**5.7 Tooth flanged bolt**

*Adhesives and Adhesive Joints in Industry Applications*

**5.3 Nut with nylon insert**

*Conventional thread locking fasteners.*

**Figure 3.**

**5.4 Tab washer**

**5.5 Castellated nut**

**5.6 Lock nut**

is required, too (see **Figure 3**) [1].

nylon insert friction, too (see **Figure 3**) [1].

loosening. This also does not seal, can damage the surface of softer or coated metals, and is not reusable, and additional cost of star washer is required (see **Figure 3**) [1].

Nylon or "plastic" deforms into void in the thread. This method allows an initial loosening, and the bolt tension is already reduced, but it can prevent a further loosening, and it is also recommended to be replaced after each disassembly with new nut in order to maintain optimal performance as when reused it loses a significant amount of its ability to fill the voids. Cost of nylon insert must be considered, too. Nylon also insulates the heat developed from thread friction making the assembly more susceptible to galling during installation. It is difficult to tighten because of

Tab washer mechanically overlaps the edge of a surface or flange. It acts as a normal washer, spreading the clamp load over a wide area. This method allows an initial loosening of bolt tension due to the empty space between threads. But due to its structure, it prevents a further loosening, and it does not seal or technically lock the assembly, and additional cost of tab washer is required (see **Figure 3**) [1].

Castellated nut uses tension to mechanically "grip" the bolt or threads. Cotter pin is also sometimes used in conjunction with this device to prevent nut from falling off. However, cotter pin will not prevent loss of clamp load after initial loosening. It fails when vibrational load or impact causes the fastener to lose clamp load. This device does not seal the threaded assembly, and the high cost of castellated nut

By "doubling nut" this method uses two nuts applied to the threaded fastener in order to provide a secondary force or lock to the initial nut. This does not significantly increase clamp load and may add additional stress to the threaded fastener.

**120**

The "tooth" on the bolt grips and digs into the surface of the material or metal that is being assembled. This method also allows an initial loss of bolt tension as the tooth bolt rotates and digs into the bearing surface and stops. The tooth may dig into coated metals or damage the coating finish. This device does not seal the assembly. Under the vibration and impact, the bolt rotates until the tooth digs into the metal surface and finally grips the metal to prevent a further loosening; however, until then, pretty much amount of bolt tension is already lost, and a high cost of tooth flanged bolt is required, too (see **Figure 3**) [1].


**4. Disease- and treatment-associated bone deterioration**

There are several diseases and treatments that destabilize the bone remodeling process and induce abnormal bone deterioration (**Figure 1**) [30]. Each disease and treatment act differently on hormones, which conducts various bone problems. In this

**Figure 1.** *Illustration of diseases and medical treatments' effect on BMD, bone matrix, and architecture.*

section, we are summarizing the most-known diseases and treatments affecting bone and their effect on BMD.


*Review* **Polyphenol-Rich Ginger (***Zingiber officinale***) for Iron Deficiency Anaemia and Other Clinical Entities Associated with Altered Iron Metabolism**

**Soo Liang Ooi 1, Sok Cheon Pak 1,\*, Ron Campbell 2 and Arumugam Manoharan 3**

**Abstract:** Ginger (*Zingiber officinale*) is rich in natural polyphenols and may potentially complement oral iron therapy in treating and preventing iron deficiency anaemia (IDA). This narrative review explores the benefits of ginger for IDA and other clinical entities associated with altered iron metabolism. Through in vivo, in vitro, and limited human studies, ginger supplementation was shown to enhance iron absorption and thus increase oral iron therapy's efficacy. It also reduces oxidative stress and inflammation and thus protects against excess free iron. Ginger's bioactive polyphenols are prebiotics to the gut microbiota, promoting gut health and reducing the unwanted side effects of iron tablets. Moreover, ginger polyphenols can enhance the effectiveness of erythropoiesis. In the case of iron overload due to comorbidities from chronic inflammatory disorders, ginger can potentially reverse the adverse impacts and restore iron balance. Ginger can also be used to synthesise nanoparticles sustainably to develop newer and more effective oral iron products and functional ingredients for IDA treatment and prevention. Further research is still needed to explore the applications of ginger polyphenols in iron balance and anaemic conditions. Specifically, long-term, well-designed, controlled trials are required to validate the effectiveness of ginger as an adjuvant treatment for IDA.

**Keywords:** blood disorder; haemoglobin; natural product; nutraceutical; nutritional disease; phenolic compounds


**4. Simulation Verification 4. Simulation Verification**

In this section, simulation results in Matlab/Simulink are shown to validate the proposed control strategy. The changes in bus voltage, inductor current, and output current of the DC microgrid before and after the application of the control strategy are shown in Figure 8. Initially, the traditional droop control was applied. Due to the influence of CPLs, the system suffers oscillation. At t = 0.5s, the control strategy is switched from the traditional droop control to the proposed control strategy. Obviously, the DC microgrid bus voltage can quickly be restored to a stable state. Compared with the virtual capacitance control strategy based on droop control (the gray curve in In this section, simulation results in Matlab/Simulink are shown to validate the proposed control strategy. The changes in bus voltage, inductor current, and output current of the DC microgrid before and after the application of the control strategy are shown in Figure 8. Initially, the traditional droop control was applied. Due to the influence of CPLs, the system suffers oscillation. At t = 0.5s, the control strategy is switched from the traditional droop control to the proposed control strategy. Obviously, the DC microgrid bus voltage can quickly be restored to a stable state. Compared with the virtual

tests are carried out with the change of droop coefficients, line lengths, and operating points.

the figure) in [18], the proposed control strategy in this paper can reduce the adjustment time and

voltage fluctuation during the regulation process. Overall, this strategy will have more advantages in improving stability. To further verify the effectiveness of the proposed strategy, the following capacitance control strategy based on droop control (the gray curve in the figure) in [18], the proposed control strategy in this paper can reduce the adjustment time and make the system reach the balance faster. In addition, the control strategy can reduce the bus voltage fluctuation during the regulation process. Overall, this strategy will have more advantages in improving stability. To further verify the effectiveness of the proposed strategy, the following tests are carried out with the change of droop coefficients, line lengths, and operating points. *Appl. Sci.* **2019**, *9*, x FOR PEER REVIEW 10 of 15

**Figure 8.** Simulation results of a DC microgrid system with the proposed control strategy.

### **Figure 8.** Simulation results of a DC microgrid system with the proposed control strategy. *4.1. Change of Droop Coe*ffi*cients*

under different droop coefficients.

*4.1. Change of Droop Coefficients*  DC microgrids can coordinate the output of resources by adjusting the droop coefficient, which means that the system may operate under different droop coefficients due to different requirements [29]. Therefore, the stable operation of the system under different droop coefficients must be ensured. Figure 9 shows the simulation result of the proposed control strategy under different droop coefficients. It can be seen that the system remained stable whether the droop coefficient was switched to 0.3 or 0.7. Thus, it is evident that the control strategy can ensure the system stability DC microgrids can coordinate the output of resources by adjusting the droop coefficient, which means that the system may operate under different droop coefficients due to different requirements [29]. Therefore, the stable operation of the system under different droop coefficients must be ensured. Figure 9 shows the simulation result of the proposed control strategy under different droop coefficients. It can be seen that the system remained stable whether the droop coefficient was switched to 0.3 or 0.7. Thus, it is evident that the control strategy can ensure the system stability under different droop coefficients.

**Figure 9.** Simulation results of DC microgrid system with the change droop coefficient. *4.2. Change of Line Lengths*

### **Figure 9.** Simulation results of DC microgrid system with the change droop coefficient. *4.2. Change of Line Lengths* The system needs to meet the energy requirements of the load, but the distance between

The system needs to meet the energy requirements of the load, but the distance between different loads and the bus are different. It is generally considered that the value of the droop coefficient is much larger than the line resistance and only the inductive component in the line is considered in this paper. The inductance of the line is proportional to the length. Hence, the variable considered in this section is the line length. As shown in Figure 10, the line length varies following the sequence of 1.070 km, 0.535 km and 0.749 km. It can be seen that no matter the length of the line increases or decreases, the DC microgrid can keep stable after applying the proposed control strategy. Thus, the effectiveness of the proposed stabilization strategy is proved when the system line length varies. different loads and the bus are different. It is generally considered that the value of the droop coefficient is much larger than the line resistance and only the inductive component in the line is considered in this paper. The inductance of the line is proportional to the length. Hence, the variable considered in this section is the line length. As shown in Figure 10, the line length varies following the sequence of 1.070 km, 0.535 km and 0.749 km. It can be seen that no matter the length of the line increases or decreases, the DC microgrid can keep stable after applying the proposed control strategy. Thus, the effectiveness of the proposed stabilization strategy is proved when the system line length varies.

**Figure 10.** Simulation results of DC microgrid system with the change of line length.

### **Figure 10.** Simulation results of DC microgrid system with the change of line length. *4.3. Change of Operating Points*

*4.3. Change of Operating Points* The load in the DC microgrid is an important part of the system and one of the main factors affecting the stability of the system. Instability problems are more likely to occur when load changes The load in the DC microgrid is an important part of the system and one of the main factors affecting the stability of the system. Instability problems are more likely to occur when load changes [30,31]. Thus, the effectiveness of the proposed control strategy was verified by changing the power of CPLs.

It proves that the control strategy can improve the system robustness in case of load variation.

[30,31]. Thus, the effectiveness of the proposed control strategy was verified by changing the power

The load doubled at 0.5 s, tripled at 0.7 s, and recovered to the initial at 0.9 s, as illustrated in Figure 11. It can be seen that the system operates steadily whether the power increases or decreases. It proves that the control strategy can improve the system robustness in case of load variation. *Appl. Sci.* **2019**, *9*, x FOR PEER REVIEW 13 of 15

**Figure 11.** Simulation results of a DC microgrid system with the change of operation points.

### **Figure 11.** Simulation results of a DC microgrid system with the change of operation points. **5. Conclusions**

acquisition, G.M.

(18A470015,18A470017, and 19A120012).

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

**5. Conclusions** A virtual negative inductance control strategy for DC microgrids with constant power loads is proposed in this paper. The particular is that this strategy improves the stability of the system from A virtual negative inductance control strategy for DC microgrids with constant power loads is proposed in this paper. The particular is that this strategy improves the stability of the system from the point of line inductance. And the main contributions of this paper lie in the following:

regulation process when compared with the virtual capacitance strategy. In this paper, the stability of a single DC microgrid is studied. For future work, the stability of a DC microgrid group will be of concern. The power generation variation of renewable energy based distributed generators will also be considered. And more detailed research will be carried out by considering more detailed transient models of distributed generation and load. Besides, we also In this paper, the stability of a single DC microgrid is studied. For future work, the stability of a DC microgrid group will be of concern. The power generation variation of renewable energy based distributed generators will also be considered. And more detailed research will be carried out by considering more detailed transient models of distributed generation and load. Besides, we also intend to extend the proposed control strategy to a hybrid alternating current (AC)/DC microgrid.

**Funding:** This work was supported by the National Natural Science Foundation of China (61803343), the China

intend to extend the proposed control strategy to a hybrid alternating current (AC)/DC microgrid. **Author Contributions:** Conceptualization, Z.C. and G.M.; methodology, G.M. and Z.L.; software, Z.C., G.M. and Z.L.; validation, Z.C. and G.M. and J.G.; formal analysis, Z.C. and G.M.; investigation, G.M.; resources, Z.L.; data curation, J.G.; writing—original draft preparation, G.M.; writing—review and editing, Z.C. and G.M.; visualization, Z.C. and G.M.; supervision, J.G., Z.L. and J.S.; project administration, Z.L.; and funding **Author Contributions:** Conceptualization, Z.C. and M.G.; methodology, G.M. and Z.L.; software, Z.C., M.G. and Z.L.; validation, Z.C. and M.G. and J.G.; formal analysis, Z.C. and M.G.; investigation, M.G.; resources, Z.L.; data curation, J.G.; writing—original draft preparation, M.G.; writing—review and editing, Z.C. and M.G.; visualization, Z.C. and M.G.; supervision, J.G., Z.L. and J.S.; project administration, Z.L.; and funding acquisition, M.G.

**Funding:** This work was supported by the National Natural Science Foundation of China (61803343), the China Postdoctoral Science Foundation (2018M630835), and the Key Projects of Higher Education of Henan Province (18A470015,18A470017, and 19A120012).

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


*2.1. Soot*

Soot is a spherical particle of impure carbon coated in polyaromatic hydrocarbons (PAHs) [16]. These pollutants are usually the result of a fuel-rich combustion at high temperatures (over 900 ◦C). Combustion at low temperatures (under 700 ◦C) results in CO, VOC, smoke species, and soot coated in oxidized PAHs [17]. Production of soot can also occur in fuel-lean conditions if some parts of the fuel cannot be accessed by the combustion air both in the fuel bed and in the freeboard flue gas.

Modelling of soot formation is based on experimental work on laminar flames of simple and clean fuels like ethylene and methylene, and to date, no model describes the formation precisely. But there is an agreement on the basic mechanism of soot formation, and a mechanism known as HACA —hydrogen abstraction–C2H2 addition, that also describes the evolution of PAHs, manages to describe the nucleation of soot [18]. For the description of this mechanism, a basic chemical and physical frame was created. In the chemical frame, the main precursor of soot formation is considered to be acetylene C2H2 that is reacting to create higher hydrocarbons (aromatics with one or two rings) that are the basis of PAH [19]. Once the PAH is formed, the physical frame can be used to describe the rest of the formation. This consists of four steps: formation (nucleation), coagulation, condensation, and surface growth [19]. Coagulation and condensation are shown in Figure 1. These two steps are creating agglomerates that, after further reactions, turn into impure carbon nuclei. Oxidation by O2 and OH appears at all steps [18]. The main source of these pollutants is incomplete combustion and is controllable to some degree, because when biomass is combusted on grate pyrolysis always takes place, by the quality of the combustion process.

**Figure 1.** Nucleation and growth of combustion particles.

#### *2.2. Fly Ash*

Biomass generally contains trace amounts of metals and the most important of them is potassium [17]. These metal elements are released during combustion and create the compounds responsible for fouling the equipment after condensing on its walls. But some of these compounds leave the combustion equipment in the form of aerosols that are dangerous for human health by themselves or when they create particles of fly ash in a similar fashion to the formation of soot particles. The reason for this is that these mechanisms are interconnected.

The inception and growth of ultra-fine particles are very complex processes in which it is difficult to quantify the intensity of individual incremental changes. A certain help in the quantification is numerical modelling, but despite the great advances in the development of models and the greater computational resources, it is not yet possible to account for every process and create an exact model of the particulate's inception and growth. Additionally, models of biomass combustion do not usually account for particulates [20].

#### **3. Experimental Procedure and Measurement Device**

From the previously stated reasons, the focus of this paper is on the laboratory measurements of the size distribution of ultra-fine particles emitted from the combustion of beech wood. The developed laboratory procedure incorporates the advantages of thermogravimetric analysis and the detailed monitoring of the size distribution of the produced fine particles. Thermogravimetric analysis (TGA) allows to monitor the exact influence temperature has on a small fuel sample according to the desired heating schedule by monitoring the weight of the heat affected sample and identifying the weight loss. TGA can also change the composition of the atmosphere flowing around the sample. By analysing the development of temperature change, it further identifies the presence of endothermic and exothermic reactions.

The measurement was carried out by utilising a STA 449 F3 Jupiter TGA device (NETZSCH, Selb, Germany). The base component of the STA-449 analyser is a very precise digital weighing system with a vertical design. The analysed samples are placed into a shielded ceramic module (TG-module). This module is linked to the weighting system itself. For the whole duration of the measurement, the entire module is located in a gas-tight laboratory furnace with a controlled heating rate. For each measurement the device provides a TGA curve showing the relationship between weight change and the temperature of the sample.

The gas phase volatiles released by pyrolysis from the fuel sample during the measurement are scattered in the test atmosphere and removed from the device. Subsequently, the resulting stream is cooled down to the ambient temperature by flowing through the connected pipeline, creating an aerosol stream that enters a Scanning Mobility Particle Sizer (SMPS). In SMPS are separated fractions of different particle size. The production of fine particles during the process of combustion of the wood sample was measured with a TSI-SMPS device (Model 3080-Series Electrostatic Classifiers including CPC 3775, TSI Inc., Minneapolis, MN, USA). The SMPS consists of an aerosol neutralizer and differential mobility analyser (DMA).

Almost every particle has some level of electric charge. The DMA requires the aerosol to achieve a uniform and steady charge distribution. This is achieved with an aerosol neutralizer device, which provides a process that neutralises the charge of particles. After neutralisation, the particles pass through a bipolar charger and are all charged to a unified level. Then, the aerosol flows into the DMA where sizing occurs, see Figure 2.

**Figure 2.** Scheme of the measuring equipment and the particles' flow.

As a particle sizing system, the DMA separates particles by size for high-resolution measurements of the particle size distribution and allows particles in the range of 10 to 1000 nanometers in diameter to be classified. The size of the particles in the polydisperse aerosol flowing though the DMA is determined by their electrical mobility and as only particles of specific sizes are selected, a highly monodisperse aerosol leaves the DMA. This aerosol continues to a condensation particle counter (CPC). The purpose of this device is to measure the particle number concentration and identify particles in the particle-size fractions.

The CPC function is based on condensation of butanol vapours on the monodisperse aerosol's particles that act as condensation nuclei. The condensation occurs in a cooled condenser and the particles grow into larger droplets of such size that they can be counted by an optical detector when passing through it [9].

#### **4. Experimental Results and Discussion**

Many parameters vary during the combustion process. Temperature and combustion air surplus being the most variable depending on the location in the combustion chamber. The measuring apparatus described in the previous section was used for the research of nucleation and growth of the fine particles in the flue gas from beechwood combustion.

Plants and trees are mainly composed by cellulose fibrils [21]. Next to the cellulose cell walls of wood are composed by lignin and hemicellulose. Cellulose and hemicellulose together are called holocellulose. These three together principally represents the total carbohydrate fraction and are considered as the bulk of wood. The proportions of holocellulose and lignin are different in various parts of woody plants, and, therefore, their residues (sawdust, bark) have different compositions. The beech is a genus of trees and the beechwood have the following composition: extractables (2%), lignin (20%) and holocellulose (78%) [22], as shown in the Table 1.

**Table 1.** Chemical composition of beechwood. Adapted with permission from Elsevier [22].

Blocks of beechwood were used as testing samples with each block weighing 80 mg. The samples were heated up in the thermogravimetric analyser from 20 ◦C to 620 ◦C over a period of 120 min. The constant temperature increase was set at +5 ◦C/min. The experiments were carried out for beech heartwood and beech bark. To simulate the wide spectrum of possible conditions of the combustion process the samples were heated up in atmospheres with different oxygen concentrations, namely with the concentrations of 0%, 5%, 10% and 15% of oxygen. Each atmosphere was prepared by mixing pure oxygen and pure nitrogen from pressurised vessels connected to the TGA device.

Mass loss occurs during the controlled heating up the samples as shown in Figure 3. This figure presents the temperature pattern of wood samples (increasing curve) and the associated weight loss of the samples (decreasing curves). Water evaporates from the tested samples during the temperature increase up to 120 ◦C, then light volatile compounds are released in the interval from 120 ◦C to 250 ◦C. In the interval from 250 ◦C to 300 ◦C occurs a rapid loss of a sample's weight induced by the intensive release of remaining volatile compounds. The release of these volatile compounds is intensified by the heat generated from exothermic reactions that commence within these temperatures. The interval from 300 ◦C to 500 ◦C is associated with the gradual decomposition of carbon in charcoal. The relations presented at the Figure 3 show the different intensity of incineration of samples in different atmospheres. Higher concentration of the oxygen causes more intensive combustion of charcoal. In the atmosphere formed only by pure nitrogen, 30% of the sample remained unburned in form of charcoal. Influence of the oxygen content in the atmosphere is similar for beech heartwood and beech bark.

**Figure 3.** Results from the thermogravimetric analysis of beech samples in different atmospheres. (**a**) Beech heartwood; (**b**) Beech bark.

The thermal decomposition of the beechwood samples is influenced by the intensity of the oxidation reactions. The result of the thermal decomposition is the production of ultra-fine particles scattered in the gaseous products that leave the TGA apparatus. Figure 4. presents the obtained distribution of the generated particle concentration for all tested concentrations of oxygen in the atmosphere. The presented results represent the sum of all particles generated during the increase of temperature from 20 ◦C to 620 ◦C over the testing period of 120 min. Significant concentrations of the ultra-fine particles occurred within the particle mobility diameter of 50 nm–340 nm and the maximum concentration corresponds to a particle size around 140 nm. This corresponds to the typical concentration peak of combustion particles formed by the coagulation process. At 300 ◦C, the highest concentrations of emitted particles were measured. This temperature is close to the ignition temperature of the samples and causes an intense production of volatile compounds that subsequently lead to the nucleation of a great number of particles that in turn, coagulate into large particles.

**Figure 4.** The distribution curves of the total particle number generated over the testing period. (**a**) Beech heartwood; (**b**) Beech bark.

Low concentrations of oxygen in the atmosphere generally caused a higher number of produced particles. This relationship is valid for particle size bigger than 50 nm. In the case of a pure nitrogen atmosphere, significant concentrations of particulate matter were obtained. This is due to the absence of most oxidation reactions, also leading to a decrease in the local temperature affecting other reactions. The dependence of the production of fine parts on the oxygen concentration in the atmosphere is more pronounced when burning beech bark compared to the beech heartwood. Beech bark produces a higher number of particles in the atmosphere of pure nitrogen. The same sample produces a lower particle number in the atmosphere with 15% oxygen and more.

Figure 5 shows the total mass of all particles generated during the increase of temperature from 20 ◦C to 620 ◦C over the testing period of 120 min. The maximum total particle mass was identified for particle sizes close to 200 nm. As oxygen concentration in the atmosphere increases, the total particle mass generally decreases. Threshold oxygen concentrations in the atmosphere were identified to be between 5% and 10% of oxygen. For oxygen concentrations up to 5%, the higher total particle mass was achieved by burning beech bark; however, for oxygen concentrations of 10% and above, the higher total particle mass was achieved by burning beech heartwood.

**Figure 5.** The relationship between the total particle mass generated over the testing period and the mobility diameter of the particles. (**a**) Beech heartwood; (**b**) Beech bark.

## **5. Conclusions**

The fine and ultra-fine particles produced by combustion processes represent a significant health risk. The entire process of inception and growth of these particles is very complex and still not sufficiently described. The study of this issue in actual combustion devices is very difficult due to the instability and diversity of the combustion process due to the wide ranges of devices and fuels. The research presented in this paper focused on the emission of ultra-fine particles from the controlled heating of small samples of beechwood (heartwood and bark). A connection between thermogravimetric analysis and the mobility diameter measurement of particulates was realised for this purpose. Other studies looking into the topic of particulate emissions from biomass combustion were interested in: (i) the chemical composition of released volatile compounds from which particulate matter can form [23–25], (ii) mass amount of particulate matter released by different types of biomass [23,26–28] and (iii) number of released particles [23,26,28]. These studies were conducted on small (domestic) biomass burners for different types of wood (beech included) and under various conditions specified by % of the nominal output of the device under observation. But wider range of atmospheric conditions is required for modern approaches for biomass combustion [29], pyrolysis (0% O2) included. The study carried out in this paper was a parametric sweep tracking the influence of different concentrations of oxygen in the atmosphere on the production of particulates during a controlled heat up.

From the experimental measurements it can be concluded that increasing the temperature leads to a higher emission of particles produced by the combustion process. This applies until the ignition temperature is reached. This is most likely due to the increasing concentration of volatile vapours. Just before the ignition temperature the highest amount of volatile vapours is evaporating from the sample leading to the most intensive nucleation of particles resulting in their high concentrations, coagulation and growth. When the ignition temperature of the volatile vapours is reached, which can only happen if oxygen is present, the concentration of these vapours diminishes and so does the production of the particulates. This diminishing process occurs until the maximum experimental temperature of 620 ◦C.

The utilisation of the thermogravimetric analysis is suitable for the experimental measurement of particulates produced by combustion and is a suitable tool for detailed insight into the sub-processes of the particulate's inception and growth during the combustion process, which can be further expanded by performing the same study for other types of woods. With the information from [30] about the effective density of the particulate matter a deeper insight into the researched problem can be obtained.

**Author Contributions:** Conceptualization, J.P. (Jan Poláˇcik) and J.P. (Jiˇrí Pospíšil); Data curation, J.P. (Jan Poláˇcik) and T.S. (Tomáš Sitek); Methodology, L.Š. (Ladislav Šnajdárek); Supervision, J.P. (Jiˇrí Pospíšil); Visualization, M.Š.; Writing—original draft, M.Š. and J.P. (Jiˇrí Pospíšil).

**Funding:** This paper has been supported by the EU projects: Sustainable Process Integration Laboratory – SPIL funded as project No. CZ.02.1.01/0.0/0.0/15\_003/0000456 and Computer Simulations for Effective Low-Emission Energy funded as project No. CZ.02.1.01/0.0/0.0/16\_026/0008392 by Czech Republic Operational Programme Research, Development and Education, Priority 1: Strengthening capacity for high-quality research and the collaboration.

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


*Edited by Yuanzhi Zhang and X. San Liang*

In recent years, coastal environments have drawn an increasing awareness globally, regionally, or locally as in many coastal regions, the rapid industrial, urban, and agricultural development has caused dramatic land use and land cover (LULC) changes and various water pollution events in coastal environments. These environmental consequences of human activities exacerbate the effects of regional and global climate change on the hydrological cycle between the land and ocean, and these effects are frequently hazardous or destructive to coastal regions around the world. Remote sensing and geographic information systems (GIS) technologies are thoroughly adopted and applied to monitor the dynamic change of coastal environments, such as coastal LULC, water quality, and marine ecosystem.

ISBN 978-1-83881-037-5

Coastal Environments

Published in London, UK © 2021 IntechOpen © oatawa / iStock


**2. General aspects of HIV lymphoma**

Lymphomas are known to occur with an increased frequency in PWHA (20,21,23). NHL (Non-Hodgkin's Lymphoma) is the commonest malignancy in the post cART (combination antiretroviral therapy) era in PWHA. The incidence of NHL in resource-rich settings has decreased in the post cART era compared to the pre cART era (23-24). However, the contrary is true in resource-poor settings, with a noticeable increase in NHL incidence (24- 26). This is particularly true of sub-Saharan Africa - the epicenter of the HIV pandemic. The increase in NHL incidence is due mainly to the high prevalence and heavy burden of HIV in sub-Saharan Africa, a region in which two thirds of PWHA reside, and additionally, in many countries in sub-Saharan Africa, there has been a lack of availability of, or delay in initiation of cART. In South Africa, which is home to over 5 million PWHA, the rollout of cART occurred in 2004, 8 years later than in the Western world (introduced in developing countries during the end of 1996 and the beginning of 1997) and until recently, cART was generally only available to individuals with CD4 counts of <200/ul. Although this practice has changed in the last two years, with access/availability of cART to individuals with a higher CD4 count of <350/ul, the burden of diseases related to the immunodeficiency state (with notable exceptions such as Kaposi's sarcoma) appear to be on the increase (17,25,26,27).

In Africa, the HIV/AIDS epidemic was first reported in 1984 (28). The major risk of HIV in Africa occurs in/with heterosexual relationships, and accounts for an approximately equal male to female ratio, as compared to the Western world in which the major risk groups involve intravenous drug use and homosexual relationships, thus predominantly affecting males. Furthermore, early in the HIV epidemic, there was no marked increase in the incidence of NHL compared to the USA. This was attributed to PWHA dying earlier in the course of their disease possibly from infectious complications such as pneumonia and tuberculosis. The decreased longevity prevented the subsequent or later development of NHL. In addition, there may be underreporting of lymphoma or the missed diagnosis of lymphoma, with a diagnosis of an infective cause of lymphadenopathy (such as tuberculosis) being favoured over lymphoma, in the absence of performing a fine needle aspirate or lymph node biopsy (28-30).

At Chris Hani Baragwanath Academic Hospital (CHBAH) – a tertiary, public sector, University of the Witwatersrand linked hospital located in Soweto, Johannesburg, studies in the 1990's with respect to HIV-NHL showed only a modest increase of NHL in seropositive individuals, with an odds ratio of 4.8, 5 and 5.9 respectively (31-33). The first patient at this hospital with HIV-NHL was seen in 1993. Since then, there has been a steady increase in HIV-NHL up to 2000. However, since 2001, the percentage seropositivity of NHL has exceeded 50% (approximately between 60 – 80%), and since 2002, there has additionally been a significant increase in the total number of patients diagnosed with NHL at CHBAH (from 20-30 new patients per year to 70-80 patients per year) (see Table 1 and Figure 1) (25). Indeed, NHL is now the commonest haematological malignancy in South Africa, in the current HIV/AIDS era and the number of seropositive patients continues to increase.

296 Immunodeficiency

(17,25,26,27).

aspirate or lymph node biopsy (28-30).

post solid organ and haematopoietic stem cell transplantation) and autoimmune disease

HIV infection is known to be associated with an increased risk of HL, based on linkage and cohort studies. The relative risk is now 10-15 fold higher compared with the general population (13-15,17,18,20-22). This review will focus on HL in southern Africa, and describe the differences compared to HL in developed countries, highlighting the emerging increase in HL in the HIV seropositive population/people living with HIV/AIDS (PWHA).

Lymphomas are known to occur with an increased frequency in PWHA (20,21,23). NHL (Non-Hodgkin's Lymphoma) is the commonest malignancy in the post cART (combination antiretroviral therapy) era in PWHA. The incidence of NHL in resource-rich settings has decreased in the post cART era compared to the pre cART era (23-24). However, the contrary is true in resource-poor settings, with a noticeable increase in NHL incidence (24- 26). This is particularly true of sub-Saharan Africa - the epicenter of the HIV pandemic. The increase in NHL incidence is due mainly to the high prevalence and heavy burden of HIV in sub-Saharan Africa, a region in which two thirds of PWHA reside, and additionally, in many countries in sub-Saharan Africa, there has been a lack of availability of, or delay in initiation of cART. In South Africa, which is home to over 5 million PWHA, the rollout of cART occurred in 2004, 8 years later than in the Western world (introduced in developing countries during the end of 1996 and the beginning of 1997) and until recently, cART was generally only available to individuals with CD4 counts of <200/ul. Although this practice has changed in the last two years, with access/availability of cART to individuals with a higher CD4 count of <350/ul, the burden of diseases related to the immunodeficiency state (with notable exceptions such as Kaposi's sarcoma) appear to be on the increase

In Africa, the HIV/AIDS epidemic was first reported in 1984 (28). The major risk of HIV in Africa occurs in/with heterosexual relationships, and accounts for an approximately equal male to female ratio, as compared to the Western world in which the major risk groups involve intravenous drug use and homosexual relationships, thus predominantly affecting males. Furthermore, early in the HIV epidemic, there was no marked increase in the incidence of NHL compared to the USA. This was attributed to PWHA dying earlier in the course of their disease possibly from infectious complications such as pneumonia and tuberculosis. The decreased longevity prevented the subsequent or later development of NHL. In addition, there may be underreporting of lymphoma or the missed diagnosis of lymphoma, with a diagnosis of an infective cause of lymphadenopathy (such as tuberculosis) being favoured over lymphoma, in the absence of performing a fine needle

At Chris Hani Baragwanath Academic Hospital (CHBAH) – a tertiary, public sector, University of the Witwatersrand linked hospital located in Soweto, Johannesburg, studies in

(12-18). There is also an increased risk of familial aggregation of HL (19).

**2. General aspects of HIV lymphoma**

With respect to Hodgkin's lymphoma (HL), the data is less dramatic, but is becoming more significant. In a study by Stein et al, 2008 (33), the percentage seropositivity of HL in a South African cohort (which included patients from CHBAH) was 19.5% (OR=1.6, 95% CI=1.0-2.7), during the period 1995-2004. The first patient with HIV-HL was seen in 1994 at CHBAH. Since then, there has been a modest increase in HIV-HL up to 2006. However, in the last 5 years (2007 - 2011) at our single institution, the percentage seropositivity is greater than 50% (see Figure 2) and the number of patients over the years are gradually increasing (doubled compared to an earlier series in the late 1980's and early 1990's – (17,34)(see Figure 3). Thus, the focus of this review relates to the emerging problem of Hodgkin's lymphoma in the setting of HIV in southern Africa.

**Table 1.** Patients with non-Hodgkin's Lymphoma seen at Chris Hani Baragwanath Academic Hospital from 1993 to 2008

Hodgkin's Lymphoma and Human Immunodeficiency Virus Infection 299

**Figure 3.** Total number of patients with Hodgkin's Lymphoma seen at Chris Hani Baragwanath

HL occurring in the setting of immunodeficiency (with particular reference to HIV/AIDS) is generally aggressive, presents with advanced stage disease, frequent constitutional ('B') symptoms, less favourable histology, more frequent bone marrow involvement and a poorer

With the advent of HAART (highly active antiretroviral therapy), now referred to as cART (combination antiretroviral therapy), the AIDS related morbidity, particularly with respect to opportunistic infections has decreased and the survival of HIV/AIDS patients has increased (35,36). In the post cART era, ADCs (AIDS-defining cancers) continue to fall, but the rates of NADCs (non-AIDS defining cancers) such as HL, anal carcinoma, lung carcinoma and skin cancers are on the increase (37). With HL, there is a noticeably increasing relative risk of approximately 10 - 15 fold, compared with the general population

Several epidemiological studies conducted in the last two decades, and summarised in the article by Carbone et al, 2009 (22) strongly support the evidence that HIV positive individuals have a higher risk of developing HL compared to their HIV negative counterparts. This is in contrast to HIV-NHL or HIV-Kaposi's sarcoma (where the incidence

Academic Hospital from 1990 - 2011

(13-15,17,18,20-22).

**3. Hodgkin's lymphoma and HIV**

**3.1. Introduction and epidemiology**

prognosis compared to immunocompetent individuals (17,18).

**Figure 1.** HIV seropositive and HIV seronegative patients with non-Hodgkin's Lymphoma from 1993 to 2008 seen at Chris Hani Baragwanath Academic Hospital

**Figure 2.** HIV seropositive and HIV seronegative patients with Hodgkin's Lymphoma from 1990 to 2011 seen at Chris Hani Baragwanath Academic Hospital

**Figure 3.** Total number of patients with Hodgkin's Lymphoma seen at Chris Hani Baragwanath Academic Hospital from 1990 - 2011


At network level:

At the level of communication systems:

The main issues to be monitored in smart grids to ensure the required quality of electricity provided to end users are:

The data obtained from the monitoring shall transmit information for the adoption of measures to frame the voltages of the nodes of the electrical network within the accepted limits of the quality of the electric power [15]:


*3.3.1 African Barred Owlet Taenioglaux capense*

One house in Lilongwe, Malawi, had at least five owl species calling often in the evenings. For instance, on 05/11/95 ABO calling together with the SwfO between 19.00 and 19:20 h in the full moon. The same species heard following nights but not so actively as during the full moon.


**1. Introduction**

Hematopoietic stem cell transplantation (HSCT) is a choice of treatment for thousands of leukemic patients. The main outcome expected from HSCT is the lifetime engraftment of the donor graft. The preferred donor is a HLA matched-related donor; however, this is available in about 25% of the patients. Other options such as matched unrelated, matched cord blood units, and haploidentical-related donor also do exist. The success of HSCT is marred by conditions such as graft-versus-host disease (GvHD), relapse, treatment-related toxicity, and infection, which lead to higher morbidity and mortality [1]. The effectiveness of HSCT is dependent on the immune reconstitution in the host, which is linked to the number of active T and NK cells present in the graft. Delayed immune reconstitution results in unfavorable transplant outcomes; hence, faster immune reconstitution of donor origin is required for long-term survival of patients.

Soon after HSCT using myeloablative conditioning, the patient experiences a period of pancytopenia. It takes several months or years for immune reconstitution and for patients to regain immunocompetence after transplant. The immune cells start re-appearing in the following order: neutrophils (0.5 months), monocytes (1 month), NK cells (1 month), T cells (2 months), and B cells (3 months); however, the normal levels are reached much later (**Figure 1**) [2].

There are various factors affecting immune reconstitution after transplant such as

Age or pre transplant chemotherapy or radiation leads to thymic damage. The severity of the damage caused to the thymus depends on the dose of the drugs used and also on the age of the patients, which in turn affect the immune recovery. In younger patients (<18 years), there is faster thymic regeneration after chemotherapy than older patients [3]. The age of the donor also affects the engraftment and reconstitution potential of hematopoietic stem cells as shown in mouse models [4]. Moreover, the thymic recovery is faster and is associated with faster T-cell reconstitution and recovery of normal T-cell repertoire in autologous (9 months) than allo-HSCT (12 months) [5]. This delayed thymic-dependent immune reconstitution is further reduced by the occurrence of aGvHD after allogeneic HSCT [6, 7].

The source of stem cells used as graft could be either bone marrow, peripheral blood, or cord blood. Source of stem cells used predicts the rate of immune reconstitution. It has been observed that platelet (20 × 109/L) reconstitution is faster in peripheral blood (11–18 days) than bone marrow (17–25 days) HSCT. Similarly, neutrophil (>0.5 × 109/L) reconstitution is also faster in peripheral blood (12–19 days) than bone marrow (15–23 days) HSCT. This is because of the presence

#### **Figure 1.**

*The time taken for different immune subsets to (A) reappear in circulation and (B) reach normal levels after hematopoietic stem cell transplantation.*

**193**

**Table 1.**

*Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation*

of long-term HSCs and more committed multipotent progenitors in the peripheral blood than bone marrow [8]. Further as compared to transplantation using in vivo or ex vivo T-cell depleted graft, faster immune reconstitution is seen in unmodified graft transplantation [9]. Using peripheral blood graft, faster reconstitution of CMV-specific cytotoxic T cells and CD4+ T cells is observed than stem cells from bone marrow source [10, 11]. The advantages of using umbilical cord blood units are its ready availability and its ability to cross the HLA barrier. The rates of engraftment and post-transplant outcomes are dependent on the number of total nucleated cells (TNCs) and CD34+ cell dose present in the graft source. Martin et al. [12] previously reported high TNC dose in association with positive transplant outcomes such as improved overall survival (OS), lower relapse rate (RR), and increased risk of chronic GvHD. Since there is a higher number of TNCs in the bone marrow and peripheral blood, there is faster engraftment (~14–21 days) after HSCT using this source of graft than umbilical cord blood source (~30 days) [13, 14]. Remberger et al. [15] reported faster engraftment but poor survival and higher relapse after HSCT using high CD34+ cell dose peripheral blood as graft source. Various researchers have reported immune cell reconstitution using different cell

Graft manipulations such as T-cell depletion (TCD) have resulted in lower chances of GvHD and graft rejection in unrelated and HLA mismatched transplants. However, T-cell depletion results in delayed immune reconstitution and increased morbidity and mortality due to infection [19–21]. An advantage of using T-cell depletion is that in case of malignancies it also leads to better GVL effect depending on the malignant disease being treated. For example, in CML, TCD is related to increased relapse rate [22], whereas in AML and AML cohorts, lower rate

The degree of HLA mismatch is an important factor in immune reconstitution. It has been observed that the outcomes from matched unrelated transplantation are at par with that of matched related transplantation [1]. Chang et al. reported similar reconstitution of T-cell subsets, except for CD4+ cells and CD4+ naïve T cells, in haploidentical and HLA-matched transplantation [16]. Various researchers have reported reconstitution of immune cells following different transplant strategies. It has been observed that the immune reconstitution is best in matched sibling related followed by matched unrelated donor, haploidentical donor, T-cell replete, and

Conditioning regimens deplete host immune system, eliminate the leukemic cells, and create space for engraftment of the donor cells. Although this eliminates the patient's leukemic cells, it also reduces the alloreactivity between host and donor cells after HSCT and further results in severe depletion of all immune cells. The use of drugs such as ATG or alemtuzumab depletes the host T cells further and results in

> **CD4+ T cells 90 days**

Matched sibling donor — 220 645 33 [16]

Haploidentical donor — 152 672 23 [16] T-cell depleted 357 7 7 55 [18] T-cell replete 183 127 181 64 [18]

**CD8+ T cells 90 days**

253 198 447 43 [17]

**B cells 90 days** **Reference**

of relapse has been observed in TCD transplantation [23–25].

**NK cells 1 month**

*Reconstitution of various immune subsets in different types of HSCT.*

*DOI: http://dx.doi.org/10.5772/intechopen.89198*

sources (**Table 1**).

T-cell depleted transplants.

**Cells/L type of transplant**

Matched unrelated

donor

#### *Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation DOI: http://dx.doi.org/10.5772/intechopen.89198*

of long-term HSCs and more committed multipotent progenitors in the peripheral blood than bone marrow [8]. Further as compared to transplantation using in vivo or ex vivo T-cell depleted graft, faster immune reconstitution is seen in unmodified graft transplantation [9]. Using peripheral blood graft, faster reconstitution of CMV-specific cytotoxic T cells and CD4+ T cells is observed than stem cells from bone marrow source [10, 11]. The advantages of using umbilical cord blood units are its ready availability and its ability to cross the HLA barrier. The rates of engraftment and post-transplant outcomes are dependent on the number of total nucleated cells (TNCs) and CD34+ cell dose present in the graft source. Martin et al. [12] previously reported high TNC dose in association with positive transplant outcomes such as improved overall survival (OS), lower relapse rate (RR), and increased risk of chronic GvHD. Since there is a higher number of TNCs in the bone marrow and peripheral blood, there is faster engraftment (~14–21 days) after HSCT using this source of graft than umbilical cord blood source (~30 days) [13, 14]. Remberger et al. [15] reported faster engraftment but poor survival and higher relapse after HSCT using high CD34+ cell dose peripheral blood as graft source. Various researchers have reported immune cell reconstitution using different cell sources (**Table 1**).

Graft manipulations such as T-cell depletion (TCD) have resulted in lower chances of GvHD and graft rejection in unrelated and HLA mismatched transplants. However, T-cell depletion results in delayed immune reconstitution and increased morbidity and mortality due to infection [19–21]. An advantage of using T-cell depletion is that in case of malignancies it also leads to better GVL effect depending on the malignant disease being treated. For example, in CML, TCD is related to increased relapse rate [22], whereas in AML and AML cohorts, lower rate of relapse has been observed in TCD transplantation [23–25].

The degree of HLA mismatch is an important factor in immune reconstitution. It has been observed that the outcomes from matched unrelated transplantation are at par with that of matched related transplantation [1]. Chang et al. reported similar reconstitution of T-cell subsets, except for CD4+ cells and CD4+ naïve T cells, in haploidentical and HLA-matched transplantation [16]. Various researchers have reported reconstitution of immune cells following different transplant strategies. It has been observed that the immune reconstitution is best in matched sibling related followed by matched unrelated donor, haploidentical donor, T-cell replete, and T-cell depleted transplants.

Conditioning regimens deplete host immune system, eliminate the leukemic cells, and create space for engraftment of the donor cells. Although this eliminates the patient's leukemic cells, it also reduces the alloreactivity between host and donor cells after HSCT and further results in severe depletion of all immune cells. The use of drugs such as ATG or alemtuzumab depletes the host T cells further and results in

#### **Table 1.**

*Reconstitution of various immune subsets in different types of HSCT.*

*Cells of the Immune System*

2. source of stem cells

allogeneic HSCT [6, 7].

3.HLA disparity between donor and host

4.post-transplant immune suppressant

5.occurrence of graft-versus-host disease.

such as

Soon after HSCT using myeloablative conditioning, the patient experiences a period of pancytopenia. It takes several months or years for immune reconstitution and for patients to regain immunocompetence after transplant. The immune cells start re-appearing in the following order: neutrophils (0.5 months), monocytes (1 month), NK cells (1 month), T cells (2 months), and B cells (3 months); how-

There are various factors affecting immune reconstitution after transplant

Age or pre transplant chemotherapy or radiation leads to thymic damage. The severity of the damage caused to the thymus depends on the dose of the drugs used and also on the age of the patients, which in turn affect the immune recovery. In younger patients (<18 years), there is faster thymic regeneration after chemotherapy than older patients [3]. The age of the donor also affects the engraftment and reconstitution potential of hematopoietic stem cells as shown in mouse models [4]. Moreover, the thymic recovery is faster and is associated with faster T-cell reconstitution and recovery of normal T-cell repertoire in autologous (9 months) than allo-HSCT (12 months) [5]. This delayed thymic-dependent immune reconstitution is further reduced by the occurrence of aGvHD after

The source of stem cells used as graft could be either bone marrow, peripheral blood, or cord blood. Source of stem cells used predicts the rate of immune reconstitution. It has been observed that platelet (20 × 109/L) reconstitution is faster in peripheral blood (11–18 days) than bone marrow (17–25 days) HSCT. Similarly, neutrophil (>0.5 × 109/L) reconstitution is also faster in peripheral blood

(12–19 days) than bone marrow (15–23 days) HSCT. This is because of the presence

*The time taken for different immune subsets to (A) reappear in circulation and (B) reach normal levels after*

1.thymic damage (age-related or pre-transplant conditioning regimens)

ever, the normal levels are reached much later (**Figure 1**) [2].

**192**

**Figure 1.**

*hematopoietic stem cell transplantation.*

a delayed recovery of donor-derived T cells. Increase in the severity of the conditioning regimen results in prolonged immune deficiency after transplant [26].

Both thymus-dependent and thymus-independent T-cell reconstitutions are affected by the increase in HLA mismatch between the patient and the donor, probably because of higher risk of GvHD [27]. Clave et al. [28] reported higher reconstitution of both CD4+ and CD8+ T cells in transplants involving unrelated cord blood grafts (190 cells × 103/μL for CD4+ and 280 cells × 103/μL for CD8+) than CD34 selected peripheral blood haploidentical donor grafts (68 cells × 103/ μL for CD4+ and 80 cells × 103/μL for CD8+). Mehta et al. [29] showed lower reconstitution of absolute CD4+ and CD8+ T cells at 3 months and higher B-cell counts (6 months) after unrelated cord blood HSCT than HLA matched HSCT (121.53 vs. 261.18 for CD4+, 36.03 vs. 190.56 for CD8+, and 210 vs. 31.2 for B cells). There was similar reconstitution of B cells but lower CD4+ and CD8+ T-cell reconstitution in single unit umbilical cord blood transplantation than HLA mismatched donor HSCT (11 vs. 9 for B cells, 15 vs. 21 for CD4+ cells, and 14 vs. 21 for CD8+ cells) [30].

Acute graft-versus-host disease occurs when donor lymphocytes react against normal host tissue to cause serious complications after allogeneic HSCT. Although there is faster recovery of the innate immune system after allo-HSCT, lymphocyte recovery is delayed due to aGvHD [3, 31]. The recovery of T cells depends on the thymic efficiency as well as the peripheral niche, which provides resources for T-cell survival. As GvHD targets the bone marrow, in patients with graft-versus-host disease, the peripheral resources are reduced because of which there is increased immunosuppression leading to delayed T-cell reconstitution in allogeneic HSCT as compared to autologous HSCT. The options to increase the efficiency of T-cell reconstitution must be selected in a manner so as to not aggravate the already present GvHD [32, 33]. Similarly, the drugs used to treat GvHD can also result in delayed immune reconstitution. Drugs such as cyclosporine A and methotrexate interfere with the T-cell receptor signaling and hence result in alteration of peripheral T-cell survival and B-cell differentiation [34, 35]. Tyrosine kinase inhibitors like imatinib mesylate used for controlling refractory cGvHD also lower T-cell survival by interfering with T-cell receptor (TCR) or IL7 signaling [36, 37]. Reconstitution of dendritic cells is decreased in GvHD [38]. Conversely, it has been suggested that depletion or inactivation of the host dendritic cells before allogeneic HSCT reduces the occurrence of GvHD [39–41].

#### **2. Reconstitution of innate immunity**

After HSCT, the first cells to engraft are the monocytes, followed by granulocytes, platelets, and NK cells [42]. Monocytes are primarily involved in phagocytosis and release of cytokines. They are classified into classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) based on the expression of CD14 and CD16 [43, 44]. Monocytes remain below the normal levels for up to a year [45, 46].

The conditioning regimen used prior transplant results in a neutropenic phase till the neutrophils reconstitute, which takes approximately 11–12 days in T-cell depleted haploidentical HSCT [47, 48]. Although neutrophil counts rise to normal numbers within 2 weeks after transplant [49], they become functionally competent only after 2 months [50, 51]. The type of graft affects the reconstitution of neutrophils: 2 weeks in case of GCSF mobilized grafts, 3 weeks in case of bone marrow, and around 4 weeks in umbilical cord blood [1]. Use of peripheral blood has decreased the neutrophil recovery time from an average of 16 to 12 days [52].

**195**

*Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation*

transplant [53], and functional reconstitution of NK cells is reached within 2 months [1]. The time taken for NK-cell reconstitution is dependent on the occurrence of GvHD [47, 54] and does not differ if the source of stem cells is peripheral blood or bone marrow [55]. However, the number of functional NK cells is higher when the transplant involves T-cell replete grafts than T-cell depleted grafts [56]. The most prominent functional NK cells after transplant are CD56brightCD16dim [57, 58]. Also, higher overall survival is seen in patients with high CD56bright NK cells at day 14 after unmanipulated haploidentical HSCT. The cytolytic function of NK cells is regulated by the interaction of inhibitory/activating killer immunoglobulin like receptors (KIRs) present on their surface and their specific HLA class I ligands. The reconstitution of the inhibitory and activating KIRs is dependent on factors such as conditioning regimen, T-cell deplete/replete graft, and immunosup-

NK cells recover in both number and function within the first few weeks after

In a study evaluating NK-cell reconstitution after matched related/unrelated donor HSCT, it has been reported that the NK-cell counts are lower for longer period (2-3 months) after MUD (156/μL) than MRD (265/μL). The most frequent immature NK cells were CD56bright and NKG2A+CD57-CD56dim NK cells [59]. Russo et al. [60] reported that in haploidentical HSCT using after transplant cyclophosphamide, the immature NK cell starts appearing at 2 weeks; however, the mature NK cells expressing CD16 and CD56 and NKG2A appear at about a year. Host dendritic cells that escape chemotherapy/radiation activate alloantigenic T cells in the donor and hence play an important role in GvHD. Since host dendritic cells present MHC antigens to donor CD8+ T cells after transplant, depleting these cells could result in lower risk of GvHD [61, 62]. Lower reconstitution of lymphoid den-

Gamma delta T cells make up ~5% of the T-cell population, and their receptors are composed to gamma and delta chains. These T cells have been reported to enhance engraftment and graft-versus-leukemia effect without an increase in GvHD [64]. Gamma delta T cells reconstitute faster in patients in whom bone marrow (60 days) is used as the graft source than peripheral blood (200 days) [65].

T-cell reconstitution is faster in transplantation with peripheral blood as graft source than bone marrow due to higher number of T cells present in the graft [55]. Ciurea et al. [18] reported better T-cell reconstitution in recipients of T-cell replete haploidentical HSCT than recipients of T-cell depleted haploidentical HSCT at 6 months after transplant. Use of ATG for T-cell depletion also affects the rate of immune reconstitution. This effect is more prominent in umbilical cord blood transplantation than bone marrow transplantation. T-cell reconstitution in allo-HSCT without the use of ATG is seen in about 7–12 months when using bone marrow and umbilical cord as stem cell source as compared to 6–24 months when using peripheral blood as stem cell source [66]. T cells recover primarily via peripheral expansion of memory T cells or endogenous T-cell development. Hence, functional thymus is required for effective reconstitution of T cells [67]. This is an issue in aging patients where there is thymus atrophy [68]. Due to this, although full immune recovery is possible in middle-aged patients, it is not possible in older patients and is a cause of morbidity and mortality [69]. Reconstitution of T cells is slow probably due to the prolonged depletion and reduced function of naïve T cells [70]. T cells that reconstitute are primarily from the donor origin in case of T-cell replete transplant or host T cells that have escaped the conditioning

dritic cells has been associated with inferior overall survival [63].

**3. Reconstitution of adaptive immunity**

*DOI: http://dx.doi.org/10.5772/intechopen.89198*

pression used after transplant.

#### *Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation DOI: http://dx.doi.org/10.5772/intechopen.89198*

NK cells recover in both number and function within the first few weeks after transplant [53], and functional reconstitution of NK cells is reached within 2 months [1]. The time taken for NK-cell reconstitution is dependent on the occurrence of GvHD [47, 54] and does not differ if the source of stem cells is peripheral blood or bone marrow [55]. However, the number of functional NK cells is higher when the transplant involves T-cell replete grafts than T-cell depleted grafts [56]. The most prominent functional NK cells after transplant are CD56brightCD16dim [57, 58]. Also, higher overall survival is seen in patients with high CD56bright NK cells at day 14 after unmanipulated haploidentical HSCT. The cytolytic function of NK cells is regulated by the interaction of inhibitory/activating killer immunoglobulin like receptors (KIRs) present on their surface and their specific HLA class I ligands. The reconstitution of the inhibitory and activating KIRs is dependent on factors such as conditioning regimen, T-cell deplete/replete graft, and immunosuppression used after transplant.

In a study evaluating NK-cell reconstitution after matched related/unrelated donor HSCT, it has been reported that the NK-cell counts are lower for longer period (2-3 months) after MUD (156/μL) than MRD (265/μL). The most frequent immature NK cells were CD56bright and NKG2A+CD57-CD56dim NK cells [59]. Russo et al. [60] reported that in haploidentical HSCT using after transplant cyclophosphamide, the immature NK cell starts appearing at 2 weeks; however, the mature NK cells expressing CD16 and CD56 and NKG2A appear at about a year.

Host dendritic cells that escape chemotherapy/radiation activate alloantigenic T cells in the donor and hence play an important role in GvHD. Since host dendritic cells present MHC antigens to donor CD8+ T cells after transplant, depleting these cells could result in lower risk of GvHD [61, 62]. Lower reconstitution of lymphoid dendritic cells has been associated with inferior overall survival [63].

Gamma delta T cells make up ~5% of the T-cell population, and their receptors are composed to gamma and delta chains. These T cells have been reported to enhance engraftment and graft-versus-leukemia effect without an increase in GvHD [64]. Gamma delta T cells reconstitute faster in patients in whom bone marrow (60 days) is used as the graft source than peripheral blood (200 days) [65].

## **3. Reconstitution of adaptive immunity**

T-cell reconstitution is faster in transplantation with peripheral blood as graft source than bone marrow due to higher number of T cells present in the graft [55]. Ciurea et al. [18] reported better T-cell reconstitution in recipients of T-cell replete haploidentical HSCT than recipients of T-cell depleted haploidentical HSCT at 6 months after transplant. Use of ATG for T-cell depletion also affects the rate of immune reconstitution. This effect is more prominent in umbilical cord blood transplantation than bone marrow transplantation. T-cell reconstitution in allo-HSCT without the use of ATG is seen in about 7–12 months when using bone marrow and umbilical cord as stem cell source as compared to 6–24 months when using peripheral blood as stem cell source [66]. T cells recover primarily via peripheral expansion of memory T cells or endogenous T-cell development. Hence, functional thymus is required for effective reconstitution of T cells [67]. This is an issue in aging patients where there is thymus atrophy [68]. Due to this, although full immune recovery is possible in middle-aged patients, it is not possible in older patients and is a cause of morbidity and mortality [69]. Reconstitution of T cells is slow probably due to the prolonged depletion and reduced function of naïve T cells [70]. T cells that reconstitute are primarily from the donor origin in case of T-cell replete transplant or host T cells that have escaped the conditioning

*Cells of the Immune System*

21 for CD8+ cells) [30].

the occurrence of GvHD [39–41].

for up to a year [45, 46].

**2. Reconstitution of innate immunity**

a delayed recovery of donor-derived T cells. Increase in the severity of the conditioning regimen results in prolonged immune deficiency after transplant [26]. Both thymus-dependent and thymus-independent T-cell reconstitutions are affected by the increase in HLA mismatch between the patient and the donor, probably because of higher risk of GvHD [27]. Clave et al. [28] reported higher reconstitution of both CD4+ and CD8+ T cells in transplants involving unrelated cord blood grafts (190 cells × 103/μL for CD4+ and 280 cells × 103/μL for CD8+) than CD34 selected peripheral blood haploidentical donor grafts (68 cells × 103/ μL for CD4+ and 80 cells × 103/μL for CD8+). Mehta et al. [29] showed lower reconstitution of absolute CD4+ and CD8+ T cells at 3 months and higher B-cell counts (6 months) after unrelated cord blood HSCT than HLA matched HSCT (121.53 vs. 261.18 for CD4+, 36.03 vs. 190.56 for CD8+, and 210 vs. 31.2 for B cells). There was similar reconstitution of B cells but lower CD4+ and CD8+ T-cell reconstitution in single unit umbilical cord blood transplantation than HLA mismatched donor HSCT (11 vs. 9 for B cells, 15 vs. 21 for CD4+ cells, and 14 vs.

Acute graft-versus-host disease occurs when donor lymphocytes react against normal host tissue to cause serious complications after allogeneic HSCT. Although there is faster recovery of the innate immune system after allo-HSCT, lymphocyte recovery is delayed due to aGvHD [3, 31]. The recovery of T cells depends on the thymic efficiency as well as the peripheral niche, which provides resources for T-cell survival. As GvHD targets the bone marrow, in patients with graft-versus-host disease, the peripheral resources are reduced because of which there is increased immunosuppression leading to delayed T-cell reconstitution in allogeneic HSCT as compared to autologous HSCT. The options to increase the efficiency of T-cell reconstitution must be selected in a manner so as to not aggravate the already present GvHD [32, 33]. Similarly, the drugs used to treat GvHD can also result in delayed immune reconstitution. Drugs such as cyclosporine A and methotrexate interfere with the T-cell receptor signaling and hence result in alteration of peripheral T-cell survival and B-cell differentiation [34, 35]. Tyrosine kinase inhibitors like imatinib mesylate used for controlling refractory cGvHD also lower T-cell survival by interfering with T-cell receptor (TCR) or IL7 signaling [36, 37]. Reconstitution of dendritic cells is decreased in GvHD [38]. Conversely, it has been suggested that depletion or inactivation of the host dendritic cells before allogeneic HSCT reduces

After HSCT, the first cells to engraft are the monocytes, followed by granulocytes, platelets, and NK cells [42]. Monocytes are primarily involved in phagocytosis and release of cytokines. They are classified into classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) based on the expression of CD14 and CD16 [43, 44]. Monocytes remain below the normal levels

The conditioning regimen used prior transplant results in a neutropenic phase till the neutrophils reconstitute, which takes approximately 11–12 days in T-cell depleted haploidentical HSCT [47, 48]. Although neutrophil counts rise to normal numbers within 2 weeks after transplant [49], they become functionally competent only after 2 months [50, 51]. The type of graft affects the reconstitution of neutrophils: 2 weeks in case of GCSF mobilized grafts, 3 weeks in case of bone marrow, and around 4 weeks in umbilical cord blood [1]. Use of peripheral blood has decreased the neutrophil recovery time from an average of 16 to 12 days [52].

**194**

regimen in case of T-cell depleted transplant. Naïve T cells/T-cell receptor excision circles (TRECs) are lower for approximately 10–30 years after transplant [71, 72]. Reconstitution of functional T cells as observed by their ability to secrete interferon gamma and interleukin-4 to normal levels returns in 30 days after haploidentical HSCT for patients in whom acute GvHD is not observed [73]. Recipients of T-cell depleted haploidentical HSCT show higher CD31+ naïve CD4+ T cells than their donors at approximately 4–6 years [74]. Homeostatic peripheral expansion is induced by various homeostatic cytokines such as IL7 and IL15, inflammatory cytokines, and viral exposure. Peripheral homeostatic expansion leads to an inverse CD4/CD8 ratio in patients for several months after transplant. CD4 counts are considered as the best predictive marker for the recovery of immune competence after HSCT, and its recovery has also been associated with lower risk of infections and improved transplant outcomes [1]. CD4+ T-cell counts are as low as <200 cells/μL in the first 3 months and reach levels of 450 cells/μL at about 5 years after transplant [55, 75]. CD8+ T-cell counts increase rapidly during the first 3 months after transplant possibly due to the expansion of herpesvirus-specific CD8 T cells [55, 76]. GvHD reduces the number of CD4+ T cells by inhibiting the thymic output, whereas CD8+ cells increase in number during GvHD or CMV reactivation [77, 78]. The reconstituting CD4+ T cells have a higher expression of CD11a, CD29, CD45RO, and HLA-DR and a lower expression of CD28, CD45RA, and CD62L than normal individuals [79, 80]. The early reconstituting CD8+ T cells are mostly memory or effector cells. Naïve or TREC+CD8+ T cells recover at a slower rate [77, 81]. The number of regulatory T cells (Tregs) is much higher after transplant than normal individuals and may contribute to remission [82, 83]. A Treg:CD4+ T cell ratio of less than 9% has been associated with higher risk of aGvHD [84]. Chang et al. [16] reported lower CD4+ T cells, dendritic cells, and higher CD28 expression on CD4+ and CD8+ T cells in patients receiving haploidentical HSCT than patients receiving HLA matched HSCT.

B-cell reconstitution is also delayed after HSCT: ~6 months for autologous and ~9 months after allogeneic transplantation and is mainly due to GvHD or its treatment. In the first 2 months after transplant, B-cell counts are low but rise higher than the normal levels in approximately 1–2 years [55, 85]. Since restoration of full humoral immune functioning requires both naïve and memory B cells, all patients who have undergone HSCT remain susceptible to infections for at least a year after transplant [1]. The reconstituted B cells express higher levels of CD1c, CD38, CD5, membrane IgM, and membrane IgD and lower levels of CD25 and CD26L than normal individuals [86].

A number of studies have reported comparisons between reconstitution of different immune cells depending on the graft source. Faster reconstitution of

**197**

outcomes.

*Assessment of Immune Reconstitution Following Hematopoietic Stem Cell Transplantation*

different immune cells was observed when bone marrow was used as graft source as

There are different methods to assess the immune recovery after transplant, such as estimation of absolute lymphocyte count (ALC), levels of immune cell subsets (NK cells, B cells, and T cells), and antibody titers to assays for T- and B-cell

ALC levels have been reported in association with overall survival and rate of relapse. ALC >500 cells/μL on day 15 is linked with better OS and lower relapse after autologous as well as allogeneic transplantation [92, 93]. An increase in the

Early recovery of CD4+ T cells is associated with overall survival, nonrelapse mortality, and risk of infections [95, 96]. Admiral et al. [97] reported the time taken by circulating CD4+ T cells to reach 0.5× 109/L as a strong marker for probability of relapse. In myeloablative allogeneic HSCT, higher levels of CD3+, CD8+ T cells, regulatory T cells, and myeloid dendritic cells are correlated with relapse-free

Recently, flow cytometric analysis has been used to differentiate between the T, B, and NK-cell subpopulations. Low levels of NK cells within the first few weeks after transplant have been associated with poor transplant outcomes like lower overall survival and higher risk of infection [99, 100]. Surface markers such as CD45RA, CD28, CD27, CD62L, and CCR7 can be used to differentiate naïve, effector, effector memory, and central memory CD4+ and CD8+ subsets [101, 102]. The surface markers expressed by naïve T cells are CD45RA+CCR7+; central memory T cells are CD45RA-CCR7+; effector memory T cells are CD45RA-CCR7–; and effector T cells are CD45RA+CCR7– [91]. CD4+ T cells also include regulatory T cells (CD25+FoxP3+) and Th17 cells [103, 104]. The expression of CD27, IgM, and IgD helps in distinguishing between naïve B cells (CD27-IgD+), memory B cells (CD27+IgD+), and isotype switched memory B cells (CD27+IgD-) [105]. Myeloid and plasmacytoid dendritic cells can be distinguished based on the expression of CD123 and CD11c: CD123low CD11c+(myeloid) and CD123bright CD11c- (plasma-

TRECs have been suggested as a marker for reconstitution of naïve T cells (CD4+CD45RA+) derived from the thymus. TRECs, however, remain low up to 6 months after HSCT [107]. Due to thymic atrophy with age, older patients have T cells with low TCR repertoire, which leads to higher risk of infections leading to lower transplant outcomes [108, 109]. Thymopoiesis can also be evaluated by measuring the number of TRECs by real-time quantitative in purified CD4+ and CD8+ T cells [110]. Lewin et al. [111] reported faster recovery of TRECs in younger patients and patients who received conventional grafts as compared to T-cell

depleted grafts. Lower levels of TRECs are associated with GvHD and opportunistic

Certain cytokines can also be used as predictive markers for transplant outcomes. One such marker is IL7, which can be used to evaluate successful T-cell recovery. Increased IL7 is associated with delayed reconstitution and increased mortality and aGvHD [113]. High levels of IL6, GCSF, and IL2α have also been indicated in association with risk of aGvHD [96, 114]. For assessing chronic GvHD, high levels of IL8 and low levels of IL17A have been suggested [103, 115]. Min et al. [104] have also correlated high levels of IL6 and IL10 with poor transplant-related

*DOI: http://dx.doi.org/10.5772/intechopen.89198*

repertoires [91].

survival [98].

cytoid) [106].

infections [77, 112].

compared to peripheral blood or cord blood (**Table 2**).

**4. Assessment of post-transplant immune recovery**

levels of CD16+ monocytes has been associated with aGvhD [94].

#### **Table 2.**

*Reconstitution of different immune cells depending on the graft source.*

different immune cells was observed when bone marrow was used as graft source as compared to peripheral blood or cord blood (**Table 2**).


**Author details**

Titus Okeke Nnamdi Azikiwe University, Awka, Nigeria

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**51**

2012

*Customer Satisfaction with Online Retail Transactions DOI: http://dx.doi.org/10.5772/intechopen.89181*

> of Management and International Business Studies. 2018;**8**(1):11-22

[10] Al- Msallam S. The relationship between customer satisfaction and customer loyalty in the banking sector in Syra. Journal of Marketing and Consumer Research. 2015;**7**:27-34

[11] Khadka K, Maharjan S. Customer satisfaction and consumer loyalty [business management thesis]. Pietarsaari: Centria University of

[12] Okeke TC, Ezeh GA, Nnedum OAU.

Service quality dimensions and customer satisfaction with online services of Nigerian banks. Journal of Internet Banking and Commerce. 2015;**20**:116. DOI: 10.4172/2165-7866.1000117

[13] Gunning JG. Models of customer satisfaction and service quality as research instruments in construction management. In: Akintoye A, editor. 16th Annual ARCOM Conference, 6-8 September 2000. Vol. 1. Glasgow Caledonian University, Association of Researchers in Construction Management. UK: ARCOM;

[14] Anderson RE. What is Customer Satisfaction and Why is it Important?

[15] Barsky JD. Customer satisfaction in the hotel industry meaning and measurement. Hospitality Research

[16] Barsky JD, Labagh R. A strategy for customer satisfaction. The Cornell Hotel and Restaurant Administration

[17] Pizam A, Milman A. Predicting satisfaction among first-time

2010. Retrieved from: https:// EzineArticles.com/expert/Rose-Elsa

Applied Sciences; 2017

2000. pp. 21-30

Anderson/725116

Journal. 1992;**16**:51-73

Quarterly. 1992;**10**:32-40

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*Customer Satisfaction with Online Retail Transactions DOI: http://dx.doi.org/10.5772/intechopen.89181*

## **References**

*Customer Relationship Management and IT*

and increasing customer satisfaction.

mining. IT tools and methods are veritable instruments in achieving robust and comprehensive CRM especially in the twenty-first century where customers generate enormous data that are essential to decision making. CRM software enables organizations to handle and coordinate their service-related inbound and outbound communications across all channels. This can enhance effectiveness and efficiency through service cost reductions, improvement service quality, lifting productivity,

**50**

**Author details**

Nnamdi Azikiwe University, Awka, Nigeria

provided the original work is properly cited.

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Titus Okeke

[1] Oluwanisola S. Customer Satisfaction. 2009. Retrieved from: https:EzineArticles.expert/ oluwanisola-seun/352487

[2] Kumar V, Arif T, Singh S. Role of ICT in driving e-commerce business in developing countries. In: National Conference on Recent Innovations & Advancements in Information Technology. 2014

[3] Srivastava N, Singh S. E-business: Scope and challenges in India. International Journal of Business and Management Invention. 2013;**2**(8):1-8

[4] Paola TP. Customer satisfaction: Modelling for mobile data services [MSc thesis]. Department of Management Technology, The Delft University of Technology; 2013

[5] Fleming E. How to Maintain Customer Satisfaction. 2010. Retrieved from: https://EzineArticles.com/expert/ Rachel Fleming/805438

[6] Evans MB. Customer satisfactionwhy it is important and how to improve it. 2009. Retrieved from: https://EzineArticles.com/expert/ melisa-B-Evans/320458

[7] Safi FOD. The relationship between customer satisfaction and customer loyalty: Emotional brand image as a moderating variable-an applied study on (Airtel) for telecom services in India. International Journal of Scientific and Research Publications. 2017;**7**(6):64-71

[8] Bae YH. Three essays on customer satisfaction customer loyalty association [doctoral thesis]. University of Iowa; 2012

[9] Kumar VS. The relationship between customer satisfaction and customer loyalty in the commercial vehicle industry in India. International Journal

of Management and International Business Studies. 2018;**8**(1):11-22

[10] Al- Msallam S. The relationship between customer satisfaction and customer loyalty in the banking sector in Syra. Journal of Marketing and Consumer Research. 2015;**7**:27-34

[11] Khadka K, Maharjan S. Customer satisfaction and consumer loyalty [business management thesis]. Pietarsaari: Centria University of Applied Sciences; 2017

[12] Okeke TC, Ezeh GA, Nnedum OAU. Service quality dimensions and customer satisfaction with online services of Nigerian banks. Journal of Internet Banking and Commerce. 2015;**20**:116. DOI: 10.4172/2165-7866.1000117

[13] Gunning JG. Models of customer satisfaction and service quality as research instruments in construction management. In: Akintoye A, editor. 16th Annual ARCOM Conference, 6-8 September 2000. Vol. 1. Glasgow Caledonian University, Association of Researchers in Construction Management. UK: ARCOM; 2000. pp. 21-30

[14] Anderson RE. What is Customer Satisfaction and Why is it Important? 2010. Retrieved from: https:// EzineArticles.com/expert/Rose-Elsa Anderson/725116

[15] Barsky JD. Customer satisfaction in the hotel industry meaning and measurement. Hospitality Research Journal. 1992;**16**:51-73

[16] Barsky JD, Labagh R. A strategy for customer satisfaction. The Cornell Hotel and Restaurant Administration Quarterly. 1992;**10**:32-40

[17] Pizam A, Milman A. Predicting satisfaction among first-time

visitors to a destination by using the disconfirmation of expectation theory. International Journal of Hospitality Management. 1993;**12**:197-209

[18] Tribe J, Snath T. From SERVQUAL to HOLSAT: Holiday satisfaction in Varadero, Cuba. Tourism Management. 1998;**19**:125-134

[19] Weber K. Assessment of tourist satisfaction, using the disconfirmation of expectations theory. A study of the German travel market in Australia. Pacific Tourism Review. 1997;**1**:35-45

[20] Bearden WO, Teel EJ. Selected determinates of consumer satisfaction and complaint report. Journal of Marketing Research. 1983;**20**:21-28

[21] Cardotte ER, Woodruff RB, Jenjins RJ. Expectations and norms in models of consumer satisfaction. Journal of Marketing Research. 1987;**24**:305-314

[22] Swan JE, Martin S. Testing the comparison level is a predictive expectation model of satisfaction. In: Kenth B, editor. Advances in Consumer Research. Ann Arbor: MI Association of Consumer Research; 1981. pp. 77-82

[23] Oliver RL, Swan EJ. Consumer perceptions of interpersonal equity and satisfaction in transactions. A field survey approach. Journal of Marketing. 1989;**53**:21-35

[24] Oliver RL, Desarbo WS. Response determinant in satisfaction judgment. Journal of Consumer Research. 1988;**14**:495-507

[25] Poele W. The rational expectation in the macro model. Brookings Papers on Economic Activity. 1976;**2**:463-514

[26] Grossman SJ. An introduction to the theory of rational expectations under asymmetric information. Review of Economic Studies. 1981;**48**:541-559

[27] Tardi C. Rational Expectation Theory. 2019. Retrieved from: https:// www.investopedia.com/terms/r/ rationaltheoryofexpecations.asp

[28] Weiner B, Frieze I, Kukla A, Reed L. Perceiving the Causes, Success, and Failure. Morristown, New Jersey: General Learning Press; 1971

[29] Yuksel A, Yulsel F. Customer Satisfaction Theories: A Critical Review. In Tourist Satisfaction and Complaining Behavior: Measurement, and Management Issues in the Tourism and Hospitality Industry. New York: Nova Science Publishers; 2008

[30] Thibaut JW, Kelly KH. The Social Psychology of Groups. New York: John Wiley & Sons Inc.; 1959

[31] Hovland CI, Harvey OJ, Sherif M. Assimilations and contrast effects in reaction to communication and attitude change. Journal of Abnormal and Social Psychology. 1957;**55**(7):244-252

[32] Prasad SS. Kano Model of Customer Satisfaction and its Importance. International School of Management Excellence Blog. 2019. Retrieved from: https://www.isme.in/kano-madelof-customer-satisfaction-and-itsimprtance.html

[33] Baki B, Basfirinci CS, Cilingir Z, Murat AR. An application of integrating SERVQUAL and Kano's model into QFD for logistics services: A case study from Turkey. Asia Pacific Journal of Marketing and Logistics. 2009;**21**(1):106-126

[34] Chen M, Chang K, Hsu C, Yang I. Understanding the relationship between service convenience and customer satisfaction in home delivery by Kano model. Asia Pacific Journal of Marketing and Logistics. 2010;**23**(3):386-410. DOI: 10.1108/13555851111143277

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*Customer Satisfaction with Online Retail Transactions DOI: http://dx.doi.org/10.5772/intechopen.89181*

from: https://EzineArticles.com/expert/

[45] Internet World Stats. Africa Internet Usage and Population Stats [Online]. 2019. http://www.internetworldstats. com/europa.html.uk [Accessed: 27 July

[46] Rosenberg A. Adapt to Nigeria's Changing Business Environment. Frontier Strategy Consulting Group. Lagos, Nigeria. Online Document; 2013. Available from: https://www.

[47] United Nations. E-Government Survey. New York: Department of Economic and Social Affairs, United Nations; 2018. Online Edition.

Publicadministration.un.org. [Accessed

[48] Buttle F. Customer Relationship

Management: Concepts and Technologies. Oxford, UK: Elsevier

howwemadeitinafrica.com

28 July 2019]

Limited; 2009

[44] Central Bank of Nigeria (CBN). Guidelines on Electronic Banking in Nigeria August. Abuja, Nigeria: CBN Publications; 2003. Accessed from:

Kiran-Bisht/2139376

www.cenbankng.com.

2019]

Customer Engagement. 2012. Retrieved from: https://EzineArticles.com/

[36] Feather K. Defining Customer Engagement. 2011. Retrieved from: https://EzineArticles.com/expert/

[37] McLean G. Examining the

[38] Ibrahim NF, Wang X,

[39] Hepola J, Karjaluoto H,

[40] Dessart L, Veloutsou C,

2015;**24**(1):28-42

Education Limited; 2016

2017;**45**(3):294-311

in online brand communities: A social media perspective. Journal of Product and Brand Management.

[41] Kotler P, Keller KL. Marketing Management. 15th ed. Essex: Pearson

[42] Pansari A, Kumar V. Customer engagement: The construct,

antecedents, and consequences. Journal of the Academy of Marketing Science.

[43] Bisht K. The Rise of Technology in Customer Engagement. 2015. Retrieved

Morgan-Thomas A. Consumer engagement

Shaikh AA. Consumer engagements and behavioural intentions towards the continuous use of innovative mobile banking applications, case study of Finland. In: International Conference on Information Systems (ICIS-2016), Dublin, Ireland, December, 11-14, 2016

2017;**72**:321-338

Bourne H. Exploring the effect of user engagement in online brand communities: Evidence from twitter. Computers in Human Behaviour. Bristol-UK: Research and Enterprise Development, University of Bristol;

determinants and outcomes of mobile app engagement, a longitudinal perspective. Computers in Human Behaviour. 2018;**84**:392-403

[35] Brarret A. Understanding

expert/A-Barret/1422815

Kate-Feathers/338455

*Customer Satisfaction with Online Retail Transactions DOI: http://dx.doi.org/10.5772/intechopen.89181*

[35] Brarret A. Understanding Customer Engagement. 2012. Retrieved from: https://EzineArticles.com/ expert/A-Barret/1422815

*Customer Relationship Management and IT*

visitors to a destination by using the disconfirmation of expectation theory. International Journal of Hospitality Management. 1993;**12**:197-209

[27] Tardi C. Rational Expectation Theory. 2019. Retrieved from: https:// www.investopedia.com/terms/r/ rationaltheoryofexpecations.asp

[28] Weiner B, Frieze I, Kukla A, Reed L. Perceiving the Causes, Success, and Failure. Morristown, New Jersey:

[29] Yuksel A, Yulsel F. Customer Satisfaction Theories: A Critical Review. In Tourist Satisfaction and Complaining Behavior: Measurement, and Management Issues in the Tourism and Hospitality Industry. New York: Nova Science Publishers; 2008

[30] Thibaut JW, Kelly KH. The Social Psychology of Groups. New York: John

Sherif M. Assimilations and contrast effects in reaction to communication and attitude change. Journal of Abnormal and Social Psychology.

[32] Prasad SS. Kano Model of Customer

Satisfaction and its Importance. International School of Management Excellence Blog. 2019. Retrieved from: https://www.isme.in/kano-madelof-customer-satisfaction-and-its-

[33] Baki B, Basfirinci CS, Cilingir Z, Murat AR. An application of integrating SERVQUAL and Kano's model into QFD for logistics services: A case study from Turkey. Asia Pacific Journal of Marketing and Logistics.

Wiley & Sons Inc.; 1959

1957;**55**(7):244-252

imprtance.html

2009;**21**(1):106-126

[34] Chen M, Chang K, Hsu C, Yang I. Understanding the relationship between service convenience and customer satisfaction in home delivery by Kano model. Asia Pacific Journal of Marketing and Logistics. 2010;**23**(3):386-410. DOI: 10.1108/13555851111143277

[31] Hovland CI, Harvey OJ,

General Learning Press; 1971

[18] Tribe J, Snath T. From SERVQUAL to HOLSAT: Holiday satisfaction in Varadero, Cuba. Tourism Management.

[19] Weber K. Assessment of tourist satisfaction, using the disconfirmation of expectations theory. A study of the German travel market in Australia. Pacific Tourism Review. 1997;**1**:35-45

[20] Bearden WO, Teel EJ. Selected determinates of consumer satisfaction and complaint report. Journal of Marketing Research. 1983;**20**:21-28

[21] Cardotte ER, Woodruff RB, Jenjins RJ. Expectations and norms in models of consumer satisfaction. Journal of Marketing Research.

[22] Swan JE, Martin S. Testing the comparison level is a predictive expectation model of satisfaction. In: Kenth B, editor. Advances in Consumer Research. Ann Arbor: MI Association of Consumer Research; 1981. pp. 77-82

[23] Oliver RL, Swan EJ. Consumer perceptions of interpersonal equity and satisfaction in transactions. A field survey approach. Journal of Marketing.

[24] Oliver RL, Desarbo WS. Response determinant in satisfaction judgment. Journal of Consumer Research.

[25] Poele W. The rational expectation in the macro model. Brookings Papers on Economic Activity. 1976;**2**:463-514

[26] Grossman SJ. An introduction to the theory of rational expectations under asymmetric information. Review of Economic Studies. 1981;**48**:541-559

1998;**19**:125-134

1987;**24**:305-314

1989;**53**:21-35

1988;**14**:495-507

**52**

[36] Feather K. Defining Customer Engagement. 2011. Retrieved from: https://EzineArticles.com/expert/ Kate-Feathers/338455

[37] McLean G. Examining the determinants and outcomes of mobile app engagement, a longitudinal perspective. Computers in Human Behaviour. 2018;**84**:392-403

[38] Ibrahim NF, Wang X, Bourne H. Exploring the effect of user engagement in online brand communities: Evidence from twitter. Computers in Human Behaviour. Bristol-UK: Research and Enterprise Development, University of Bristol; 2017;**72**:321-338

[39] Hepola J, Karjaluoto H, Shaikh AA. Consumer engagements and behavioural intentions towards the continuous use of innovative mobile banking applications, case study of Finland. In: International Conference on Information Systems (ICIS-2016), Dublin, Ireland, December, 11-14, 2016

[40] Dessart L, Veloutsou C, Morgan-Thomas A. Consumer engagement in online brand communities: A social media perspective. Journal of Product and Brand Management. 2015;**24**(1):28-42

[41] Kotler P, Keller KL. Marketing Management. 15th ed. Essex: Pearson Education Limited; 2016

[42] Pansari A, Kumar V. Customer engagement: The construct, antecedents, and consequences. Journal of the Academy of Marketing Science. 2017;**45**(3):294-311

[43] Bisht K. The Rise of Technology in Customer Engagement. 2015. Retrieved from: https://EzineArticles.com/expert/ Kiran-Bisht/2139376

[44] Central Bank of Nigeria (CBN). Guidelines on Electronic Banking in Nigeria August. Abuja, Nigeria: CBN Publications; 2003. Accessed from: www.cenbankng.com.

[45] Internet World Stats. Africa Internet Usage and Population Stats [Online]. 2019. http://www.internetworldstats. com/europa.html.uk [Accessed: 27 July 2019]

[46] Rosenberg A. Adapt to Nigeria's Changing Business Environment. Frontier Strategy Consulting Group. Lagos, Nigeria. Online Document; 2013. Available from: https://www. howwemadeitinafrica.com

[47] United Nations. E-Government Survey. New York: Department of Economic and Social Affairs, United Nations; 2018. Online Edition. Publicadministration.un.org. [Accessed 28 July 2019]

[48] Buttle F. Customer Relationship Management: Concepts and Technologies. Oxford, UK: Elsevier Limited; 2009

**Chapter 4**

**Abstract**

solution, system

**1. Introduction**

**55**

Qualitative Analysis of Different

*Christoph Weiss, Johannes Keckeis and Manfred Kofler*

**Keywords:** analyze, business management, CRM, customer relationship management, criteria, decision, evaluation, evaluation models, normalize, market information, model, negotiation, project, requirements, selection,

Customer relationship management (CRM) systems help companies to manage their business processes. Specially for sales, campaigns, contact management, etc. The simpler and more efficient the business processes are executed, the more profitable these companies can be. Therefore, the process of selecting and evaluating a CRM system is an important success factor for each company in every industry and in every company size. The qualitative analysis of CRM evaluation models examines the necessary phases and activities for selecting a new CRM system. It is important to go through the relevant phases in the selection in order to be able to

A customer relationship management (CRM) system is a business management software [1]. CRM software solutions usually include relevant modules for managing and executing business processes in a company such as operational CRM processes (marketing processes, sales processes, or service processes), analytical CRM processes (target group analysis, cross-selling analysis, or customer risk analysis), comprehensive processes (customer value analysis, customer segmentation, or customer characterization), or strategic processes (strategic analysis, strategic conception, or strategic controlling) [2]. A CRM system helps various parts of sales and marketing departments of an organization to organize and share data and knowledge, reduce costs, and improve the management of their business processes [3]. Various architectures of CRM systems exist on the market: proprietary CRM systems, modules as a part of ERP systems, and original equipment manufacturer (OEM) systems in enterprise system landscapes. CRM vendors and implementation partners offer similar bundles of functionalities in their software-products: a set of application modules that fit together. Each module includes a variety of functions [3]. There are different approaches for evaluating and implementing a CRM system. Thus, software evaluation is not a simple technical activity; it is a decision process including subjectivity and uncertainty with no possibility of arbitrary reduction [4]. As listed in the Appendix, several authors developed evaluation models with different methods between 1998 and 2017. These models are structured in different

CRM Evaluation Models

make a decision in a structured manner.

phase sequences and are used as a base for this paper.

#### **Chapter 4**