology of invasive fungal infections have been conducted in large center studies in North America [8]. In European countries data is most commonly derived from single-center reports or regional reports from single countries [8]. Though local epidemiology is a cornerstone of clinical decision making, efforts are now undertaken worldwide to start multi-national surveys on fungal infections in order to improve

Until 2 decades ago, infections by Candida were the most common fungal pathogen in patients treated for ALL. However, with the introduction of Fluconazole as primary antifungal prophylaxis and the application of more aggressive treatment protocols, including allogeneic hematopoietic stem cell transplantation, a notable shift towards the advent of invasive aspergillosis has been noted [9]. Whereas almost all of the fungal infections were attributable to candidiasis (11/11) in autopsy studies of the late seventies, mould infections were respon‐ sible for 62% of IFIs (16/26) two decades later [9]. Concordantly, a large multi-centre report from the SEIFEM-2004 study (Sorveglianza Epidemiologica Infezioni Fungine nelle Emopatie Maligne) confirms this trend, indicating, that over half of all fungal infections (346/538) were caused by moulds, in most cases Aspergillus species (310/346) [10]. Most importantly, such infections have become a prime cause of death in patients with hematologic malignancies. The IFI-attributable mortality rate was 39% (209/538). The highest IFI-attributable mortality rates were associated with zygomycosis (64%) followed by fusariosis (53%), aspergillosis (42%), and

Along with the increased incidence of mould infections caused by Aspergillus species, other emerging mould opportunistics, such as Zygomycetes and Fusarium species, have progres‐ sively been noted; interestingly, frequency varies by geographical location [8]. Another trend in changing the face of epidemiology is that infections caused by non-albicans Candida species (e.g. Candida glabrata, C. krusei, C. tropicalis, C. parapsilosis) have steadily increased,

gin, but high MIC90 for liposomal Amphothericin.

tation and has been in complete molecular remission since.

**4. Epidemiology**

uniformity of clinical trials.

candidemia (33%) [10].

particularly in patients with ALL [11].

In general, diagnostic testing should begin with non-invasive methods and only approach invasive steps if needed. Diagnostic options include conventional or high-resolution CT (this has less radiation exposure and was performed in this case report), positron emission tomog‐ raphy (PET), magnetic resonance imaging (MRI), GM assay, 1,3-ß-D-Glucan test, Polymerase chain reaction (PCR), bronchoalveolar lavage, blood culture and tissue biopsy. At this time,

assay, PCR and the CT scan will be described in detail.

MRI and PET are more research-oriented than commonly used clinical approaches. The utility of standard blood cultures is limited because of a high percentage of false-negative results, particularly in patients with disseminated aspergillosis. Of the listed options, the GM and 1,3 ß-D-Glucan serum assay, PCR and the CT scan will be described in detail.

in Europe but which was lowered to 0.5 after review by the FDA. Studies have shown that using an index cutoff for positivity of 0.5 versus greater indices substantially increases sensitivity, with only minimal loss in specificity [15]. Factors, which increase false positivity and influence the specificity of the assay, include a low level of cut-off (<0.5), colonization with Bifidobacterium bifidum in the intestinal flora, which mimics the epitope recognized by the EB-A2 in the enzyme-linked immunosorbent assay kit [16] and invasive infections with other fungi, such as Penicillium spp., histoplasmosis, and blastomycosis [13]. Moreover, crossreactivity of the assay has been shown with the use of piperacillin/ tazobactam or amoxicillin/ clavulanate antibiotic therapy and in infants with the nutrition of milk-based formulas [17]. The IDSA guidelines currently recommend using the GM EIA in conjunction with CT scans for early, noninvasive diagnosis of invasive aspergillosis in high-risk patients [13]. The test should be performed serially, at least twice per week through the periods of highest risk,

Invasive Fungal Infections in ALL Patients http://dx.doi.org/10.5772/54990 323

When GM in serum is used for screening for invasive mold infection in children with hema‐ tological malignancies/undergoing HSCT, data should be interpreted with caution, since the assay has a number of limitations in the sensitivity and specificity profile. Prospective monitoring of GM in serum every three to four days in children at high risk for IFD is reason‐ able for early diagnosis of invasive aspergillosis. Although the optimal cut-off value of GM in the serum of children is not well defined, published data support the use of a threshold of an optical density index 0.5 (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/

1,3-ß-D Glucan (BG) is a fungal cell wall component circulating in the blood of patients with invasive aspergillosis, candidemia, but also Fusarium*,* Trichosporum, Saccharomyces, and Pneumocystis jirovecii. Moreover, BG is also detected in patients with infections due to bacteria such as Streptococcus pneumoniae, Pseudomonas aeruginosa and in healthy individuals. However, BG is absent in patients with cryptococcosis and zygomycosis [18]. Antibiotics such as cefepime, piperacillin/tazobactam or meropenem may cause positive BG levels. Investiga‐ tions using different BG assays in 2979 patients (594 with proven or probable IFI) have reported a pooled sensitivity of 76.8% and specificity of 85.3% [19]. Differences in study design (popu‐ lation studies versus case-control, variation in the number of proven or probable IFIs, propor‐ tions of patients with candidemia and aspergillosis, case-mix of neutropenic and nonneutropenic patients, and previous antifungal prophylaxis) highlight the need for further investigations. In children, data is very limited: elevated levels of BG were reported in a casecontrol study of only four children with IFI (3 patients with candidemia, one patient probable

The Fungitell assay (Associates of Cape Cod) for detection of 1,3-ß-D Glucan is approved by the FDA for the diagnosis of invasive mycoses, including aspergillosis [13] and is included as mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group [6]. Unfortunately, there is no recommendation from ECIL or IDSA for clinical practice. However, BG testing in adults is considered as having good

whether the periods involve neutropenia or active GVHD [13].

ECIL.aspx).

**5.2. 1,3-ß-D Glucan**

aspergillosis) [20].

Figure 3. Simplified view of antifungal strategy in acute lymphoblastic leukemia (ALL) patients. Clinical practice (not EORTC criteria) in the management of IFIs depends on the population at risk (e.g. genetics, clinical), availability/value of diagnostic tests and availability/effectiveness of antifungal drugs. HR-ALL: high risk – acute lymphoblastic leukemia; SCT: stem cell transplantation; GM: Galactomannan; CT: computed tomography. **Figure 3.** Simplified view of antifungal strategy in acute lymphoblastic leukemia (ALL) patients. Clinical practice (not EORTC criteria) in the management of IFIs depends on the population at risk (e.g. genetics, clinical), availability/value of diagnostic tests and availability/effectiveness of antifungal drugs. HR-ALL: high risk – acute lymphoblastic leukemia; SCT: stem cell transplantation; GM: Galactomannan; CT: computed tomography.

#### **6. Galactomannan (GM) 5.1. Galactomannan (GM)**

ECIL/Pages/ECIL.aspx).

**7. 1,3-ß-D Glucan**

GM testing with the Platelia Aspergillus Enzyme Immunoassay (EIA; Biorad Laboratories, Redmond, WA) has been approved by the U.S. Food and Drug Administration (FDA) for Aspergillus diagnostics and is included as a mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group[6]. The test is based on detection of a component of the Aspergillus cell wall, Galactomannan (GM), which is released in the surrounding environment by growing Aspergillus species. Concentration of serum GM correlates with fungal burden in animals with experimental pulmonary aspergillosis – and, according to the 2011 ECIL clinical practice guidelines may be considered as surrogate marker for detection of invasive aspergillosis (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ECIL.aspx). Recent data suggest that sequential measuring of GM serum levels may be used for therapeutic monitoring in children and adults with pulmonary aspergillosis. The guidelines from the Infections Disease Society of America (IDSA) state, that duration of antifungal therapy must not only rely on disappearance of GM levels, but also on resolution of clinical and radiological findings[13]. The GM EIA has been most studied in hematologic malignancy and bone marrow transplantation populations. Both the specificity and sensitivity of the GM EIA for invasive aspergillosis are high for infected, neutropenic adult patients from these populations. Comparison of 5 studies which use EORTC/MSG criteria and give adequate information for individual patients with results of a formal meta-analysis, indicate sensitivity, specificity of 76% to 73%, 86% to 90% in children and adults respectively[14]. Controversy of GM testing exists about the interpretation of the assay cutoff level (0.5, 1.0), which was originally set at 1.5 and was applied in Europe but which was lowered to 0.5 after review by the FDA. Studies have shown that using an index cutoff for positivity of 0.5 versus greater indices substantially increases sensitivity, with only minimal loss in specificity[15]. Factors, which GM testing with the Platelia Aspergillus Enzyme Immunoassay (EIA; Biorad Laboratories, Redmond, WA) has been approved by the U.S. Food and Drug Administration (FDA) for Aspergillus diagnostics and is included as a mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group [6]. The test is based on detection of a component of the Aspergillus cell wall, Galactomannan (GM), which is released in the surrounding environment by growing Aspergillus species. Concentration of serum GM correlates with fungal burden in animals with experimental pulmonary aspergillosis – and, according to the 2011 ECIL clinical practice guidelines may be considered as surrogate marker for detection of invasive aspergillosis (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ECIL.aspx). Recent data suggest that sequential measuring of GM serum levels may be used for therapeutic monitoring in children and adults with pulmonary aspergillosis. The guidelines from the Infections Disease Society of America (IDSA) state, that duration of antifungal therapy must not only rely on disappearance of GM levels, but also on resolution of clinical and radiological findings [13].

Bifidobacterium bifidum in the intestinal flora, which mimics the epitope recognized by the EB-A2 in the enzyme-linked immunosorbent assay kit[16] and invasive infections with other fungi, such as Penicillium spp., histoplasmosis, and blastomycosis[13]. Moreover, cross-reactivity of the assay has been shown with the use of piperacillin/ tazobactam or amoxicillin/clavulanate antibiotic therapy and in infants with the nutrition of milk-based formulas[17]. The IDSA guidelines currently recommend using the GM EIA in conjunction with CT scans for early, noninvasive diagnosis of invasive aspergillosis in high-risk patients[13]. The test should be performed serially, at least twice per week through the periods of highest risk, whether the periods involve neutropenia or active GVHD[13]. The GM EIA has been most studied in hematologic malignancy and bone marrow transplan‐ tation populations. Both the specificity and sensitivity of the GM EIA for invasive aspergillosis are high for infected, neutropenic adult patients from these populations. Comparison of 5 studies which use EORTC/MSG criteria and give adequate information for individual patients with results of a formal meta-analysis, indicate sensitivity, specificity of 76% to 73%, 86% to 90% in children and adults respectively [14]. Controversy of GM testing exists about the interpretation of the assay cutoff level (0.5, 1.0), which was originally set at 1.5 and was applied

increase false positivity and influence the specificity of the assay, include a low level of cut-off (<0.5), colonization with

When GM in serum is used for screening for invasive mold infection in children with hematological malignancies/undergoing HSCT, data should be interpreted with caution, since the assay has a number of limitations in the sensitivity and specificity profile. Prospective monitoring of GM in serum every three to four days in children at high risk for IFD is reasonable for early diagnosis of invasive aspergillosis. Although the optimal cut-off value of GM in the serum of children is not well defined, published data support the use of a threshold of an optical density index 0.5 (http://www.ebmt.org/Contents/Resources/Library/

1,3-ß-D Glucan (BG) is a fungal cell wall component circulating in the blood of patients with invasive aspergillosis, candidemia, but also Fusarium*,* Trichosporum, Saccharomyces, and Pneumocystis jirovecii. Moreover, BG is also detected in patients with infections due to bacteria such as Streptococcus pneumoniae, Pseudomonas aeruginosa and in healthy individuals. However, BG is absent in patients with cryptococcosis and zygomycosis[18]. Antibiotics such as cefepime, piperacillin/tazobactam or meropenem may cause in Europe but which was lowered to 0.5 after review by the FDA. Studies have shown that using an index cutoff for positivity of 0.5 versus greater indices substantially increases sensitivity, with only minimal loss in specificity [15]. Factors, which increase false positivity and influence the specificity of the assay, include a low level of cut-off (<0.5), colonization with Bifidobacterium bifidum in the intestinal flora, which mimics the epitope recognized by the EB-A2 in the enzyme-linked immunosorbent assay kit [16] and invasive infections with other fungi, such as Penicillium spp., histoplasmosis, and blastomycosis [13]. Moreover, crossreactivity of the assay has been shown with the use of piperacillin/ tazobactam or amoxicillin/ clavulanate antibiotic therapy and in infants with the nutrition of milk-based formulas [17].

The IDSA guidelines currently recommend using the GM EIA in conjunction with CT scans for early, noninvasive diagnosis of invasive aspergillosis in high-risk patients [13]. The test should be performed serially, at least twice per week through the periods of highest risk, whether the periods involve neutropenia or active GVHD [13].

When GM in serum is used for screening for invasive mold infection in children with hema‐ tological malignancies/undergoing HSCT, data should be interpreted with caution, since the assay has a number of limitations in the sensitivity and specificity profile. Prospective monitoring of GM in serum every three to four days in children at high risk for IFD is reason‐ able for early diagnosis of invasive aspergillosis. Although the optimal cut-off value of GM in the serum of children is not well defined, published data support the use of a threshold of an optical density index 0.5 (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ ECIL.aspx).

#### **5.2. 1,3-ß-D Glucan**

MRI and PET are more research-oriented than commonly used clinical approaches. The utility of standard blood cultures is limited because of a high percentage of false-negative results, particularly in patients with disseminated aspergillosis. Of the listed options, the GM and 1,3-

> • GM • 1,3-ß-D-Glucan • CT scan **PRE-EMPTIVE**

Figure 3. Simplified view of antifungal strategy in acute lymphoblastic leukemia (ALL) patients.

**Figure 3.** Simplified view of antifungal strategy in acute lymphoblastic leukemia (ALL) patients. Clinical practice (not EORTC criteria) in the management of IFIs depends on the population at risk (e.g. genetics, clinical), availability/value of diagnostic tests and availability/effectiveness of antifungal drugs. HR-ALL: high risk – acute lymphoblastic leukemia;

levels, but also on resolution of clinical and radiological findings[13].

highest risk, whether the periods involve neutropenia or active GVHD[13].

leukemia; SCT: stem cell transplantation; GM: Galactomannan; CT: computed tomography.

GM testing with the Platelia Aspergillus Enzyme Immunoassay (EIA; Biorad Laboratories, Redmond, WA) has been approved by the U.S. Food and Drug Administration (FDA) for Aspergillus diagnostics and is included as a mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group [6]. The test is based on detection of a component of the Aspergillus cell wall, Galactomannan (GM), which is released in the surrounding environment by growing Aspergillus species. Concentration of serum GM correlates with fungal burden in animals with experimental pulmonary aspergillosis – and, according to the 2011 ECIL clinical practice guidelines may be considered as surrogate marker for detection of invasive aspergillosis (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ECIL.aspx). Recent data suggest that sequential measuring of GM serum levels may be used for therapeutic monitoring in children and adults with pulmonary aspergillosis. The guidelines from the Infections Disease Society of America (IDSA) state, that duration of antifungal therapy must not only rely on disappearance of GM levels, but also on resolution

Clinical practice (not EORTC criteria) in the management of IFIs depends on the population at risk (e.g. genetics, clinical), availability/value of diagnostic tests and availability/effectiveness of antifungal drugs. HR-ALL: high risk – acute lymphoblastic

• Biopsy/Blood sample • Histology/ Culture

**TARGETED**

GM testing with the Platelia Aspergillus Enzyme Immunoassay (EIA; Biorad Laboratories, Redmond, WA) has been approved by the U.S. Food and Drug Administration (FDA) for Aspergillus diagnostics and is included as a mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group[6]. The test is based on detection of a component of the Aspergillus cell wall, Galactomannan (GM), which is released in the surrounding environment by growing Aspergillus species. Concentration of serum GM correlates with fungal burden in animals with experimental pulmonary aspergillosis – and, according to the 2011 ECIL clinical practice guidelines may be considered as surrogate marker for detection of invasive aspergillosis (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ECIL.aspx). Recent data suggest that sequential measuring of GM serum levels may be used for therapeutic monitoring in children and adults with pulmonary aspergillosis. The guidelines from the Infections Disease Society of America (IDSA) state, that duration of antifungal therapy must not only rely on disappearance of GM

The GM EIA has been most studied in hematologic malignancy and bone marrow transplantation populations. Both the specificity and sensitivity of the GM EIA for invasive aspergillosis are high for infected, neutropenic adult patients from these populations. Comparison of 5 studies which use EORTC/MSG criteria and give adequate information for individual patients with results of a formal meta-analysis, indicate sensitivity, specificity of 76% to 73%, 86% to 90% in children and adults respectively[14]. Controversy of GM testing exists about the interpretation of the assay cutoff level (0.5, 1.0), which was originally set at 1.5 and was applied in Europe but which was lowered to 0.5 after review by the FDA. Studies have shown that using an index cutoff for positivity of 0.5 versus greater indices substantially increases sensitivity, with only minimal loss in specificity[15]. Factors, which increase false positivity and influence the specificity of the assay, include a low level of cut-off (<0.5), colonization with Bifidobacterium bifidum in the intestinal flora, which mimics the epitope recognized by the EB-A2 in the enzyme-linked immunosorbent assay kit[16] and invasive infections with other fungi, such as Penicillium spp., histoplasmosis, and blastomycosis[13]. Moreover, cross-reactivity of the assay has been shown with the use of piperacillin/ tazobactam or

The IDSA guidelines currently recommend using the GM EIA in conjunction with CT scans for early, noninvasive diagnosis of invasive aspergillosis in high-risk patients[13]. The test should be performed serially, at least twice per week through the periods of

When GM in serum is used for screening for invasive mold infection in children with hematological malignancies/undergoing HSCT, data should be interpreted with caution, since the assay has a number of limitations in the sensitivity and specificity profile. Prospective monitoring of GM in serum every three to four days in children at high risk for IFD is reasonable for early diagnosis of invasive aspergillosis. Although the optimal cut-off value of GM in the serum of children is not well defined, published data support the use of a threshold of an optical density index 0.5 (http://www.ebmt.org/Contents/Resources/Library/

1,3-ß-D Glucan (BG) is a fungal cell wall component circulating in the blood of patients with invasive aspergillosis, candidemia, but also Fusarium*,* Trichosporum, Saccharomyces, and Pneumocystis jirovecii. Moreover, BG is also detected in patients with infections due to bacteria such as Streptococcus pneumoniae, Pseudomonas aeruginosa and in healthy individuals. However, BG is absent in patients with cryptococcosis and zygomycosis[18]. Antibiotics such as cefepime, piperacillin/tazobactam or meropenem may cause

amoxicillin/clavulanate antibiotic therapy and in infants with the nutrition of milk-based formulas[17].

The GM EIA has been most studied in hematologic malignancy and bone marrow transplan‐ tation populations. Both the specificity and sensitivity of the GM EIA for invasive aspergillosis are high for infected, neutropenic adult patients from these populations. Comparison of 5 studies which use EORTC/MSG criteria and give adequate information for individual patients with results of a formal meta-analysis, indicate sensitivity, specificity of 76% to 73%, 86% to 90% in children and adults respectively [14]. Controversy of GM testing exists about the interpretation of the assay cutoff level (0.5, 1.0), which was originally set at 1.5 and was applied

ß-D-Glucan serum assay, PCR and the CT scan will be described in detail.

322 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

• Prolonged fever (> 96h)

**EMPIRIC**

**6. Galactomannan (GM)**

SCT: stem cell transplantation; GM: Galactomannan; CT: computed tomography.

•Risk groups (e.g. HR‐ ALL, SCT) **PROPHYLAXIS**

**5.1. Galactomannan (GM)**

ECIL/Pages/ECIL.aspx).

of clinical and radiological findings [13].

**7. 1,3-ß-D Glucan**

1,3-ß-D Glucan (BG) is a fungal cell wall component circulating in the blood of patients with invasive aspergillosis, candidemia, but also Fusarium*,* Trichosporum, Saccharomyces, and Pneumocystis jirovecii. Moreover, BG is also detected in patients with infections due to bacteria such as Streptococcus pneumoniae, Pseudomonas aeruginosa and in healthy individuals. However, BG is absent in patients with cryptococcosis and zygomycosis [18]. Antibiotics such as cefepime, piperacillin/tazobactam or meropenem may cause positive BG levels. Investiga‐ tions using different BG assays in 2979 patients (594 with proven or probable IFI) have reported a pooled sensitivity of 76.8% and specificity of 85.3% [19]. Differences in study design (popu‐ lation studies versus case-control, variation in the number of proven or probable IFIs, propor‐ tions of patients with candidemia and aspergillosis, case-mix of neutropenic and nonneutropenic patients, and previous antifungal prophylaxis) highlight the need for further investigations. In children, data is very limited: elevated levels of BG were reported in a casecontrol study of only four children with IFI (3 patients with candidemia, one patient probable aspergillosis) [20].

The Fungitell assay (Associates of Cape Cod) for detection of 1,3-ß-D Glucan is approved by the FDA for the diagnosis of invasive mycoses, including aspergillosis [13] and is included as mycological criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group [6]. Unfortunately, there is no recommendation from ECIL or IDSA for clinical practice. However, BG testing in adults is considered as having good diagnostic accuracy for early diagnosis of IFD; in children, data are too limited to make any recommendations (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/ ECIL.aspx).

lesion size and number in patients with invasive pulmonary aspergillosis [30]. The appearance of cavities on serial CT scans (frequently accompanied by the appearance of the air-crescent sign as neutropenia resolves) may be indicative of patient recovery. Similarly, if antifungal therapy is initiated and subsequent scans show an increase in the number or size of lesions, this is more likely a reflection of the typical progression of disease rather than failed therapy. According to the ECIL recommendations, in high-risk patients with persistent febrile neutro‐ penia that persists beyond 96 hours or with focal clinical findings, imaging studies (e.g., CTscan of the lung or adequate imaging of the symptomatic region) should be performed. Further diagnostic work-up (e.g., BAL, biopsy) should be considered and mold-active antifungal

Invasive Fungal Infections in ALL Patients http://dx.doi.org/10.5772/54990 325

Antifungal strategies include prophylaxis, empiric antifungal therapy, pre-emptive antifungal therapy and treatment of established invasive fungal infection (Figure 3). For individual patient populations, each strategy needs to consider the patients risk, the local epidemiology, the availability of diagnostic tools and the availability and effectiveness of antifungal agents. Last, but not least a cost – benefit analysis (i.e. toxicity, financial aspects) is mandatory. For the purpose of this textbook spectrum, potency, mode of action, and clinical indication of anti‐

Amphotericin deoxycholate (DAMB) and its lipid formulations, including amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), and liposomal ampho‐ tericin B (LAMB,) have a wide range of activity against most fungal pathogens. Only Asper‐

In comparison to DAMB, nephrotoxicity is rarely seen with the use of the lipid formula‐ tions; infusion-related reactions, such as fever, chills and rigor are substantially less frequent with LAMB. Mild increases in bilirubin and alkaline phosphatase are associated with all three lipid formulations, elevation of transaminases with LAMB only. Currently, DAMB is licensed for neonatal invasive candidiasis and induction therapy for cryptococcal meningi‐ tis; LAMB is approved as first line empirical treatment of suspected invasive aspergillosis and candidiasis; ABCD is licensed for second-line treatment of patients with invasive aspergillosis, and ABLC for second-line treatment of patients with invasive Candida or

The recommended therapeutic dosages are 0.7 to 1.0 mg/kg/day for DAMB, 3–4 mg/kg/day for ABCD, 5 mg/kg/day for ABLC, and 3 (to 5) mg/kg/day for LAMB, respectively. The available evidence does not suggest pharmacokinetic differences of LAMB between adults and

gillus terreus and Fusarium species are less susceptible (Table 1.) [31].

treatment should be initiated.

fungal agents will be discussed.

**6.1. Amphotericin B**

Aspergillus infections [34].

children including preterm and newborn infants [33].

**6. Treatment**

#### **5.3. PCR**

Detection of antifungal DNA has been advocated as a promising, rapid and more sensitive diagnostic tool, but false-positive results can occur, and a standardized commercial method is not yet available. Several PCR assays to detect fungal DNA have been described, but most have shown that the global performance was too low to be of clinical interest. Different situations have been reported: PCR either has high sensitivity and NPV, while specificity and PPV is low, or, conversely, high specificity and PPV with low sensitivity and NPV [21-24]. These discrepancies can be due to the different technical approaches used. Indeed, a major difference is the type of PCR method used in these studies, i.e., nested PCR, PCR–enzymelinked immunosorbent assay, or RT-PCR [22;24]. Also, the superiority of large serum volumes (> 1 ml) in comparison with conventional serum samples (100 μl to 200 μl) has clearly been shown [23]. In view of changing epidemiology a panfungal PCR might be advantageous to permit the detection of a wide range of fungal pathogens. Its sensitivity of 96%, negative predictive values of 98%, whereas the specificity and positive predictive value were 77% and 62%, respectively is far superior to single PCR measurements [25].

In summary, despite ISDA and ECIL do not give any recommendations, combining nonculture based diagnostics is an important research direction that may improve the overall predictive value of these systems [26].

#### **5.4. Chest CT scan**

Systematic chest CT scan allows early diagnosis of invasive pulmonary aspergillosis, is more sensitive and specific than traditional chest radiographs and is a clinical criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group. Characteristic findings consist of nodules surrounded by the 'halo sign', an area of haziness or ground-glass opacity, or pleura-based, wedge-shaped areas of consolidation [27]. These findings correspond to areas of hemorrhagic infarcts. In severely neutropenic patients, the halo sign is highly suggestive of angioinvasive aspergillosis. However, a similar appearance has been described in a number of other conditions, including infections with herpes virus or cytomegalovirus, Kaposi sarcoma, Wegener granulomatosis, and bronchiolitis obliterans organizing pneumonia [12]. The air crescent sign, a crescent-shaped area of radiolucency in a region of nodular opacity, is usually seen during convalescence in angioinvasive aspergillosis (i.e., 2–3 weeks after initiation of treatment and concomitant with resolution of the neutropenia) [28]. Of note, some studies suggest that cavitation and the air-crescent sign are more likely to be observed in adults, and may frequently be absent from CT scans obtained from young children with pulmonary invasive aspergillosis [29]. When obtaining serial CT scans, it is also important to realize that irrespective of antifungal therapy, the pattern is characterized by an initial rise in number and size of lesions, followed by a plateau in lesion size, and gradual reduction [12]. Moreover, is time until complete radiologic remission and outcome independent of initial or maximum lesion size and number in patients with invasive pulmonary aspergillosis [30]. The appearance of cavities on serial CT scans (frequently accompanied by the appearance of the air-crescent sign as neutropenia resolves) may be indicative of patient recovery. Similarly, if antifungal therapy is initiated and subsequent scans show an increase in the number or size of lesions, this is more likely a reflection of the typical progression of disease rather than failed therapy. According to the ECIL recommendations, in high-risk patients with persistent febrile neutro‐ penia that persists beyond 96 hours or with focal clinical findings, imaging studies (e.g., CTscan of the lung or adequate imaging of the symptomatic region) should be performed. Further diagnostic work-up (e.g., BAL, biopsy) should be considered and mold-active antifungal treatment should be initiated.

## **6. Treatment**

diagnostic accuracy for early diagnosis of IFD; in children, data are too limited to make any recommendations (http://www.ebmt.org/Contents/Resources/Library/ ECIL/Pages/

Detection of antifungal DNA has been advocated as a promising, rapid and more sensitive diagnostic tool, but false-positive results can occur, and a standardized commercial method is not yet available. Several PCR assays to detect fungal DNA have been described, but most have shown that the global performance was too low to be of clinical interest. Different situations have been reported: PCR either has high sensitivity and NPV, while specificity and PPV is low, or, conversely, high specificity and PPV with low sensitivity and NPV [21-24]. These discrepancies can be due to the different technical approaches used. Indeed, a major difference is the type of PCR method used in these studies, i.e., nested PCR, PCR–enzymelinked immunosorbent assay, or RT-PCR [22;24]. Also, the superiority of large serum volumes (> 1 ml) in comparison with conventional serum samples (100 μl to 200 μl) has clearly been shown [23]. In view of changing epidemiology a panfungal PCR might be advantageous to permit the detection of a wide range of fungal pathogens. Its sensitivity of 96%, negative predictive values of 98%, whereas the specificity and positive predictive value were 77% and

In summary, despite ISDA and ECIL do not give any recommendations, combining nonculture based diagnostics is an important research direction that may improve the overall

Systematic chest CT scan allows early diagnosis of invasive pulmonary aspergillosis, is more sensitive and specific than traditional chest radiographs and is a clinical criterion in the revised definitions of invasive fungal disease from the EORTC/MSG consensus group. Characteristic findings consist of nodules surrounded by the 'halo sign', an area of haziness or ground-glass opacity, or pleura-based, wedge-shaped areas of consolidation [27]. These findings correspond to areas of hemorrhagic infarcts. In severely neutropenic patients, the halo sign is highly suggestive of angioinvasive aspergillosis. However, a similar appearance has been described in a number of other conditions, including infections with herpes virus or cytomegalovirus, Kaposi sarcoma, Wegener granulomatosis, and bronchiolitis obliterans organizing pneumonia [12]. The air crescent sign, a crescent-shaped area of radiolucency in a region of nodular opacity, is usually seen during convalescence in angioinvasive aspergillosis (i.e., 2–3 weeks after initiation of treatment and concomitant with resolution of the neutropenia) [28]. Of note, some studies suggest that cavitation and the air-crescent sign are more likely to be observed in adults, and may frequently be absent from CT scans obtained from young children with pulmonary invasive aspergillosis [29]. When obtaining serial CT scans, it is also important to realize that irrespective of antifungal therapy, the pattern is characterized by an initial rise in number and size of lesions, followed by a plateau in lesion size, and gradual reduction [12]. Moreover, is time until complete radiologic remission and outcome independent of initial or maximum

62%, respectively is far superior to single PCR measurements [25].

324 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

predictive value of these systems [26].

**5.4. Chest CT scan**

ECIL.aspx).

**5.3. PCR**

Antifungal strategies include prophylaxis, empiric antifungal therapy, pre-emptive antifungal therapy and treatment of established invasive fungal infection (Figure 3). For individual patient populations, each strategy needs to consider the patients risk, the local epidemiology, the availability of diagnostic tools and the availability and effectiveness of antifungal agents. Last, but not least a cost – benefit analysis (i.e. toxicity, financial aspects) is mandatory. For the purpose of this textbook spectrum, potency, mode of action, and clinical indication of anti‐ fungal agents will be discussed.

#### **6.1. Amphotericin B**

Amphotericin deoxycholate (DAMB) and its lipid formulations, including amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), and liposomal ampho‐ tericin B (LAMB,) have a wide range of activity against most fungal pathogens. Only Asper‐ gillus terreus and Fusarium species are less susceptible (Table 1.) [31].

In comparison to DAMB, nephrotoxicity is rarely seen with the use of the lipid formula‐ tions; infusion-related reactions, such as fever, chills and rigor are substantially less frequent with LAMB. Mild increases in bilirubin and alkaline phosphatase are associated with all three lipid formulations, elevation of transaminases with LAMB only. Currently, DAMB is licensed for neonatal invasive candidiasis and induction therapy for cryptococcal meningi‐ tis; LAMB is approved as first line empirical treatment of suspected invasive aspergillosis and candidiasis; ABCD is licensed for second-line treatment of patients with invasive aspergillosis, and ABLC for second-line treatment of patients with invasive Candida or Aspergillus infections [34].

The recommended therapeutic dosages are 0.7 to 1.0 mg/kg/day for DAMB, 3–4 mg/kg/day for ABCD, 5 mg/kg/day for ABLC, and 3 (to 5) mg/kg/day for LAMB, respectively. The available evidence does not suggest pharmacokinetic differences of LAMB between adults and children including preterm and newborn infants [33].

**Figure 4.** Schematic overview of current antifungal agents in regard to its target. Flucytosine inhibits RNA and DNA synthesis, Triazoles inhibit ergosterol biosynthesis, polyenes bind to sterols in the plasma membrane and echinocan‐ dines inhibit beta [1,3]-D-Glucan-synthesis. LAMB: liposomal Amphotericin B; DAMB: Amphotericin B deoxycholate; ABCD: Amphotericin B colloidal dispersion; ABLC: amphotericin B lipid complex.

#### **6.2. Fluconazole**

Fluconazole has a very narrow fungal susceptibility against Candida species (Candida glabrata and krusei have a high MIC index) and lacks activity against Aspergillus species and zygo‐ mycetes (Table 1.). Fluconazole is not metabolized and mainly renally excreted, and drug levels correlate with strictly with renal function [33]. It is licensed for prophylactic use in patients at risk for IFIs and for targeted treatment of candidiasis. For pediatric patients (they show a more rapid excretion and shorter half-life), the recommended dosage is higher than for adults, 8 to 12 mg/kg/day versus 5 mg/kg/day, respectively [34].

ECIL and IDSA guidelines, Itraconazole should be used as second-line therapy in the preven‐

**Table 1.** Susceptibility of important fungal pathogens against some common antifungal agents.

+ = high activity rate; (+) = little reduced activity rate; -/+ = higher resistant rates in some areas; - = mostly resistant

Voriconazole has similar activity as Itraconazole and is active against most Candida and Aspergillus species, but not zygomycetes, Candida glabrata and C. krusei (Table 1.). The effectiveness of this compound has been demonstrated in large clinical trials in both adults and children, and has led to its approval for empirical and pre-emptive antifungal therapy [31]. Because of its wide use, breakthrough infections with zygomycetes have been reported [37]. Additionally, breakthrough infections with susceptible strains have been noted in patients with low plasma levels, necessitating the monitoring of through plasma levels [38]. In children, Voriconazole is more rapidly metabolized, suggesting a higher dosage of 7-8 mg/kg/b.i.d. than in adults (4-5 mg/kg/b.i.d.) [33]. Relevant side effects of Voriconazole include elevations of liver enzymes, visual disturbances and photosensitivity skin reactions, particularly if com‐ bined with nucleoside analoga, which are commonly used in the treatment of ALL. In addition,

tion of IFIs.

**6.4. Voriconazole**

[11;32;33].C.: Candida; Asp.: Aspergillus; spp.: species.

**Amphothericn B**

**Fluconazole** **Voriconazole**

Candida albicans + (+) + + + + + C. parapsilosis + + + + + +/- +/- C. lusitaniae -/+ + + + + + + C. tropicalis + -/+ + + + + + C. glabrata + - -/+ + -/+ + + C. krusei + - -/+ + -/+ + + Asp. fumigatus + - + + + + + Asp. flavus (+) - + + + + + Asp. terreus - - + + + + + Asp. niger + - (+) + (+) + + Zygomycetes + - - (+) - - - Fusarium spp. (+) - - - - - -

**Posaconazole** **Itraconazole** **Caspofungin**

Invasive Fungal Infections in ALL Patients http://dx.doi.org/10.5772/54990

**Micafungin**

327

#### **6.3. Itraconazole**

The compound is active against most Candida and Aspergillus species, but the susceptibility against Candida glabrata and C. krusei is limited (Table 1). There is no activity against zygomycetes. The pharmacokinetics is characterized by inter-individual variability of gastro‐ intestinal absorption and hepatic metabolism [35]. Accordingly, measurement of drug levels is necessary and results of meta-analysis suggest that the trough plasma level should be higher than 0.5 μg / mL [36]. Concerns have arisen on the interaction with drugs such as vincristine and cyclosporine, which are major components of both induction ALL therapy and prevention of GvHD in ALL transplanted patients. Moreover, 10% of patients experience gastrointestinal adverse effects, such as nausea and diarrhea, which limits its acceptance [34]. According to the

+ = high activity rate; (+) = little reduced activity rate; -/+ = higher resistant rates in some areas; - = mostly resistant [11;32;33].C.: Candida; Asp.: Aspergillus; spp.: species.

**Table 1.** Susceptibility of important fungal pathogens against some common antifungal agents.

ECIL and IDSA guidelines, Itraconazole should be used as second-line therapy in the preven‐ tion of IFIs.

#### **6.4. Voriconazole**

**6.2. Fluconazole**

**6.3. Itraconazole**

12 mg/kg/day versus 5 mg/kg/day, respectively [34].

ABCD: Amphotericin B colloidal dispersion; ABLC: amphotericin B lipid complex.

326 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**NUCLEIC ACID SYNTHESIS** *Flucytosine*

**TRIAZOLES** *Fluconazole Itraconazole Voriconazole Posaconazole*

Fluconazole has a very narrow fungal susceptibility against Candida species (Candida glabrata and krusei have a high MIC index) and lacks activity against Aspergillus species and zygo‐ mycetes (Table 1.). Fluconazole is not metabolized and mainly renally excreted, and drug levels correlate with strictly with renal function [33]. It is licensed for prophylactic use in patients at risk for IFIs and for targeted treatment of candidiasis. For pediatric patients (they show a more rapid excretion and shorter half-life), the recommended dosage is higher than for adults, 8 to

**Figure 4.** Schematic overview of current antifungal agents in regard to its target. Flucytosine inhibits RNA and DNA synthesis, Triazoles inhibit ergosterol biosynthesis, polyenes bind to sterols in the plasma membrane and echinocan‐ dines inhibit beta [1,3]-D-Glucan-synthesis. LAMB: liposomal Amphotericin B; DAMB: Amphotericin B deoxycholate;

**CELL WALL** Echinocandines: *Anidulafungin Caspofungin Micafungine*

**CELL MEMBRANE** Polyenes: *LAMB DAMB ABLC ABCD*

The compound is active against most Candida and Aspergillus species, but the susceptibility against Candida glabrata and C. krusei is limited (Table 1). There is no activity against zygomycetes. The pharmacokinetics is characterized by inter-individual variability of gastro‐ intestinal absorption and hepatic metabolism [35]. Accordingly, measurement of drug levels is necessary and results of meta-analysis suggest that the trough plasma level should be higher than 0.5 μg / mL [36]. Concerns have arisen on the interaction with drugs such as vincristine and cyclosporine, which are major components of both induction ALL therapy and prevention of GvHD in ALL transplanted patients. Moreover, 10% of patients experience gastrointestinal adverse effects, such as nausea and diarrhea, which limits its acceptance [34]. According to the

Voriconazole has similar activity as Itraconazole and is active against most Candida and Aspergillus species, but not zygomycetes, Candida glabrata and C. krusei (Table 1.). The effectiveness of this compound has been demonstrated in large clinical trials in both adults and children, and has led to its approval for empirical and pre-emptive antifungal therapy [31]. Because of its wide use, breakthrough infections with zygomycetes have been reported [37]. Additionally, breakthrough infections with susceptible strains have been noted in patients with low plasma levels, necessitating the monitoring of through plasma levels [38]. In children, Voriconazole is more rapidly metabolized, suggesting a higher dosage of 7-8 mg/kg/b.i.d. than in adults (4-5 mg/kg/b.i.d.) [33]. Relevant side effects of Voriconazole include elevations of liver enzymes, visual disturbances and photosensitivity skin reactions, particularly if com‐ bined with nucleoside analoga, which are commonly used in the treatment of ALL. In addition, the interaction of Voriconazole with a number of drugs (e.g. Vincristine, Cyclosporine A, and Omeprazole) has to be considered [33].

questions regarding antifungal treatment have to be addressed in future studies, such as the

Invasive Fungal Infections in ALL Patients http://dx.doi.org/10.5772/54990 329

, Adrian Kneer, Bernhard Meister and Gabriele Kropshofer

[1] Pui, C, Relling, M. V, & Downing, J. R. Mechanisms of disease: Acute lymphoblastic

[2] Arico, M, Valsecchi, M. G, Camitta, B, Schrappe, M, Chessells, J, Baruchel, A, et al. Outcome of treatment in children with philadelphia chromosome-positive acute lym‐

[3] Marr, K. A, Carter, R. A, Crippa, F, Wald, A, & Corey, L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clinical Infec‐

[4] Mcneil, M. M, Nash, S. L, Hajjeh, R. A, Phelan, M. A, Conn, L. A, Plikaytis, B. D, et al. Trends in mortality due to invasive mycotic diseases in the United States, Clinical In‐

[5] Zaoutis, T. E, Heydon, K, Chu, J. H, Walsh, T. J, & Steinbach, W. J. Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the

[6] de PBWalsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T et al. Revised defi‐ nitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG)

phoblastic leukemia. New England Journal of Medicine (2000). , 998-1006.

leukemia. New England Journal of Medicine (2004). , 1535-1548.

duration of treatment or the benefit of costly combination antifungal therapy.

We thank Kinderkrebshilfe Tirol und Vorarlberg for funding.

\*Address all correspondence to<EMAIL_ADDRESS>
tious Diseases (2002). , 909-917.

fectious Diseases (2001). , 1980-1997.

United States, 2000. Pediatrics (2006). EE716., 711.

Consensus Group. Clin Infect Dis (2008). , 1813-1821.

Department of Pediatrics, Medical University of Innsbruck, Austria

**Acknowledgements**

**Author details**

Roman Crazzolara\*

**References**

#### **6.5. Posaconazole**

This compound has a potent and broad-spectrum activity against most clinically important fungal infections, including zygomycetes, distinguishing it from the other azoles [33]. Accord‐ ing to the ECIL/ IDSA guidelines it is recommended as second-line treatment of aspergillosis, fusariosis, chromoblastomycosis and coccidioidomycosis. In addition, Posaconazole is approved for prophylaxis in high-risk patients older than 13 years of age with ALL and in hematopoietic stem cell transplant patients with graft-versus-host disease [31;39]. The dosage for prophylaxis is 200 mg three times daily, for salvage treatment the dose is increased to 400 mg two times daily. Similar to Voriconazole, interference with cytochrome P450 dependent metabolites (e.g. Cyclosporine) need to be considered [34].

#### **6.6. Caspofungin**

Caspofungin is active against Candida spp. and Aspergillus spp., but resistant against Cryptococcus species and zygomycetes (Table 1.). It is licensed for adult and pediatric patients, including neonates, for empirical antifungal therapy in persistently febrile neutropenic patients, for second-line pre-emptive therapy of suspected aspergillosis and for primary therapy in non-neutropenic patients with invasive Candida infections. The recommended dose regimen in adults consists of a single 70-mg loading dose on day 1, followed by 50 mg daily thereafter [34]. A dosage of 1 mg/kg for children has been suggested [31]. A favorable safety profile has been described, the most common drug-related adverse events were fever, increased ALT, and rash; few events were serious or required treatment discontinuation [40].

#### **6.7. Micafungin**

Micafungin was recently licensed for neonates, children and adults for prophylaxis and treatment of invasive candidiasis in patients with prolonged neutropenia and after hemato‐ poietic stem cell transplantation [41]. The spectrum of activity is similar to that of Caspofungin (Table 1). The recommended dosage is 100 mg/day for invasive candidiasis (≤40 kg body weight: 2 mg/kg) with the option of dose escalation to 200 mg/day or 4 mg/kg/day; and 50 mg/ day (≤40 kg: 1 mg/kg) in the preventive indication [34]. The most frequent adverse events include vomiting, high fever, diarrhea, nausea, and hypokalemia [41].

#### **7. Conclusion**

Although various guidelines on antifungal management have been published, we suggest using a simple approach, which is guided by local factors, such as the pattern of resistance and the availability of diagnostic tools. As newer strategies might soon be implemented, we are unable to assess the efficacy of our approach to date. Our report underlines that many questions regarding antifungal treatment have to be addressed in future studies, such as the duration of treatment or the benefit of costly combination antifungal therapy.

#### **Acknowledgements**

the interaction of Voriconazole with a number of drugs (e.g. Vincristine, Cyclosporine A, and

This compound has a potent and broad-spectrum activity against most clinically important fungal infections, including zygomycetes, distinguishing it from the other azoles [33]. Accord‐ ing to the ECIL/ IDSA guidelines it is recommended as second-line treatment of aspergillosis, fusariosis, chromoblastomycosis and coccidioidomycosis. In addition, Posaconazole is approved for prophylaxis in high-risk patients older than 13 years of age with ALL and in hematopoietic stem cell transplant patients with graft-versus-host disease [31;39]. The dosage for prophylaxis is 200 mg three times daily, for salvage treatment the dose is increased to 400 mg two times daily. Similar to Voriconazole, interference with cytochrome P450 dependent

Caspofungin is active against Candida spp. and Aspergillus spp., but resistant against Cryptococcus species and zygomycetes (Table 1.). It is licensed for adult and pediatric patients, including neonates, for empirical antifungal therapy in persistently febrile neutropenic patients, for second-line pre-emptive therapy of suspected aspergillosis and for primary therapy in non-neutropenic patients with invasive Candida infections. The recommended dose regimen in adults consists of a single 70-mg loading dose on day 1, followed by 50 mg daily thereafter [34]. A dosage of 1 mg/kg for children has been suggested [31]. A favorable safety profile has been described, the most common drug-related adverse events were fever, increased ALT, and rash; few events were serious or required treatment discontinuation [40].

Micafungin was recently licensed for neonates, children and adults for prophylaxis and treatment of invasive candidiasis in patients with prolonged neutropenia and after hemato‐ poietic stem cell transplantation [41]. The spectrum of activity is similar to that of Caspofungin (Table 1). The recommended dosage is 100 mg/day for invasive candidiasis (≤40 kg body weight: 2 mg/kg) with the option of dose escalation to 200 mg/day or 4 mg/kg/day; and 50 mg/ day (≤40 kg: 1 mg/kg) in the preventive indication [34]. The most frequent adverse events

Although various guidelines on antifungal management have been published, we suggest using a simple approach, which is guided by local factors, such as the pattern of resistance and the availability of diagnostic tools. As newer strategies might soon be implemented, we are unable to assess the efficacy of our approach to date. Our report underlines that many

include vomiting, high fever, diarrhea, nausea, and hypokalemia [41].

Omeprazole) has to be considered [33].

metabolites (e.g. Cyclosporine) need to be considered [34].

328 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

**6.5. Posaconazole**

**6.6. Caspofungin**

**6.7. Micafungin**

**7. Conclusion**

We thank Kinderkrebshilfe Tirol und Vorarlberg for funding.

### **Author details**

Roman Crazzolara\* , Adrian Kneer, Bernhard Meister and Gabriele Kropshofer

\*Address all correspondence to<EMAIL_ADDRESS>
Department of Pediatrics, Medical University of Innsbruck, Austria

### **References**

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332 Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

nal of Clinical Oncology (2003). , 4615-4626.

(2011). Suppl 1:SS74., 71.

451-456.

38, 335-347.

## *Edited by Juan Manuel Mejia-Arangure*

This book describes different perspectives of childhood acute lymphoblastic leukemia. The approach includes aspects of molecular epidemiology, particularly molecular features that influence the genesis and prognosis of the disease. Some aspects of the prognosis of lymphoblastic leukemias are very detailed, highlighting the use of molecular biology in the early identification of complications that may occur in diseased patients. The authors of the present book conform a Mexican group who identifies the causes of leukemia, and they summarize their experience in research, results and proposals for future studies. A causal model is included in which the authors hypothesized the origin of acute lymphoblastic leukemias, particularly in children. This hypothesis can be useful to better understand other cancers during childhood. This book will help the reader to identify different molecular aspects involved in leukemia, and its relation to the development and evolution of the disease.

Clinical Epidemiology of Acute Lymphoblastic Leukemia - From the Molecules to the Clinic

Clinical Epidemiology

of Acute Lymphoblastic

Leukemia

From the Molecules to the Clinic

*Edited by Juan Manuel Mejia-Arangure*


**4. Conclusions**

Following previous findings related to the droplet size increase in pneumatic spraying, a study was carried out to check the influence of modifications in the liquid hose position with respect to the air spout. In both tested nozzles, namely cannon and hand types, the air speed decreased consistently from the inner to the outer part of the spout, with higher decrease outside of the spout.

Therefore, the strategy to move the liquid release hose to outer positions with respect to the conventional one is as an e ffective way to substantially increase the droplet size spectra generated by pneumatic sprayers. This e ffect was certified by the Volume Median Diameter (D50) increase equal to 280% for the cannon and 270% for the hand spouts just by changing the liquid hose position from the inner to the outermost spout position. Similar results were obtained for D10 and D90. In particular, the variation of liquid hose position from conventional to extreme out of spout position (XP) allowed to vary the spray quality generated from very fine (VF) to coarse (C)/very coarse (VC), giving farmers a wide range of options during the spray application. The droplet driftability, measured by the V100 parameter, decreased with the increase of the liquid hose distance from its original position. This suggests that when the liquid hose is in the extreme outer position, the pneumatic nozzle behaves similarly to a hydraulic drift reducing nozzle.

The findings of this study could significantly help in reducing the spray drift in pneumatic spraying just by slightly modifying the spray nozzle, which could have important practical implications. For the first time it is possible to design a device that gives farmers and technicians the possibility to match the drift-reduction environmental requirements using pneumatic sprayers for 3D crops, balancing at the same time the treatment specifications for every spray application.

**Author Contributions:** Conceptualization, M.G., A.M.F., P.M. and P.B.; methodology, M.G., A.F.M., P.M. and P.B.; validation, M.G., A.F.M. and P.M.; formal analysis, M.G. and A.F.M.; investigation, M.G., A.F.M., P.M. and F.G; resources, P.B.; data curation, M.G. and A.F.M.; writing—original draft preparation, M.G. and A.F.M.; writing—review and editing, M.G., A.F.M., P.M., P.B and F.G.; visualization, M.G.; supervision, M.G., P.B. and F.G.; project administration, F.G.; funding acquisition, P.B.; All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors would like to thank CIMA S.p.a. (Pavia, IT) for providing the spouts used in the experimental work.

**Conflicts of Interest:** The authors declare no conflict of interest.


*2.4. Custom Design*

Gómez-García et al. [47] mentioned that, in general, the short stem design has five basic defined characteristics: the anatomical region they occupy, geometric characteristics of the design, areas where stress transmission occurs, osteotomy and insertion. The short stem occupies and transmits stresses toward the metaphysis, due to which it is known as a metaphyseal stem. Therefore, throughout this section, geometry, osteotomy and insertion are integrated into the custom design of the short stem. As mentioned in the *Morphological study* (Section 2.3), the three femoral parameters play an important role in muscle action and range of motion; therefore, their preservation is crucial in order not to alter the femoral biomechanics.


**4.2. Creating techniques**

**Figure 14.** Reverse scan [8].

**3.5. The design output stage**

44 Product Lifecycle Management - Terminology and Applications

**4. Product design methods**

**4.1. Design survey**

involved in the main four steps of product design.

beginning of the design particularly important.

The design output stage mainly refers to the expression of design results and the preliminary preparation for the following production. At this stage, through the design renderings, dimensional drawings, parts drawings, construction drawings, detail display drawings, structural drawings, etc., the design results are presented in a detailed and complete manner. Through this way, the above design work is closed and integrated on one the hand. On the other hand, these outputs also provide the basis for production and construction after the design phase.

In different design stages and target objects, the complexity of the steps is slightly different and so as the design methods involved.  The factors that people choose products are increasingly influenced by the individual and the mainstream. At the same time, in the whole product design process, each step has a series of internal or external constraints. The design is just like "dancing with shackles." Every involved part needs information intervention and guidance and gradually coordinates, optimizes, and iterates so as to initiate better ideas and works. This factor makes the investigation and research at the

Common survey methods include comprehensive surveys, typical surveys, and sample surveys. The main difference is the coverage of survey samples. When carrying out the survey, The creating technique is an important part to improve the design quality. It is a means to use the multi-directionality, the differentiation, the suddenness, the broadness, and the flexibility of creative thinking to propose new ideas. According to different classification criteria, creating techniques can be divided into different types. Such as according to the personality characteristics of the creative team members, the creating techniques can be divided into open speech and anonymous expression. The typical representative techniques are brainstorming

**Figure 15.** Design survey.

and 635 method. The former is free expression of team members, not bound to each other, and open to freedom. By this free style, the creativities of the group are stimulating, while the latter is to be silence in the whole previous period. Each one needs to avoid mutual interference and privately express their ideas in a recorded way. According to the nature of the creative proposal, it can be divided into active stimulating and passive stimulating. The typical representatives are the comprehensive method and enumeration method. The former uses abstract expressions to let the team members of different professional backgrounds associate with each other freely; the latter is based on existing objects, enumerate expressions and deep cognition one by one, and then use these expressions as sources of creativity. Flexible selection of different creative techniques at different stages of design is needed. As shown in **Figure 16**, it is a passive method by which we can make ourselves much more aware about the design purpose and processes after the relevant technique.

if we change parts of it, including face skin color and facial features and any other aspects. In principle, the number of new schemes is the same exponential power of the changeable part.

Product Design Process and Methods http://dx.doi.org/10.5772/intechopen.80821 47

Design evaluation is to compare and evaluate the solution to the problem in the design process, thereby determining the value of each program and judging its merits and demerits in order to screen out the best design. The meaning of "program" here is extensive and can be in various forms, such as principle program, structural program, modeling program, etc. From the perspective of its carrier, it can be a component or an overall drawing, or it can be a model, a prototype, a product, etc. In general, the "program" referred to in the evaluation is essentially the answer to the problems encountered in the design. The significance of design evaluation is to consciously control the design process, to target the direction of the design, and to assess the design plan with scientific analysis rather than subjective feeling, which provides designers with the basis for judging design ideas. Through design evaluation, the quality of design can be effectively guaranteed, and the best solution in which all aspects of performance meet the target requirements can be selected among many design programs. Secondly, proper design evaluation can reduce the blindness in the design and improve the efficiency of it. In addition, the applicative performance of evaluation can effectively verify the design plan, find out deficiencies during the process, and provide the basis for deeper design improvement.

In the actual evaluation process, due to the complexity of the design factors, the main influencing factors are generally selected. According to different design objects and different stages of the design, different evaluation objectives are determined, and the most appropriate content is selected to establish the evaluation target system. After selecting the evaluation items, the

As shown in **Figure 17**, the principle sum of the complete scheme is nn.

**4.4. Design evaluation method**

**Figure 17.** Questioning method in general form design.

### **4.3. Product form design method**

This stage of creating techniques is designed to complete the visualization process from design concept to product modeling. After completing the functional positioning of the product, the product structure and the later modeling design become the final platform for design creativity. Therefore, the product design method mainly includes the following three steps.

Firstly, decompose the product into individual parts according to the previous function and form positioning. Secondly, confirm the changeable parts of each shape. Thirdly, the changeable part is changed. Finally, recompose the relevant individual parts into a complete one, and select the best shape you evaluated. For example, a simple face will be a brand-new one

**Figure 16.** Questioning.

if we change parts of it, including face skin color and facial features and any other aspects. In principle, the number of new schemes is the same exponential power of the changeable part. As shown in **Figure 17**, the principle sum of the complete scheme is nn.


**Acknowledgments:** The authors owe thanks to Eng. Paolo Saccenti of Boldrocchi S.r.l. (Biassono, Monza-Brianza, Italy) for the technical support in this research. The authors wish to gratefully acknowledge Luca Marchetti and Matteo Seno for their support in the experimental campaign. Thanks are also due to Iuri Boromei for his contribution to the GD-OES analyses.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

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