**1. Introduction**

Landscapes1 transform over time as land use changes, infrastructure develops, human populations fluctuate, and impactful natural events occur. Ideally, landscape governance and management will adapt to these changing conditions to safeguard ecosystem functionality and guarantee sustainability. However, in large parts of the world, landscapes have been modified such that their carrying capacities have been exceeded, and irreversible environmental degradation ensued [5]. This situation often coincides with severe conflicts over natural resources that a ffect peoples' livelihoods and security [6]. Accordingly, over the last few decades, the need to balance human-induced developments and

1 The term landscape is used by several scientific disciplines drawing on a wide range of definitions and concepts [1,2]. Considering a number of definitions developed more recently by various authors [1–4], we understand landscapes as dynamic, interactively developing social-ecological systems that often combine a mosaic of alternative land uses and different governance structures.

environmental resilience became increasingly obvious [7], with landscapes considered to be a suitable spatial unit for the governance and management of social-ecological systems [8,9].

To address and resolve the conflicts among di fferent interest groups in a specific landscape, stakeholder participation, engagement, and collaboration is increasingly considered to be a major decisive factor [3,10]. In a landscape framework that includes operational governance structures and functioning institutions, stakeholder engagement is an important element to successfully negotiate inevitable trade-o ffs as part of conflict resolution [3,10–12]. However, as landscape institutions interact with superior levels of governance structures or ecological systems and the stakeholder spectrum expands, complexity and interdependences also grow further [1].

In this context, the concept of biosphere reserves and its implementation—conceptualized by the United Nations Educational Scientific and Cultural Organization's (UNESCO) science program "Man and the Biosphere" (MAB) and globally implemented since 1976 [13]—may o ffer valuable insights and experiences for landscape governance and management that focus on environmentally balanced sustainable development. As biosphere reserves are "designed to combine biodiversity conservation with socio-economic development and knowledge production (both scientific and local) and dissemination" [9], this concept proposes to address actual and future landscape challenges. Today, 701 biosphere reserves have been designated by UNESCO in 124 countries; together, they form the World Network of Biosphere Reserves (WNBR) [14]. Within its regional or thematic sub-networks (e.g., AfriMAB, the network of biosphere reserves in Sub-Saharan Africa), the WNBR promotes the sharing of best practices and experiences from biosphere reserves around the world [15]. Each biosphere reserve designation precedes a stakeholder participation process and a formal request by the respective national government. Biosphere reserves are areas of di fferent sizes and focuses, but they often emphasize one ecosystem type or natural or cultural landscape.

This study aims to explore the potential and realized contribution of UNESCO's biosphere reserve concept and its implementation to landscape governance and management in Africa. Its objective is to provide a common understanding of biosphere reserve structures, functions, and processes and to illustrate their relevance for landscape approaches based on four case studies. According to our knowledge, investigating biosphere reserves in Africa from a landscape perspective is somewhat novel. The majority of references investigate biosphere reserves from an intrinsic perspective, while only a few studies [16] take a broader perspective and analyze biosphere reserves as implementing units for landscape governance and management. The focus of the present study is on key components of a landscape approach, as obtained from a review of the literature. The case study findings are reported in the form of narratives to complement the literature review and to illustrate first-hand practical experiences. The motivation for this study is derived from the notion that di fferent landscape concepts and approaches, which have emerged over time in various situations, can build upon and complement each other [7,12]. Thus, alternative approaches to natural resource management that aim to link conservation with sustainable development in Africa are likewise taken into consideration and contrasted. The focus of this study is on Africa, where multiple drivers of global and local change currently significantly impact landscapes [4]. At the same time, the implementation of the MAB program has made progress in parts of the continent, with the goal to establish model regions for sustainable development.

In this context, the overall guiding question of the study is the following: what can we learn from the concept of biosphere reserves and their implementation for landscape governance and management in Africa? We hypothesize that biosphere reserves: (1) provide a structural framework for landscape governance and management and foster links between di fferent hierarchies; (2) coordinate intersectoral activities to achieve mutual conservation and sustainable development objectives in the designated area; (3) provide opportunities for knowledge generation and learning for stakeholders; and (4) address trade-o ffs between nature and people in a holistic manner, while contributing to conflict resolution among di fferent interest groups. This study focuses on stakeholder engagement and collaboration, assuming these to be overarching conditions for the development and maintenance of governance

and management structures and the implementation of programs and projects to achieve sustainable development targets.

The following section describes the concept of biosphere reserves, as well as alternative landscape approaches, in Africa. Section 3 depicts the methods applied in the study and outlines an analytical framework that identifies four crucial components for integrated approaches to landscapes. Through this analytical lens, the results from a literature review are presented in Section 4 to analyze the biosphere reserve concept considering the four components. The analysis is complemented by findings from four case studies of biosphere reserves located in western and southern Africa and a discussion of factors that may impact success and failure in different contexts. In Section 5, we relate the results of the analysis of biosphere reserves to the wider discussion on conservation and development in African landscapes and draw lessons learnt from the investigation of biosphere reserves as potential models for landscape governance and management. The final section draws some general conclusions of the study.

#### **2. The Concept of Biosphere Reserves and Alternative Landscape Approaches in Africa**

#### *2.1. United Nations Educational Scientific and Cultural Organization (UNESCO) Biosphere Reserves*

Biosphere reserves are the primary tool of UNESCO's MAB program. This program was established in 1971 to strengthen the research on and implementation of human interactions with ecosystems and to explore conservation strategies that facilitate the sustainable use of natural resources and ecosystem services [17]. According to UNESCO's definition, biosphere reserves are "learning places for sustainable development. They are sites for testing interdisciplinary approaches to understanding and managing changes and interactions between social and ecological systems, including conflict prevention and management of biodiversity. They are places that provide local solutions to global challenges" [18].

The concept of biosphere reserves has been adapted continuously since its establishment [19]. Initially, areas were mainly designated based on biodiversity criteria and their capacity to support research activities [11]. In 1995, the MAB program's "Seville Strategy and the Statutory Framework of the WNBR" was adopted. This strategy identifies the specific role of biosphere reserves in developing a new vision of the relationship between conservation and development. It further stresses the need for sustainable development, participatory landscape governance, and management and the role of biosphere reserves to provide interactions between society and ecosystems through dialogue among relevant actors [20]. Thus, biosphere reserves presently serve as "model regions for sustainable development" [21] worldwide [9,10], aiming to integrate conservation with the improvement of local livelihood. To realize this vision, biosphere reserves concurrently aim to achieve the following three complementary functions:

Biosphere reserves are designated by an intergovernmental body, the MAB International Coordinating Council (MAB ICC). The designation process follows a common set of globally agreed-upon rules and principles. The designated area remains fully under national jurisdiction, however, according to the Statutory Framework of the WNBR, an integrated governance framework and management plan is obligatory for a biosphere reserve [20]. The nomination process involves a profound understanding of the bio-geographic and socio–economic situation of the area but also demands the development of a clear strategy on how to fulfill the three functions of the biosphere reserve and the engagement of major local stakeholders. Eventually, the nomination dossier requires

the formal acceptance of all relevant authorities and political representatives at different governance levels (local, provincial, and national), before it can be submitted to UNESCO by the responsible national authority [20].

#### Characteristic Tools and Features of Biosphere Reserves

A characteristic tool to pursue the three functions of a biosphere reserves is the zonation concept. A biosphere reserve is zoned into one or more "core areas", a "buffer zone" surrounding the core areas, and a "transition area" (see Figure 1). A core area represents a legally protected site for the conservation of biodiversity and limits activities beyond conservation to research and education only. Some form of national or local legal protection of the core zone(s) is the only condition prescribed by the MAB program in terms of zonation. Hence, biosphere reserves have one or more legally protected core area(s), while their respective buffer zone(s) and surrounding transition zones have limited (or non-existent) legal protection status [22]. Many biosphere reserves integrate pre-existing protected sites as core areas and connect them through buffer zones forming "ecological corridors" [23]. The buffer zone is used for ecologically sound practices, e.g., for farming or tourism. The transition zone denotes an area with a variety of activities (including economic activities from subsistence crop and livestock farming to commercial agriculture, trade, industry, and tourism), where multiple stakeholders cooperate to manage and sustainably develop the area's resources [20]. Examples across the world show that biosphere reserves indeed have the potential to foster local economic development by generating additional income and employment opportunities associated with different economic sectors [22,24,25]. Specifically, the development of new technologies related to the sustainable use of land and water resources and the use of renewable energy or institutional innovations (like smallholder co-operatives or conservation associations) provide the potential to stimulate employment [16,22,26].

**Figure 1.** The zonation concept of the United Nations Educational Scientific and Cultural Organization (UNESCO) Biosphere Reserves; picture: Volcans Biosphere Reserve, Rwanda, with the volcanoes being the core zone; compiled by the authors.

In recent decades, UNESCO Biosphere Reserves have contributed to raising awareness of the need for global standards to integrate conservation with social and economic development. Today, other national and international designations of protected areas follow the notion of zonation and likewise interlink conservation and local development [27]. UNESCO Biosphere Reserves, however, accentuate their priorities differently compared to most other categories of protected areas, as their primary goal is the harmonization of the human–nature relationship within the designated area [9,28].

It is mandatory that the core zone of a biosphere reserve be a protected site under national or sub-national law. Hence, in most cases, biosphere reserves integrate pre-existing protected areas. Depending on the local and national importance of the protected area, this situation can substantially impact the landscape and its governance and management system.

The designation of a specific area as a UNESCO Biosphere Reserve also has the potential to further strengthen existing conservation activities, specifically by linking these activities to developments beyond the boundaries of the actual protected area and by providing a supportive and integrated institutional frame [16]. However, encompassing conservation sites under other formal arrangements (e.g., National Parks) within a biosphere reserve also bears the risk that a biosphere reserve will fail to achieve its potential as an "open concept" that links conservation and development due to disagreements, a lack of support, and conflicts among local stakeholders [9].

To ensure the long-term quality of designated sites, the Statutory Framework of the WNBR entails a 10-year-periodic review process to monitor, assess, and report on developments within a biosphere reserve. The results of this reporting process were mixed during the first two decades of its implementation [19]. However, since 2013, the MAB ICC has introduced several additional measures to further ensure the quality of the WNBR. These include an "excellence process" to support mechanisms for biosphere reserves that do not fully conform with the standards of the WNBR, as well as an "exit strategy" for Biosphere Reserves that remain non-compliant with UNESCO's designation criteria [9,29].

An important feature that determines the success of a biosphere reserve in achieving its goals is local ownership through identification of local stakeholders with the vision and mission of a biosphere reserve [23,30,31]. UNESCO Biosphere Reserves are characterized by involving local communities and interested stakeholders in the decision-making processes and implementation of e ffective benefit-sharing mechanisms [16]. Such inclusive engagement can reduce conflicts of interest and generate economic opportunities for the local population and the likelihood for development-oriented approaches to achieve successful outcomes [11].

#### *2.2. Alternative Natural Resource Management Approaches in Africa*

While UNESCO Biosphere Reserves were established in Africa as early as the late 1970s2 [18], alternative approaches to natural resource management that integrate biodiversity conservation with the socio-economic development of local communities have gained prominence since the mid-1980s [4]. These approaches, which were first introduced by the World Wide Fund for Nature (WWF), can be summarized under the term Integrated Conservation and Development Projects (ICDPs) [32,33]. Biosphere reserve initiatives and ICDPs interacted or complemented each other, primarily where both approaches coincided on site, as described in Section 4.1 for Ghana [30,34].

#### 2.2.1. Development of Alternative Approaches over Time

Until the 1970s, land management in many African countries was mostly conducted under sectoral approaches. While many traditional African societies used to apply holistic approaches to administer their natural resources, the socio–economic consequences of colonial and post-colonial governance systems led to landscapes that were widely characterized by single-purpose and exclusive-use approaches, with the management and distribution of land under the broad authority of central governments. Often the needs of local communities were not reflected in landscape planning, as shown in reports about the relocations of populations for di fferent purposes of land use [29,35].

The conservation sector, until the 1970s, focused primarily on the preservation of natural landscapes inside protected areas. It widely ignored the situation outside conservation sites and the roles of humans in maintaining them. Beyond legally protected areas, natural resources on communal lands were—mainly as a result of population pressure—increasingly a ffected by the overutilization and

2 Today, 79 UNESCO Biosphere Reserves have been designated in 29 African countries [18].

degradation of natural resources and a loss of biodiversity [36]. Realizing these flaws and their consequences for general environmental protection at the end of the 1970s, conservation across Africa experienced a change in mindset [33]. It was acknowledged that previous conservation approaches, which focused primarily on the establishment of protected areas, had been ineffective in stopping general habitat losses and the poaching of protected species [37]. Moreover, conservationists realized that protected area development in the past often came with social injustices among local populations [33].

On these grounds, ICDPs promoted a shift from the "traditional fortress conservation model" [12] towards integrated approaches, which included the livelihood needs of local communities. While the literature assessed the implementation of this "first generation of ICDPs" [4] as predominantly oriented towards conservation with often only symbolic participation mechanisms for local communities, they were forerunners of a paradigm shift in addressing land management and conservation [4], specifically in Africa but also in other parts of the world [32,38]. This movement was fostered through the parallel emergence of the scientific discipline of "Landscape Ecology", which aims to better understand the relationship between spatial formations and ecological processes at different scales and levels of organization [12].

In the 1990s, change could also be observed in the field of development cooperation. Biodiversity was increasingly addressed as a socio–economic asset for economic development, which led to the growing integration of conservation perspectives into the conceptualization of rural development projects [12]. The development theory discourse in the 1980s changed and began to emphasize in particular the potential of decentralization and local empowerment approaches [12]. For these reasons, in the late 1980 and early 1990s, ICDPs became increasingly popular development instruments. Following the Rio Conference in 1992, a number of different integrated landscape approaches gained further popularity, e.g., under the names of integrated natural resource management, integrated rural development or community-based natural resource management (CBNRM) [12]. While these approaches have been differentiated in the literature, it is important to stress that, in practice, they often represent similar initiatives, albeit applied within different contexts and under different strategies [12].

#### 2.2.2. The Case of Community-Based Natural Resource Management

The CBNRM approach gained high levels of attention in the conservation and development sectors, especially in southern Africa, and has been vital for the implementation of many ICDPs since the 1990s. While under colonial and post-colonial legislation, the utilization of wildlife through local communities was broadly prohibited; however, in the 1970s and 1980s perceptions towards wildlife use rights started to slowly change in some countries [34]. New laws would allow private landowners and communities to make use of local natural resources and directly benefit from wildlife on communal lands. The first large-scale CBNRM-project was CAMPFIRE (Communal Area Management Program for Indigenous People) in Zimbabwe. This project was launched in 1989 and implemented at the district level, promoting income generation for communities through the sustainable use of natural resources, mainly by licensing wildlife access to safari and tourism operators [36,39]. The implementation in Zimbabwe sparked the introduction of similar programs in other countries, such as in Botswana, Mozambique, and Namibia. During this time, CBNRM became part of the development strategies and conservation policies in a number of countries and was increasingly supported by international funding organizations, the African Union (AU), and multilateral organizations [34].

CBNRM-approaches can take many forms and emphasize different subjects according to their regional or national implementation contexts or corresponding bio-geographic landscapes. CBNRM can be implemented as communal conservancies, as in the case of Namibia; as Community Resource Management Areas (CREMAs), to regulate natural resources in the forests of Ghana; or as Wildlife Management Areas (WMAs), such as in Tanzania. In some countries, CBNRM is predominantly regarded as a rural development tool; in others, there is a clear emphasis on the conservation aspect of CBNRM and its potential to protect ecosystems [34,36].While the scope and scale of CBNRM-approaches

di ffer, they all share the general principle of advancing the sustainable management of wildlife and natural resources while fostering the empowerment and livelihood of local communities [40]. In all instances, CBNRM involves some degree of the co-management of resources between central authorities, the local government, and local communities, which share rights and responsibilities through diverse institutional arrangements [34]. The conservancy-approach, as implemented (e.g., in Namibia), is based in particular on relatively broad-based stakeholder participation and the devolution of management rights over local resources to local communities.

Despite mixed performance assessments [34], due to its potential for inter-sectoral sustainable development, CBNRM has been widely acknowledged by conservationists and development organizations as a useful tool to foster conservation and livelihoods and to implement international agreements, conservation strategies, and development agendas, such as the Convention on Biological Diversity (CBD). All over Africa, CBNRM-projects have become important partners for international organizations to test innovations related to linking environment and development, finance mechanisms (like Payments for Ecosystem Services), or innovative approaches associated with climate change adaptation [4,34].


**4. Methodology**

The methodology adopted to develop this research encompasses various steps as described in the flowchart shown in Figure 2.

**Figure 2.** Flowchart of the procedures followed in this study (TM—Thematic Mapper, OLI—Operational Land Imager).

## *4.1. Image Co-Registration*

Image co-registration has been conducted for Landsat *TM* and *OLI* data for eliminating the errors that may occur in the satellite data, due to image rotation, skew and scale. In this case, we proceeded to correct the images, since the study constituted of multitemporal dynamics, in which the images were compared and required to be perfectly coincident in space. Image co-registration is the adjustment of the coordinate system (pixel/lines) of one image to be equivalent to the other image of the same region [9,12]. In this work, we applied pixel resampling method using the nearest neighbor interpolation obtaining the GLS image from the National Institute of Space Research (INPE—*Instituto Nacional de Pesquisas Espaciais*) for choosing the control points. The image co-registration was conducted using SPRING software, in which the first phase was characterized by modifying the extension of the Landsat scenes (path/row: 221/79) for all the years studied with an average of 15 control points, accepting an error of less than one pixel, with a maximum value of 0.55.

#### *4.2. Principal Component Analysis*

After the co-registration of images, Principal Component Analysis (PCA) has been conducted with the objective of detecting the land use/land cover (LULC) changes that occurred within the 10 km buffer area surrounding the RCSP. This analysis will allow us to conclude, first, concerning the impact of the construction of the power plant and, second, whether the environmental compensation regarding the Park area was indeed incentivized and implemented properly. Another fact worth mentioning is the inclusion of the buffer zone to analyze is there were any changes in the area surrounding the park for this study to provide subsidy and aid in the future proposal of outlining the buffer zone, given that, until now, it is not present in the management plan or posterior projects. The study of the multitemporal dynamics in 1990, 2004, and 2016 were aided by the Principal Component Analysis to compare the changes before and after the formation of the Campos Novos Hydroelectric Power Plant.

The PCA is a digital image processing technique that uses statistical parameters is considered as efficient in detecting changes in the landscape. In general, the calculation of the principal components of a set of data is conducted by obtaining the eigenvalues and eigenvectors using the correlation matrix or the variance-covariance matrix between the variables of the set [13]. PCA reduces the dimensionality of satellite data that leads to improved data visualization and manageability of data analysis [14,15] and is recognized as one of the best methods for mapping and monitoring interannual and interdecadal vegetation anomalies [16]. The application of PCA, however, depends on the objective of the researcher who can analyze each component according to the work schedule. According to Duarte et al. [17], to identify LULC changes, comparing the differences in the information contained in two or more satellite images is necessary. This identification (of LULC changes) is possible by the application of PCA, which also has the function of determining the extension of the correlation of the image bands and removes them, reducing the dimension of the data and excluding the redundant information that is of no interest (to the user).

Vegetation mapping using automatic methods, such as band rations or vegetation indices are relatively straight forward. However, these methods are not always suitable for differentiating exactly where the changes occurred, but good for what types of changes occurred (native and reforested areas in this case) and PCA has the advantage of mitigating this limitation to some extent by reducing the data dimensionality [14]. Furthermore, the actual nature of changes occurred has been identified by a field visit in this study. It has been observed in a previous study that the overall accuracy and kappa coefficient in vegetation mapping increase when PCA has used along with the main bands of satellite data [18].

The first Principal Component is comprised of the information that is common to all original bands (PC1), the second (PC2) contains the most significant spectral feature of the set. The higher the order of the PCs are, the less significant the spectral features will be. The last principal component has only the information that remained from the set or the noise. We analyzed the correlations of the bands related to the red wavelength (TM3) of the Landsat 5 (1990 and 2004) along with near-infrared (TM4) of the year 2004, generating a new set of images denominated principal components, in a total of three PCs. The use of only three bands is justified by presenting the number of iterations and scenes distinct from when processed by the PCA, resulting in the information of change detection during the period, as confirmed by Lopes [19]. Furthermore, it has been affirmed that the inclusion of the first three PCs corresponds to more than 99.5% of the total variance of satellite data [20].

The same procedure was conducted with the same band combination for comparing the period between 2004 and 2016 after the construction of the RCSP in 2004. The false-color composite image used is comprised of the 2nd (G) and 3rd (R) principal component and the band related to the shortwave infrared (B5) of the original image referent to the most recent year. After applying the PCA, we proceeded to the supervised classification per region based on the Bhattacharyya distance (B). The Bhattacharyya distance can be used as a class separability measure for feature selection [21]. For two normally distributed classes, the Bhattacharyya distance (b) between two classes is defined as:

$$b = \frac{1}{8} (\mu\_2 - \mu\_1)^{\mathrm{T}} \left[ \frac{\sum\_1 + \sum\_2}{2} \right]^{-1} (\mu\_2 - \mu\_1) + \frac{1}{2} \ln \frac{\left| (\sum\_1 + \sum\_2) / 2 \right|}{\left| \sum\_1 \right|\_{1/2} \left| \sum\_1 \right|^{1/2}},\tag{1}$$

where, μi and Σi are the mean vector and covariance matrix of class i, respectively. This algorithm is inbuilt in the SPRING software for image processing.

## *4.3. Supervised Classification*

To proceed with the supervised classification, it is necessary that the user has previous knowledge of the study area. This classification requires the field observation of specific locations shown in the image, from which one can obtain ground-truth data [9,22]. The supervised classification is based on the statistical functions that analyze and compare the characteristics of the spectral reflectance of the pixels associated with a standard class defined by the user. Generally, we calculate the average values, and standard deviations of the defined classes and these values serve as criteria to group the pixels that fulfill the limits close to a specific class [8]. According to Novo [23], the classification process can be distinguished regarding the unit to be grouped. In this work, we used the region-growth algorithm from which we extract homogeneous regions according to the limits tested and established and from the group of contiguous pixels grouped.

The limit of similarity and area used were equal for all images (30). Despite the images being di fferent and from di fferent years, these limits were the most adequate for the identification of LULC. It is worth mentioning that the similarity limit demonstrates the smallest di fference accepted between the average value of two pixels (or a set of pixels) and is considered the maximum distance between the spectral centers of two regions. The area limit represents the minimum size of the segment the user wishes to analyze.

In the supervised classification stage, we identified the areas with changes and no changes occurred comparing data acquired between 1990 and 2004, 2004 and 2016, and from 1997 to 2016. Using the false-color composite images from principal components, we observed the areas in which change occurred and those that remained with the same characteristics over the years using the multitemporal Landsat data. We determined the existence of cultivation and reforestation areas with the economic survey and fieldwork studies. However, when analyzing the images, we verified the presence of exposed soil in some regions, with well-formed texture and form. Based on the experience of the user knowledge of the area, allied to the analysis of images from di fferent dates, we perceived that most regions were undergoing an exchange in monocrops or a shallow cutting of exotic species for replanting.

Furthermore, when analyzed the areas in which change occurred or not, we observed an intense increase of the bed of Rio Canoas, due to the creation of the Campos Novos Hydroelectric Power Plant managed by ENERCAN. The power plant is in operation since 2006 and provided approximately 1 4 of the total energy consumption for the state of Santa Catarina. Therefore, we conducted a supervised classification of the areas in which change occurred on the riverbed before and after the creation of the power plant using a historical raifall data series encompassing 30 years in the Campos Novos station and the monthly total rainfall data for 2016 and 2004 to remove the influence of rainfall on the increase of the riverbed and analyze these di fferences.


**9. Hepatitis C Virus (HCV)**

mixture of cells (R-Mix) has become commercially available [109]. Rapid antigen detection using several different techniques is available for Influenza, RSV, and Adenovirus. Direct fluorescent antibody (DFA) testing of primary patient specimens has documented sensitivity that approached PCR [110]. Nucleic acid amplification assay appears to be the most sensitive diagnostic tool available, and most allow for simultaneous detection of a broad range of

Treatment depends on the etiological agent. Reduction of immune suppression, if possible, is recommended for all the transplanted recipients. For infections caused by RSV, combination therapy with aerosolized ribavirin and intravenous immunoglobulins appears to have the greatest benefit in reducing mortality [103, 112]. PIV and hMPV infections are treated with oral, aerosolized, or intravenous ribavirin in a combination with intravenous immunoglobu‐ lins [113]. Adenovirus infections are treated with cidofovir, vidarabin, and gancyclovir. Lymphocyte reconstitution plays a crucial role in the clearance of Adenovirus [114]. Treatment of Rhinovirus infections is done with pleconaril and 3C-protease inhibitors, but there is insufficient experience with them and this limits their application. Topical interferon might be efficacious in moderating viral shedding and symptoms [115, 116]. Prevention of Influenza depends on aider vaccination with Influenza vaccine [117] or antiviral therapy. Vaccination is not suitable for bone marrow transplant patients 6–12 months after the transplantation. Patients with severe Influenza should be treated with both M2 inhibitors (rimantadin and

Acute infection with HBV can result in fulminant hepatic failure, whereas chronic HBV infection can lead to end-stage liver disease, including cirrhosis and hepatocellular carcinoma. Understanding of the natural history and basic biology of HBV has increased greatly in recent years. HBV infection is by far the most common chronic viral infection affecting the liver [119]. Reactivation of HBV replication in patients undergoing immunosuppressive therapy is well recognized and is a frequently reported complication of considerable clinical importance [120, 121]. HBV reactivation following immunosuppression is defined by an abrupt rise in HBV replication followed by laboratory signs of hepatocellular injury in "silent" HBV-infected individuals (HBsAg carriers). Reactivation can also occur at a lower rate in patients with "occult" HBV infections. The clinical presentation of reactivation is variable, ranging from an asymptomatic course to severe hepatitis, liver failure, and death. It is most frequently observed in patients with lymphoma treated with rituximab and corticosteroids, as well as in patients undergoing stem cell and bone marrow transplantation. Others risk groups include patients with solid tumors, subjects infected with HIV, organ transplant recipients, and those with autoimmune diseases [122, 123]. It is believed that about 12% of patients with malignancy have chronic HBV infection. In transplanted patients, infection can also reactivate after immuno‐ suppressive therapy. For these reasons, high-risk individuals should be identified and screened. Recommendation for screening for all three serologies, including HBcAb, HBsAg, and HBsAb in those planned for immunosuppression is available [124]. Despite advances in

respiratory pathogens from a simple sample [111].

114 Immunopathology and Immunomodulation

**8. Hepatitis B Virus (HBV)**

amantadin) and neuraminidase inhibitors (relenza and tamiflu [118].

Infections with HCV can result in both acute and chronic hepatitis. Acute HCV typically leads to chronic infection in about 80% of cases. This condition leads to both extrahepatic and hepatic disorders, mainly chronic liver inflammation, cirrhosis and liver cancer [127, 128]. Chronic HCV infection is usually slowly progressive. Approximately 20% to 30% of chronic-infected individuals develop cirrhosis over a 20–30-year period of time. HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation among adults. It is well docu‐ mented, that recurrence of HCV and reinfection of the graft following liver transplantation more frequently occurs. The observations indicate that up to 40% of the patients experience recurrent hepatitis and cirrhosis 5 years later [129]. This progression depends on the age of the donor (below 40 years old), the gravity of the immunosuppression, viral status of the patient before transplantation and a month after it. Prevention and treatment of HCV reinfection and reactivation after liver transplantation remains an unsolved major clinical challenge. HCVpositive patients have poorer long-term outcomes after liver transplantation in comparison with patients with other underlying liver diseases. While treatment with pegilated interferon alpha and ribavirin can cure up to one-third of HCV-positive transplanted patients, there are many promising drugs in clinical and preclinical development targeting either the virion or essential host factors. New strategies to prevent HCV reinfection include neutralizing anti‐ bodies or drugs targeting cellular HCV entry factors. Unfortunately, it will take at least several years until most of these drugs will reach routine clinical practice.

The relationship between HCV infection and immunosuppression is complex. The complexity is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. After HCV discovery, it was shown that HCV is also a lymphotropic virus, and as a consequence of lymphatic infection, several lymphoproliferative disorders have been associated. Although HCV-related hepatocytolysis is classically interpreted as secondary to attack by cytotoxic T-lymphocytes against infected cells, the liver disease is usually exacer‐ bated and more rapidly evolutive in immunosuppressed patients [130, 131]. Liver disease secondary to chronic HCV infection is an important cause of morbidity and mortality in dialysis patients and kidney transplant recipients. Eradication of infection before transplan‐ tation seems to reduce the risk for HCV-associated renal dysfunction after transplantation, and may reduce risk of HCV disease progression. For dialysis patients, ribavirtin is generally contraindicated and alternatives are needed to enhance antiviral effects of interferon. New therapies with taribavirin may offer specific advantage in this patient group [132, 133]. In individuals with defects in cell-mediated immunity, predominantly CD4Th1, occurring in HIV infection and in patients requiring multi-drug immunosuppression following solid organ transplantation, chronic liver disease caused by HCV progresses more rapidly than in immunocompetent individuals. The rate of progress seems to correlate with the degree of immunosuppression. The prolonged suppressive therapy aggravates liver function [134]. Liver-related mortality is higher in those patients who are co-infected with HCV and HIV. All immunosuppressed and HIV infected patients should be screened for HCV infection using sensitive immunoassay licensed for detection of antibodies to HCV. For laboratory tests, ELISA is most widely used from the serological methods. HCV seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection by RT PCR. Patients with positive HCV-RNA test should be genotyped and should be evaluated for HCV therapy [134, 135]. Liver disease in an immunosuppressed patient is typically severe with unusual progression to cirrhosis. However, accurate screening and specialized advice is recommended as soon as possible in HCV-positive patients.

For the last few years, there has been great progress in the production and application of drugs for prophylaxis and treatment of latent and chronic viral infections in immunosuppressed and transplanted patients. Various schemes for drug usage have been developed and have been permanently completed. Immunosuppressed patients very often are affected with nosocomial infections in hospitals, and with infections in the society. For this reason, accurate screening and prompt and precise diagnosis can be performed to prevent exacerbation of diseases and provide appropriate treatment.

#### **Author details**

Liliya Ivanova\* , Denitza Tsaneva, Zhivka Stoykova and Tcvetelina Kostadinova

\*Address all correspondence to<EMAIL_ADDRESS>
Medical University "Prof. d-r Paraskev Stoyanov" – Varna, Department of Microbiology and Virology, St. Marina University Hospital – Varna, Bulgaria

#### **References**

[1] Cohen LI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481-492.

[2] Ivanova L. Herpesvirus infections in human population in Northeastern Bulgaria. Scr Sci Med (ISSN 0582-3250). 2007;39(2):1-6.

secondary to chronic HCV infection is an important cause of morbidity and mortality in dialysis patients and kidney transplant recipients. Eradication of infection before transplan‐ tation seems to reduce the risk for HCV-associated renal dysfunction after transplantation, and may reduce risk of HCV disease progression. For dialysis patients, ribavirtin is generally contraindicated and alternatives are needed to enhance antiviral effects of interferon. New therapies with taribavirin may offer specific advantage in this patient group [132, 133]. In individuals with defects in cell-mediated immunity, predominantly CD4Th1, occurring in HIV infection and in patients requiring multi-drug immunosuppression following solid organ transplantation, chronic liver disease caused by HCV progresses more rapidly than in immunocompetent individuals. The rate of progress seems to correlate with the degree of immunosuppression. The prolonged suppressive therapy aggravates liver function [134]. Liver-related mortality is higher in those patients who are co-infected with HCV and HIV. All immunosuppressed and HIV infected patients should be screened for HCV infection using sensitive immunoassay licensed for detection of antibodies to HCV. For laboratory tests, ELISA is most widely used from the serological methods. HCV seropositive patients should be tested for HCV RNA using a sensitive quantitative assay to confirm the presence of active infection by RT PCR. Patients with positive HCV-RNA test should be genotyped and should be evaluated for HCV therapy [134, 135]. Liver disease in an immunosuppressed patient is typically severe with unusual progression to cirrhosis. However, accurate screening and

specialized advice is recommended as soon as possible in HCV-positive patients.

provide appropriate treatment.

116 Immunopathology and Immunomodulation

\*Address all correspondence to<EMAIL_ADDRESS>
and Virology, St. Marina University Hospital – Varna, Bulgaria

**Author details**

Liliya Ivanova\*

**References**

For the last few years, there has been great progress in the production and application of drugs for prophylaxis and treatment of latent and chronic viral infections in immunosuppressed and transplanted patients. Various schemes for drug usage have been developed and have been permanently completed. Immunosuppressed patients very often are affected with nosocomial infections in hospitals, and with infections in the society. For this reason, accurate screening and prompt and precise diagnosis can be performed to prevent exacerbation of diseases and

, Denitza Tsaneva, Zhivka Stoykova and Tcvetelina Kostadinova

Medical University "Prof. d-r Paraskev Stoyanov" – Varna, Department of Microbiology

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